A comprehensive review of clinical trials and Progress in stem cell therapies for advanced heart failure

Abstract

Heart failure (HF) is a global epidemic with a rising burden on individuals and healthcare systems. Advanced HF is characterized by severe symptoms at rest and marked limitations in physical activity. Stem cell therapies potentially address the limitations of current conventional treatments by reversing damage to cardiac tissue via their unique capacity for self-renewal and multilineage differentiation.

This article summarized the mechanism of action and methods for each stem cell approach and provided a detailed summary of associated clinical trials focusing on efficacy, safety profiles, and future directions.

We conducted a systematic review with a comprehensive search from 2014 to 2024 using databases such as PubMed, SCOPUS, and Google Scholar. Articles that met the inclusion criteria were selected by abstract review and subsequent assessment of the full text.

This review analyzes 27 clinical trials investigating stem cell-based therapies for advanced HF across different clinical phases (Phases I, II, and III) conducted between 2014 and 2024. These approaches include adult stem cells (ASCs) such as cardiac stem cells (CSCs), cardiosphere-derived cells (CDCs), cardiac progenitor cells (CPCs), unfractionated bone marrow-derived mononuclear cells (BMMNCs), mesenchymal stem cells (MSCs) and pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs, induced pluripotent stem cells (iPSCs).

While the exact mechanisms through which stem cells exert their therapeutic effects in advanced HF remain under investigation, recent attention has shifted toward the paracrine signaling effects of injected cells. All approaches have demonstrated clinically acceptable safety profiles; however, their efficacy varies and has yet to be conclusively confirmed. MSC-based therapy is the most widely used among the different cell choices and has consistently exhibited promising outcomes. Although ESCs are promising for heart regeneration, their use is significantly limited by ethical issues that advancements in iPSCs may potentially address. With further efficacy validation, especially in phase III clinical trials, stem cell therapies hold promising potential for clinical application in advanced HF.

Abbreviations

6MWT

6-min walk test

BM-MSCs

bone marrow mesenchymal stem cells

CPCs

cardiac progenitor cells

CRP

C-reactive protein

EF

ejection fraction

IC

intracoronary

IM

intramyocardial

IV

intravenous

LV

left ventricular

LVEDD

left ventricular end-diastolic diameter

LVEDV

left ventricular end-diastolic volume

LVES

left ventricular end-systolic volume

LVEF

left ventricular ejection fraction

MACE

major adverse cardiovascular events

MLHFQ

Minnesota Living with Heart Failure Questionnaire

MM

myocardial mass

MSC

mesenchymal stem cells

NI-proBNP

Nterminal pro b-type natriuretic peptide

NYHA

New York Heart Association

QoL

quality of life

WM

wall motion

WT

wall thickness

SS

scar score

SV

stroke volume

VT

ventricular tachycardia

Vfib

ventricular fibrillation

1. Introduction

Heart failure (HF) is a global epidemic that affects more than 64 million people worldwide [1], with the incidence approaching 10 per 1000 people after 65 years of age [2]. HF impacts a patient's quality of life, functionality, and life expectancy and, at a systems level, represents a significant economic and healthcare burden. As the global burden of HF increases, the prevalence of advanced disease also increases (see Fig. 1).

Fig. 1.

Overview of current stem cell approaches for heart failure

(TNF: tumor necrosis factor, ILs: interleukins, EGFR: epidermal growth factor receptor; VEGFR: vascular endothelial growth factor).

Advanced HF is classified as New York Heart Association (NYHA) class III or IV, or American College of Cardiology/American Heart Association (ACC/AHA) stage D, representing the most severe stage characterized by symptoms at rest and significant discomfort with physical activity. Conventional treatments for advanced HF in clude pharmacological management, mechanical support, and heart transplantation. Medical interventions aimed at enhancing outcomes and alleviating symptoms involve the utilization of neurohormonal agonists, sodium‒glucose cotransporter 2 (SGLT2) inhibitors, diuretics, and inotropic agents [3,4]. In advanced HF patients, heart transplantation is the gold standard approach, with a 1-year survival of almost 90 % and a median survival of 12.5 years [5]. However, the imbalance between the increasing number of advanced HF patients and the availability of donor organs, along with the high prevalence of contraindications to heart transplantation, limits this therapeutic option for most patients. When conventional treatments are insufficient for advanced HF patients, a search for more innovative and effective treatments is needed.

HF is currently incurable because of irreversible myocardial damage and the lack of regenerative capacity of the heart [6]. Stem cell therapies offer an emerging breakthrough by promoting cardiac tissue repair via self-renewal and multilineage differentiation. Its potential application in regenerating damaged heart tissue and releasing paracrine factors has shown promise in improving cardiac function, structural integrity, symptom relief, and overall quality of life in several studies [7]. For example, intracoronary (IC) infusion of bone marrow-derived mesenchymal stem cells (BM-MSCs) has been effective in improving left ventricular (LV) function and reducing infarct size in acute myocardial infarction patients [8,9]. Intramyocardial (IM) infusion of mesenchymal stem cells (MSCs) has also been shown to improve cell retention, myocardial repair, and exercise capacity [10]. Furthermore, many studies have explored innovative gene therapy for coronary artery disease [11] and the use of autologous CD34⁺ stem cells and bone marrow-derived mononuclear cells (BMMNCs) to improve blood flow and wound healing in critical limb ischemia [12]. These findings underscore the potential of stem cell therapies in advancing the treatment of cardiovascular conditions.

2. Mechanism of action of cellular therapy in HEART failure

Advanced HF presents a promising target for cell therapy due to its complex pathophysiology and the significant limitations of existing treatments, which primarily focus on symptom management and disease progression slowing without effectively addressing underlying myocardial tissue damage. Contrary to the traditional view of the heart as a terminally differentiated organ, evidence suggests the presence of a subpopulation of undifferentiated cardiomyocytes (CMs) with limited but notable regenerative capacity in vivo, commonly referred to as cardiac stem cells (CSCs), which contribute to a slow turnover of cardiac cells [13].

Over the years, significant efforts have been dedicated to isolating and expanding CSCs directly from human cardiac tissue, which has led to evolving terminology and enhanced understanding of the cardiac cellular niche. For example, “cardiospheres” (CS) describe self-adherent clusters composed of heterogeneous cell populations, including CSCs, differentiating progenitors, mature CMs, and vascular cells, obtained from percutaneous endomyocardial specimens of human atrial or ventricular tissue [13]. The progeny of cells within these cardiospheres, termed cardiosphere-derived cells (CDCs), and cardiac progenitor cells (CPCs) committed to differentiation into all cardiac lineages and can be cultured in cardiosphere-based systems [[14], [15], [16]].

While numerous studies have reported the regenerative potential of various stem cell types, including CSCs and MSCs, key questions remain regarding the relative contributions of true CM regeneration versus paracrine-mediated transient functional improvements [17]. The dominant mechanism attributed to transplanted stem cell efficacy is their paracrine activity, wherein transplanted cells secrete a repertoire of cytokines, chemokines, and growth factors [18] that can enhance angiogenesis and reduce apoptosis by activating intracellular signaling pathways such as PI3K/Akt [19] and ERK1/2 through receptors including EGFR and VEGFR [20]. However, the complexity of these molecular interactions also includes factors like pro-inflammatory cytokines (TNF, IL-1, IL-6) that may contribute to adverse ventricular remodeling, contrasting with anti-inflammatory cytokines (IL-4, IL-13) that may activate resident CSCs [21] and facilitate intrinsic cardiac repair [22].

Moreover, although some studies provide evidence that MSC therapy contributes to myocardial regeneration and functional recovery [23,24], the extent to which administered cells engraft and differentiate into mature CMs remains contentious. Fewer engrafted MSCs express cardiac-specific markers or form functional gap junctions with native myocardium [25], suggesting that direct cell replacement is limited. Instead, the immunomodulatory properties of MSCs, including dose-dependent suppression of alloreactive T-cell proliferation [26], have emerged as an important alternative mechanism that may underlie some therapeutic effects [27].

These findings highlight ongoing scientific uncertainties regarding the precise cellular fate, retention, and long-term engraftment of transplanted stem cells, as well as the complex interplay between paracrine signaling, immunomodulation, and endogenous cardiac regeneration. Further experimental and clinical investigations are critical to delineate these mechanisms, optimize cell delivery strategies, and fully harness stem cells' therapeutic potential in reversing myocardial damage and improving outcomes in advanced HF.

3. STEM cell delivery routes

There are different routes to transfer cells to the heart, and the delivery method significantly influences their therapeutic efficacy (Table 1) [28]. While a definitive consensus on the optimal route is lacking, trials have explored various approaches, including IM, epicardial, transendocardial, retrograde coronary venous (RCV), IC, and intravenous (IV) methods. IM injection has emerged as a robust approach, in which cells are directly implanted into damaged myocardial tissue (heart tissue), which enhances cell retention and integration with the existing cardiac structure [29,30]. This method has been shown to improve LV function and reduce scar size in clinical trials. In contrast, IC infusion, which involves the delivery of stem cells directly into the coronary arteries, although less invasive, may not achieve comparable levels of tissue integration and functional improvement because of factors such as cell washout and systemic distribution [31,32]. Studies comparing different delivery methods, including IV administration and intracavitary injections, underscore the importance of optimal cell delivery for maximizing therapeutic outcomes. Furthermore, compared with IC injections, transendocardial delivery, which involves injecting stem cells into the endocardium, promotes increased vascularity and results in greater functional improvement [8,28]. RCV infusion delivers stem cells through the coronary veins, potentially enhancing cell distribution within the myocardium [31]. Finally, epicardial injection, where cells are delivered to the outer layer of the heart, has been effective in preclinical studies for myocardial repair [29].

Table 1.

Benefits and limitations of different delivery routes.

Delivery method	Description	Potential benefits	Limitations
Intramyocardial (IM) injection	Direct injection into the myocardium	Enhances cell retention and integration with cardiac tissue; improves left ventricular function; reduces scar size.	Invasive; limited to localized delivery.
Epicardial injection	Cells injected into the epicardium	Shown effective in preclinical myocardial repair studies.	Invasive procedure; typically used in conjunction with surgical interventions.
Transendocardial injection	Cells injected into the endocardium	Promotes vascularity; greater functional improvement than intracoronary methods.	Requires catheter-based procedure; may involve higher technical complexity.
Intracoronary (IC) infusion	Cells delivered into coronary arteries	Less invasive; direct access to heart via blood vessels.	Cell washout; less tissue integration; potential systemic distribution.
Retrograde coronary venous (RCV) infusion	Cells delivered via the coronary veins	Enhances cell distribution within the myocardium.	May be less efficient than direct injection methods.
Intravenous (IV) infusion	Cells administered through systemic venous circulation	Minimally invasive; easier to administer.	Low cell retention in the heart; systemic distribution dilutes local therapeutic effects

4. Cell-therapy approaches to HF and relevant clinical trial results

4.1. Bone marrow-derived mononuclear cells (BMMNCs)

Bone marrow-derived mononuclear cells (BMMNCs) were the first cell type to be investigated in patients with HF [56]. BMMNCs are a heterogeneous population harvested from bone marrow that consists of various cell types, mainly stem cells such as hematopoietic progenitor cells and mesenchymal and endothelial precursors [57]. Preclinical and early clinical research indicates that transplanted cells transdifferentiate into CMs and support the vasculature, leading to improved LV function [58]. Despite these initially promising results, subsequent studies have not demonstrated a significant level of transdifferentiation. While BMMNCs promote angiogenesis and enhance microcirculation, they do not stimulate vasculogenesis [58]. Various stem cell delivery methods have been used for BMMNCs, including intramyocardial [8,59,60], intracoronary [61,62] or retrograde [63] methods. IM injection has been shown to be more useful for targeting discrete segments of the myocardium, such as ischemic regions, but it may be less effective for treating HF worldwide, particularly in the context of nonischemic cardiomyopathy [57].

Over the past decade, five clinical trials have investigated the application of bone marrow-derived cells for treating advanced HF (Table 2). Overall, these trials support the safety of BMMNC therapy, which may provide some functional or structural improvements. However, the evidence for therapeutic benefit remains mixed across trials, and the substantial variation in study designs makes it challenging to draw definitive conclusions about clinical efficacy.

Table 2.

Clinical trials conducted between 2014 and 2024 using stem cell therapies for advanced heart failure.

Trial name	Status	Trial design	Enrollment	Baseline	Cell dose	Delivery route	Longest follow-up length	Endpoints	Results	Limitations	Reference
1. Bone marrow-derived mononuclear cells (BMMNCs)
A Trial of Autologous Bone Marrow-Derived Stem Cells in Pediatric Heart Failure NCT02479776	Completed	Pilot study, randomized, placebo-controlled	10 (BMMNCs: 5, placebo: 5)	Mean EF ∼40 %, NYHA II-III	Unfractionated BMMNCs: 11.8-115.1x10^6 cells/mL	IC	6 mo	- Primary safety endpoint: free from death and SAEs - Primary efficacy endpoint: LVEF - Other end-points: MRI measurements and NT-proBNP	- Safe - Primary efficacy endpoints: not achieved (p = 0.37) + Average of 7 % reduction in EDV (p = 0.01) + Average of 10 % reduction in ESV (p = 0.05)	Small single-center sample, heterogeneous etiologies, short follow-up, crossover design, one sedation deviation, no cell function assays, mostly stable outpatients	[33]
AsseSsment of Efficacy, Safety and Utility of intRa myocardiAl iNjection of Stem Cells in Patients With End Stage Heart Failure Undergoing LVAD Implantation (ASSURANCE) NCT00869024	Completed	Phase I & II, randomized, double-blind, sham-controlled	25 (BMMNCs: 16, placebo: 9)	LVEF <30 %, NYHA class III and IV	Unfractionated BMMNCs: 20x106 cells/400 μL	IM	2 y	- Primary safety endpoints: AE, improvement in myocardial viability on PET/CT scan, death - Secondary efficacy endpoints: number of LVAD turn-down, change in LV dimensions, histological assessment	- Primary safety endpoints: + All-cause mortality was lower in the stem cell therapy group (12.5 %) compared to the placebo group (33.33 %) + SAEs were slightly more frequent in the stem cell therapy group (81.25 %) than in the placebo group (77.78 %)	No publications and no specific limitations mentioned	No publications
NBS10 (Also Known as AMR-001) Versus Placebo Post ST Segment Elevation Myocardial Infarction (PreSERVE-AMI) NCT01495364	Completed	Phase II, randomized, double-blind, placebo-controlled	195 (cell-treated: 100, placebo: 95)	LVEF <48 %, NYHA class I, II or III	Autologous bone marrow-derived CD34+ cells (AMR-001): ≥10x10^6 cells (±20 %)	IC	3 y	- Primary safety endpoints: AEs, SAEs and MACE - Primary efficacy endpoint: change in resting myocardial perfusion over 6 months (gated SPECT) - Secondary efficacy endpoints: changes in LVEF, LVESV, LVEDV and infarct size (by CMR)	- Safety: No significant differences in myocardial perfusion or adverse events were observed between the control and treatment groups. However, both groups showed increased perfusion from baseline to 6 months (p < 0.001) - Efficacy: After adjusting for ischemia duration, a consistent and favorable cell dose–dependent effect was noted in the improvement of LVEF, reduction in infarct size, and the duration of time participants remained alive and out of the hospital (p = 0.05). - Other: At 1 year, mortality rates were 3.6 % (N = 3) in the control group and 0 % in the treatment group.	Low reproducibility of SPECT myocardial perfusion, longer follow-up required to assess outcomes related to cell dose threshold	[34]
An Efficacy, Safety and Tolerability Study of Ixmyelocel-T Administered Via Transendocardial Catheter-based Injections to Subjects With Heart Failure Due to Ischemic Dilated Cardiomyopathy (ixCELLDCM) NCT01670981	Completed	Phase IIb, randomized, double-blind, placebo-controlled, multicentered	108 (Imyxelocel-T: 57, placebo: 51)	LVEF ≤35 %, NYHA class III or IV	Imyxelocel-T: 35-295 × 10^6 cells	IM	1 y	- Primary efficacy endpoints: total number of clinical cardiac events - Secondary efficacy endpoints: the win ratio, LVEF, LVESV, LVEDV, SV, NYHA class, 6MWT	- Primary efficacy endpoints: The ixmyelocel-T group experienced a 37 % reduction in cardiac events compared to the placebo group (risk ratio: 0.63 [95 % CI 0.42–0.97]; p = 0.0344). SAEs occurred in 75 % of participants in the placebo group, compared to 53 % (31 of 58) in the ixmyelocel-T group (p = 0.0197). - Secondary efficacy endpoints: + No significant difference in win ratio between the arms (p = 0.1391) + No significant changes in LVESV, LVEDV, LVEF in either arms + No significant difference between treatment groups in terms of NYHA class and 6MWT (p = 0.8689 and p = 0.9303, respectively)	Modest size, results need to be confirmed in larger prospective studies, the improvements in clinical events were more significant than improvements in LV function	[35]
Safety and Efficacy of Autologous Cardiopoietic Cells for Treatment of Ischemic Heart Failure (CHART-1) NCT01768702	Completed	Phase III, randomized, double-blind, sham-controlled, multicentered	315 (cell-treated: 157, sham-control: 158)	LVEF ≤35 %, NYHA class III or IV	57-60x10^6 cells/mL	Endocardial	1 y	- Primary efficacy endpoint: Finkelstein–Schoenfeld hierarchical composite (all-cause mortality, worsening HF, MLHFQ score, 6MWT, LVESV, and LVEF)	- Primary efficacy endpoint: neutral (Mann–Whitney estimator 0.54, 95 % CI 0.47–0.61, p = 0.27) - Other: At 1 year, the LVEDV and LVESV of treated patients decreased by 17.0 mL and 12.8 mL greater than control. Greater improvement in 6MWT. The largest reverse remodeling was evident in the patients receiving moderate injections (<20). A significantly lower incidence of sudden or aborted sudden deaths was documented in cardiopoietic cell-treated patients compared to controls.	Neutral results	[36]
2. Mesenchymal stem cells (MSCs)
2.1 Bone marrow mesenchymal stem cells (BM-MSCs)
Autologous Mesenchymal Stromal Cell Therapy in Heart Failure (MSC-HF) NCT00644410	Completed	Phase II, randomized, double-blind, placebo-controlled	60 (cell-treated: 40, placebo: 20)	LVEF <45 %, NYHA II-III	77.5 ± 67.9 × 10^6 (interquartile range 53.8 × 10^6)	Transendocardial	4 y	- Primary endpoint: change in LVESV (MRI/CT scan) at 12 months - Secondary endpoints: + Imaging: LVEDV, LVEF, SV, cardiac output, LV MM/WT/wall thickening, scar volume + Clinical: NYHA class, CCS class, 6MWT, KCCQ, and safety at 4 years	- Primary endpoint: LVESV was significantly reduced in the MSC group (not in the placebo group) - Secondary: + Improved in LVEF of 6.2 % (P < 0.0001), SV of 16.1 mL (P < 0.0001) and MM (P = 0.009) between groups + Reduce scar tissue and quality of life score in the MSC group but not in the placebo group + After 4 years, there were significantly fewer hospitalizations for angina in the MSC group and otherwise no differences in hospitalizations or survival (22.5 % and 50 %, p = 0.031). No side effects were identified.	Require confirmation in larger randomized trials	[37]
The TRansendocardial Stem Cell Injection Delivery Effects on Neomyogenesis STudy (TRIDENT) NCT02013674	Completed	Phase II, randomized, double-blind, no control	30 (20 million MSC: 15, 100 million MSC: 15)	LVEF ∼36 %, NYHA II-IV	20x10^6 or 100 x10^6 (0.5 cc per injection × 10 injections)	Transendocardial	1 y	- Primary safety endpoint: treatment-emergent SAEs (TE-SAEs) - Secondary efficacy endpoints: regional and global LV function, shape, and infarct size - Other pre-specified endpoints: VO2, 6MWT, NYHA class, MACEs, and proBNP	- Safe - Secondary efficacy endpoints: + Similar reduction in scar size in both groups + Increase in LVEF only with 100 million group - Other pre-specified endpoints: + Improved NYHA class in the 20 million group (35.7 %) and 100 million group (42.9 %) + Increased proBNP in the 20 million group (0.32 log pg/mL p = 0.039), but not in the 100 million group	Small sample size, dose-comparison study of only two doses	[38]
Combination of Mesenchymal and C-kit + Cardiac Stem Cells (CPC) as Regenerative Therapy for Heart Failure (CONCERT-HF) NCT02501811	Completed	Phase II, randomized, placebo-controlled, multicentered	125 (MSC + CPC: 33, MSC: 29, CPC: 31, placebo: 32)	LVEF ∼28.6 ± 6.1 %, NYHA II-III	150 × 10^6 BM-MSCs vs 5 × 10^6 CPCs alone and in combination	Transendocardial	1 y	- Safety endpoints: HF-related-MACE (HF-MACE) - Efficacy endpoints: HF-MACE, MLHFQ score, LV structure and function (MRI), peak VO2 consumption, 6MWT, NT-proBNP	- Safety: MACE was significantly decreased by CPCs alone (−22 % vs. placebo, p = 0.043) - Efficacy: + MLHFQ score was significantly improved by MSCs alone (p = 0.050) and MSCs + CPCs (p = 0.023) vs. placebo + LVEF, LV volumes, scar size, 6MWT, and peak VO2 consumption did not differ significantly among groups	Early cessation and no significant differences between groups for LV function, scar size, or functional capacity endpoints.	[39]
Double-blind, Randomized, Sham-procedure-controlled, Parallel-Group Efficacy and Safety Study of Allogeneic Mesenchymal Precursor Cells (Rexlemestrocel-L) in Chronic Heart Failure Due to LV Systolic Dysfunction (Ischemic or Nonischemic) (DREAM HF-1) NCT02032004	Completed	Phase III, randomized, double-blind, sham-controlled, multicentered	565 (BM-MSC: 283, sham control: 282)	LVEF ≤40 %, NYHA class II-III	150 million MPCs in 15–20 injection sites (in 0.2 mL volume containing 8–10 million MPCs)	Transendocardial	3 y	- Primary endpoint: time-to-recurrent events caused by decompensated HFrEF or successfully resuscitated symptomatic ventricular arrhythmias - Hierarchical secondary endpoints: components of the primary endpoint, time-to-first terminal cardiac events, and all-cause death	Primary endpoint, terminal cardiac events, and secondary endpoints: similar between treatment groups	Primary and secondary endpoints were negative	[40]
2.2 Umbilical cord-derived mesenchymal stem cells (UC-MSCs)
Safety and efficacy of intracoronary human umbilical cord-derived mesenchymal stem cell (hUC-MSC) treatment for very old patients with coronary chronic total occlusion (Li et al., 2015)	Completed	Phase I, randomized, blinded, dose-escalating	15 (1:1:1)	LVEF 38.6 ± 5.13 %, NYHA III	3 × 10^6, 4 × 10^6, 5 × 10^6	IC into epicardial coronary artery supplying collateral circulation	2 y	- Primary endpoints: safety and feasibility of hUCMSC infusion (MACE, arrhythmia, neoplasia, death) - Secondary efficacy endpoints: infarct size reduction (SPECT), LVEF improvement, functional class, angina symptoms, exercise tolerance	- Safe - Secondary efficacy endpoints: + Significant reduction of the infarct size at 24 months compared to 12 months (54.6 ± 5.32 % vs. 46.3 ± 6.21 %, p < 0.001 and a remarkable rise in LVEF at 24 months compared to 12 months (21.2 ± 5.21 % vs. 29.3 ± 4.13 %, p < 0.001), with no apparent difference among the 3 doses + At 12 and 24 months, significant improvements in NYHA (P < 0.001)	Very small sample size, no placebo-control	[41]
Clinical observation of umbilical cord mesenchymal stem cell treatment of severe systolic heart failure (Zhao et al., 2015)	Completed	Phase I/II, randomized, double-blind, placebo-controlled	59 (cell-treated: 30, placebo: 29)	LVEF ≤35 %, NYHA III-IV	UC-MSC suspension (∼20 mL; viability ≥95 %)	IC: ⅔ injected into LCA, and 1/3, into RCA	6 mo	Safety and efficacy: Cardiac structure/function (LVEDD, LVEF, NT-proBNP), 6MWT, clinical symptoms, rehospitalization, and mortality	- Safe - Efficacy: + At 6 months, difference in LVEDV (T: 56.39 ± 5.17 vs. C: 63.13 ± 6.40, P < 0.05), LVEF (T: 0.49 ± 0.051 vs. C: 0.39 ± 0.035, P < 0.01), NT-proBNP (T: 1648.96 ± 304.54 vs. C: 2835.09 ± 412.03, P < 0.01), 6MWT (T: 466.36 ± 82.86 vs. C: 334.27 ± 43.75, P < 0.01) were statistically significant + At 6 months, there is no change in readmission rate (P > 0.05) but change in mortality rate (T: 2 vs. C: 7, P < 0.05) after treatment	Small number of participants and short follow-up period	[42]
Functional characterization of human umbilical cord-derived mesenchymal stem cells for treatment of systolic heart failure (Fang et al., 2016)	Completed	Pilot study	3 patients	LVEF 39.1 %, 20.3 %, 31.6 %, NYHA II-III	10 mL HUC-MSC suspension of 5–10 × 10^6 cells/mL	IV infusion	1 y	- Primary safety endpoints: AEs, MACE, arrhythmia, infection - Secondary efficacy endpoints: LVEF, LVEDV, LVESV, 6MWT, NYHA class	- Safe - Efficacy: + LVEF: 2 patients increased (65.1 % 3 months; 47.8 % 12 months) 1 patient decreased (16 %) +6MWT: 2 patients significantly improved (12 months) + NYHA: 3 patients improved (class III → II and class II → I)	Small number of participants, no control group, heterogeneous responses among patients, limited generalizability	[43]
Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy (RIMECARD) NCT01739777	Completed	Phase I/II, randomized, double-blind, placebo-controlled	30 (cell-treated: 15, placebo: 15)	LVEF mean ∼32.1 % ± 6.7, NYHA II-III	1 × 10^6 UC-MSCs/kg body weight (average ∼70 × 10^6 cells)	IV peripheral vein	1 y	- Primary safety endpoints: death, MACE, infection, malignancy, hemodynamic instability - Secondary efficacy endpoints: LVEF, LV volumes, 6MWT, BNP, MLHFQ score, NYHA class	- Safe - Efficacy: + Significant improvements in LVEF +7.07 ± 6.22 % vs C: +1.85 ± 5.60 % (p = 0.028) + Improved NYHA −0.62 ± 0.46 (p = 0.003) + Improved MLHFQ (p < 0.05 vs. baseline) +6MWT increased significantly (p < 0.05) + BNP trended down but not significant	Small sample size, single-dose design, short follow-up, not powered for mortality/hard outcomes	[44]
Human Umbilical Cord-derived Mesenchymal Stem Cells With Injectable Collagen Scaffold Transplantation for Chronic Ischemic Cardiomyopathy (He et al., 2020) NCT02635464	Completed	Phase I, randomized, double-blind, placebo-controlled	50 (collagen/cell group: 18 (T1), cell group: 17 (T2), CABG alone: 15 (C))	LVEF (CMR) mean 31.32 %, LVEF 3D echo mean 35.56 %, NYHA III-IV	Collagen/cell: hUC-MSCs 1 × 10^8 cells in 1.5 mL PBS + 1 mL collagen hydrogel Cell arm: hUC-MSCs 1 × 10^8 cells in 2.5 mL PBS Control: none	IM	1 y	- Primary safety endpoins: SAE - Secondary: + Efficacy endpoints: CMR LVEF, infarct size + Exploratory: CMR remodeling indices, NYHA class, MLHFQ score	- Safety: No significant differences in serious adverse events among groups (P = 0.68) - Efficacy: + Mean infarct size decreased in T1 but increased in T2 & C with T1: 3.1 % (95 % CI, −6.20 % to −0.02 %; P = 0.05) vs. T2: +5.19 % (−1.85 %–12.22 %, P = 0.35) vs. C: +8.59 % (−3.06 %–20.25 %, P = 0.21) + LVEF increased in all groups with T1: +9.35 % (95 % CI, 1.96 %–16.75 %; P = 0.02) vs. T2: +6.59 % (95 % CI, 2.61 %–10.56 %; P = 0.004) vs. C: +3.62 % (95 % CI, −3.25 %–10.50 %; P = 0.25) => T1 > T2 & C + MLHFQ improved in T1: −22.60 (95 % CI, −40.18 to −5.02; P = 0.02) vs. T2: −24.20 (95 % CI, −34.82 to −13.58; P < 0.001) vs. C: −16.17 (95 % CI, −26.31 to −6.02; P = 0.005) + Improved NYHA in all groups with no significant differences among groups (P > 0.05)	No collagen-only arm (can't separate hydrogel vs cell effects), surgeons not fully blinded, small sample, imbalance in anterior infarction prevalence across arms	[45]
Human Umbilical Cord Stroma MSC in Myocardial Infarction (HUC-HEART) NCT02323477	Terminated with results	Phase I/II, randomized, single-blinde, placebo-controlled, multicentered	54 (T1:C1:C2 = 2:1:1 with T: hUC-MSCs + CABG, C1: BMMNCs + CABG, C2: CABG)	LVEF ∼30–35 %, NYHA II-III	hUC-MSCs: 21-26 x 10^6, BMMNCs: 70 x 10^7	IM	1 y	- Primary safety endpoints: MACE composite (death, HF hospitalization, nonfatal MI, arrhythmia) - Primary efficacy endpoint: LVEF (MRI, SPECT, Echo) - Secondary endpoints: NT-proBNP, MRI remodeling indices (WM, SS, WT, MM), PET necrosis/hibernation, 6MWT, NYHA class	- Safe - Efficacy: + No significant LVEF change between the groups (cumulative from MRI, SPECT, Echo: p = 0.376; p = 0.110, and p = 0.765, respectively) + WT: no significant difference between the groups (χ2 = 2.400; p = 0.301). + MM: no difference between groups (p = 0.440). + Reduced infarct size in all groups: C2: 2.3 % (Z = 2.033; p = 0.042) vs. C1: 4.5 % (Z = 2.666; p = 0.008) vs. T: 7.7 % (Z = 3.517; p < 0.001) +6MWT: significant increase in C2 (14.5 %; p = 0.007) vs. T (13.8 %; p = 0.037) + NYHA seen in all groups but no different between groups (p = 0.338) + NT-proBNP decreased from baseline in C1 (p = 0.017) and T (p = 0.035)	No placebo injection for controls, vehicle volume differed between groups, only male patients included, relatively small sample size, budget/time-limited enrollment, some missing imaging (PET/MRI) due to comorbidities, cell doses not compared across ranges	[46]
Randomized Clinical Trial to Evaluate the Regenerative Capacity of CardioCell in Patients With Chronic Ischemic Heart Failure (CIHF trial (CIRCULATE project)) NCT03418233	Completed, no results posted	Phase II/III, randomized, placebo-controlled	115 patients (2:1)	LVEF ≤45 %, NYHA II-III	30 x 10^6 cells suspended in 20 ml of 0.9 % NaCl and 5 % albumin	Transcoronary	1 y	Efficacy	NA
Multi-intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Heart Failure With Reduced Ejection Fraction (PRIME-HFrEF) NCT04992832	Completed, no results posted	Phase I/II, randomized, double-blind, placebo-controlled	40 patients	LVEF ≤40 %, NYHA II-IV	1.0 x 10^6/kg	IV	1 y	- Primary safety endpoints: SAEs, AEs - Primary efficacy endpoint: LVEF	NA
2.3 Adipose-derived mesenchymal stem cells (AD-MSCs)
MesenchYmal STROMAL CELL Therapy in Patients With Chronic Myocardial Ischemia (MYSTROMALCELL) NCT01449032	Completed	Phase II, randomized, double-blind, placebo-controlled	60 (cell-treated: 40, placebo 20)	LVEF in ASC 52 ± 8 %, LVEF in placebo 54 ± 8 %, NYHA II-III	Mean 72 ± 45 × 10^6 autologous ASCs, 3 mL total injected	IM	3 y	- Primary efficacy endpoint (6 mo): change in bicycle exercise capacity - Other efficacy endpoints: CCS class, NYHA class, SAQ domains, weekly angina attacks, weekly short-acting nitrate use, safety events	- Primary efficacy endpoint: Exercise capacity over 3 yrs: preserved in ASC group (time 383 ± 30  →  370 ± 44 s, P = 0.052; watts 81 ± 6  →  78 ± 10, P = 0.123), declined in placebo (time 437 ± 53  →  383 ± 58 s, P = 0.001; watts 87 ± 12  →  80 ± 12, P = 0.019) - Other efficacy endpoints: + Symptoms: CCS improved in ASC (2.5 ± 0.9  →  1.8 ± 1.2, P = 0.002) not placebo; NYHA modestly improved in ASC (2.4 ± 0.6  →  2.2 ± 0.8, P = 0.007) not placebo; weekly angina attacks decreased only in ASC; SAQ domains improved in both; no significant between-group differences across endpoints at 3 yrs + Safety: 4 deaths in ASC group over 3 yrs; cancers: 1 ASC (meningioma) vs 3 placebo (prostate, stomach, myeloid leukemia)	Small sample, imbalances at baseline (all male in placebo; trends in hypertension and prior CABG), variable autologous cell dose, no long-term perfusion imaging, likely underpowered for between-group differences, logistical constraints of autologous expansion	[47]
Autologous Adipose-Derived Regenerative Cells (ADRCs) for Refractory Chronic Myocardial Ischemia with Left Ventricular Dysfunction (ATHENA and ATHENA II) NCT02052427	Completed	Phase II, randomized, double-blind, placebo-controlled	31 patients (ATHENA: 28 patients (40 M cells), ATHENA II: 3 patients (80 M cells))	LVEF ∼31 %, NYHA II-III	0.4 x 10^6 cells/kg of ASCs (in ATHENA), 0.8 x 10^6 cells/kg of ASCs (in ATHENA II)	IM	1 y	- Safety endpoints: MACE- Efficacy endpoint: VO2 max, treadmill time, MLHFQ, SF-36, LVEF/LVEDV/LVESV (echo), perfusion defects (SPECT), NYHA/CCS class	- Feasible small volume fat harvest - Low safety level due to presence of non-ADRC-related AEs - No differences in LVEF between ADRC and control groups (p = not reported) - Improved functional outcomes and quality of life (p = 0.038)	Premature termination (only 31/90 enrolled), limited power for efficacy, safety signal (neurologic events) halted enrollment, small sample prevented dose-response evaluation, results inconclusive but suggest symptomatic/QOL benefit	[48]
Allogeneic Adipose Tissue-derived Stromal/Stem Cell Therapy in Patients With Ischemic Heart Disease and Heart Failure—A Safety Study (CSCC_ASCI) NCT02387723	Completed	Phase I, no control group, open label	10 patients	LVEF 28.8 %, NYHA II–III	15 injections of 0.3 mL of CSCC_ASCs (total 100 million)	IM	6 mo	- Primary endpoint: safety/immunologic reactions - Secondary endpoints: + Imaging: LVESV, LVEDV, LVEF + Functional: NYHA class, CCS class, KCCQ, 6MWT	- Safe - Primary endpoint: 4/10 de novo donor-specific HLA class I antibodies without clinical immune sequelae - Secondary endpoints: + LVESV -23 mL (95 % CI: 23 to 49; p = 0.073) + LVEF +2.9 % (95 % CI: 0.2 to 6.1; p = 0.065) + Significant gain in 6MWT +35 min (95 % CI: 24 to 47; p < 0.0001), and NYHA -0.6 (95 % CI: 0 to 1.2; p = 0.06) + No differences in KKCQ scores and CCS class - Other: proBNP unchanged from baseline, tissue type-specific donor antibodies seemed to have no negative effect	Small sample, not powered for efficacy, potential placebo effect, day-to-day assay variation hampers direct comparison of HLA antibody MFI, multiple donors may introduce variability, short follow-up	[49]
Rationale and Design of the First Double-Blind, Placebo-Controlled Trial with Allogeneic Adipose Tissue-Derived Stromal Cell Therapy in Patients with Ischemic Heart Failure: A Phase II Danish Multicenter Study (CSCC_ASCII) NCT03092284	Completed	Phase II, randomized, double-blind, placebo-controlled, multicentered	81 (ASC: 54, placebo: 27)	LVEF ∼ 33 %, NYHA II-III	12–20 injections of 0.3–0.4 mL allogeneic CSCC_ASCs (total 100 million)	IM	1 y	- Primary endpoint: LVESV at 6 months - Secondary endpoints: LVEF, LVEDV, 6MWT, NT-proBNP, NYHA class, KCCQ, safety/clinical events	- Primary: No significant difference in LVESV change at 6 months (ASC vs placebo, p = 0.96) - Secondary: No significant changes in LVEF, LVEDV, 6MWT, NT-proBNP, or NYHA - Safety: No major issues, but 36 % ASC group developed donor-specific HLA antibodies vs 0 % placebo	Modest sample size, not powered for mortality, heterogeneity in LV imaging (MRI vs CT), 12-month follow-up may be too short, immune response remains a concern	[50]
3. Cardiac stem cells and Cardiospheres
ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) NCT01458405	Terminated with results	Phase I/II, randomized, double-blind, placebo-controlled, multicentered	134 (cell-treated: 90, placebo: 44)	LVEF mean ∼ 40 ± 7 %, NYHA I-III	2.5x10^7 allogeneic CDCs (CAP-1002) per dose unit in 11.5 mL cryopreservation solution	Single artery IC	1 y	- Primary safety endpoint (1-month): SAEs, MACE - Primary efficacy endpoint (12-month, antibody-matched): % change in MRI scar size - Secondary efficacy endpoints: LVEDV, LVESV, EF, SV, scar mass, 6MWT, NYHA class, NT-proBNP, QoL, immunologic assays	- Safety: After 1 month, there were no adverse events - Efficacy: After 6 months, no significant difference in the relative change in scar size (mean ± SD -5.0 % ± 7.4 % vs. −4.1 % ± 9.1 %, P = 0.54) but significant change in favor of CDCs in LVEDV (mean ± SD 1.1 ± 11.02 vs. 5.6 ± 10.74, P = 0.02), LVESV (mean ± SD 0.60 ± 14.31 vs. 5.4 ± 11.93, P = 0.02), NTproBNP (mean ± SD -429 ± 884 vs. −126 ± 622 pg/mL, P = 0.02)	Early termination and underpowered for planned 12-month primary endpoint, single-artery single-dose intracoronary stop-flow delivery (may limit efficacy), relatively low-risk cohort (mean LVEF ∼40 %), some baseline clinical data incomplete	[51]
4. Human-induced pluripotent stem cells (hiPSCs)
Clinical Trial of Human (Allogeneic) iPS Cell-derived Cardiomyocytes Sheet for Ischemic Cardiomyopathy NCT04696328	Uncompleted	Phase I, single-arm, open label	10 patients	LVEF ≤35 %, NYHA III-IV	3 circular iPSC-CM patches, each containing 3.3 × 107 cells	Implantation	1 y	- Primary endpoint: LVEF, safety and tolerability - Secondary endpoint: contraction function of the entire LV, LV remodeling (LVESVI), NYHA class, QoL, BNP, NT-proBNP, exercise tolerance	First 3 cases reported: - Safety: No transplanted-cell–related AEs, 4 severe AEs judged unrelated, no tumors - Improvement in cardiac function (LVEF, anterolateral wall contraction, myocardial blood flow) and heart failure symptom NYHA class III to class II and I	Single-arm without controls, first-in-human safety focus (not powered for efficacy), inability to perform histologic assessment of grafts, potential influence of pre-existing anti-HLA and degree of residual myocardium	[52]
Safety and Efficacy of Induced Pluripotent Stem Cell-derived Engineered Human Myocardium as Biological Ventricular Assist Tissue in Terminal Heart Failure (BioVAT-HF ) NCT04396899	Uncompleted	Phase I/II, single-arm, open label	53 patients	LVEF ≤35 %, NYHA class III-IV	NA	Implantation	1 y	Primary endpoint: Heart wall thickness and heart wall thickening fraction	NA
Epicardial Injection of Allogeneic Human Pluripotent Stem Cell-derived Cardiomyocytes to Treat Severe Chronic Heart Failure (HEAL-CHF) NCT03763136	Uncompleted	Phase I/IIa, randomized, placebo-controlled, dose escalation	20 patients (CABG + hiPSC-CMs vs CABG alone)	LVEF 20–40 %, NYHA III-IV	1 × 10^8, 2 × 10^8, 4 × 10^8 hiPSC-CMs	IM injection (epicardial) during CABG	1 y	- Primary safety endpoint: SAEs, AEs, - Secondary efficacy endpoint: LV systolic performance, myocardial perfusion, 6MWT, NYHA class, MLHFQ score, NT-proBNP, changes in penal reactive antibodies, changes in donor specific antibodies, MACE	NA		[53,54]
A Phase I/II Study of Human Induced Pluripotent Stem (iPS) Cell-derived Cardiomyocyte Spheroids (HS-001) in Patients With Severe Heart Failure, Secondary to Ischemic Heart Disease (LAPiS Study) NCT04945018	Uncompleted	Phase I/II, open label, no control, dose escalation	10 (low-dose group: 5, high-dose group: 5)	NYHA class II or over	0.5x10^8, 1.5x10^8	Implantation during CABG	52 w	- Primary endpoint: safety and tolerability - Secondary endpoint: LVEF, myocardial wall motion, myocardial blood flow, myocardial viability, 6MWT, the KCC Questionnaire, 5-level EQ-5D version, and NT-proBNP	NA
5. Human embryonic stem cells (hESC)
Transplantation of Human Embryonic Stem Cell-derived CD15+ Isl-1+ Progenitors in Severe Heart Failure (ESCORT) NCT02057900	Completed	Phase I, single-arm, open label	6 patients	LVEF ∼26 % ± 6 %, NYHA III-IV	8.2 x 10^6 cells per fibrin patch	Epicardially delivered a cell-loaded fibrin patch during CABG	26 mo	- Primary safety endpoints (1 year): tumor formation, arrhythmia, graft-related AEs - Secondary endpoints: feasibility, LV function, scar size (MRI), NYHA class, functional status	- Safety: No arrhythmias, no tumor, 3/6 developed symptomatically silent alloimmunization. 1 perioperative death (not cell-related), 1 late death (HF progression) - Efficacy signals: Modest LVEF increase (from 26 % to ∼36 % at 12 months in some patients), decreased scar size, improved NYHA class in survivors	Very small cohort, open-label and uncontrolled design, concomitant CABG confounds efficacy, heterogeneity in patient severity, short/variable follow-up, generalizability limited	[55]

sAbbreviations in this table: 6MWT: 6-min walk test, AE: adverse effect, ASC: adult stem cell, BM-MSC: bone marrow mesenchymal stem cell, BMMNC: bone marrow-derived mononuclear cells, CABG: coronary artery bypass grafting, CCS: Canadian Cardiovascular Society, CDC: cardiosphere-derived cells, CMR: cardiac magnetic resonance imaging, CPC: cardiac c-kit positive progenitor cell (in the context of the CONCERT-HF clinical trial), CT: computed tomography, Echo: echocardiography, EDV: end-diastolic volume, ESV: end-systolic volume, EF: ejection fraction, HF: heart failure, HFrEF: heart failure with reduced ejection fraction, hiPSC: human-induced pluripotent stem cells, HLA: human leukocyte antigen, IC: intracoronary, IM: intramyocardial, IV: intravenous, KCCQ: Kansas City Cardiomyopathy Questionnaire, LCA: left coronary artery, LV: left ventricular, LVAD: left ventricular assist device, LVEF: left ventricular ejection fraction, MACE: major adverse cardiac events, MI: myocardial infarction, MLHFQ: Minnesota Living with Heart Failure Questionnaire, MM: myocardial mass, mo: month, MPC: mesenchymal precursor cells, MSC: mesenchymal stem cell, MRI: magnetic resonance imaging, NA: not available, NT-proBNP: N-terminal pro-B-type natriuretic peptide, NYHA: New York Heart Association, PET: positron emission tomography, QoL: quality of life, RCA: right coronary artery, SAE: serious adverse effects or events, SAQ: Seattle Angina Questionnaire, SF-36: 36-Item Short Form Health Survey, SPECT: single photon emission computed tomography, SS: systolic shortening, SV: stroke volume, UC-MSC: umbilical cord mesenchymal stem cell, w: week, WM: wall motion, WT: wall thickness, y: year.

The earlier pilot study (NCT02479776) administered autologous bone marrow-derived stem cells in pediatric HF [33]. Although the primary efficacy endpoint of ejection fraction was not met, the study demonstrated several positive outcomes in the stem cell treatment group compared to the control group, such as lower end-diastolic volume (EDV) and end-systolic volume (ESV) and significantly decreased LV volumes at 6 months. Given the limited sample size of 10 participants, randomization alone was insufficient to overcome the statistical limitations and vulnerability of the findings, making these results exploratory rather than conclusive. Similarly, the follow-up ASSURANCE trial (NCT00869024), which was among the first to assess IM injection of unfractionated BMMNCs in patients supported by left ventricular assist device (LVADs), revealed interesting potential, the therapy seemed to reduce overall mortality. Despite its small sample size (n = 25), the study reported lower all-cause mortality in the treatment group (12.5 % vs. 33.3 %) over 24 months. However, serious adverse events were paradoxically more common in the treatment arm (81.25 %), raising questions about the risk-benefit ratio. Moreover, while the trial's reliance on composite and histological endpoints (e.g., myocardial viability and ventricular dimensions) was appropriate for early-phase research, it underscores a broader issue in early BMMNC studies: surrogate outcomes were frequently prioritized over functional or survival metrics.

Despite their frequent use in both early and recent trials, current evidence suggests that unfractionated BMMNCs lack efficacy in treating either ischemic or nonischemic HF [56]. Consequently, there is a growing need to refine cell selection strategies to harness the therapeutic potential of these cells more effectively. Recent advances in scientific technology have led to the identification and study of alternative stem cell sources that offer substantial potential for specific cardiac cell differentiation with less invasive approaches. Hematopoietic stem cells, a subset of BMMNCs, improved LV function in the COMPARE-AMI trial, although it remains uncertain whether this improvement is due to their differentiation into CMs [64,65]. Another subset, endothelial progenitor cells (EPCs), has also been shown to improve heart function through different mechanisms [66,67]. Rather than differentiating into CMs, EPCs enhance angiogenesis by differentiating into endothelial cells, thereby increasing oxygen and nutrient delivery to host CMs and endogenous stem cells [68]. More recent research has focused on specific, selectively identified BMMNC types with distinct markers, exemplified by trials such as PreSERVE-AMI and ixCELL DCM. These trials yielded promising primary endpoint results, including a 37 % reduction in cardiac events in the ixCELL DCM trial compared with the placebo [35] and a 0 % mortality rate at one year in the PreSERVE-AMI trial [34]. However, secondary endpoints, such as LV volume, NYHA functional class, and the 6-min walk distance, did not significantly differ, with the results remaining consistent across patients and studies. In addition, the CHART-1 trial examined cultured bone marrow-derived cardiopoietic stem cells, although their advantages and disadvantages are relative to those of fresh BMMNCs remain under evaluation. On the basis of available preclinical and clinical data, IM delivery of bone marrow-derived cells, particularly CD34⁺ and mesenchymal stem cells, has produced the most consistent and promising results [69].

BMMNCs present significant potential, primarily because they can be obtained from patients themselves without expansion and are easy to collect, prepare, and preserve, thus avoiding potential ethical issues or immune-related problems [57]. The findings from the aforementioned trials suggest that BMMNCs are associated with improved safety profiles, enhanced quality of life and exercise capacity, increased perfusion in the ischemic myocardium, and a notable reduction in the frequency and duration of anginal episodes. These outcomes indicate a promising capacity to reverse microvascular dysfunction. However, evidence also suggests that unfractionated BMMNCs lack efficacy in both ischemic and nonischemic HF, leading to the discontinuation of their investigation. The focus has since shifted toward specific cell types, such as BM-MSCs, which will be further discussed in the next section.

4.2. Mesenchymal stem cells (MSCs)

Mesenchymal stem cells (MSCs) are currently the most widely used cell source for regenerative cardiovascular stem cell therapy, especially for advanced ischemic HF. In 2006, the International Society for Cellular Therapy (ISCT) position statement released minimal criteria for defining mesenchymal stromal cells that 1-are plastic adherent when maintained under standard culture conditions; 2-are expressed with the surface markers CD73, CD90, and CD105 (≥95 %) and lack expression of the hematopoietic lineages CD45, CD34, CD14/CD11b, CD79 alpha, CD19, and HLA-DR (≤2 %); and 3-have the ability to differentiate into adipocytes, osteoblasts, and chondrocytes under standard differentiation conditions [70]. MSCs can be isolated from various tissues, including bone marrow [71], adipose tissue [72], the umbilical cord [73], dental pulp [74], the endometrium [75], and peripheral blood (studies on culture and in vitro osteogenesis of blood-derived human mesenchymal stem cells). Currently, the MSCs most commonly used in clinical studies are derived from bone marrow, adipose tissue or umbilical cord blood [76].

MSCs possess many properties that make them potential candidates for cell therapy in the treatment of HF. However, the precise mechanism of action of MSCs remains unclear. Reported studies have demonstrated that MSCs have antifibrotic, antiapoptotic, anti-inflammatory, immunomodulatory [77], and proangiogenic factors (including cytokines, growth factors, and microRNAs) [[78], [79], [80]], metalloproteinase [81], and exosomes [82] that stimulate cardiac repair. All of these effects may be related to HF disease progression and the treatment outcomes of MSC-based therapies, such as the participation of MSCs in the generation of new blood vessels in ischemic tissues and the instigation of resident cardiac cells [83], as well as their antifibrotic effects in the clinic with HF [84,85]. In particular, MSCs can be easily isolated from autologous sources and rapidly expanded ex vivo, and a well-established clinical MSC production process based on a bioreactor system can produce large amounts of good-quality MSCs [86]; therefore, it has been the most widely used cell source for regenerative HFs.

In 2012, the first trial on the use of MSCs, the POSEIDON trial of Hare and coworkers in a U.S. tertiary-care referral hospital [87], was completed and revealed initial encouraging results that both allogeneic and autologous cells were safe and improved structural and functional in patients with LV dysfunction following myocardial infarction. These robust findings strongly support the development of future trials of the use of MSC-based therapy for cardiovascular diseases.

4.2.1. Bone marrow mesenchymal stem cells (BM-MSCs)

Following the publication of the POSEIDON trial, four other trials have evaluated BM-MSCs for HFs, namely, MSC-HF, TRIDENT, CONCERT-HF, and DREAM-HF, which study allogenous and allogenic BM-MSCs. These are phase II/III randomized, double-blinded trials with no control, control or sham-treatment-control trials on HF patients in different NYHA classes. All the stem cells were transendocardially transferred into the patients’ hearts, and the patients were followed for 12–48 months. Within 12 months of posttreatment, the patients were followed up with serious adverse events, changes in heart structure and function, clinical symptom improvement, and quality of life. Rehospitalization and mortality were assessed at 3 and 4 years in the MSC-HF and DREAM-HF groups.

The primary endpoints were changes in the left ventricular end-systolic volume (LVESV) and left ventricular ejection fraction (LVEF). These parameters have been demonstrated to be positively changed in all trials, except for CONCERT-HF, which showed no difference among patient groups [39]. In the MSC-HF trial, after 12 months, the LVESV was significantly lower (17.0 ± 16.2 mL; p < 0.0002) in the BM-MSC group than in the placebo group. There were also substantial improvements in LVEF (6.2 %, p < 0.0001), stroke volume (16.1 mL, p < 0.0001) and myocardial mass (p = 0.009) between the groups [37]. The TRIDENT trial revealed an increase in LVEF only in the group treated with a 100 million-cell dose, highlighting the crucial role of the optimal cell dosage in cell therapy [38]. The BM-MSC-treated group in the DREAM-HF study also experienced improvements in LV remodeling, and the LVESV was reduced by 7 mL (p = 0.015) [88] at 6 months compared with baseline and increased LVEF from baseline to 12 months, especially in patients with inflammation with high-sensitivity C-reactive protein (hsCRP) ≥ 2 mg/L (n = 298; p = 0.008) [40]. Moreover, a significant reduction in the amount of scar tissue was also observed in all studies [[37], [38], [39],88].

Cardiac adverse events, clinical improvement and quality of life measured by NYHA class changes, the major adverse cardiovascular event (MACE) score and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) score have yielded various results among studies and different patient groups. For example, in the CONCERT-HF study, HF-related MACE did not significantly change in the BM-MSC-treated group but was reduced by 68 % (p = 0.061) in the MSC-CPC combination-treated group [39]. In the DREAM-HF study, compared with control subjects, MPCs decreased the risk of myocardial infarction or stroke by 58 % (hazard ratio (HR): 0.42; 95 % confidence interval (CI): 0.23–0.76) and the risk of 3-point MACE by 28 % (HR: 0.72; 95 % CI: 0.51–1.03) in the analysis population (n = 537), and by 75 % (HR: 0.25; 95 % CI: 0.09–0.66) and 38 % (HR: 0.62; 95 % CI: 0.39–1.00), respectively, in patients with inflammation (baseline hsCRP ≥2 mg/L). These findings raise the possibility that treating HFrEF patients with MPC may improve outcomes by targeting local and systemic inflammatory changes in patients with HF. In the MSC-HF study, there were significant improvements in the NYHA class in both groups, but there were no significant differences between the groups [38]. Moreover, the data collected at 4 years of follow-up demonstrated that the BM-MSC group had a significant reduction in angina during hospitalization compared with the placebo group (22.5 % and 50 %, p = 0.031).

Among those trials, the DREAM-HF trial is the largest clinical trial to date of cell therapy for HF [88] and is the first phase III clinical trial in which MSCs are used for the treatment of HF. Although the results revealed no improvement in the primary endpoint, they have improved the secondary endpoints. However, these are only partial results published by the sponsor, and important parameters such as LV volume and function, N-terminal pro-B-type natriuretic peptide (NT-proBNP), functional capacity, and quality of life have not been published.

4.2.2. Umbilical cord mesenchymal stem cells (UC-MSCs)

A more popular approach to MSC-based therapy is the use of MSCs from umbilical cord blood. From 2015 to 2023, eight prospective in-human clinical trials were conducted with full results, five of which were based in China. These are phase I/II, with the exception of CIRCULATE project (CIHF) phase II/III, randomized, placebo-controlled, double/single-blinded studies. A wide selection of parameters were used to measure the outcomes, with LVEF as the primary marker in multiple trials, along with infarct or necrotic myocardium size. Additionally, 6-min walking test (6MWT) and the NYHA class were frequently used to assess functionality.

In almost all the studies, safety was the primary endpoint. The general findings supported the use of allogeneic UC-MSCs as safe, with few to no major adverse events reported across different delivery routes (IC, IV, and IM) and doses (from 1 × 10^6 to 7 × 10^8). Except for the two studies of Zhao, Xu [42] and He, Wang [45], none of the clinical trials reported adverse effects at the final follow-up after intervention therapy. Zhao, Xu [42] reported a series of adverse effects (chest discomfort and ST-T changes) in 1 patient treated with IC injections of UC-MSCs, which were attributed to interventional surgery. Nonetheless, spontaneous remission was achieved 15 min after the physiological saline flush. Regarding the trial by He, Wang [45], no adverse effects were observed in the control group, and one hospitalization for HF in each of the treatment groups was reported, both of which were confirmed to be unrelated to the treatment. Hence, there was no significant difference in serious adverse events among the groups (P = 0.68) [45].

Efficacy outcomes are often positive, showing improvements in LVEF, NYHA functional class, and patient quality of life, validating that UC-MSC transplantation in patients with chronic ischemic heart diseases helps increase cardiac function. However, one exception was that IV infusion of allogeneic UC-MSCs at a cell dose of 5–10 × 10^6 led to a decrease in LVEF in one out of three patients at the 12-month follow-up of a pilot study in the absence of any other identifiable contributing factors [43]. In addition, three studies have also noted reductions in infarct size using different methods, including single photon emission computed tomography (SPECT) [41], cardiovascular magnetic resonance imaging (CMR) [45], and positron emission tomography (PET)-the only one out of three not suffering from lack of control limitation [46]. As will be mentioned soon in the text, it should be accounted that the two out of three respective studies suffer from lack of control limitation.

One major limitation of these clinical trials is their scale of the population. Except for the CIRCULATE trial, which recorded results from 115 participants, almost all UC-MSC transplantations performed in patients with ischemic cardiomyopathy were small in scale (from 3 to 59 participants). After cell injection, most trials only monitor up to 12 months after intervention therapy, with the study of Li, Hu [41] being the only study that displayed no adverse effects at 24 months after IC transplantation of UC-MSCs. Another limitation is the study design without control group, as seen in three studies, including that of Li, Hu [41], Fang, Yin [43], and He, Wang [45]. For this reason, the positive effects observed in the collagen/cell group could not be attributed to the transplanted stem cells, the collagen hydrogel itself, or even a synergistic effect of both. These shortcomings, including small sample sizes, short monitoring periods, and inadequate control groups collectively undermine the reliability and generalizability of the findings and calls for more rigorous methodological approaches in future research.

The earliest two studies of human UC-MSCs transplantation therapy for chronic ischemic HF demonstrate encouraging trends in efficacy, albeit methodological limitations. The first study by Li, Hu [41] infused three escalating dosages of cells (3–5 × 10^6) via the IC route without a control group. Instead, the conclusions were drawn by comparing results at 24 and 12 months of follow-up and the differences among the three doses. Results showed significant improvements in both infarct size and LVEF at 24 months compared to 12 months (54.6 ± 5.32 % vs. 46.3 ± 6.21 %, p < 0.001; 21.2 ± 5.21 % vs. 29.3 ± 4.13 %, p < 0.001, respectively), with no apparent difference among the three doses. The reduction in infarct size could suggest a mechanistic explanation for the LVEF improvement. However, the lack of control group makes it impossible to definitively attribute the observed improvements solely to the UC-MSC treatment and not other factors, such as the natural progression of the disease. The second study by Zhao, Xu [42] was a randomized, placebo-controlled study, involving IC infusion of UC-MSCs into both the left and right coronary artery. Contrasting to the escalating doses commonly used in early-stage trials to test for safety and efficacy, Zhao and Xu used a fixed dose. At 6 months, there was a significant increase in LVEF (0.49 ± 0.051 vs. 0.39 ± 0.035, P < 0.01). However, the unknown status of research blinding and the limited monitoring window of 6 months limited the ability to evaluate the long-term effectiveness and safety of UC-MSCs. These two studies underscore the need for larger, well-designed, long-term, and blinded studies to confirm these promising early findings.

The RIMECARD trial (Randomized Clinical Trial of Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells for Cardiopathy) was the first double-blind, randomized, placebo-controlled trial to confirm the safety and feasibility of IV infusion of UC-MSCs. The IV administration route simplifies the therapy and may reduce costs. Notably, data on the surface molecular disappearance of infused cells in the RIMECARD trial confirmed the immune privilege of MSCs [44]. With regard to this specific delivery route, a lower dose of 1 × 10^6 was used, as compared to the dose of 5–10 × 10^6 used in the study of Fang, Yin [43].

The Human Umbilical Cord Stroma MSC in Myocardial Infarction (HUC-HEART) trial was a controlled, randomized, phase I/II, multicenter, single-blind, three-arm study, comparing allogeneic HUC-MSCs to autologous BMMNCs and a control group. HUC-HEART trial interestingly involved the transplantation of UC-MSCs from female infant donors into a male-only participant population with the goal of tracking cells on the basis of sex chromosomes on subsequent cardiac biopsy [89]. According to the author, the recruitment of only male participants is a major limitation to the study design but does confer a benefit of an easier process (the fact that there is a higher incidence of chronic ischemic cardiomyopathy requiring coronary artery bypass grafting (CABG) in men than in women) and eliminating the confounding factor arising from sex variation, thus resulting in more accurate results in a relatively small-scale trial [46]. Another limitation is that the second control group (C2) did not receive a placebo injection because of ethical concerns, which could decrease the reliability of the results.

No significant changes in LVEF were seen among the groups. Aside from functional markers like LVEF, the HUC-HEART trial used the four magnetic resonance imagint (MRI)-based parameters (wall motion (WM), scar score (SS), wall thickness (WT) and myocardial mass (MM)) as the direct measure of changes in the size of the necrotic myocardium. Efficacy outcomes were notable for the HUC-MSC group leading to the highest decrease in necrotic myocardium of 7.7 %, compared to 4.5 % in the BMMNC group and 2.3 % in the control group (C: 2.3 %; (p = 0.042), T2: 4.5 % (p = 0.008) and T1: 7.7 % (p < 0.001)). This result suggests that HUC-MSCs demonstrate superior efficacy in repairing damaged heart muscle compared to other cell types. This effect extends beyond functional improvements such as LVEF, revealing physical cardiac regeneration and offering deeper insight into the treatment's underlying mechanism of action.

NCT02635464 was the first randomized, double-blind clinical trial to demonstrate that collagen hydrogel is a safe and feasible method for cell delivery, which could improve cell retention [45]. The mean infarct size percentage change was −3.1 % in the collagen-laden cell group at 12 months, though the differences in scar size between the groups were not statistically significant. This provides a basis for larger clinical studies.

A common notation is that the field of UC-MSCs is still in its exploratory phase, with most clinical trials in phase I/II, and after decades of research, the optimal dose and route of administration for HF remain unsettled. These clinical trials demonstrated the safety of UC-MSCs therapy for ischemic HF, but its efficacy outcomes have not been definitively proven. From here, future large-scale randomized clinical trials are needed to elucidate the efficacy of this therapy.

4.2.3. Adipose-derived mesenchymal stem cells (AD-MSCs)

Adipose-derived mesenchymal stem cells (AD-MSCs) are multipotent adult stem cells that found in adipose tissue that can differentiate into different cell types, such as adipocytes, osteoblasts, and chondrocytes [90]. Although not being pluripotent, their availability, ease of isolation through liposuction procedures, and paracrine signaling properties have made them promising candidates for cardiac regenerative therapies.

After extraction from adipose tissue, AD-MSCs are isolated and cultured ex vivo to yield appropriate quantities. They then undergo specification, in which exposure to certain growth factors and signaling molecules drives their differentiation toward cardiomyogenic lineages [91]. This process aims to maximize their therapeutic application for cardiac usage. AD-MSCs can be delivered through several routes, including IM, IC, and IV injections.

In the condition of HF, preclinical studies have demonstrated the potential of AD-MSC transplantation to enhance cardiac function, decrease infarct size, and increase angiogenesis [92]. These benefits are attributed to their paracrine secretion of cytokines, growth factors, and exosomes that have an effect on inflammation, cell survival, and endogenous repair mechanisms [93]. While the ability of AD-MSCs to differentiate into functional CMs remains controversial, their immunomodulatory effects and ability to establish a pro-regenerative microenvironment are key to their therapeutic action [94].

To date, there have been four notable clinical trials investigated AD-MSC therapy in ischemic heart disease, all using IM injection. Protocols varied in dosage, cell preparation, and patient population.

The MYSTROMALCELL trial used 10–15 injections of VEGF-A165-stimulated culture-expanded adipose-derived stromal cell (ASCs), while the ATHENA trials administered adipose-derived regenerative cells (ADRCs) at two different concentrations. The CSCC_ASCI and CSCC_ASCII trials focused on culture-expanded allogeneic ASCs, with the latter using a placebo-controlled design to evaluate the efficacy of the therapy.

The MYSTROMALCELL trial illustrated a favorable safety profile, with improvements in the NYHA class, hinting potential benefits in alleviating the severe symptoms of HF [47]. Positive trends were also noted in the ASC group for angina frequency, quality of life, and functional class, indicating that ASCs may have broader therapeutic effects beyond simply enhancing cardiac function. However, these improvements, though encouraging, were not quantified with regards to specific changes in LVEF or other cardiac parameters, leaving some uncertainty about the degree of clinical benefit.

In contrast, the ATHENA and ATHENA II trials reported more variable results. Although they confirmed that small-volume fat collection could be used to harvest ADRCs with feasibility, they did not detect any differences between the placebo-treated and ADRC-treated patient groups in LVEF. This lack of efficacy could perhaps have been due to use of a relatively small cell dose, or it may indicate that ADRCs, with their delivery in these trials, are not so effective in activating cardiac repair. Non-ADRC-related adverse effects, including cardiac arrhythmias, and other adverse effects have also caused concern regarding the overall safety of this treatment. These adverse effects underscore the requirement for sensitive monitoring and potentially tighter patient selection criteria in future trials.

The CSCC_ASCI trial was similarly disappointing in terms of efficacy, as it failed to meet its predefined endpoints for improving cardiac function or clinical symptoms. Despite the administration of a higher dose of 100 million culture-expanded ASCs, there was no significant improvement in LVEF or some of the most important markers of progression of heart disease [49]. This finding implies that boosting cell dose by itself may not be enough to yield desired therapeutic effects. Nonoptimal engraftment of cells, poor survival of transplanted cells, or reduced paracrine activity may be some of the reasons for a lack of efficacy.

In contrast, the CSCC_ASCII trial provided modestly encouraging results, demonstrating safety and feasibility [50]. However, no significant improvements were observed in key functional or structural cardiac parameters, including LVESV, LVEF, LVEDV, or exercise capacity. Importantly, while the treatment was generally well tolerated, a notable proportion of patients developed donor-specific HLA antibodies, raising concerns about potential immune sensitization. These findings suggest that although ASC therapy is feasible, further refinement of cell preparation, delivery strategies, and immune monitoring is required to realize its therapeutic potential in chronic ischemic cardiac failure. This was possibly due to an improved cell preparation and delivery regimen, together with a placebo-controlled design, which made the findings more reproducible. Nevertheless, despite these encouraging findings, improvement in LVEF was modest, and dramatic restoration of cardiac function was not achieved by the trial. Specifically, the trial reported no significant differences in LVEDV (−5.7 mL; 95 % CI –16.7 to 5.3 mL; p = 0.306) or LVEF (−1.7 %; 95 % CI –4.4 to 1.0; p = 0.212) between ASC-treated patients and placebo. This implies that, while ASCs play a useful role in treating HF, their effect might be small-scale rather than revolutionary.

The main limitation with these trials is small study sizes, which decrease both the statistical power and generalizability of the results. Variability in cell preparation, dose, and administration routes further hinders direct comparison of trials. Even though overall safety was generally established, efficacy was inconsistent, with some studies not achieving their major endpoints. Noncell-related adverse effects in the ATHENA trials are of concern regarding overall therapy safety and points to an indication that larger, better-controlled studies are needed.

These trials identify potential therapeutic application of ASCs and AD-MSCs for treatment of HF, especially by virtue of their paracrine effects and capacity to enhance cardiac function in certain instances. Nonetheless, the variable outcomes and issues of potential toxicity indicate that additional study is required to maximize the cell preparation, dose, and delivery. Most encouraging were the findings from the CSCC_ASCII trial, which achieved both safety and efficacy in enhancing primary cardiac endpoints. This trial's protocol could extend to future studies, underscoring the priority of properly conducted, placebo-controlled trials to definitively delineate therapeutic effects of ASC-based treatments.

4.3. Cardiac stem cells and cardiospheres (CSCs/CPCs and CDCs)

Within the timeframe of this review, two major trials using CDCs, intracoronary ALLogeneic heart stem cells to achieve myocardial regeneration (ALLSTAR; NCT01458405) and a combination of mesenchymal and c-kit + cardiac stem cells as regenerative therapy for HF (CONCERT-HF; NCT02501811), were conducted. Both studies are phase I/II multicenter, randomized studies with double-blinding and placebo.

Overall, two trials use different sources of cells and delivery routes. In the ALLSTAR, 2.5x10^7 allogeneic favoring CD105+/CD45- CDCs were delivered via intracoronary infusion into the infarct-related artery using a stop-flow technique. While in the CONCERT-HF, the MSCs and c-kit positive cardiac cells (CPCs) were delivered via transendocardial injection. Following cell injections, patients in both trials were to be evaluated at baseline, 6 months, and 12 months to assess therapy feasibility, safety and efficacy. The preliminary results of the two trials solidified the safety of intracoronary infusion of allogeneic and autologous CDCs, with no primary safety endpoint events occurring. Unfortunately, both trials were terminated early for different reasons. The ALLSTAR trial was terminated due to a low probability of a significant treatment effect [51], while the CONCERT-HF trial was paused by the National Heart, Lung, and Blood Institute (NHLBI) on the recommendation of the Data and Safety Monitoring Board (DSMB). The DSMB concerned about the CPCs, as reported from an independent panel that evaluated cell production protocols and records, as well as an analysis of interim data to assess the power for the efficacy endpoints [39].

The ALLSTAR trial (NCT01458405) investigated the safety and efficacy of IC allogeneic CDCs in patients with LV dysfunction following a myocardial infarction. Allogenic transplantation of stem cells (regardless of the cell lines used) can mitigate the disadvantages of autologous stem cell therapy by offering “off-the-shelf” cell banks readily for patients with acute conditions, allowing patients to receive injections earlier and bypass endomyocardial biopsy. Proof-of-concept studies in which allogenic stem cells were used in rats and minipigs revealed both safety and efficacy [[57], [58], [59]].

An interim analysis was conducted after 6-month MRI data was available for 120 patients in the antibody-matched cohort. The analysis revealed a low conditional probability (1.1 %) of rejecting the primary efficacy null hypothesis based on the primary endpoint. Specifically, the primary endpoints showed no difference in the change in scar size on MRI (mean ± standard deviation (SD) −5.0 % ± 7.4 % vs. −4.1 % ± 9.1 %, p = 0.54), and the secondary efficacy endpoints demonstrated significant improvements in both the LVEDV (mean ± SD 1.1 ± 11.02 vs. 5.6 ± 10.74, p = 0.02) and the LVESV (mean ± SD 0.60 ± 14.31 vs. 5.4 ± 11.93, p = 0.02). Because the probability was so low, the trial sponsor concluded that the study was unlikely to achieve its main objective and decided to terminate it early due to a concern for futility [51].

The CONCERT-HF trial (NCT02501811) was a phase II, multicenter study that evaluated the safety and efficacy of mesenchymal stromal cells and CPCs, alone and in combination, for patients with ischemic HF. The rationale behind hybrid therapy involving MSCs and CPCs is rooted in the discovery that MSCs increase the viability of transplanted CSCs in pigs [95]. Notably, the combination of MSCs and CPCs showed superior efficacy to either therapy alone [96]. To demonstrate this concept in human models, CONCERT-HF was used to test the potential of combination therapy by evaluating it individually and in combination with autologous BM-MSCs and CPCs. Cell doses of 1.5x10^8 for MSCs and 5x10^6 for c-kit + cells were transendocardially delivered into the infarcted area.

Transendomyocardial transplantation of MSCs, CPCs or both in CONCERT-HF improved quality of life despite no changes in cardiac function, suggesting possible systemic or paracrine cellular mechanisms and calling for future research. Compared with that of the placebo group, the quality of life (MLHFQ score) was significantly improved by MSCs alone (p = 0.050) and MSCs + CPCs (p = 0.023). However, LVEF, LV volume, scar size, the 6MWT, and peak oxygen consumption did not differ significantly among the group. A general implication of the CONCERT-HF trial is that cell therapy can improve a patient's quality of life without directly altering traditional measures of cardiac function. This suggests that the therapeutic benefits may stem from systemic or paracrine mechanisms rather than direct tissue regeneration, highlighting the need for further research into these alternative pathways.

The two clinical trials, ALLSTAR and CONCERT-HF, demonstrate the safety of CDCs therapies, though both were terminated early. ALLSTAR was stopped due to a low probability of treatment efficacy, showing no significant reduction in scar size. Conversely, CONCERT-HF, despite not improving cardiac function endpoints like LVEF, did show a significant improvement in patients' quality of life. These findings suggest that while these specific cell therapies may not directly regenerate myocardial tissue, they could offer therapeutic benefits through paracrine mechanisms, warranting further investigation into these alternative pathways.

4.4. Human-induced pluripotent stem cells (iPSCs)

Induced pluripotent stem cells (iPSCs) are a type of pluripotent stem cell (PSC) that can be reprogrammed from a somatic state to an embryonic stem cell (ESC)-like state [97]. In 2006, Yamanaka and colleagues first reported the successful generation of iPSCs from mouse fibroblasts through the overexpression of four transcription factors (Oct4, Sox2, Klf4, and c-myc) [98]. Subsequently, human iPSCs were produced via the same methods [99]. The generated iPSCs exhibit key features similar to those of ESCs, including self-renewal and the potential to differentiate into cells from all three embryonic germ layers. Notably, these cells offer advantages over ESCs because of their lack of ethical concerns regarding their cellular origin and a reduced risk of immune rejection [100].

To date, four early-phase clinical trials have explored human iPSC-derived cardiomyocytes (iPSC-CMs) in treating severe HF using four different delivery formula: sheets, engineered patches, injections during CABG and spheroids.

The first clinical trial was initiated in Japan in 2019 (NCT04696328), employing an implanted iPSC-CM sheet in patients with end-stage ischemic cardiomyopathy and an LVEF of 35 %. In this study, three circular iPSC-CM patches, each containing 3.3 × 10⁷ cells and approximately 3.5 cm in diameter, were transplanted onto the LV anterior and lateral walls through left thoracotomy. One-year follow-up in the first three patients demonstrated improvement in myocardial blood flow, coronary flow reserve (CFR), LV diameter, contractility, and NYHA functional class (from III to I or II). Importantly, no tumorigenesis was observed but several adverse events occurred such as chest discomfort, urinary tract infection, acute HF, and amiodarone pneumonia [101]. Overall, this study highlights the feasibility and potential biological activity of iPSC-CM sheets.

One year later, BioVAT-HF trial (NCT04396899) was launched in Germany, evaluated engineered heart muscles (EHM) constructed from defined mixtures of iPSC-CM and stromal cells in a bovine collagen type I hydrogel in patients with reduced ejection fraction ≤35 %. Initial findings suggest that high cell doses (up to 800 million cells) were well tolerated, with no major adverse events. Imaging data also showed regional improvements in wall thickness and function, indicating early evidence of remuscularization. Importantly, this trial positions EHM as a potential “biological ventricular assist tissue” but large grafts may pose logistical and immunological challenges.

In 2021, HEAL-CHF trial (NCT03763136) in China began investing the safety and efficacy of intramyocardially injected allogeneic iPSC-CMs, with or without concomitant CABG. The phase I/IIa, placebo-controlled, dose-escalation design, included three dosage levels of 1 × 10⁸, 2 × 10⁸, and 4 × 10⁸ cells in patient with LVEF from 20 % to 45 % [54]. Early data from two patients undergoing CABG showed improvements in cardiac function and no signs of tumor growth, arrhythmias, or severe adverse events related to immunosuppression. However, it remains unclear whether these improvement were due to cell therapy or surgical revascularization [53]. This trial provides less invasive delivery method, but cell retention and functional integration remain key concerns with injection-based strategies.

Another Japanese trial, the LAPiS study (NCT04945018) also initiated in 2021, tested HS-001, a spheroid formulation of iPSC-CMs, administrated directly into the myocardium during coronary CABG. Ten patients with ischemic HF and LVEF <40 % were enrolled in this open-label phase I/II trial. Two dosage levels 0.5 × 10⁸ and 1.5 × 10⁸ cells were evaluated, with safety and efficacy assessed at 26 and 52 weeks after transplantation [102]. Preliminary reports confirmed initial safety of both low-dose and high-dose group [102]. The spheroid structure may enhance cell survival and engraftment compared to single-cell suspensions, and combining transplantation with CABG improves procedural efficiency.

Across all four trials, the central reproducible finding is feasibility and short-term safety in the selected patients with advanced HF. None reported tumorigenesis, which has been a theoretical concern for pluripotent cell therapies. Arrhythmic events, while present, were generally manageable, and no sustained ventricular tachycardia directly attributable to grafts was documented. Importantly, early clinical readouts suggest possible functional benefits: modest improvements in LVEF, enhanced wall motion in engrafted areas, and patient-reported improvement in NYHA class. Furthermore, the capacity to produce patient-specific iPSC lines opens a theoretical pathway toward immunologically compatible grafts, potentially reducing the need for chronic immunosuppression.

Despite the encouraging signals, lack of data on long-term functional integration of transplanted cells and clinical improvement in the late-phase trials put iPSC at the center of intense debate. There has been no trial proceeded into phase IIb or III on human and follow-up data only reached 13 months post-implantation. The question of whether these grafts provide true remusculization or mainly paracrine support also remained unanswered. Osaka's sheet reports and LAPiS's spheroid early narratives highlight symptomatic and functional gains that could equally be explained by improved perfusion and anti-fibrotic signaling, while BioVAT-HF's engineered myocardium and HEAL-CHF's injection strategy aim explicitly at restoring contractile mass. Yet, the histologic and electrophysiologic evidence available on primate graft so far showing partial maturation favours a hybrid model: an early paracrine benefit with gradual, variable in-vivo maturation in some patients [103].

Design remains several limitations in the aforementioed trials. Research cohorts have been small and typically open-label, which inflates susceptibility to placebo effects and regression to the mean and prevents adequate detection of rare but serious harms (late arrhythmia, tumorigenesis). Where CABG or other concomitant interventions were used (notably HEAL-CHF and some LAPiS/CABG patients), attribution of functional gains to cells versus revascularization is fundamentally confounded unless randomized CABG-only controls and blinded imaging core-labs are used. Even in stand-alone sheet or patch studies (Osaka, BioVAT-HF), reliance on echo-based LVEF or non-core-lab functional readouts is load-sensitive and vulnerable to bias, objective, blinded CMR with regional strain and scar quantification is preferable. Finally, rhythm and immune safety monitoring have been inconsistent across trials: routine implantable loop recorder (ILR) surveillance, pre-specified end-point adjudication, and standardized anti-human leukocyte antigen (anti-HLA) monitoring are rarely embedded comprehensively in the early cohorts, leaving arrhythmia and immunological risk incompletely quantified. These design gaps are evident in the registry and protocol documents for the four trials and the recent reviews of the clinical landscape.

4.5. Embryonic stem cells (ESCs)

ESCs are undifferentiated inner mass cells of human embryos that are pluripotent and can differentiate into all three germ layers (entoderm, endoderm and mesoderm), which give rise to all major somatic lineages. In HFs, ESCs possess high specificity, plasticity, and potency for cardiac regeneration. These unique characteristics enable them to replace damaged cardiac tissue with healthy and functional heart muscle cells [104]. After being extracted from embryoid bodies by either mechanical dissection or enzymatic methods [105], the pluripotent ESCs undergo a sequence of amplification, specification and purification that harvest a population of differentiated ESC-derived CMs and eliminate the nonresponder cells that are associated with the risk of tumorigenesis. These differentiated cells exhibit adult CM morphology with organized sarcomeric proteins and express cardiac-specific transcription factors such as Nkx2.5, GATA-4, and MEF2C. They also demonstrate spontaneous cardiac beating activity with full atrial, ventricular, and nodal action potentials [106]. ESC dosing for clinical treatment varies among individuals, depending on the extent of cardiac injury and disease severity. These factors can be predicted and evaluated through the use of imaging techniques.

Despite their promising application in regenerative medicine, the current clinical usage of human ESCs (hESCs) is limited by ethical issues due to the destruction of embryos and immune rejection risks, teratomas and unwanted risks associated with their pluripotency and allogeneic nature [55,107]. However, hESCs still hold great promise as a research avenue. Efforts are being made to address ethical concerns surrounding their use [7] and to standardize hESC mass production under optimal safety conditions, which may be better suited for industrial applications [108].

As recorded up to 2024, the ESCORT (Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction), an uncontrolled, open-label, phase I trial conducted by Mernache and colleagues from 2013 to 2018, is the only clinical trial using ESCs for HF [55].

This trial has provided encouraging results concerning the outcomes of ESC treatment for HF. Six patients with ischemic HF NYHA III and IV who underwent CABG were enrolled in this trial. There was no control group involved. In this trial, a fibrin scaffold containing hESC-derived progenitor cells (CD15⁺ Isl1+) was implanted in the epicardium of these patients. The patients were followed up for a median of 18 months postoperatively, and the efficacy of the treatment was assessed via four major endpoints: 1-LV function assessed through ejection fraction and LV volume; 2-Viability of the grafted area; 3-Functional status via the 6MWT, Quality of Life score, and self-assessed NYHA functional class; and 4-Major adverse cardiovascular events. Despite the small sample size and the absence of a control group for meaningful statistical comparisons, all patients in the study demonstrated improvements in all assessed parameters. Apart from one patient who died shortly after surgery due to unrelated comorbidities, the remaining enrolled patients had uneventful recoveries. Clinical improvement was observed in terms of increased ejection fraction and systolic motion in the treated area. Notably, no tumors were detected during the follow-up computed tomography (CT) and PET scans conducted at 6 and 12 months postsurgery. Additionally, none of the patients developed arrhythmias. Although three patients were found to have clinically silent alloimmunization, all antibody levels decreased to undetectable levels within 4 months, and no associated clinical cardiac dysfunction was observed.

Despite the remaining controversies surrounding the efficacy of ESCs in the ESCORT study (due to factors such as the small sample size and the double treatment received by patients), the experimental findings related to the cardioprotective effects of the SSEA-1+ Isl-1+ cells used in this trial are intriguing. These effects may stem from the secreted extracellular vesicles produced by these cells, which predominantly express miR-302 [109]. This microRNA has been reported to stimulate CM proliferation. These findings have opened the possibility of a paradigm shift toward cell-based acellular therapy, which holds potential as a future approach in regenerative medicine [109,110].

Taken together, the results of this study provide evidence of the scalability and pluripotency of ESCs, as well as the technical feasibility of generating clinical-grade ESC-derived cardiovascular progenitor cells. These findings suggest the possibility of developing a clinically applicable product utilizing ESCs, contingent upon addressing the ethical concerns surrounding their utilization.

5. Factors that determining the success of cell therapies for HEART failure

The process of engrafting cells within a patient's cardiac tissue is intricate and time-consuming and requires meticulous research and preparation at each stage. Key considerations include the selection of an optimal cell line, the identification of a suitable delivery method, the assessment of patient eligibility, and the implementation of strategies for immune response management, all of which are pivotal to the success of a treatment.

5.1. Cell type and quality

Choosing the right cell type is a critical step in realizing the potential of this therapeutic approach. Nonetheless, to date, the source and type of stem cells that are most effective in alleviating HF in patients remain unclear. An ideal stem cell for cardiac regeneration would exhibit contractile and electrophysiological properties tailored to its function; possess the ability to proliferate, engraft and survive in an ischemic area; and induce a paracrine effect to stimulate endogenous cardiac regeneration [6]. However, no type of stem cell has met all of these expectations in clinical trials. Among all stem cell types, MSCs currently stand out as the most promising candidates because of their strong paracrine effects [111], which enhance the PI3K/AKT signaling pathway to prevent apoptotic cell death and reduce the secretion of proinflammatory molecules; the release of mTORC1 and SIRT1 plays a role in helping cells adapt to stress [112]. However, the immunomodulatory effects of MSCs in increasing the recruitment and retention of immune cells (eg. neutrophils, B cells) within the infarct myocardium promote a sustained proinflammatory state, making it a careful consideration in cocultured stem cell therapy [113].

Although there have been no completed clinical trials using iPSCs for advanced HF, iPSCs are believed to be the most useful stem cell choice for HF [56]. In contrast, BM-MNCs, CDCs and ESCs are unlikely to become clinical therapies for HF in the future.

5.2. Dosage

Similar to cell type, there has been no consensus on the optimal dose of cell to achieve therapeutic effects. The TRIDENT trial highlighted the role of cell dosage in achieving therapeutic effects by comparing the outcomes in 20 million and 100 million cell-treated groups. Findings from the aforementioned trials indicate that the common dose ranges from 1 × 10⁶ to 3 × 10^{8 vary} across cell types. However, this dose is much lower than the number of cells lost after myocardial injury, and the number of engrafted cells is even lower, given the low retention rate, leading some to suggest a need to increase cell doses to sufficiently regenerate injured myocardium. Interestingly, lower cell doses have been reported to be more effective than higher doses, yet no consensus on defining a low or a high dose in the published clinical trials [36,87,114]. Data from CHART-1 trial suggested that reverse remodeling was most evident with a mid-range number of injections, leading to a suggestion of an inverted U-shape curve in dosage of cell therapy with worse outcomes at higher dose attempts [36]. Potential explanations could be the limit capacity of the microenvironment, increased paracrine effects, protective factors and the activation of angiogenesis. First, the myocardial environment limits cell survival and engraftment. After transplantation, only a small proportion of stem cells persist in the ischemic heart. At higher doses, cells compete for limited oxygen and nutrients, leading to accelerated death and reduced retention, whereas lower doses may fit the microenvironment more effectively, allowing proportionally greater survival [115]. Second, stem cells primarily act through paracrine signaling, releasing growth factors, cytokines, and extracellular vesicles that stimulate endogenous repair. At excessive doses, paracrine signals can become saturated or even detrimental, for example, by inducing maladaptive angiogenesis or fibrosis.

5.3. Cell delivery

Cell delivery methods are associated with improvements in the retention of transplanted cells. Although IM injection has been found to achieve a higher transfer rate than intravenous or intracoronary routes do, it tends to be rapidly cleared through the venous system within just a few heartbeats [116]. Real-time visualization of IM stem-cell injections in living pigs has shown that a high engraftment rate just 3 days after transplantation is sufficient to trigger an improved functional outcome by 1 month [117]. This finding implies that even a short retention time can lead to sustained benefits, underscoring the importance of paracrine effects over cell engraftment itself. Moreover, for transplanted cells to effectively enhance heart function, stable, homogenous electromechanical connections with host CMs must be established to mitigate the risk of proarrhythmic complications [118]. To improve the homogenous distribution of transplanted cells, delivery methods should focus on optimizing catheter design, flow rates, and cell incorporation into biomaterials. While intravenous delivery offers accessibility, it presents challenges in accurately targeting cells to tissues, which often require adjunctive therapies. Nevertheless, the intravenous route is believed to hold transformative potential.

5.4. Patient selection and characteristics

Aging, disease severity and comorbidities are associated with the outcome of therapies. Research suggests that patients with low cardiac function and larger infarct areas tend to benefit more from treatments than those with better baseline conditions do [119]. However, there is no consensus on which specific heart function parameters significantly influence posttreatment improvement.

Notably, the response to therapy among patients may be secondary to their comorbidities. Conditions such as diabetes, hypertension, and dyslipidemia may influence the efficacy of stem cell therapy. For example, Fadini et al. [120] noted that CD26/DPP-4 on CD34⁺ cells was not upregulated in diabetes, whereas Vrtovec et al. [121] reported that CD34⁺ stem cells failed to elicit a favorable outcome in patients with diabetes, but the response to this treatment was preserved in patients with insulin resistance. Therefore, managing patients’ comorbidities well before initiating therapy is essential for enhancing the efficacy of treatment and preventing potential adverse events during therapy. Moreover, it is advisable to prioritize stem cell donations from young, healthy donors or the patients themselves rather than using cells from older individuals, who may have additional health issues that could compromise cell quality. This concern is particularly relevant in the context of MSCs, as they lose some form of efficacy due to aging [119].

5.5. Immunogenicity and immune reaction

Immune rejection poses a significant challenge in stem cell therapy, as it can jeopardize the whole process if the patient's body rejects the transplanted cells. An essential factor contributing to cell death is the immune response directed against transplanted allogeneic cell products, particularly in the case of ESC derivatives. Although efforts are being made to develop HLA-matched cell lines to avoid rejection, the cornerstone of immune rejection prevention is likely to remain the use of immunosuppressive drugs, which raises even more concerns in patients with many comorbidities. However, these concerns could be alleviated with the replacement of iPSCs, which are less likely to provoke a significant immune response in cell therapy settings.

6. Current challenges and limitations

6.1. Ethical and regulatory concerns

Ethical and regulatory concerns are primary obstacles, particularly with respect to hESCs. The use of hESCs raises both religious and moral concerns. ESCs, as their name suggests, are pluripotent cells that are derived from embryos. The first way of sourcing ESCs involves the destruction of blastocysts of surplus embryos that were created for in vitro fertilization (IVF) treatments and are no longer needed by the patients. This action gives rise to the religious and moral concerns from opponents, as they consider life to start at fertilization and an embryo to be a person. The second way is Somatic Cell Nuclear Transfer (SCNT) (into an enucleated oocyte) - the technique behind animal reproductive cloning, which also faces religious and ethical barriers. The central question is about the intentional creation of an embryo and its ultimate destruction for the sole purpose of research [55,122]. Regulatory frameworks are stringent, reflecting these ethical concerns, and efforts to mitigate these issues include developing alternative stem cell sources such as iPSCs and improving safety standards [123]. Despite all the difficulties and debates, the outlook for future clinical application of hESCs is vividly potential for being therapeutics for incurable neural and eye diseases [122].

Developing PSCs therapies presents a number of regulatory complexities because regulations and guidelines were not initially created with PSC-derived products in mind and the biological complexity of the therapies themselves. The regulatory path for PSC-derived products is more ambiguous than the path for traditional drug development. The U.S. Food and Drug Administration (FDA) regulates stem cell products as drugs, biologics, and human tissues (HCT/Ps) and therefore both current Good Tissue Practice (cGTP) and current Good Manufacturing Practice (cGMP) regulations must be complied. In addition, iPSCs that have been genetically modified are also regulated as gene therapies. While fully cGMP-compliant stem cell products are challenging to make as they require expensive research-grade reagents not made under cGMPs, the FDA offers flexibility by not requiring a complete cGMP process for early-phase clinical trials. The heterogeneity of stem cell populations also challenges consistent manufacturing of reproducible products [124].

Another consideration is the risk of falsely advertising to medical markets for regenerative therapy. Websites typically portray therapies as both safe and effective while also being suitable for widespread use in a diverse range of health conditions. However, the scientific evidence published in clinical studies has not been able to consistently endorse the use of these therapies for the standard treatment of diseases [125]. Additionally, there are doctors in developing countries such as Costa Rica, Russia, China, and Peru who treat patients with ASC without waiting for clinical trials to validate the safety of using them for health problems [126]. Unregulated clinics provide unproven advertisements and are not approved by the Center for Biologics Evaluation and Research of the U.S. FDA. Current “right-to-try” laws in the U.S. are in favor of giving terminally ill patients the choice to experiment with therapies that are currently under trial. Nevertheless, governments and regulatory bodies should construct laws and policies that balance access and innovation with safety, ensuring adherence to the most rigorous standards when conducting research so that the field can advance [119].

These issues have fuelled the establishment of a World Health Organization (WHO) Expert Advisory Committee on Regenerative Medicine to unite ideas from national regulations, provide guidance and regulatory approaches responsive to unmet patient needs, and formulate an education campaign against misinformation [127].

6.2. Clinical relevance and therapeutic scalability

Scalability remains a central bottleneck for cardiac cell therapy, as the complex manufacturing processes needed to ensure purity, potency, and reproducibility across large patient cohorts remain far from standardized. The design choices of current trials, often small, single-center, and reliant on bespoke production pipelines, limit both interpretability and generalizability, as they may inadvertently select for patients or conditions in which manufacturing constraints are less acute. Maturity of the graft product compounds this challenge: partially differentiated cells may deliver early paracrine effects but require longer in-vivo maturation to achieve meaningful remuscularization, introducing variability that scale-up will likely amplify. This interplay between trial design, graft maturity, and manufacturing scale means that future studies must address standardization early optimizing differentiation protocols, defining release criteria tied to functional potency, and embedding manufacturing feasibility into trial planning. A pragmatic next step would be multicenter, harmonized pilot trials with built-in manufacturing stress tests, to ensure that any observed clinical benefit can be realistically reproduced beyond the confines of specialized, small-scale facilities.

7. Emerging strategies and future perspectives

7.1. Study design

As of the 27 clinical trials presented, the scalability highly varies, with the participants ranging between 3 and 565 patients. Only one trial proceeded to phase III with limited results on the safety and efficacy of therapy. With a small sample size, randomization alone was insufficient to overcome the statistical limitations and vulnerability of the findings, making these results exploratory rather than conclusive. To move beyond feasibility and toward regulatory-grade evidence, future trials should: (1) adopt randomized designs with blinded, core-lab CMR primary endpoints (LV volumes, Late gadolinium enhancement (LGE) scar, regional strain) to minimize confounding; (2) standardize and mandate ILR or equivalent continuous rhythm monitoring plus pre-specified EP adjudication to quantify arrhythmia risk; (3) embed mechanistic substudies (early cell-tracking where feasible, PET metabolic or reporter imaging, and predefined biomarker panels including donor-specific nucleic acids and anti-HLA antibodies); (4) harmonize CMC release criteria (transcriptomic maturity signatures, sarcomere metrics, residual pluripotent cell limits, genomic quality control) and link these to outcomes in pre-planned correlative analyses; and (5) plan scalability early, choose delivery formats that balance biological plausibility (for durable remuscularization) with manufacturing and logistic feasibility for multicenter trials. If these measures are implemented coherently, the field can answer whether iPSC-CM therapy is a true remuscularizing approach or primarily a complex biologic whose active moieties might be delivered more simply. Reviews and expert consensus pieces argue for exactly this harmonized approach as the pragmatic path forward.

7.2. Safety considerations

Safety concerns remain one of the most formidable barriers preventing the full regulatory approval of cell-based therapies for HF, despite decades of clinical exploration. Synthesized information from the trials included in this review emphasized five interrelated risks: (1) arrhythmogenesis from immature or electrically heterogeneous grafts; (2) tumorigenicity from residual pluripotent cells; (3) immune rejection and the tradeoffs of immunosuppression for allogeneic “off-the-shelf” products; (4) unpredictable biodistribution/engraftment (including microvascular obstruction or ectopic tissue formation); and (5) product heterogeneity (batch-to-batch variation in maturity, purity and potency) that undermines predictability and scalability. These safety topics are repeatedly raised in preclinical reviews and echoed in the emerging human reports and trial protocols [128,129].

Regulators have responded with both supportive and cautious policies. In the U.S. the FDA created and strongly promotes expedited pathways for high-need biologics (Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review) and a specific Regenerative Medicine Advanced Therapy (RMAT) designation to accelerate development while maintaining standards for evidence. These programs facilitate earlier dialogue and rolling review, but they do not substitute for the randomized, mechanistic, safety-rich phase-III evidence regulators require for broad approval [130]. Japan implemented a conditional/time-limited early approval pathway for regenerative medical products (the Pharmaceutical and Medical Device Act (PMDA) changes), which has encouraged earlier patient access under strict post-approval data collection and close PMDA oversight; Japan's pathway has catalyzed commercial activity (e.g., programs pursuing conditional approval) but still demands robust post-marketing safety/efficacy evidence [131].

Because of the specific safety challenges, regulators and sponsors are implementing concrete mitigations and initiatives: (a) enhanced arrhythmia surveillance (routine Holter/ILR monitoring and independent EP adjudication in trials), (b) robust tumorigenicity testing and purification strategies in CMC (including nucleic-acid QC, suicide-gene strategies in research settings, and consensus frameworks for teratoma risk assessment), (c) standardized immune monitoring (anti-HLA/donor-specific antibody measurement and T-cell assays) and protocolized immunosuppression/taper strategies, and (d) harmonization of potency assays and critial quality attributes (CQAs) to reduce batch heterogeneity and allow cross-lot comparability. These approaches are now frequently mandated or strongly recommended in trial protocols and regulatory consultations [132].

Overall, regulatory bodies are not blocking innovation but rather requiring robust, mechanistic, and safety-focused evidence that addresses known high-impact risks and ensures manufacturing consistency. With future clinical trials prioritizing long-term in-human safety and efficacy, the pathway toward approval and broader adoption of stem cell therapy appears promisingly supported by regulatory authorities.

7.3. Combination therapy

Data from several studies have demonstrated that transplanted cells can maximize the efficacy of support with cotransplantation of endothelial and stromal cells [133]. This idea is based on the rationale that combined cells can activate different regenerative pathways given their unique physiologic roles. The CONCERT HF trial illustrated the feasibility of this approach through experimentation with combination therapy involving MSCs and c-kit + cells. Despite these promising results, the long-term engraftment capacity of this combined therapy has not been sufficiently validated, and its implementation adds layers of technical complexity to the treatment process. Additionally, combining stem cell therapies with mechanical devices, such as ventricular assist devices (VADs) or bioengineered cardiac patches, will be explored to provide comprehensive support for failing hearts.

7.4. Tissue engineering

With respect to enhancing the retention and engraftment rates, tissue engineering has drawn the attention of scientists to approaches that can help increase the rate at which cells are successfully transplanted into patient hearts. In cardiovascular therapy, tissue engineering can be utilized via two approaches: scaffolds that provide progenitor cells with appropriate chemical and physical signals to differentiate into the desired cell phenotype and constructs interlaced with cells or biologically active molecules that are cotransplanted into the heart to improve cell retention rates [134]. Both approaches have already been validated in preclinical studies, as it was demonstrated that with appropriate physical conditioning, human immature iPSC-CMs could generate human heart microtissues after culture on a fibrin gel [135].

7.5. Cell-free approaches

The findings from clinical trials support the theory that stem cells work via paracrine effects, raising the question of the cost-effectiveness of transplanting cells. In light of this, interest in the use of extracellular vesicles or exosomes as alternative approaches, which are less complex and promote QC, is increasing. By characterizing the content of these vesicles, a deeper understanding of the essential factors involved in cardiac regeneration can be gained. This understanding can lead to standardization and scalability, making the process more feasible and potentially more effective.

One significant translational advancement in regenerative medicine is the use of allogeneic exosomes, which could achieve clinical objectives without concerns of immune rejection. While exosomes show promise in the field of cardiac regeneration, trials have not been conducted to definitively prove the effectiveness of this approach. However, with ongoing research and the accumulation of clinical evidence in the future, exosomes hold significant potential for advancing cardiovascular regeneration therapies.

7.6. Precision medicine

With respect to individualized treatment, the emergence of gene editing technologies, especially Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR-Cas9), has drawn the attention of scientists and physicians to the future of disease-modifying treatments involving stem cells and gene editors, increasing the effectiveness of these methods in addressing specific causes of HF. Furthermore, the development of biomarker profiles may play a pivotal role in customizing treatment strategies. These profiles will aid in pinpointing patients who are likely to derive the greatest benefit from stem cell therapies while also predicting their individual responses to treatment.

7.7. Global access to standardized cell lines - stem cell banking

The development of networks for hESC banks has ensured global accessibility to standardized and quality-controlled stem cell lines for researchers. Human iPSC technology also supports the possibility of establishing stem cells, simplifying the process of matching donor cells with potential recipients. The opportunity to preselect donors with a desirable haplotype for the generation of human iPSC lines opens up an opportunity, which is not feasible with hESCs, to create a bank of cell lines specifically chosen to match the widest possible number of recipients worldwide [136]. This is accomplished by recruiting donors who are blood group O and are homozygous for common HLs. The biobank would allow the matching of human iPSCs and recipients for selected HLA loci (in particular, HLA-A, HLA-B and HLA-DR), as well as for solid organ transplantation. It is important to realize the exciting benefits of access to large numbers of human iPSC lines from both ethnically diverse and disease-affected backgrounds.

8. Conclusion

Stem cell therapies for HF represent a major advancement in regenerative medicine, offering an innovative treatment avenue for a condition where conventional options remain limited. This review critically evaluates the potential of different stem cell approaches to restore cardiac function. While the precise mechanisms underlying their benefits in HF remain incompletely understood, paracrine effects, particularly evident in MSCs, have consistently shown promise by promoting angiogenesis, reducing inflammation, and inhibiting apoptosis.

Early-phase clinical trials have established the safety of MSC-based therapies; however, whether they can fully reverse HF remains uncertain. Widespread clinical adoption continues to face challenges, including immunorejection, affected by cell type, dosage, and delivery method, which is especially problematic for iPSCs and ESCs. Ethical concerns surrounding ESCs and the technical complexity of large-scale stem cell production further complicate translation to clinical practice. For now, there is no stem-cell therapy is standard of care for advaced HF, and no product has regulatory approval to treat HF.

As stem cell-based therapies are being cautiously yet strategically supported by regulatory authorities, future efforts should prioritize robust late-phase clinical trial designs. These should include larger patient cohorts, standardized assessment criteria, and extended follow-up periods, with a strong emphasis on both safety and efficacy, to bring these therapies closer to routine clinical application. Novel strategies, including exosome-based cell-free therapies and advancements in tissue engineering, may help overcome some of the current challenges associated with cell transplantation. Moreover, a more personalized approach to stem cell therapy, tailored to patient-specific factors such as age, comorbidities, and the severity of HF, could enhance treatment outcomes.

Submission statement

The contributing authors agreed with this manuscript. Furthermore, this manuscript is not under consideration in other journals.

Ethics approval and consent to participate

Not applicable. The authors have no ethical issues related to human or animal rights.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Authors' contributions

TTTH participated in conceptualization, methodology, validation, investigation, analysis and interpretation of the data and was a major contributor to the writing of the manuscript. TTL participated in the investigation, analysis and interpretation of the data and contributed to the writing of the manuscript. NHTC participated in the investigation, analysis and interpretation of the data and contributed to the writing of the manuscript. LTH participated in the investigation, analysis and interpretation of the data and contributed to the writing of the manuscript. NMA participated in the investigation, analysis and interpretation of the data and contributed to the writing of the manuscript. PTA participated in the investigation, analysis and interpretation of the data and contributed to the writing of the manuscript. NTN participated in methodology and validation and contributed to writing the manuscript, supervision and project administration. All the authors read and approved the final manuscript.

Funding

The authors declare no financial conflicts of interest. This research was supported by the VinUniversity Fast Track Grant (Grant No. 400054), awarded by VinUniversity.

Declaration of competing interest

We, the authors of the above-mentioned manuscript, declare the following: All authors have participated in the preparation of this manuscript and have approved the final version submitted.- We confirm that there are no financial, personal, or professional conflicts of interest that could be perceived to have influenced the content or interpretation of the manuscript.- No author has received any financial support or benefits from any commercial source related directly or indirectly to the subject of this manuscript.- If any potential conflict arises in the future, we will promptly notify the journal.