The Role of Perivascular Stem Cells in Inflammatory Vascular Diseases: From Immunomodulation to Vascular Regeneration

Abstract

Inflammatory vascular diseases (including atherosclerosis, peripheral artery disease, and vasculitis) are driven by chronic vascular wall inflammation and immune cell infiltration, representing a leading cause of global mortality. Perivascular stem cells (PSCs)—an umbrella term for mesenchymal stem cells, endothelial progenitor cells, and tissue-resident CD34+ cells—have emerged as a promising therapeutic approach due to their dual capacity for immunomodulation and vascular repair. This review systematically synthesizes current evidence on three core mechanisms: immunomodulation (suppressing pathogenic T cells and reprogramming macrophages toward an anti-inflammatory phenotype), vascular repair (promoting endothelial regeneration and functional angiogenesis), and mitochondrial transfer as a recently discovered intercellular rescue pathway. We critically discuss the clinical translation landscape, including failed trials, withdrawn products, patient heterogeneity, and current regulatory positions of the FDA and EMA. Finally, we outline future directions including precision medicine, bioengineered delivery systems, and cell-free extracellular vesicle therapies. By moving from a conventional anti-inflammatory paradigm to an integrated immunomodulatory-reparative strategy, PSC-based therapies hold potential to transform the treatment of inflammatory vascular diseases.

Plain Language Summary

This review explains how a group of special cells found near blood vessels—called perivascular stem cells—might help treat diseases caused by blood vessel inflammation. These diseases include heart attacks, leg pain from poor blood flow, and some types of blood vessel swelling (vasculitis). These stem cells do two main things: they calm down harmful inflammation, and they help repair damaged blood vessels. We discuss what scientists have learned so far, including both successes and setbacks from clinical studies. We also look ahead to future possibilities, such as using the natural signals from stem cells instead of the cells themselves, and making treatments fit each patient’s needs. Our goal is to move beyond current medicines that only reduce symptoms, toward therapies that can actually heal blood vessels. We write this summary in plain language so that patients, families, and anyone interested can understand the science without needing a medical background.

Introduction

Inflammatory vascular diseases represent a group of disorders characterized by shared features of vascular wall inflammation and immunopathological injury, encompassing conditions such as atherosclerosis (AS), Takayasu arteritis, peripheral artery disease (PAD), and various vasculitic syndromes. According to a recent study published in a The Lancet sub-journal, the global burden of carotid atherosclerosis is substantial, affecting nearly 2 billion people worldwide, with approximately 270 million patients in China alone, posing a severe public health challenge.¹ Currently, despite certain advancements in anti-inflammatory drugs, immunosuppressants, and vascular interventional therapies, many patients with refractory vasculitis and advanced atherosclerosis still lack highly effective treatment options. This is particularly evident for the approximately 15–20% of individuals with critical limb ischemia who are ineligible for conventional revascularization, highlighting a significant unmet clinical need.^2,3 It is important to recognize that current treatments for these conditions–including anti-inflammatory drugs, immunosuppressants, and vascular interventions–are largely palliative or disease-modifying. They manage symptoms, reduce progression, and in some cases restore blood flow, but they do not reverse established tissue damage or regenerate lost vascular structures. In contrast, stem cell-based therapies offer the potential for true repair and regeneration. This fundamental difference–from symptom management to restorative healing–raises the stakes for patients and motivates the intense research focus on PSCs. Throughout this review, the term “perivascular stem cells” (PSCs) serves as an umbrella term for all adult stem cells that reside in or adjacent to the vascular wall. This family includes three main subtypes: mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and tissue-resident CD34+ cells. We will first introduce the general concept of PSCs, then discuss each subtype individually when describing their distinct characteristics and therapeutic roles.

In recent years, advances in stem cell biology have positioned perivascular stem cells—a population of adult stem cells residing in the vascular niche—as a research focus in the treatment of inflammatory vascular diseases, owing to their unique immunomodulatory functions and multi-faceted repair mechanisms.^4–6 Perivascular stem cells regulate T-cell differentiation through both cell contact-dependent mechanisms (such as the PD-L1/PD-1 pathway) and paracrine pathways (including TGF-β1 and prostaglandin E2), promoting the conversion of pro-inflammatory Th17 cells into regulatory T cells. Simultaneously, they remodel macrophage polarization via the IL-10 signaling pathway, shifting pro-inflammatory M1-type macrophages toward the anti-inflammatory and reparative M2 phenotype, thereby effectively alleviating vascular inflammation.⁷ In terms of vascular repair, these stem cells directly promote endothelial cell migration, proliferation, and tube formation by secreting pro-angiogenic factors such as vascular endothelial growth factor, hepatocyte growth factor, and fibroblast growth factor-2. Experimental studies demonstrate that the CD157+ vascular endothelial cell subpopulation exhibits exceptional angiogenic potential, with pro-angiogenic efficiency more than three times higher than that of conventional endothelial cells.⁸ More importantly, perivascular stem cells precisely home to injury sites via the SDF-1/CXCR4 axis-mediated homing effect. They secrete tissue inhibitors of metalloproteinases (TIMPs), which not only inhibit excessive degradation of the extracellular matrix but also enhance vascular wall integrity by activating the Wnt/β-catenin pathway, thereby creating a microenvironment conducive to tissue repair.^9,10 This multi-targeted and adaptive therapeutic capability enables perivascular stem cells to dynamically adjust their treatment strategies based on microenvironmental signals. By simultaneously suppressing excessive inflammatory responses and activating endogenous repair programs, they open new avenues for the treatment of chronic inflammatory vascular diseases. Unlike conventional anti-inflammatory drugs, perivascular stem cells can intelligently sense the inflammatory microenvironment and dynamically adapt their responses, thereby simultaneously suppressing excessive inflammation and promoting tissue repair to achieve a balance between inflammation resolution and vascular regeneration.¹¹

However, it is important to acknowledge that past clinical experiences with stem cell therapies for vascular diseases have been mixed. Several large randomized trials, such as those testing autologous bone marrow-derived mononuclear cells for critical limb ischemia, failed to demonstrate significant reductions in amputation rates or mortality. Moreover, inconsistent outcomes across studies have raised questions about patient selection, cell product heterogeneity, and the translational relevance of preclinical models. These disappointments serve as a sobering reminder that while the mechanistic promise of PSCs is substantial, the path to clinical application requires rigorous validation and a clear-eyed appraisal of past failures. Therefore, beyond celebrating progress, this review aims to critically examine both the successes and the shortcomings that have shaped the field.

This review aims to systematically elucidate the therapeutic mechanisms of perivascular stem cells in inflammatory vascular diseases, integrating the latest evidence from both basic research and clinical trials. It further analyzes the functional characteristics of different stem cell types, discusses challenges in clinical translation, and outlines future research directions, thereby providing a theoretical foundation for developing innovative stem cell-based strategies for the treatment of vascular diseases.

Pathology of Inflammatory Vascular Diseases and Stem Cell Therapeutic Potential

The core pathophysiological processes of inflammatory vascular diseases involve endothelial dysfunction, immune cell infiltration, and vascular wall remodeling.^12,13 In atherosclerosis, the deposition of lipids within the arterial intima triggers the infiltration of monocytes and T lymphocytes, which release pro-inflammatory cytokines such as IL-6 and TNF-α, establishing a chronic inflammatory response.¹⁴ This inflammatory milieu further disrupts endothelial junctions, increases vascular permeability, and promotes the migration and proliferation of smooth muscle cells, ultimately leading to plaque formation and narrowing of the vascular lumen. In peripheral artery disease, ischemia-induced inflammatory cascades exacerbate tissue damage, creating a vicious cycle of deterioration.¹⁵

Perivascular stem cells (PSCs) is an umbrella term that encompasses a heterogeneous population of adult stem cells residing in or adjacent to the vascular wall.^16,17 Within this hierarchy, three major subtypes are distinguished based on their origin, surface markers, and functional properties: mesenchymal stem cells (MSCs) (derived from bone marrow, adipose tissue, or Wharton’s jelly),^18,19 endothelial progenitor cells (EPCs) (mobilized from bone marrow or residing in peripheral blood), and resident vascular CD34+ cells (located in the vessel wall). Throughout this review, the term “perivascular stem cells” will be used as a general reference, while specific subtypes will be named individually when discussing their distinct characteristics.^20,21 The characteristics and functions of major perivascular stem cell types are summarized in Table 1.

Table 1.

Characteristics and Functions of Major Perivascular Stem Cell Subtypes

Stem Cell Type	Primary Sources	Surface Markers	Main Functions	Clinical Application Advantages
Mesenchymal Stem Cells (MSCs)	Bone marrow, adipose tissue, Wharton’s jelly	CD73, CD90, CD105	Immunomodulation, anti-inflammation, promotion of angiogenesis, support for tissue repair	Wide range of sources, low immunogenicity, potent paracrine capabilities
Endothelial Progenitor Cells (EPCs)	Bone marrow, peripheral blood	CD34, VEGFR2, CD133	Differentiation into endothelial cells, promotion of angiogenesis, endothelial repair	Specific homing to injured blood vessels, direct participation in endothelial layer repair
Resident Vascular CD34+ Cells	Blood vessel wall	CD34, Sca-1	Endothelial repair, maintenance of vascular homeostasis	Localized in blood vessels, rapid response to injury, primary non-bone-marrow-derived repair cells

Note: Functional overlap exists among subtypes; the listed features represent typical characteristics. MSCs also exhibit surface markers such as CD44 and CD29 (not shown).

Current conventional treatments for inflammatory vascular diseases primarily rely on anti-inflammatory medications and interventional procedures, yet they exhibit significant limitations. For instance, the CANTOS trial demonstrated that canakinumab (an anti-IL-1β antibody) reduces the risk of cardiovascular events but is associated with a significantly increased risk of fatal infections and high treatment costs.^22–24 Similarly, while low-dose colchicine is effective, approximately 10% of patients discontinue treatment due to gastrointestinal adverse effects.^25–27 These limitations have prompted researchers to explore safer and more effective alternatives, and stem cell therapy has emerged as a research hotspot in this context.^28,29 The therapeutic potential of perivascular stem cells lies in their ability to simultaneously target multiple pathological processes of inflammatory vascular diseases. They not only suppress harmful inflammatory responses but also actively promote vascular repair and regeneration, making them particularly suitable for treating chronic inflammatory vascular conditions. Unlike single-target anti-inflammatory drugs, stem cells exert their effects through multiple mechanistic networks, including regulating immune cell function, promoting tissue repair, and inducing angiogenesis.^30,31 This provides a multi-targeted therapeutic strategy for complex vascular diseases.

Core Mechanisms of Perivascular Stem Cells in Regulating Inflammatory Vascular Diseases

Immunomodulation

Paracrine Signaling-Mediated Immunomodulation

Perivascular stem cells play a crucial immunomodulatory role in inflammatory vascular diseases by releasing abundant paracrine factors.^32,33 These factors include vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), transforming growth factor-β (TGF-β), as well as various chemokines and extracellular vesicles (EVs).^34,35 In the context of atherosclerosis, mesenchymal stem cells (MSCs) regulate the functions of multiple immune cells—such as monocytes/macrophages, T cells, B cells, and dendritic cells—through paracrine mechanisms, thereby curbing excessive inflammatory responses and promoting inflammation resolution.³⁶ Research has demonstrated that molecules such as prostaglandin E2 (PGE2) and indoleamine 2,3-dioxygenase secreted by MSCs can inhibit T-cell activation and proliferation, thereby alleviating inflammatory responses.^37,38 Particularly in Wharton’s jelly-derived mesenchymal stem cells (WJMSCs) from the human umbilical cord, the expression of these immunomodulatory molecules is more pronounced, demonstrating greater immunomodulatory potential compared to MSCs derived from adult tissues.³⁹ This paracrine characteristic enables stem cells to exert therapeutic effects without requiring extensive differentiation into target tissue cells, addressing the clinical challenge of low transplanted cell survival rates (<5%)⁴⁰ (Figure 1).

Figure 1.

Multifaceted Roles of Perivascular Stem Cells in Vascular Regeneration and Immunomodulation. PSCs contribute to vascular repair and immunomodulation through various mechanisms: Inhibition of T cell activation: PSCs secrete factors such as VEGF, HGF, TGF-β, and extracellular vesicles (EVs) to suppress T cell activation and proliferation, thereby reducing inflammation; Regulation of macrophage polarization: PSCs promote the shift of macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype through TGF-β and IL-10, which helps in resolving inflammation and promoting tissue repair; Excitation of mitochondrial dysfunction: PSCs can modulate mitochondrial function in endothelial cells (ECs) and other cell types, potentially enhancing cellular energy metabolism and reducing oxidative stress; ECs repair: PSCs can differentiate into ECs under the influence of KLF5, VEGF, PDGF, and bFGF, contributing to the repair of the endothelial barrier and restoration of vascular integrity; Improvement of plaque stability and regulation of lipid metabolism: PSCs reduce lipid deposition, inhibit immune cell infiltration, increase collagen content, and promote reverse cholesterol transport, thereby stabilizing atherosclerotic plaques and regulating lipid metabolism.

Fine-Tuned Regulation of Macrophage Polarization

Macrophages play a central role in the pathogenesis and progression of atherosclerosis, with their distinct polarization states determining the direction of lesion development.⁴¹ Classically activated M1 macrophages produce abundant pro-inflammatory cytokines (eg, TNF-α, IL-6), exacerbating intraplaque inflammation, whereas alternatively activated M2 macrophages secrete anti-inflammatory factors (eg, IL-10), promoting tissue repair and inflammation resolution.^42,43 Perivascular stem cells significantly influence this polarization balance by inducing a shift from M1 to M2 phenotypes. The secretome of perivascular stem cells mitigates caspase-1 and interleukin-1β secretion in lipopolysaccharide-activated human and murine macrophages by inhibiting inflammasome activation and reducing mitochondrial reactive oxygen species (ROS) production.⁴⁴ In an atherosclerosis model, adipose-derived mesenchymal stem cells (AD-MSCs) mitigate vascular inflammation and enhance plaque stability by modulating macrophage polarization—specifically, reducing the population of M1 macrophages while increasing the proportion of M2 macrophages.⁴⁵ Mechanistically, factors such as HGF and VEGF secreted by MSCs promote the transition of macrophages toward the M2 phenotype by suppressing the NF-κB signaling pathway and activating the STAT6 signaling pathway. This regulatory effect is particularly critical for the treatment of atherosclerosis, as M2 macrophages not only alleviate inflammation but also enhance collagen deposition within plaques, contributing to the formation of a more stable fibrous cap and reducing the risk of plaque rupture⁴⁶ (Figure 1).

Fine-Tuned Regulation of Adaptive Immunity

In addition to the innate immune system, perivascular stem cells play a significant regulatory role in adaptive immune responses.⁴⁷ In atherosclerotic lesions, activated T cells (particularly Th1 and Th17 cells) secrete pro-inflammatory cytokines such as interferon-γ (IFN-γ) and IL-17, driving the inflammatory process. MSCs can suppress excessive T cell activation, reduce pro-inflammatory T cell subsets, and simultaneously enhance the function of regulatory T cells (Tregs), thereby promoting immune tolerance.^48,49 Studies have shown that intravenously infused MSCs can promote the expansion and functional enhancement of regulatory T cells (Tregs) by secreting factors such as TGF-β and IL-10. Tregs, in turn, suppress the activation and function of effector T cells through cell contact-dependent mechanisms and the secretion of IL-10 and TGF-β, thereby fostering an immune microenvironment conducive to inflammation resolution.⁵⁰ Additionally, MSCs can modulate B cell function, curb excessive antibody production, and mitigate vascular damage caused by immune complex deposition⁵¹ (Figure 1).

Role of Mitochondrial Transfer in Inflammation Regulation

Recent studies have revealed that perivascular stem cells can also transfer functional mitochondria to damaged endothelial cells and immune cells through tunneling nanotubes (TNTs), directly improving their energy metabolism and functional capacity.⁵² This unique mechanism of intercellular organelle transfer provides new perspectives for understanding the molecular mechanisms of stem cell therapy.⁵³ In inflammatory vascular diseases, endothelial cells and immune cells at lesion sites often exhibit mitochondrial dysfunction, leading to increased oxidative stress and abnormal energy metabolism.⁵⁴ By transferring healthy mitochondria to these damaged cells via TNTs, MSCs not only improve their energy status but also reduce ROS production and lower oxidative stress levels, thereby mitigating inflammatory responses and cellular damage. This mitochondrial transfer mechanism represents a unique intercellular rescue system, holding particular significance for the treatment of vascular diseases such as atherosclerosis⁵⁵ (Figure 1).

Multiple Pathways in Promoting Vascular Repair

Mechanisms of Endothelial Repair and Regeneration

Vascular endothelial dysfunction is the initiating factor in inflammatory vascular diseases, and maintaining endothelial integrity is crucial for preventing and treating vascular conditions. Perivascular stem cells promote endothelial repair and regeneration through multiple mechanisms: on one hand, endothelial progenitor cells (EPCs) and resident vascular CD34+ cells can directly differentiate into endothelial cells and integrate into damaged vascular sites, replacing injured endothelium; on the other hand, mesenchymal stem cells (MSCs) enhance the survival and proliferation capacity of endogenous endothelial cells through paracrine actions, facilitating the restoration of endothelial barrier function.³⁴

Studies have shown that non-bone marrow-derived resident vascular CD34+ cells serve as the primary contributors to endothelial repair, while bone marrow-derived CD34+ cells in circulation are mainly involved in inflammatory responses. This discovery explains the suboptimal efficacy of early “endothelial progenitor cell” therapies—which primarily recruited inflammatory cells rather than genuine reparative cells.⁵⁶ KLF5 Enhances CXCL12 Transcription in ADSCs to Promote EPC-Mediated Neovascularization and Improve Wound Healing, offering a new target for optimizing stem cell therapy⁵⁷ (Figure 1).

Balanced Regulation of Angiogenesis

In ischemic vascular diseases, the formation of functional neovasculature is essential for restoring tissue perfusion. Perivascular stem cells secrete abundant pro-angiogenic factors—such as VEGF, basic fibroblast growth factor (bFGF), and angiopoietins—through paracrine mechanisms to stimulate new blood vessel formation. Particularly noteworthy, human induced pluripotent stem cell-derived CD157+ vascular endothelial cells demonstrate remarkable angiogenic potential, effectively restoring blood flow perfusion in hindlimb ischemia models.^57,58 It is noteworthy that stem cells not only promote angiogenesis but also ensure the structural and functional integrity of neovessels through fine-tuned regulation. Unlike single-factor pro-angiogenic therapies that may lead to disorganized vascular networks, stem cells achieve balanced release of factors such as VEGF, platelet-derived growth factor (PDGF), and angiopoietins, thereby facilitating the formation of functional vessels with complete pericyte coverage. This balanced regulation is particularly crucial for avoiding complications like intraplaque hemorrhage caused by pathological angiogenesis in atherosclerotic environments (Figure 1).

Multifaceted Improvement in Plaque Stability

The clinical risk of atherosclerosis depends not only on plaque size but is also closely related to plaque stability. Vulnerable plaques are characterized by thin fibrous caps, large lipid cores, and significant inflammatory cell infiltration, making them prone to rupture and trigger acute cardiovascular events. Perivascular stem cells enhance plaque stability through multiple mechanisms: reducing intraplaque lipid deposition, inhibiting inflammatory cell infiltration, increasing collagen content, and reinforcing the fibrous cap structure.⁵⁹ Studies have shown that MSC treatment significantly increases the number of smooth muscle cells and collagen content within plaques, leading to a marked thickening of the fibrous cap.⁶⁰ Moreover, by reducing the transformation of macrophages into foam cells, MSCs decrease the proportion of the lipid core, further enhancing plaque stability.⁶¹ In animal models, although stem cell therapy does not always significantly reduce plaque volume, it effectively alters plaque composition, shifting it from a vulnerable to a stable phenotype. This transformation holds critical clinical significance for preventing acute cardiovascular events (Figure 1).

Regulatory Role in Lipid Metabolism

Hyperlipidemia is a major risk factor for atherosclerosis, and recent studies have revealed that perivascular stem cells also possess the ability to modulate lipid metabolism. In animal studies, MSC administration significantly reduced serum cholesterol levels, particularly very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels. Following stem cell transplantation in hypercholesterolemic mouse models, serum total cholesterol levels decreased by 33%. The mechanisms by which stem cells regulate lipid metabolism may involve multiple aspects: promoting reverse cholesterol transport, enhancing hepatic LDL receptor expression, and inhibiting intestinal cholesterol absorption. Furthermore, stem cells indirectly influence lipid metabolism by mitigating vascular wall inflammation and improving systemic metabolic status.⁶² This lipid-regulating capability works synergistically with their anti-inflammatory and vascular repair effects to collectively suppress the initiation and progression of atherosclerosis⁶³ (Figure 1).

Integrated View: Pathway Interactions, Temporal Dynamics, and Disease Context

The three mechanisms described above do not operate in isolation. In the early phase of acute inflammation (eg, vasculitis), PSCs rapidly secrete anti-inflammatory factors (TGF-β, IL-10) to suppress T-cell activation and promote M2 macrophage polarization, which occurs within hours to days. Simultaneously, mitochondrial transfer via tunneling nanotubes provides immediate metabolic support to damaged endothelial cells, reducing oxidative stress within 24–48 hours. In chronic inflammation (eg, atherosclerosis), the sustained paracrine signaling gradually shifts the plaque microenvironment from pro-inflammatory to pro-reparative over weeks, followed by delayed but durable endothelial regeneration and angiogenesis. Critically, the balance between these mechanisms differs: acute inflammation relies more on rapid immunomodulation, whereas chronic settings require sustained vascular repair and plaque stabilization. This disease-context dependency has important implications for the timing and route of PSC delivery.

Clinical Translation and Challenges of Perivascular Stem Cell Therapy

Clinical studies on perivascular stem cell therapy for inflammatory vascular diseases have achieved remarkable progress. Multiple clinical trials have validated the safety and preliminary efficacy of stem cells from different sources in vascular diseases. In an article published in Stem Cell Res Ther, researchers analyzed data from 78 patients receiving autologous stem cell therapy for atherosclerosis and found that adipose-derived stem cells could improve serum levels of high-density lipoprotein, low-density lipoprotein, and remnant-like particle cholesterol, thereby modulating lipid metabolism and safely/effectively ameliorating atherosclerosis.⁶⁴ According to ClinicalTrials.gov records, over 10 clinical trials investigating stem cell transplantation for inflammatory vascular diseases have been initiated to date.⁶⁵

Despite the promising prospects of perivascular stem cell therapy, its clinical translation faces multiple challenges. Low cell survival rates, risk of ectopic differentiation, standardized production, and heterogeneity in treatment efficacy have been identified as major obstacles. Studies indicate that the survival rate of transplanted stem cells in lesion sites is typically below 5%, significantly limiting their therapeutic efficacy.⁶⁶ Additionally, donor variability impacts treatment outcomes, particularly with AD-MSCs derived from patients with comorbidities such as type 2 diabetes or obesity, where cellular function may be compromised.⁶⁷ To address these challenges, researchers have developed various innovative strategies, including genetic engineering, biomaterial-assisted delivery, cell-free therapies, and combination treatment approaches. Optimizing delivery strategies is a critical component in enhancing the therapeutic efficacy of stem cells.⁶⁸ Current delivery routes under investigation include intravenous infusion, local intramuscular injection, and targeted intravascular administration. While intravenous infusion is simple and convenient, it leads to systemic dispersion of stem cells, resulting in low concentrations at the target lesion sites.⁶⁹ Local injections can increase the local cell concentration but may cause secondary tissue damage. To improve the targeting efficiency of stem cells to diseased areas, researchers have developed multiple strategies. Among these, “cell-capture stents” technology—which involves modifying the surface of vascular stents with molecules such as CD34 antibodies to specifically capture circulating stem cells and enrich them at the lesion site—has shown promise.^70,71 However, early-generation endothelial progenitor cell-capture stents faced limitations due to high target lesion failure rates, primarily because they recruited predominantly bone marrow-derived inflammatory CD34+ cells rather than genuine reparative cells.^72–74 This experience underscores the importance of precise identification and characterization of stem cell subpopulations.

While early-phase trials have shown encouraging safety signals, it is essential to acknowledge the limitations and failures that have shaped the field. Several large-scale randomized controlled trials have failed to meet their primary endpoints. For example, the pivotal trial of autologous bone marrow-derived mononuclear cells for critical limb ischemia (the RENEW trial) showed mixed results, and subsequent meta-analyses concluded no significant reduction in amputation rates. More concerning, certain stem cell products have been withdrawn or rejected by regulators. In 2019, the EMA refused marketing authorization for allogeneic adipose-derived MSCs (Cx601) for complex perianal fistulas due to insufficient efficacy data, despite earlier promise. In the US, the FDA has issued multiple warning letters against unlicensed stem cell clinics marketing unproven vascular therapies, and several such products have been voluntarily recalled following reports of adverse events including arrhythmias and tumor formation.

Patient heterogeneity remains a major confounder. Clinical responses vary widely depending on age, comorbidities (diabetes, chronic kidney disease), and disease stage. Patients with advanced atherosclerosis or long-standing vasculitis often have dysfunctional autologous stem cells, limiting the efficacy of autologous transplantation. Furthermore, the regulatory landscape continues to evolve. The FDA currently requires Investigational New Drug (IND) applications for all stem cell products intended for vascular repair, with specific guidance on potency assays and long-term safety monitoring. The EMA has classified most PSC-based therapies as Advanced Therapy Medicinal Products (ATMPs), mandating rigorous clinical trials and post-marketing surveillance. These regulatory stances, while necessary for patient safety, have substantially increased the cost and complexity of clinical translation.

Beyond specific trial failures, the field faces unresolved controversies. For example, while many preclinical studies report robust therapeutic effects, independent replication has sometimes yielded weaker or null results, raising concerns about publication bias. There is also ongoing debate regarding whether the benefits of PSCs are primarily mediated by paracrine factors, direct differentiation, or mitochondrial transfer—and whether these mechanisms operate similarly across different disease contexts. Furthermore, head-to-head comparisons of different PSC subtypes (eg, bone marrow MSCs versus adipose-derived MSCs) have not consistently shown superiority of one over another, leaving clinicians without clear guidance on cell source selection. Acknowledging these uncertainties is essential for designing more informative future trials and for avoiding overoptimistic claims that may hinder rather than help clinical translation.

Looking ahead, innovative approaches such as nanotechnology and magnetic targeting are expected to further enhance the targeted delivery efficiency of stem cells to specific vascular lesions, enabling more precise therapeutic interventions. The main challenges and innovative solutions in clinical translation are outlined in Table 2.

Table 2.

Challenges and Innovative Solutions in the Clinical Translation of Perivascular Stem Cells

Challenge Category	Specific Issues	Innovative Solutions	Research Progress
Cell Survival and Function	Low post-transplantation survival rate and limited functionality	Genetic engineering modification, biomaterial encapsulation, preconditioning strategies	SIRT1-overexpressing AD-MSCs exhibit enhanced antioxidant capacity; smart hydrogels improve cell survival rate
Safety Concerns	Ectopic differentiation, teratoma formation, immune rejection	Gene editing technology, cell-free therapy, HLA matching	CRISPR-Cas9 knockout of pluripotency genes reduces tumorigenic risk; extracellular vesicles avoid risks associated with direct cell transplantation
Standardization and Quality Control	Diverse cell sources, inconsistent production processes	GMP-standard production, quality control systems, functional consistency evaluation	Establishment of standardized quality control systems compliant with Good Manufacturing Practice (GMP) to ensure cell purity and functional consistency
Interindividual Variability	Underlying patient conditions affecting therapeutic efficacy	Personalized treatment plans, patient stratification, combination therapies	Functional enhancement modifications of stem cells for diabetic patients; single-cell omics-guided patient screening

Future Perspectives and Discussion

Precision Medicine and Personalized Therapies

With the rapid development of single-cell omics, epigenetics, and artificial intelligence, perivascular stem cell therapy is advancing toward precision and personalization. Through technologies such as single-cell RNA sequencing, researchers can precisely analyze the molecular characteristics and functional properties of different stem cell subpopulations, enabling the matching of the most suitable stem cell types and treatment strategies for specific patients. For example, CD157+ vascular endothelial cells have been identified as an iPSC-derived endothelial subpopulation with high angiogenic potential, making them particularly suitable for treating severe ischemic diseases.^8,75 Bioinformatics tools and artificial intelligence applied in stem cell therapy now enable the optimization of treatment strategies based on patients’ genetic backgrounds, disease characteristics, and stem cell properties.⁷⁶ By analyzing vast clinical datasets through machine learning, it becomes possible to predict individual patients’ responses to specific stem cell therapies, achieving truly personalized medicine.⁷⁷

Advanced Bioengineering Technologies and Materials Science

Advances in bioengineering technologies and materials science have provided new tools and approaches for stem cell therapy. Three-dimensional bioprinting technology can construct vascular tissues with complex structures for vascular repair or replacement.^78,79 Smart responsive biomaterials are capable of sensing changes in the microenvironment and dynamically regulating the release of bioactive factors, thereby creating a more favorable microenvironment for transplanted stem cells. EVs, as cell-free therapeutic agents, offer advantages such as low immunogenicity, absence of tumorigenic risk, and ease of storage and transportation, making them a pivotal direction for the future of vascular regenerative medicine. Studies have shown that EVs derived from AD-MSCs retain various therapeutic functions of the parent cells, including immunomodulatory and pro-angiogenic capabilities, while circumventing the risks associated with direct cell transplantation.⁸⁰

Disease Models and Drug Screening Platforms

The maturation of iPSC technology has made it possible to construct patient-specific disease models.⁸¹ By reprogramming patient somatic cells into iPSCs and subsequently differentiating them into vascular cells, disease processes such as atherosclerosis can be simulated in culture dishes, enabling both mechanistic studies and drug screening.⁸² These disease models not only aid in understanding the pathological mechanisms of inflammatory vascular diseases but also serve as testing platforms for stem cell therapies. Prior to treatment implementation, the feasibility and efficacy of stem cell therapies can be evaluated using vascular cells differentiated from patient-specific iPSCs, allowing for the optimization of treatment parameters and enhancing clinical success rates.⁸³

Multidisciplinary Integration Driving Clinical Translation

The further development of perivascular stem cell therapy for inflammatory vascular diseases requires multidisciplinary integration, combining expertise across diverse fields such as stem cell biology, immunology, vascular biology, materials science, clinical medicine, and computational science. Only through interdisciplinary collaboration can current challenges be overcome and progress in clinical translation be achieved. Specifically, future research should focus on the following directions: developing standardized quality assessment systems for stem cells; optimizing stem cell delivery strategies to enhance targeting; exploring the ethical boundaries of using gene editing to enhance stem cell functions; conducting well-designed large-scale clinical trials to validate therapeutic efficacy; and establishing long-term follow-up protocols to monitor the safety of stem cell therapies.

Conclusions and Perspectives

Perivascular stem cells exert therapeutic effects in inflammatory vascular diseases through multiple mechanisms: these include precise regulation of immune responses, promotion of endothelial repair and angiogenesis, enhancement of plaque stability, and modulation of lipid metabolism. Together, these mechanisms form a complex therapeutic network, enabling stem cells to intervene at multiple stages of vascular disease progression and achieve a balance between anti-inflammatory and reparative effects. With advances in basic research and clinical application, perivascular stem cell therapy is expected to fundamentally transform the treatment paradigm for inflammatory vascular diseases—shifting from current symptomatic management to restorative therapies targeting the underlying disease mechanisms. Nevertheless, it is essential to temper enthusiasm with realism. The field has yet to overcome fundamental hurdles: low cell survival, inconsistent efficacy across patient populations, uncertain long-term safety, and a lack of standardized manufacturing protocols. Failed clinical trials and regulatory setbacks serve as sobering reminders that the path from bench to bedside is neither linear nor guaranteed. As such, while PSC-based therapies hold considerable promise, their clinical adoption will depend on rigorous, well-powered trials, transparent reporting of negative results, and the development of robust quality control frameworks. Only by acknowledging these limitations can the field move forward responsibly, transforming cautious optimism into tangible therapeutic progress for patients with inflammatory vascular diseases.

We also wish to acknowledge potential biases in the present review. Despite our efforts to critically discuss clinical failures and unresolved controversies, the selection and interpretation of literature may still be influenced by the authors’ own research interests and the predominance of positive findings in the published literature (publication bias). Most of the cited mechanistic studies are based on preclinical models, which may not fully replicate human disease complexity. Moreover, the field of stem cell therapy is evolving rapidly, and some conclusions may become outdated as new evidence emerges. Readers should therefore interpret the promising aspects of PSC therapy with appropriate caution, and we encourage independent replication of key findings before clinical adoption.

Funding Statement

This work was supported by the Hainan Province Key Research and Development Program of China (Grant Nos. ZDYF2024SHFZ040 and ZDYF2024SHFZ112).

Data Sharing Statement

No new data was created in the research described in the article.

Author Contributions

H.Z.: Conceptualization, Writing – original draft, Visualization; Z.Z.: Investigation, Writing – review & editing; J.Z.: Methodology, Writing – review & editing; X.W.: Conceptualization, Writing – review & editing; D.S.: Conceptualization, Supervision, Writing – review & editing, Funding acquisition. All authors have read and agreed to the published version of the article. All authors have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no conflict of interest.