Stem cell therapy for type-2 diabetes: keeping the pedal to the metal to deliver translation to the clinic

1. Introduction

Type-2 diabetes mellitus (T2DM) is a chronic metabolic disorder representing one of the largest global health burdens. Despite great progress in its pharmacotherapy, gaps remain in treatment efficacy and adverse effects. A significant proportion of T2DM patients fail to achieve sustained glycemic control and experience end-organ complications like cardiovascular disease, nephropathy, and neuropathy.

Mesenchymal stem cells (MSCs), adult stem cells harvested from many tissues, exhibit multi-lineage differentiation potential, high self-renewal capacity, immune regulation properties, and low immunogenicity. They also circumvent ethical issues restricting use of embryonic stem cells. MSCs therefore offer potential benefits beyond traditional treatments in both type-1 and T2DM. In recent years, both preclinical and clinical studies demonstrated the robust efficacy of MSC therapy in T2DM and its complications, positioning MSCs as a promising future therapy for T2DM. Nevertheless, challenges and concerns remain regarding their precise mechanisms of action, the optimal dose and timing regimen, and safety of MSCs. Herein, this brief review aims to summarize currently known mechanisms of action and discuss the efficacy, safety, and challenges in advancing clinical application of MSCs therapy for T2DM.

2. Mechanisms of MSC therapy for T2DM

While the potential efficacy of MSC therapy for T2DM has been demonstrated, the underlying repair mechanisms remain elusive. Likely, MSCs target multiple pathways responsible for T2DM pathogenesis, including pancreatic β-cell dysfunction, insulin resistance (IR), and systemic inflammation. MSCs might initiate endogenous insulin production and stimulate pancreatic islet β-cell regeneration. Under selective conditions, MSCs may differentiate into insulin-producing cells (IPCs) by directed differentiation [1]. Yet, MSCs implement most of their reparative properties through release of a rich secretome comprising extracellular vesicles (EVs) [2], cytokines, and myriad growth factors, including vascular endothelial growth factor [3], insulin-like growth factor, platelet-derived growth factor, and transforming growth factor -β, thereby stimulating intrinsic pancreatic islet regeneration and restoring β-cell function. MSCs can alleviate IR in insulin target tissues by increasing the function of glucose transporter-4, phosphorylation of insulin receptor substrate-1 and protein kinase-B [4], and inhibiting NOD-like receptor protein-3 inflammasome formation through immune regulation [5]. While the mechanism by which MSCs alleviate IR remains incompletely understood, increasing evidence implicates immune dysfunction in T2DM and IR. Hence, the ability of MSCs to modulate multiple immune cells via their secretome might in turn improve pancreatic β-cell function and alleviate IR [6] (Figure1).

Figure 1. MSCs Therapy for T2DM.

A. Potential tissue sources for MSCs used for treatment of clinical T2DM included BM-MSC, BM-MNC, AD-MSC and HUC-MSC. B. MSC injection routes used in T2DM studies included intravenous and pancreatic artery infusion. C. Mechanism activated by MSC in T2DM therapy include increased pancreatic islet β-cells by IPCs differentiation and remedial secretome, decreased insulin resistance by activation of ISR-1/AKT/GLU4 and inhibition of NLRP3, and alleviating inflammation by immunomodulation. Created with Biorender.com.

Abbreviations: T2DM: type-2 diabetes mellitus; BM-MSC: bone marrow mesenchymal stem cell; BM-MNC: bone marrow mononuclear cells; AD-MSC: adipose tissue-derived MSCs; HUC-MSC: human umbilical cord tissue-derived MSCs; IPCs: insulin-producing cells; VEGF: vascular endothelial growth factor; IGF-1:insulin-like growth factor; PDGF-BB: platelet-derived growth factor; TGF-β:transforming growth factor-beta; IRS-1: insulin receptor substrate-1; AKT: protein kinase-B; GLUT4: glucose transporter-4; NLRP3: NOD-like receptor protein-3.

3. Efficacy of MSCs therapy for T2DM

In 2008, Estrada initiated a pioneering bone-marrow-derived (BM)-MSCs therapy for T2DM [7]. This strategy has been translated from preclinical investigations to clinical research. Early phase clinical trials applying MSCs for T2DM demonstrated safety and capacity to improve glucose levels (fasting, postprandial, and hemoglobin A1c), reduce insulin requirements, and improve IR [8]. Bone marrow (BM-MSC) is the most widely use source of MSC in T2DM clinical trials. Human umbilical cord tissue-derived MSCs (HUC-MSCs) have greater differentiation potential compared to other common MSC types and are the second most commonly used in T2DM trials[9]. Adipose-derived MSCs (AD-MSC) have also been utilized but few clinical trials applied AD-MSC therapy for T2DM.

Importantly, MSCs therapy has also shown promise for treatment of T2DM complications, such as diabetic nephropathy (DN), diabetic foot ulcer, erectile dysfunction and diabetic peripheral neuropathy. DN is the most common cause of end stage kidney disease (ESKD) and despite recent therapeutic advances, lacks a cure. Recently, an interim assessment of the Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM) study showed that anti-CD362 antibody-selected allogeneic BM-MSCs slowed the median annual rate of kidney function decline and improved the profile of circulating immune cells in 12 patients with progressive DKD [10]. Our ongoing clinical trials in the U.S. aim to evaluate the safety, dosage, and early efficacy of AD-MSCs (NCT04869761) and BM-MSCs (NCT05362786) in DN and other kidney diseases[11]. Diabetic foot ulcers are a common complication of diabetes and the most common cause for non-traumatic lower extremity amputations. Numerous clinical studies with small sample sizes have confirmed that both allogeneic and autologous MSC therapy effectively enhances ulcer healing and reduces amputation rates [12]. However, large-scale trials are needed to further confirm the efficacy of MSC therapy in diabetic foot ulcers. In 2021, the first human study demonstrated the tolerability, safety, and efficacy of allogeneic Wharton’s jelly-derived MSCs (WJ-MSCs) in treating diabetic patients with erectile dysfunction. MSC therapy significantly improved the International Index of Erectile Function and the Erection Hardness Score, with no severe adverse events observed [13]. Clinical trials of MSC therapy for T2DM and its complications currently registered in ClinicalTrials.gov are listed in Table 1.

Table 1.

Clinical trials of MSC Therapy for T2DM and its complications registered in ClinicalTrials.gov.

Number	Country/Start time	Study Type	Number of Enrollment	Type of MSC	Dosage	Primary Outcome	Follow-Up Time (Month)	Study Status Time	Study result
1	China, 2010	Interventional, Open Label Self-Controlled, Phase 1	24 (Estimated)	BM-MSC	Unknown	ITT, Insulin dosage, Hemoglobin A1c, FBG, PBG, C-peptide levels, Serum Insulin	12	Unknown	No
2	China, 2011	Randomized Interventional Open Label, Phase 1/2	22 (Actual)	BM-MSC BM-MNC	Unknown	Macrovascular and microvascularcomplications	96	Completed 2020–01	No
3	China, 2011	Randomized Interventional, Phase 1/2	30 (Estimated)	HUC-MSC	1.0×6/kg Twice with 90 days interval	To assess efficacy of transplantation treatment using umbilical cord/placenta-derived MSC in T2DM	12	Unknown	No
4	India, 2012	Randomized Interventional, Phase 2/3	30 (Actual)	BM-MSC MNC	Dose unknown Single injection	Reduction of insulin requirement by ≥ 50% by the end of 6 months; Improvement in Glucagon stimulated C-peptide levels and hyperglycemic clamp for assessment of β cell function	6	Completed 2015–10	90% patients achieved the primary end-point; At 6 months, there was a signifcant reduction in insulin requirement as compared to baseline (P < 0.003); A signifcant increase in the 2nd phase C-peptide response during hyperglycemic clamp (P = 0.018); No significant difference in insulin sensitivity, glucose disposal rate, HOMA-β, stimulated C-peptide and mixed meal tolerance test.
5	China, 2013	Single Center, Double-blind, Randomized, Placebo-controlled Trial	103 (Actual)	HUC-MSC	1.5×106/kg 3 times with 4 weeks interval	The efficacy of HUC-MSC in Chinese adults with T2DM	48 weeks	Completed 2020–12	More patients in the UC-MSCs group reached the primary endpoint (20% vs control 4.55%, P < 0.05); The UC-MSCs group showed a significantly higher percentage of insulin reduction (27.78% vs control 15.62%, P < 0.05); HbA1c levels decreased more in the UC-MSCs group (1.31% vs control 0.63%, P = 0.0081); GIR significantly increased in the UC-MSCs group (from 3.12 to 4.76 mg/min/kg, P < 0.01); There was no improvement in islet β-cell function; No major adverse events related to UC-MSCs transfusion occurred.
6	China, 2013	Non-Randomized Interventional Open Label, Phase 1/2	100 (Estimated)	HUC-MSC	Unknown	HbA1C	12	Unknown	LIRA treatment in combination with HUC-MSCs improves glucose metabolism and the β cell function in T2DM
7	China, 2015	Randomized Interventional, Phase 1	30 (Estimated)	HUC-MSC	1.5×107	AE	12	Unknown	No
8	China, 2015	Interventional, Phase 1	0 (Actual)	HUC-MSC	1.5×107	Improvements in IIEF scores	12	Withdrawn	No
9	Indonesia, 2016	Interventional, Non-Randomized Open Label, Phase 1/2	15 (Estimated)	BM-MNC HUC-MSC	1× 105–1× 106 /kg (BM-MNC) 2× 106 /kg (HUC-MNC) Twice with 3 months interval	Decreasing total daily dose of insulin (≥ 30%) 1st, 3rd, 6th and 12th month	12	Unknown	No
10	Israel, 2016	Interventional, Open Label Phase 1	12 (Estimated)	Allogeneic BM-MSC	1–2 × 107 Multiple injections	Frequency of AE	6	Unknown	No
11	Jordan, 2017	Interventional, Open Label Phase 1	9 (Actual)	Wharton Jelly MSC	2 ×107 Twice with 3 weeks interval	AE	12	Completed 2018–11	No
12	USA, 2017	Randomized, Double Blind Pilot Trial, Phase 1/2	16 (Actual)	Allogeneic BM-MSC	2 ×107, 10×107 Single injection	Number of Treatment Emergent SAE	12	Completed 2020–09	No
13	Vietnam, 2017	Interventional, Open Label Phase 1/2	30 (Actual)	BM-MSC	Dose unknown Twice with 6 months interval	Insulin dose and AE	12	Completed 2019–08	No SAE; No statistically significant differences in the changes in HbA1c, FBG and C-peptide levels
14	Vietnam, 2019	Non-Randomized Interventional Open Label, Phase 1/2	60 (Estimated)	BM-MNCs Allogeneic HUC-MSC	1–2 × 106/kg (HUC-MSC)	C-peptid, HOMA-β, HbA1c Blood glucose level HOMA-IR, cytokines TNF-α, IL-1β AE	6	Unknown	No
15	USA, 2019	Interventional, Non-Randomized Open Label, Phase 1	2 (Actual)	AD-MSC	2.5×105 /kg 5×105/kg Twice with 3 months interval	AE	15	Terminated	No
16	China, 2020	Single center, Randomized Double Blind Placebo-Controlled Trial	30 (Estimated)	HUC-MSC	0.75× 106 /kg, At 0, 1, 5, 6 week	The changes in HbA1C level	24 weeks	Unknown	No
17	Ukraine, 2020	Multicenter, Observational Prospective	91 (Actual)	Unknown	Unknown	Overall survival of subject with T2DM	120	Active not recuiting	No
18	USA, 2021	Non-Randomized Interventional Open Label, Phase 1	10 (Actual)	Allogeneic AD-MSC	7.5×107 (twice infusion) 3 months interval 15×107 (single infusion)	AE/SAE	22	Active not recuiting	No
19	China, 2022	Randomized, Interventional Phase 1/2	42 (Estimated)	HUC-MSC	5×106	Change of TCSS scale Change of nerve conduction velocities in the lower extremity	24 weeks	Recruiting	No
20	China, 2022	Multicenter, Randomized Double Blind Placebo-Controlled Trial	54 (Estimated)	HUC-MSC	1.5× 106 /kg At 0, 8, 16, 24, 32 week	UACR	48 weeks	Unknown	No
21	Malaysia, 2024	Randomized, Interventional Phase 1/2	20 (Estimated)	Allogeneic BM-MSC	2×106 / cm2 of foot ulcer	Proportion of patients with complete healing/closure of the target ulcer in 6-weeks	12 weeks	Not yet recruiting	No

Abbreviations: T2DM: type-2 diabetes mellitus; BM-MSC: bone marrow mesenchymal stem cells; BM-MNC: bone marrow mononuclear cells; HUC-MSC: human umbilical cord tissue-derived MSCs; AD-MSC: adipose tissue-derived MSCs; FBG: Fast blood glucose; PBG: post-meal blood glucose; HOMA-IR: Homeostatic Model Assessment for Insulin Resistance; LIRA: liraglutide; ITT: Insulin Tolerance Test; GIR: the glucose infusion rate; IIEF: International Index of Erectile Function; TCSS scale: Total Clinical Symptom Score scale; AE: adverse events; SAE: serious adverse events; UACR: urine albumin-creatinine ratio.

4. Safety of MSCs therapy for T2DM

MSCs are often delivered in T2DM through intravenous or intra-arterial (renal or pancreatic) infusion at doses ranging from 1×10⁵ to 15×10⁷ cells. Despite inherent benefits of intra-arterial delivery, technical challenges and potential risks may limit widespread adoption. Potential infusion-related side effects of MSCs include respiratory or allergic adverse events. Other minor symptoms, like fever, transient self-limiting nausea, vomiting, headache, abdominal pain, and upper respiratory tract infection and minor hypoglycemia have also been reported. Overall, adverse effects are not commonly prohibitive and MSCs therapy for T2DM is considered relatively safe. Long-term worrisome complications, including tumorigenesis, immunogenicity, and ectopic tissue formation, are rare, and malignancy has not been reported.

5. Limitations of MSC-based therapy

Although substantial advancements have been achieved in MSC-based therapy for T2DM, several challenges remain. MSC transplantation into injured tissues yields low therapeutic efficacy due to poor viability and diminished regenerative activity.. Diabetes disrupts multiple stem cell functions, including mobilization, differentiation, migration, and secretion. Hence, MSC functionality may be affected by the noxious microenvironment in the diabetic milieu. Other considerations include the choice between an autologous or allogeneic MSCs therapy given that allogeneic source may elicit low-level immune responses,and autologous source may have diminished cell functionality. The optimal MSCs source, dose, route of administration, frequency and timing of intervention also needs to be determined to improve the power of clinical trials and reach a consensus regarding the optimal regimen. The variability in heterogeneity and batch-to-batch differences among MSCs isolated even from the same source limit response prediction. Moreover, concerns regarding the long-term safety of MSCs remain somewhat unresolved and should be monitored. Importantly, MSC costs are a necessary consideration and are highly dependent upon tissue source, donor source, manufacturing methods, storage, distribution, cell dosing regimen, and administration route. A cost-effectiveness analysis to understand the benefits of MSC-based therapy showed that sodium/glucose co-transporter-2 inhibitors were the most cost-effective, but MSC performed better against usual care in treating patients with DN, given the increased lifetime benefit from delaying progression to ESRD [14]. To date, no U.S. FDA market approval has been garnered for MSC for any indication. However, regulatory agency approvals have been reported in Korea, Japan, Iran, and India, albeit none for the indication of diabetes [15]. In these markets, MSC-approved treatments may range between USD5,000–200,000. Of note, stem cell tourism is generally discouraged due to potential risks (e.g., infection, financial exploitation, severe adverse events). Lastly, to embrace this therapy, additional studies are needed to elucidate and define the therapeutic mechanisms activated by MSCs in T2DM.

6. Expert opinion

The limitations inherent to MSC therapy are largely addressable. Advances in stem cell engineering, including nanoparticle-based delivery systems, CRISPR/Cas9 editing, and tissue engineering approaches, may improve MSC characteristics, modulate their cytokine and growth factors, and enhance the therapeutic efficacy and safety of MSCs-based interventions. Possibly, preconditioning for either the cells or the patients prior to treatment may prolong MSC survival and functionality in tissues exposed to the diabetic milieu. Extensive research and longer follow-up periods are needed to establish standard regimens for MSCs therapy, elucidate the mechanisms underlying their beneficial effects, and ensure their sustenance for T2DM.

Therefore, MSC therapy has the potential to revolutionize a multi-pronged management of T2DM, paving the way for more effective, personalized, and sustainable treatment strategies in the future. Hopefully, rapid technological developments in MSC engineering will accelerate, maintaining safety and improving efficacy to advance it closer to the patient bed.