Umbilical cord mesenchymal stem cells in diabetes mellitus

Abstract

Diabetes mellitus (type 1 diabetes mellitus and type 2 diabetes mellitus) results from a failure of pancreatic β cells at different velocities and time frames resulting insulin deficiency. Currently, management of type 1 diabetes mellitus relies on replacing insulin, without changing the natural course of progressive β cell loss. Stem cell therapy can prevent autoimmune destruction as well replenish pancreatic β cells. Among various sources, human umbilical cord mesenchymal stem cells (hUC-MSCs) have the advantage of generating progenitor cells, greater immunosuppression, cell proliferation and clonality. Further they are less immunogenic. Practical advantages for their use include painless extraction and potential of long term storage. In this review we provide a brief of interventions available to prevent and slow down immune destruction of pancreatic β cell cells, and discuss evidence obtained from cell and animal studies, combined use with adjuvants, their potential on microvascular complications, human clinical trials, meta-analysis and umbrella reviews. We then discuss the limitations and challenges, and offer future perspectives. Currently, hUC-MSC is a treatment with promise. Further large randomized clinical trials with diverse populations, proper trial protocol with inclusion criteria, treatment methods and pre-defined outcome measures in the long term are necessary to bring hUC-MSC therapy into mainstream clinical use.

Key Words: Pancreatic transplantation; Immunotherapy; Cell replacement; Extracellular vesicles; Immunomodulation; Pre-clinical; Biobanking; Regulations; Cost benefit

Core Tip: Umbilical cord mesenchymal stem cells have the potential to modify the course of diabetes mellitus, eventually leading to its possible cure. They regulate immune destruction of pancreatic β cells and can also regenerate them. Animal studies showed their effectiveness. Early human reports showed positive results. Larger long term human randomized clinical trials are needed to bring prospect to practice.

INTRODUCTION

The prevalence of diabetes is increasing in both adults and in children[1,2]. Management options are confined to either agents that improve insulin resistance, or eventually when the pancreatic β cells fail, replacement with insulin. Existing treatments cannot correct the underlying pathophysiological process nor replicate the fine control in normal subjects. Despite advances in glucose monitoring and insulin delivery, euglycemia is rarely maintained, leading to increased morbidity and mortality[3]. Interventions for type 1 diabetes mellitus (T1DM) consist of systems to deliver insulin using external devices such as insulin pumps, preservation of β cells by immunosuppression[4,5], regenerate existing β cells targeting antigens or replace β cells or a combination of the above. Pancreas transplantation or β cell transplantation are limited by donor availability and the need for immunosuppression[6].

Immune destruction of β cell results from a complex interplay between adaptive and innate immune dysfunction, autoreactive islet cells, genetic and environmental factors[7]. This renders a single disease-modifying treatment impractical.

A literature search was made on major databases including National Center for Biotechnology Information (PubMed) and Google Search with terms “umbilical cord (UC) mesenchymal stem cells, diabetes, T1DM, type 2 diabetes mellitus (T2DM)” between the years 2015 and 2026. Studies on diabetic foot and injuries were excluded. In all there were 180 articles. Important references from the selected articles were included. 57 references were included of which 29 were related to animal and cell studies, co-administration of other agents, representative studies on microvascular complications, human studies, clinical trials, reviews and meta-analyses.

IMMUNOTHERAPY STRATEGIES

Antigen-based therapies that induce passive tolerance by anergy can promote immune suppression: Agents in the early phases of evaluation include oral insulin, human recombinant GAD65, modified insulin-derived peptides, altered human heat-shock proteins and tolerogenic dendritic cells[8].

Altered Foxp3+ regulatory T cells cause immunological disruption in T1DM. A phase 2 trial of autologous polyclonal Tregs infusion, and a combination with rituximab led to transient biochemical improvement[8].

Targeting CD3 2ith anti-CD3 monoclonal antibodies with Otelixizumab, and anti-CD3 antibody target T cell activation stage were ineffective[9,10]. The Food and Drug Administration approved the use of teplizumab, a humanized Fc receptor nonbinding CD3 monoclonal antibody to delay the progression of stage 2 T1DM in children under the age of eight[11].

Other interventions targeting pathological T cell function involve the co-stimulation process, which refers to the signal that is required to fully activate T cells and prevent tolerance[8]. Potential target includes the interaction between CD80/86 on the antigen producing cells on the T-lymphocytes after first interaction[12] which was used in the context of renal transplantation.

Immunotherapy targeting the B lymphocytes

In animal models, rituximab, an anti-CD20 monoclonal antibody selectively depleted B lymphocytes and reduced insulin requirement[13].

Cytokines, key mediators in the interaction between pancreatic β cells and the immune system were targeted by etanercept (tumour necrosis factor-a) and anakinra and canakinumab (interleukin-1)[14]. Alternatively, Janus kinase inhibitors such as baricitinib, abrocitinib and ritlecitinib that suppress cytokine intracellular signalling are being studied[9].

A hypothesis generating systematic review and network meta-analysis of randomised controlled trials to preserve pancreatic β cells using immunomodulators[15] showed that eleven interventions preserved β cells. The evidence is preliminary and requires further studies addressing potential effect modifiers through sensitivity analysis and correlating them with treatment effects. It is difficult to perform such trials in real world conditions[15].

CELL REPLACEMENT THERAPY FOR DIABETES

Replacement of β cells in T1DM is a logical approach to treatment. However, due to lack of donors, the procedure is confined to subjects with troublesome hypoglycemia. Outcomes can improve by refining manufacturing, transplantation procedures, recipient management and protocols for immunosuppressive therapy[16].

Mesenchymal stem cells for clinical use

Stem cells, derived either from embryos or induced pluripotent stem cells are being used in osteoarthritis, myocardial infarction, multiple sclerosis, systemic lupus erythematosus and amyotropic lateral sclerosis[17,18]. Beginning with the pioneering studies of Gurdon et al[19] who identified induced pluripotent stem cells from Xenopus laevis, progress in the field led to the award of the Nobel prize (2012) to Gurdon and Shinya Yamanaka who created induced pluripotent stem cells through transfection of mouse somatic cells using specific transcription factors[20].

Human UC mesenchymal stem cells

Among the potential sources of mesenchymal stem cells, those derived from the human UC mesenchymal stem cells (MSCs) (hUC-MSCs) have the advantages of being non-invasive and being abundantly available because the UC is discarded after parturition[21]. Ethical issues with hUC-MSC are of lesser concern than other cells. In view of their accessibility, safety and non-invasive source, UC mesenchymal stem cells (UC-MSCs) are an attractive source in regenerative medicine. Through the secretion of cytokines and growth factors, they help in regeneration of pancreatic islet cells both directly, and by their anti-inflammatory and immunomodulatory effects (Table 1)[22].

Table 1 Potential mechanisms of human umbilical cord mesenchymal stem cell in diabetes mellitus.

Number	Characteristics
1	Transform to pancreatic cells
2	Promote regeneration of pancreatic cells
3	Promote dedifferentiation of pancreatic cells
4	Immunomodulation to suppress pancreatic cell destruction
5	Reduce insulin resistance

Animal and cell studies of hUC-MSC

hUC-MSCs act through a number of biological actions (Table 2). Tissue of origin of hUC-MSC influences the outcomes. When the comparing the efficacy of hUC-MSCs, Wharton’s jelly, dental pulp, and adipose tissue, UC-MSCs showed the largest metabolic benefit[23]. Animals can be administered UC-MSC via a number of routes such as pancreas injection, tail vein injection, intraperitoneal injection, and dorsal pancreatic artery injection. Tao et al[24] showed that the dorsal tail vein injection showed the best outcomes in terms of oral glucose tolerance test and recovery of islet structure.

Table 2 Studies of stem cell therapy in diabetes mellitus.

Ref.	Source	Method	Observations
Ma et al[23]	hUC-MSC	-	hUC-MSC showed the greatest metabolic benefit
Tao et al[24]	Rat	-	Dorsal tail vein injection best outcomes
Pan et al[25]	Tree shrews	-	Islet-like cells reduced inflammation and improved metabolic control
Isildar et al[26]	Rat	-	Promoted regeneration of cells and had immunomodulatory effects
Li et al[27]	Mice	-	De-differentiation of cells in type 2 diabetes
Yin et al[28]	Mice	-	Homing of hUC-MCH to cells
Song et al[29]	Cell study	-	Improved cell mitochondrial dysfunction and hyperglucagonemia
Chen et al[30]	Mice	-	Ameliorated insulin resistance
Tao et al[31]	Rat	-	Downregulated inflammation and reduced cell apoptosis
Gao et al[32]	Mice	-	Addition of decitabine increased the duration of metabolic control
Aierken et al[33]	Mice	-	Addition of melatonin improved metabolic control via PI3K/AKT signalling pathway
Zhou et al[34]	Mice	-	Pretreatment with ginsenoside had metabolic benefits
Sun et al[35]	Rat	-	Fufang Xueshuantong capsule ameliorated aortic lesions in T2DM
Chen et al[36]	Human	-	Addition of liraglutide improved cell function
Ko et al[37]	Mice	-	Attenuated progression of diabetic kidney disease
Nie et al[38]	Rat	-	Attenuated renal oxidative damage and apoptosis
Zhao et al[39]	Rat	-	Promoted differentiation of retinopathy model to nerve cells
Feng et al[40]	Rat	-	Ameliorated erectile dysfunction
Li et al[41]	Mice	-	Ameliorated nonalcoholic fatty liver disease
Cai et al[42]	Human	-	Safe, improved metabolic control for upto 1 year in T1DM
Kong et al[43]	Human	-	Improved metabolic control for upto 1 year in T2DM
Wang et al[44]	Human	-	Subjects with greater AUCC-pep had better response
Papadopoulou and Papadopoulos[45]	Human	-	Adherence to lifestyle advice to be considered
Lu et al[46]	Human	Open-label, parallel-armed, prospective, T1DM	At one year, C-peptide increased
Zang et al[47]	Human	Single-centre, double-blinded randomized, placebo-controlled phase 2 trial, T2DM	Five times as many study group subjects had HbA1c below 7%
Lian et al[48]	Human	Open-label randomized phase 2 trial for 24 months	Safe, well tolerated without serious adverse effects
Nada et al[49]	Human	Meta-analysis, T1DM and T2DM	Lowering of HbA1C, but no improvement of C-peptide
Chin et al[50]	Human	Retrospective registry, T1DM and T2DM	Sustained metabolic benefits for upto 12 months

hUC-MSC: Human umbilical cord mesenchymal stem cell; P13K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; AUCC: C-peptide area under the curve; HbA1C: Glycated hemoglobin.

Pan et al[25] used islet-like cells differentiated from (UC-MSCs) of tree shrews for the treatment of T2DM. They reduced inflammatory cytokines and improved metabolic parameters[25]. Dual beneficial effects of MSC-conditioned medium on immunomodulation and regeneration of β-cells was reported in an animal T1DM model[26-28].

Dysregulated α cells lead to hyperglycemia and hyperglucagonemia in T2DM. hUC-MSC improved α-cell mitochondrial dysfunction and hyperglucagonemia[29]. They reduced insulin sensitivity and hyperglycemia through sirtuin 1/forkhead box O3a signaling, suggesting they could have a potential therapeutic role in T2DM. To further assess, db/db mice received intramuscular injections of hUC-MSC. The metabolic outcomes were better compared to tail vein injection and intraperitoneal injection[30]. It was postulated that hUC-MSC downregulated inflammation by regulating the balance between phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase/mitogen-activated protein kinase signaling pathway via phosphatase and TENsin homolog, by inhibiting toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells signaling and attenuating apoptosis of pancreas[31].

Co-administration of other agents with hUC-MSC

To prolong effectiveness, other agents were co-administered with hUC-MSC. In a high-fat diet and streptozocin induced T2DM mouse model, decitabine, was given in addition to hUC-MSC[32]. The combination with the agent that an agent that regulates macrophage polarization extended the effectiveness to four weeks, compared to only one week when hUC-MSC given alone. The combination acted by activating the interleukin-4 receptor/signal transducer and activator of transcription 6/signal transducer and activator of transcription 3/peroxisome proliferator-activated receptor gamma axis[32]. Similar effects were observed by pre-treatment with melatonin, a regulator of the phosphoinositide 3-kinase/protein kinase B signaling pathway[33]. Pre-treatment by 20(R)-Rg3, a ginsenoside which has anti-inflammatory and antioxidant properties, was also effective[34].

To address the atherogenic risk in T2DM, Fufang Xueshuantong capsule, which protects endothelial function was given with hUC-MSC. The combination reduced lipid levels and ameliorated aortic lesions in T2DM-induced rats via upregulation of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 expression[35].

In a human study, liraglutide was given with hUC-MSC in subjects with T2DM. When initially administered through the pancreatic artery, followed by intermittent infusion via a peripheral vein until day 22, the combination therapy improved glucose metabolism and β cell function[36].

Effect of hUC-MSC on diabetes complications

In a db/db mouse model, the effect of SMUP-cell, a type of HUC blood-derived MSC was studied on diabetic kidney disease in T2DM. Over three months of intervention reduced albumin-to-creatinine ratio and tubular injury markers[37]. In mouse models, Nie et al[38] showed that hUC-MSCs attenuated renal oxidative damage and apoptosis and nuclear factor erythroid 2-related factor 2 activation in T2DM mouse models.

hUC-MSC were effective in diabetic retinopathy. Alltrans retinoic acid used to promote the proliferation of rat UC derived MSCs and their differentiation into nerve cells attenuated diabetic retinopathy in rats, while alleviating retinal damage and apoptosis[39].

hUC-MSC ameliorated erectile dysfunction in rat models of T1DM and T2DM with equal efficiency whether given into the corpus cavernosum or the tail vein[40]. Reduced oxidative stress, tissue iron and mitochondrial morphology in the corpus cavernosum could have mediated the improvement.

Nonalcoholic fatty liver disease, now known as metabolic dysfunction-associated fatty liver disease is associated in T2DM. When male C57BL/6 db/db mice were infused weekly hUC-MSCs, for six weeks, metabolic dysfunction-associated fatty liver disease and metabolic syndrome were attenuated[41].

Human studies with hUS-MSC

An early studied assessed the effects of hUC-MSCs and autologous bone marrow mononuclear cell stem cell transplantation without immunotherapy in established T1DM. Performed between January 2009 and December 2010, they were followed for one year. The intervention was safe and improved metabolic measures moderately[42]. Similar results were obtained in subjects with T2DM[43]. In a post hoc analysis of 37 patients with T2DM who received hUC-MSC transfusions, at the end of nine weeks of follow up, those with greater C-peptide area under the curve-pep were more likely to have a good clinical response[44]. While interpreting results of UC-MSC therapy, adherence to lifestyle factors must be considered as a crucial variable[45].

Clinical trials

In a nonrandomized, open-label, parallel-armed prospective study, subjects with T1DM were infused with hUC-MSC either once or by a repeat course at three months. At the end of one year, the primary end point, defined as 10% increase from baseline in the level of fasting and/or postprandial C-peptide; 40.7% subjects in hUC-MSC-treated group achieved the primary endpoint. Lower fasting C-peptide and higher dose of hUC-MSC correlated with better clinical remission[46]. In the same year, Zang et al[47] published their results of a single-center, double-blinded, randomized, placebo-controlled phase II trial involving 91 patients with T2DM. They were randomly assigned to receive intravenous infusion of UC-MSCs (n = 45) or placebo (n = 46) three times with 4-week intervals. The follow up period was for 48 weeks from October 2015 to December 2018. Unlike the previous study[46], the primary endpoint was the percentage of patients who achieved glycated hemoglobin (HbA1c) levels of < 7.0% and daily insulin reduction of ≥ 50% at 48 weeks[47]. Nearly five times as many patients in the intervention group (20% vs 4.55%) reached the primary endpoint. The β-cell function did not improve in either group, nor were there any significant adverse effects.

Yet another report from China in 2022, assessed the safety of hUC-MSC transplantation in T2DM in an open-label randomized phase 2 clinical trial. Twenty-four patients in the hUC-MSC intervention group received hUC-MSCs intravenously once per week for three weeks, and were compared with ten controls[48]. Follow up assessment was done weekly for the first month and then at weeks 12 and 24 post-treatment. Treatment with hUC-MSC had good tolerance and safety profile in the treatment of T2DM, without serious adverse effects.

These reports can be considered preliminary because of small sample sizes, different study protocols and outcome measures.

Meta analyses and umbrella reviews

Three major meta analyses and umbrella reviews on the efficacy and safety of hUC-MSC were published in 2025. Nada et al[49] included randomized controlled trials investigating the effects of UC-MSCs on diabetes mellitus (types 1, 2) till January 2024. Eight trials involving 334 patients (172 experimental and 162 controls) were included. hUC-MSCs substantially lowered HbA1c levels (MD = -1.06, 95% confidence interval: -1.27 to -0.85, P < 0.00001), but there was no improvement in C-peptide levels.

There was a reduction in daily insulin requirement in T1DM. Chin et al[50] from Malaysia published a study from the Cytopeutics’ Registry. This retrospective registry included subjects with diabetes who had received UC-MSCs infusion between November 2014 and July 2022 (n = 301). The data came from 218 T2DM patients who attended for follow-up after 6 months, and 83 patients after 12 months following allogeneic hUC-MSCs use. Sustained benefits were observed up to 12 months in glycemic control, liver and renal profile and systemic subclinical inflammation[50].

In 2025, an umbrella review by Koishybayeva et al[51] synthesized evidence from systematic reviews and meta-analyses to evaluate the efficacy and safety of MSC therapy for diabetes. Articles were included based on the PRISMA guidelines up to July 30, 2025. Included were systematic reviews and meta-analyses assessing hUC-MSC therapy in T1DM or T2DM patients, with outcomes of glycemic control, beta-cell function, and safety. It included 17 systematic reviews and meta-analyses (n = 8000 patients). hUC-MSC therapy led to improved glycemic control especially in T2DM, with reductions in HbA1c (up to 1.45%) and insulin requirements (up to 2.05 U/kg/day) in T2DM. In T1DM, therapy improved C-peptide levels and HbA1c; effects on insulin dependence were inconsistent.

One of the bottlenecks is lack of adequate sample size and long term follow up. This must be addressed by multicentric trials using improved study design and standardized protocols.

Ethical issues must be carefully addressed in stem cell therapy. These exist across informed consent, autonomy, commercial exploitation, equitable access and patient safety. National regulatory bodies construct guidelines, often restricting to clinical trials.

LIMITATIONS AND CHALLENGES OF hUC-MSC THERAPY IN DIABETES

Despite early clinical trials showing promise and optimism, evidence for the use of hUC-MSC is still preliminary with results from single centres, limited sample size, inconsistent treatment protocols and outcomes[22]. Potential ways in which hUC-MSC act by transforming into induced pluripotent stem cells, promoting β cell regeneration, dedifferentiation, regulating immune response and improve insulin resistance[52] are yet to be translated to mainstream clinical practice.

Biobanking and workflow of hUC-MSC administration

The workflow begins with identifying the donor and checking her health status, age and parity and mode of delivery. This is followed by packing hUC-MSC into microcarriers or being encapsulated and administered as an intravenous infusion or intramuscularly[53].

hUC-MSC are stored in biobanks, which are repositories maintained publicly, privately or in hybrid mode. Mandatory Food and Drug Administration safety, purity, identity and potency tests include, but are not limited to testing for maternal blood infection (bacterial and fungal) and for hemoglobinopathies. The Association for the Advancements of Blood and Biotherapies made it mandatory for testing of granulocyte-macrophage progenitor cells using colony-forming unit assays, which predict the chances of engraftment. Cord Blood Apgar score is based on weighted accumulative score before and after cryopreservation. To ensure paracrine signaling is not compromised with cryopreserving, quantitative reverse transcription polymerase chain reaction, flow cytometry, enzyme-linked immunosorbent assay, liquid chromatography-mass spectrometry and proteomics based profile are additional methods that are available[54].

To ensure safety and generalizability, shared protocols must be harmonized and standardized action is required. These involve procurement, collection, processing, quality assessment and storage of samples. Issues of informed consent, confidentiality and pseudo-anonymization must be addressed. Artificial intelligence can help in regulation and administration of biobanks.

COST-BENEFIT ANALYSIS OF hUC-MSC IN DIABETES

Given the preliminary status of hUC-MSC therapy, limited data exists to assess the cost-benefit ratio in diabetes. Barcelona et al[55] published a review on UC-MSC as an effective and cost-beneficial alternative for stem cell treatment. The cost of cord stem cell therapy steadily increased from 2010 to 2020. It depends on accessibility to equipment, medical and biobanking costs. Private cord blood banking costs $300 to $2300 plus annual fees. Therapy costs range between $5000 to $50000, with an average of $25000.

Inoue et al[6] compared the cost of islet transplantation with stem cell therapy. In 2012, islet transplantation cost $13872; it was more cost-effective than insulin therapy for high risk T1DM patients after nine to ten years[56]. With increasing demand for the procedure, the cost of labour and facilities are bound to decrease. Scaling-up of manufacturing capability and supply chain must be carefully monitored.

Economic viability depends on averting expensive long-term complications of diabetes. Even though upfront costs are high, the returns must be measured in terms of glycemic and metabolic results: Lowered glycosylated hemoglobin levels, improved C-peptide and heightened time-in-range continue glucose monitoring. In addition need for exogenous insulin is reduced. In subjects with T1DM, they protect and preserve pancreatic β cells and reduce insulin resistance, thereby lowering the cost of treating diabetic microvascular disease such as nephropathy and retinopathy. However, the limited duration of effect of hUC-MSC is a drawback in such an analysis. Combination therapy may extend the effectiveness, but that is still some time away.

CONCLUSION

hUC-MSC has the potential of changing the way diabetes mellitus is treated. Despite establishing clinical feasibility and cost efficiency to being produced under good manufacturing practice conditions[57] and the documented mechanistic studies, hUC-MSC treatment faces hurdles in being translated into routine clinical use. It remains in the exploration stage because of safety and efficacy issues. Potential risk of tumorogenesis in the recipient is another unresolved concern. Although there have been no serious reports in the trials conducted so far; that does not negate the risk which needs robust evidence.

Large standardized trials are required to clarify unknowns such as optimal source of cells, safe and efficient biobanking, optimal tissue source, more precise bio-markers for personalized treatment, the number, duration and route of administrations, increased duration of effectiveness, the stage of the disease at which they are optimally given, potential of priming approaches and as result evidence indicates, the effectiveness of stem cell-secretome and extracellular vesicles.

As of now hUC-MSC shows potential in the treatment of T1DM and T2DM. Future progress hinges on evidence from methodologically rigorous high-quality randomized clinical studies.