Repeated Umbilical Cord MSC Transplantation for Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive and irreversible loss of insulin-producing beta cells. Once diagnosed, T1D patients require lifelong exogenous insulin injections. Although intensive insulin therapy can improve glucose homeostasis, it cannot replace the function performed by the pancreatic islets, nor can it suppress the continued destruction of remaining beta cells by the autoimmune system. Therefore, preserving residual β-cell function and smoothing blood sugar fluctuations to reduce the incidence of chronic diabetic complications [1,2] , blocking autoimmune attacks, retaining or even restoring endogenous β-cell function have been long-sought solutions for T1D. .

In an open- in Stem Cell Research & Therapy , researchers compared MSCs intervention with standard insulin in patients with type 1 diabetes admitted from 2013 to 2019. The effect of treatment . ( Registration number: ChiCTR2100045434 )

All participants had obvious symptoms of hyperglycemia at the time of onset, and 62.3% of the participants were complicated by diabetic ketosis or diabetic ketoacidosis (DKA). Participants were 8 to 55 years old at enrollment, required insulin injections since diagnosis of T1D, and had fasting C-peptide levels ≥100 pmol/L. Cardiopulmonary insufficiency, failure of one or more organs, HIV or viral hepatitis positivity, pregnancy, and underlying hematological, rheumatic, psychiatric, or malignant diseases were excluded.

Prior to the launch of clinical trials, the research team's studies in T1D animal models have obtained substantial evidence that transplantation of MSCs can delay the onset of T1D, reverse post-onset hyperglycemia, and improve β-cell function and quality [8,9,10 , 11,12] . MSCs mainly accumulated in pancreatic tissue 28 days after systemic infusion in non-obese diabetic (NOD) mice. MSC infusion significantly reduced islet inflammation, at least in part, by modulating the balance between pro- and anti-inflammatory and effector and regulatory T cells .

According to the research team's previous data, the effect of MSCs on maintaining beta cell function and regulating inflammation was dose-dependent in diabetic NOD mice, and multiple doses of MSCs prolonged their presence in pancreatic tissue and showed longer effect [9] . Furthermore, in a pilot trial of MSC transplantation for T1D, C-peptide levels trended downward after three months in recipients who received a single dose of MSCs (data not shown ) . Therefore, the research team decided to modify the mesenchymal stem cell-based immunomodulatory therapy and increase the course to repeat transplants three months apart. The aim was to evaluate the safety and efficacy of repeated allogeneic UC-MSCs in the treatment of T1D subjects.

At the end of 1-year follow-up, 11 subjects in the MSC treatment group maintained clinical remission ( 11/27, 40.7% ), while the clinical remission rate in the control group was significantly reduced ( 3/26, 11.5%, p = 0.041 ) . The HbA1c level in the MSC treatment group decreased significantly and reached the lowest level ( 6.6±0.8% ) at 3 months , but gradually increased to 6.9±1.1% and 7.3±1.3% at 6 and 12 months, respectively. The mean daily insulin dose requirements of MSC-treated individuals were relatively stable during follow-up.

The results of the study showed that both the control group and the MSC treatment group experienced clinical remission, but the subjects who received MSC treatment were four times more likely to achieve clinical remission than those who received regular insulin (OR=4.38, p= 0.044 ) . In addition, intravenous infusion of MSCs is safe, and the research team increased the course of repeated infusions of mesenchymal stem cells. Three recipients developed mild fever but recovered within 24 hours. This post-infusion febrile reaction has been reported in clinical trials for other diseases [21] , no serious adverse events were observed, and it was well tolerated by both adolescent and adult recipients.

Overall, this trial is the first to demonstrate that repeated intravenous infusion of allogeneic UC-MSCs is feasible and safe in individuals with T1D. In addition, it provides evidence that compared with standard treatment alone, the clinical response rate in the MSC-treated group was 40.7%, which was 2.5 times higher than that in the control group, and that this cell therapy may be beneficial in maintaining the function of endogenous beta cells .