Investigating the safety and efficacy of hematopoietic and mesenchymal stem cell transplantation for treatment of T1DM: a systematic review and meta-analysis.

BACKGROUND: Stem cell transplantation (SCT) has paved the way for treatment of autoimmune diseases. SCT has been investigated in type 1 diabetes mellitus (T1DM) as an autoimmune-based disorder, but previous studies have not presented a comprehensive view of its effect on treatment of T1DM. METHODOLOGY: After registration of the present systematic review and meta-analysis in the PROSPERO, a search was done according to the Cochrane guidelines for evaluation of clinical trials to find eligible clinical trials that investigated the effect of SCT on T1DM (based on ADA® diagnostic criteria) from PubMed, Web of science, Scopus, etc, as well as registries of clinical trials from January 1, 2000, to September 31, 2019. A search strategy was designed using MeSH and EM-tree terms. Primary outcome included the changes in the insulin total daily dose (TDD) (U/kg) level, and secondary outcomes included the changes in the HbA1c, c-peptide, and adjusted HbA1c levels. The Q Cochrane test and I2 statistic were performed to assess the heterogeneity and its severity in primary clinical trials. The Cochrane ROB was used to determine risk of bias, and Cochrane Handbook for Systematic Reviews of Interventions was used in the full text papers. The meta-analysis was accomplished in the STATA software, and the results were shown on their forest plots. Confounders were evaluated by the meta-regression test. RESULTS: A total of 9452 studies were electronically screened, and 35 papers were included for data extraction. The results of this review study showed that 173 (26.5%) diabetic patients experienced insulin-free period (from 1 to 80 months), and 445 (68%) showed reduction in TDD of insulin after the SCT. Combination of hematopoietic stem cell (HSC) with mesenchymal stem cell (MSC) transplantation were significantly associated with improvement of the TDD (SMD: - 0.586, 95% CI: - 1.204/- 0.509, I2: 0%), HbA1c (SMD: - 0.736, 95% CI: - 1.107/- 0.365, I2: 0%), adjusted HbA1c (SMD: - 2.041, 95% CI: - 2.648/- 1.434, I2: 38.4%), and c-peptide (SMD: 1.917, 95% CI: 0.192/3.641, I2: 92.5%) on month 3 of follow-up, while its association had a growing trend from 3 to 12 months after the transplantation. Considering severe adverse events, HSC transplantation accompanied with conditioning could not be suggested as a safe treatment. CONCLUSION: Most of the clinical trials of SCT in T1DM were single arm. Although meta-analysis illustrated the SCT is associated with T1DM improvement, well-designed randomized clinical trials are needed to clarify its efficacy. RECOMMENDATION: Based on the results of this meta-analysis, the MSC and its combination with HSC could be considered as "Safe Cell" for SCT in T1DM. Furthermore, to evaluate the SCT efficacy, calculation of insulin TDD (U/kg/day), AUC of c-peptide, and adjusted HbA1c are highly recommended.

Placenta derived Mesenchymal Stem Cells transplantation in Type 1 diabetes: preliminary report of phase 1 clinical trial.

INTRODUCTION: Type 1 Diabetes Mellitus (T1DM) is an auto immune reaction against insulin secreting beta cells. Exogenous insulin administration is the only standard treatment for T1DM. However, despite tight glycemic control many patients will develop chronic life-threatening complications. Recently, stem cell transplantation has been suggested as a novel treatment for eliminating the beta cell damage and promoting their regeneration by modulating auto-immunity. To our knowledge; this is the first preliminary report of placenta derived MSCs (PLMSCs) transplantation in juvenile T1DM. METHOD: An Open label non-randomized phase 1 clinical trial was designed to evaluate the safety of PLMSCs transplantation in new onset juvenile T1DM (IRCT20171021036903N2). PLMSCs were manufactured in our clean room facility using a Xeno-free/GMP compliant protocol. The first series of patients (n = 4) received one dose of1 × 106 PLMSCs/kg intravenously. Diabetic clinical and laboratory parameters and side effects were evaluated weekly for the first month, monthly for 6 months, and then every 3 month till 1 year. RESULTS: Serious adverse events were not seen during 1 year follow-up. Partial remission and hypoglycemic attacks were happened one month after transplantation in two patients. ZnT8-Ab decreased till month 3 and then increased again in all patients. Anti Gad-Ab decreased till month 3 of follow up then increased. DISCUSSION: This preliminary report of our phase I clinical trial demonstrated the short term safety of PLMSCs transplantation in juvenile T1DM. To prove the long term safety and probable efficacy of this treatment more investigations are needed. TRIAL REGISTRATION: Iranian Registry of Clinical Trials: IRCT20171021036903N2.