Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
Syst Rev. 2022 May 2;11(1):82. doi: 10.1186/s13643-022-01950-3.
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.
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 I 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.
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, I: 0%), HbA1c (SMD: - 0.736, 95% CI: - 1.107/- 0.365, I: 0%), adjusted HbA1c (SMD: - 2.041, 95% CI: - 2.648/- 1.434, I: 38.4%), and c-peptide (SMD: 1.917, 95% CI: 0.192/3.641, I: 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.
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.
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.
干细胞移植（SCT）为治疗自身免疫性疾病铺平了道路。SCT 已在 1 型糖尿病（T1DM）作为一种自身免疫性疾病中进行了研究，但以前的研究并没有全面展示其对 T1DM 治疗的影响。
在 PROSPERO 中注册了本次系统评价和荟萃分析后，根据 Cochrane 指南对临床试验进行评估，以查找合格的临床试验，这些临床试验从 PubMed、Web of science、Scopus 等中根据 ADA®诊断标准调查了 SCT 对 T1DM 的影响，并从临床试验登记处查找了 2000 年 1 月 1 日至 2019 年 9 月 31 日的临床试验。使用 MeSH 和 EM-tree 术语设计了搜索策略。主要结局包括胰岛素总日剂量（TDD）（U/kg）水平的变化，次要结局包括 HbA1c、c 肽和调整后的 HbA1c 水平的变化。使用 Q Cochrane 检验和 I 统计量评估初级临床试验中的异质性及其严重程度。使用 Cochrane 偏倚风险工具（ROB）确定偏倚风险，并在全文论文中使用 Cochrane 干预系统评价手册。使用 STATA 软件进行荟萃分析，并在其森林图上显示结果。使用荟萃回归检验评估混杂因素。
共电子筛选了 9452 项研究，并纳入了 35 篇论文进行数据提取。本综述研究的结果表明，173 名（26.5%）糖尿病患者经历了胰岛素无剂量期（1 至 80 个月），445 名（68%）患者在 SCT 后胰岛素 TDD 减少。造血干细胞（HSC）与间充质干细胞（MSC）联合移植与 TDD 的改善显著相关（SMD：-0.586，95%CI：-1.204/-0.509，I：0%），HbA1c（SMD：-0.736，95%CI：-1.107/-0.365，I：0%），调整后的 HbA1c（SMD：-2.041，95%CI：-2.648/-1.434，I：38.4%）和 c 肽（SMD：1.917，95%CI：0.192/3.641，I：92.5%）在随访第 3 个月，而其相关性从移植后 3 个月到 12 个月呈增长趋势。考虑到严重不良事件，不能建议 HSC 移植伴预处理作为安全治疗。
T1DM 的 SCT 临床试验大多为单臂。尽管荟萃分析表明 SCT 与 T1DM 的改善有关，但需要精心设计的随机临床试验来阐明其疗效。
基于荟萃分析的结果，MSC 及其与 HSC 的联合可被视为 T1DM 中 SCT 的“安全细胞”。此外，为了评估 SCT 的疗效，建议计算胰岛素 TDD（U/kg/天）、c 肽 AUC 和调整后的 HbA1c。
