Comparison of therapeutic effects of mesenchymal stem cells from umbilical cord and bone marrow in the treatment of type 1 diabetes

Abstract

Background: The therapeutic potential of mesenchymal stem cells (MSCs) in type 1 diabetes (T1D) has been demonstrated in both preclinical and clinical studies. MSCs that have been used in research on T1D are derived from various tissue sources, with bone marrow (BM) and umbilical cord (UC) tissues being the most commonly used. However, the influence of tissue origin on the functional properties and therapeutic effects of MSCs in T1D remains unclear. This study aimed to compare the therapeutic efficacy of UC-MSCs and BM-MSCs in a mouse model of T1D as well as in patients with T1D.

Methods: In non-obese diabetic (NOD) mice, the development of diabetes was accelerated by streptozotocin injections. Thereafter, diabetic mice were randomized and treated intravenously with UC-MSCs, BM-MSCs or phosphate-buffered saline as a control. Blood glucose and serum insulin were measured longitudinally after transplantation. At 14 days post-transplantation, pancreatic tissues were collected to assess insulitis and the β-cell mass. Flow cytometry was performed to evaluate the composition of T lymphocytes in the spleen and pancreatic lymph nodes of the NOD mice. In our retrospective study of patients with T1D, 28 recipients who received insulin therapy alone or a single transplantation of UC-MSCs or BM-MSCs were enrolled. The glycaemic control and β-cell function of the patients during the first year of follow-up were compared.

Results: In NOD mice, UC-MSC and BM-MSC transplantation showed similar effects on decreasing blood glucose levels and preserving β cells. The regulation of islet autoimmunity was examined, and no significant difference between UC-MSCs and BM-MSCs was observed in the attenuation of insulitis, the decrease in T helper 17 cells or the increase in regulatory T cells. In patients with T1D, MSC transplantation markedly lowered haemoglobin A1c (HbA1c) levels and reduced insulin doses compared to conventional insulin therapy. However, the therapeutic effects were comparable between UC-MSCs and BM-MSCs, and they also exerted similar effects on the endogenous β-cell function in the patients.

Conclusion: In conclusion, both UC-MSCs and BM-MSCs exhibited comparable therapeutic effects on improving glycaemic control and preserving β-cell function in T1D. Considering their abundance and higher cell yields, UC-MSCs appear to be more promising than BM-MSCs in clinical applications. Trial registration NCT02763423. Registered on May 5, 2016-Retrospectively registered, https://www.

Clinicaltrials: gov/ .

Keywords: Bone marrow-derived mesenchymal stem cells; Cell transplantation; Type 1 diabetes; Umbilical cord-derived mesenchymal stem cells.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Characterization of BM-MSCs and UC-MSCs. A Representative micrographs of BM-MSCs and UC-MSCs observed under light microscopy. Scale bar, 200 μm. B Expression of CD14, CD73, CD19, CD90, CD34, CD105, CD45 and HLA-DR in BM-MSCs and UC-MSCs analysed by flow cytometry. C Representative micrographs of adipogenesis identified by Oil Red O staining, and osteogenesis identified by Alizarin Red staining of BM-MSCs and UC-MSCs. Scale bar, 100 μm

Fig. 2

Effects of BM-MSCs or UC-MSCs infusion on body weights and blood glucose levels in NOD mice. A The treatment schedule for STZ and MSC transplantation. Body weights (B) and blood glucose levels (C) were measured twice a week after MSC transplantation for 14 days (N = 13 in each group). Data are presented as mean ± SEM. *P < 0.05 versus the control group

Fig. 3

Effects of BM-MSCs or UC-MSCs infusion on β-cell mass and insulin production. A Representative micrographs of insulin immunohistochemical staining showing β cells preserved in islets at 14 days post-transplantation. Scale bar, 100 μm. B The insulin-positive staining areas (%) in pancreatic islets were quantified using the Image-Pro Plus 6.0. Four slides per mouse (four mice per group) were analysed, and at least 20 islets from the pancreatic tissue of each mouse were evaluated. C Random serum insulin concentration (N = 4–5). Data are presented as mean ± SEM. *P < 0.05 versus the control group

Fig. 4

Effects of BM-MSCs or UC-MSCs infusion on insulitis in NOD mice. A Representative micrographs of H&E staining of pancreas at 14 days post-transplantation. Scale bar, 100 μm. B The percentage of islets in each of the infiltration categories (score 0, no insulitis; score 1, leukocyte infiltration ≤ 25%; score 2, leukocyte infiltration > 25%, but ≤ 50%; score 3, leukocyte infiltration > 50%; score 4, leukocyte infiltration 100% and β-cell destruction). C Insulitis score in pancreatic islets. Four slides per mouse (four mice per group) were analysed, and at least 20 islets from the pancreatic tissue of each mouse were evaluated. Data are presented as mean ± SEM. *P < 0.05 versus the control group

Fig. 5

Effects of BM-MSCs or UC-MSCs infusion on T cell proportion in NOD mice. Percentage of CD8 + T cells (A) and CD4 + T cells (B) in gated CD3 + T cell population in the spleen and PLNs from NOD mice killed at 14 days post-treatment. Representative cytofluorometric dot plots (C) and summary data (D) of Th17 in gated CD4 + T cell population in the spleen and PLNs from NOD mice killed at 14 days post-treatment. Representative cytofluorometric dot plots (E) and summary data (F) of Tregs in gated CD4 + T cell population in the spleen and PLNs from NOD mice killed at 14 days post-treatment (N = 4–6). PLN, pancreatic lymph node

Fig. 6

Change in HbA1c, exogenous insulin dosage and C-peptide in patients with T1D at 1-year follow-up. Rate of change in HbA1c (A), doses of daily insulin (B), FCP (C) and PCP (D) of the control group and MSC-treated group between baseline and 1-year follow-up. Rate of change in HbA1c (E), doses of daily insulin (F), FCP (G) and PCP (H) of the BM-MSC subgroup and UC-MSC subgroup between baseline and 1-year follow-up. Data are presented as mean ± SEM. *P < 0.05 versus the control group. FCP, fasting C-peptide; PCP, postprandial C-peptide