Infusion with Human Bone Marrow-derived Mesenchymal Stem Cells Improves β-cell Function in Patients and Non-obese Mice with Severe Diabetes.

Lirong Li,Ying Liu,Hui Hui,Jie Zhang,Xiaolei Jia,Dalong Zhu,Qianyue Xu

doi:10.1038/srep37894

Abstract

Mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for type 1 diabetes (T1D). However, little is known on whether MSC transplantation can benefit T1D patients with ketoacidosis and its potential actions. Here, we show that infusion with bone marrow MSCs preserves β-cell function in some T1D patients with ketoacidosis by decreasing exogenous insulin requirement and increasing plasma C-peptide levels up to 1–2 years. MSC transplantation increased plasma and islet insulin contents in non-obese diabetic (NOD) mice with severe diabetes. In comparison with severe diabetes controls, MSC infusion reduced insulitis, decreased pancreatic TNF-α, and increased IL-10 and TGF-β1 expression in NOD mice. MSC infusion increased the percentages of splenic Tregs and levels of plasma IL-4, IL-10 and TGF-β1, but reduced the percentages of splenic CD8+ T and levels of plasma IFN-γ, TNF-α and IL-17A in NOD mice. Finally, infused MSCs predominantly accumulated in pancreatic tissues at 28 days post infusion. The effects of MSCs on preserving β-cell function and modulating inflammation tended to be dose-dependent and multiple doses of MSCs held longer effects in NOD mice. Hence, MSC transplantation preserved β-cell function in T1D patients and NOD mice with severe diabetes by enhancing Treg responses.

Highlights

Mesenchymal stem cells (MSCs) have capacity of self-renewal and multi-lineage differentiation to form mesodermal, ectodermal and endodermal tissues, including the bone, muscle, neurons, hepatocytes and skin[1]
Two out of four patients responded to MSC transplantation by reducing exogenous insulin requirement to control hyperglycemia for [1,2] years and one patient became insulin-independent for three months (Fig. 1a)
We tested the effects of bone marrow MSC infusion on five Type 1 diabetes (T1D) patients with ketoacidosis

Summary

Introduction

Mesenchymal stem cells (MSCs) have capacity of self-renewal and multi-lineage differentiation to form mesodermal, ectodermal and endodermal tissues, including the bone, muscle, neurons, hepatocytes and skin[1]. Therapeutic effects of MSC transplantation are associated with modulation of autoimmunity[4,5,6], the mechanisms underlying the action of infused MSCs in a severe diabetic condition have not been clarified. Whether the therapeutic effects of MSC transplantation is dose-dependent and whether repeated infusion is necessary for preserving β-cell function are still in debate[15,16]. We first tested the effects of MSC infusion on β-cell function in T1D patients with ketoacidosis and examined the impact of different doses and frequencies of MSCs on β-cell function and Treg responses in NOD mice with severe T1D. We provided the evidence that the infused MSCs effectively accumulated in the pancreatic tissues of severe diabetic NOD mice. The therapeutic effects of MSC infusion tended to dose-dependent and repeated infusion with MSCs held longer effects in NOD mice

Methods

Results

Conclusion