Effect of hTIMP‐1 overexpression in human umbilical cord mesenchymal stem cells on the repair of pancreatic islets in type‐1 diabetic mice

Abstract

Mesenchymal stem cells (MSCs) have been suggested for pancreatic islet repair in Type 1 diabetes mellitus (T1DM). This study aimed to investigate the effect of human umbilical cord MSCs (hUC-MSCs) transfected with tissue inhibitors of matrix metalloproteinase (TIMP)-1 on the regeneration of β-cell islets in vitro and in vivo. hUC-MSCs were isolated, cultured, and transfected with lentiviruses for the overexpression of hTIMP-1. An in vitro coculture system of hUC-MSCs and streptozotocin-induced islets was established to examine the morphology, apoptosis, and insulin secretion of the cocultured islets. Diabetic mouse models were injected with lenti-TIMP-1-enhanced green fluorescent protein (EGFP)-hUC-MSCs to test the effect of hTIMP-1 on insulin levels and glucose tolerance in vivo. The expression of insulin and glucagon was evaluated by immunofluorescence staining. The results showed that coculture with hUC-MSCs or Lenti-TIMP-1-EGFP-hUC-MSCs improved islet viability rates. Lenti-TIMP-1-EGFP-hUC-MSC coculture increased the insulin and C-peptide secretion function of the cultured islets and increased the secretion of tumor necrosis factor-β1, interleukin-6, IL-10, and hTIMP-1. hUC-MSCs, especially those transfected with Lenti-hTIMP-1-EGFP, showed a strong protective effect in diabetic mice by alleviating weight loss and improving glucose and insulin metabolism. In addition, transplantation rescued islet histology and function in vivo. The overexpression of TIMP-1 by hUC-MSCs seems to exert beneficial effects on pancreatic islet cells. In conclusion, this study may provide a new perspective on the development of hUC-MSC-based cell transplantation therapy for T1DM.