Mesenchymal stem cells protect islets from hypoxia/reoxygenation‐induced injury

Abstract

Hypoxia/reoxygenation (H/R)-induced injury is the key factor associated with islet graft dysfunction. This study aims to examine the effect of mesenchymal stem cells (MSCs) on islet survival and insulin secretion under H/R conditions. Islets from rats were isolated, purified, cultured with or without MSCs, and exposed to hypoxia (O(2) ≤ 1%) for 8 h and reoxygenation for 24 and 48 h, respectively. Islet function was evaluated by measuring basal and glucose-stimulated insulin secretion (GSIS). Apoptotic islet cells were quantified using Annexin V-FITC. Anti-apoptotic effects were confirmed by mRNA expression analysis of hypoxia-resistant molecules, HIF-1α, HO-1, and COX-2, using semi-quantitative retrieval polymerase chain reaction (RT-PCR). Insulin expression in the implanted islets was detected by immunohistological analysis. The main results show that the stimulation index (SI) of GSIS was maintained at higher levels in islets co-cultured with MSCs. The MSCs protected the islets from H/R-induced injury by decreasing the apoptotic cell ratio and increasing HIF-1α, HO-1, and COX-2 mRNA expression. Seven days after islet transplantation, insulin expression in the MSC-islets group significantly differed from that of the islets-alone group. We proposed that MSCs could promote anti-apoptotic gene expression by enhancing their resistance to H/R-induced apoptosis and dysfunction. This study provides an experimental basis for therapeutic strategies based on enhancing islet function.

Harnessing the Immunomodulatory and Tissue Repair Properties of Mesenchymal Stem Cells to Restore β Cell Function

“…[78] Freshly isolated islets were susceptible to β cell loss from apoptosis, but when co-cultured with cord-blood derived MSCs, these islets showed improved viability and function. [79] This enhanced viability and function was due to anti-apoptotic proteins and active trophic agents secreted by the MSCs, [79] such as HO-1,[80] IL-6, hepatocyte growth factor (HGF), and SDF-1. [62, 79] IL-6 may induce expression of β cell anti-apoptotic signaling molecules Bcl-2 and Bcl-xL.…”

Stem Cells as a Tool to Improve Outcomes of Islet Transplantation

“…In an in vitro model of islet hypoxia and reoxygenation, rat islets cocultured with bone marrow MSCs had increased expression of protective hypoxia-induced genes, along with decreased apoptotic rates, and improved glucose-stimulated insulin secretion when compared to islets cultured alone [46]. Cocultured islets also had an increased ATP/ADP ratio leading to improved glucose-stimulated insulin release [42, 47, 79].…”

Current Status of Immunomodulatory and Cellular Therapies in Preclinical and Clinical Islet Transplantation

“…Superior vascular engraftment as shown by increased EC numbers within the endocrine tissue as well as improved graft function demonstrated by normoglycemia achieved in 92% of mice indicated that MSCs profoundly influenced the remodeling process, by improving islet revascularization and maintaining islet organisation [224, 225]. In order to study the effect of MSCs on islet survival and insulin secretion under hypoxia/reoxygenation- (H/R-) induced injury conditions that are associated with islet graft dysfunction, purified rat islets cultured with or without MSCs, were exposed to hypoxia (O(2) ≤ 1%) for 8 h followed by reoxygenation for 24 and 48 h, respectively [226]. MSCs maintained a higher level of stimulation index (SI) of GSIS in islets in vitro , protected islets from H/R-induced injury by decreasing the apoptotic cell ratio and increasing HIF-1 α , HO-1, and COX-2 mRNA expression, and significantly increased insulin expression following islet transplantation.…”