Hypoxia-Preconditioned Wharton’s Jelly-Derived Mesenchymal Stem Cells Mitigate Stress-Induced Apoptosis and Ameliorate Human Islet Survival and Function in Direct Contact Coculture System

Abstract

Protection of isolated pancreatic islets against hypoxic and oxidative damage-induced apoptosis is essential during a pretransplantation culture period. A beneficial approach to maintain viable and functional islets is the coculture period with mesenchymal stem cells (MSCs). Hypoxia preconditioning of MSCs (Hpc-MSCs) for a short time stimulates the expression and secretion of antiapoptotic, antioxidant, and prosurvival factors. The aim of the present study was to evaluate the survival and function of human islets cocultured with Hpc-MSCs. Wharton’s jelly-derived MSCs were subjected to hypoxia (5% O2: Hpc) or normoxia (20% O2: Nc) for 24 hours and then cocultured with isolated human islets in direct and indirect systems. Assays of viability and apoptosis, along with the production of reactive oxygen species (ROS), hypoxia-inducible factor 1-alpha (HIF-1α), apoptotic pathway markers, and vascular endothelial growth factor (VEGF) in the islets, were performed. Insulin and C-peptide secretions as islet function were also evaluated. Hpc-MSCs and Nc-MSCs significantly reduced the ROS production and HIF-1α protein aggregation, as well as downregulation of proapoptotic proteins and upregulation of antiapoptotic marker along with increment of VEGF secretion in the cocultured islet. However, the Hpc-MSCs groups were better than Nc-MSCs cocultured islets. Hpc-MSCs in both direct and indirect coculture systems improved the islet survival, while promotion of function was only significant in the direct cocultured cells. Hpc potentiated the cytoprotective and insulinotropic effects of MSCs on human islets through reducing stressful markers, inhibiting apoptosis pathway, enhancing prosurvival factors, and promoting insulin secretion, especially in direct coculture system, suggesting the effective strategy to ameliorate the islet quality for better transplantation outcomes.

Possible Underlying Mechanisms for the Renoprotective Effect of Retinoic Acid-Pretreated Wharton’s Jelly Mesenchymal Stem Cells against Renal Ischemia/Reperfusion Injury

“…Moreover, the antioxidant effect of the WJ-MSCs pretreated with ATRA was more potent than WJ-MSCs alone, suggesting that ATRA potentiates the antioxidant effect of WJ-MSCs in ischemic kidney tissues. Keshtkar et al [37] found that WJ-MSCs protected the kidney against ischemia-reperfusion injury by reducing oxidative and endoplasmic reticulum stresses via activation of hypoxiainducible factor-1 α (HIF-1α), so in the current study we investigated the effect of WJ-MSCs and its combination with ATRA on the expression of HIF-1α. HIF-1α plays a critical role in cellular oxygen homeostasis and mitochondrial respiration and protects the kidney against cisplatin-induced tubular cell apoptosis and oxidative stress.…”

Immune Protection of Stem Cell-Derived Islet Cell Therapy for Treating Diabetes

“…This stress-induced resistance induction may not only be beneficial by direct exposure, but also beneficial by indirect exposure to co-cultured cells. Hypoxia-preconditioned mesenchymal stem cells or primary hepatocytes were shown to significantly reduce reactive oxygen species (ROS) production and induce pro-apoptotic proteins, such as Bcl-2, to improve islet survival when co-cultured with human islets ( 147 , 148 ). Alternatively, pancreatic islets can be directly preconditioned via strategic drug delivery.…”