Addressing bioenergetic deficits and restoring mitochondrial health in transplanted islets using mesenchymal stem cells.

During the process of islet transplantation, islets undergo isolation and are then introduced into a new microenvironment where they need to adapt and revascularize. This transition imposes substantial stress on islets, leading to mitochondrial dysfunction and oxidative stress, adversely affecting islet function and vitality. Mesenchymal stem cells (MSCs) offer a promising therapy to mitigate these adverse effects by restoring their bioenergetic capacity and overall functionality of islets. Our study investigates how human MSCs (hMSCs) from different sources-adipose tissue (AD), bone marrow (BM), and umbilical cord (UC)-can restore the bioenergetic capacity of inflamed pancreatic islets. We assess how hMSCs can improve islet survival, function, and mitochondrial health, by analyzing key mitochondrial oxidative stress-related genes. In addition, this study examines the functional effect of co-transplanting islets with hMSCs in vivo in diabetic mice. hMSCs, particularly those from UC and BM, can effectively sustain islet viability, enhance mitochondrial function, and alleviate oxidative stress, as evidenced by increased expression of key mitochondrial markers such as PPARGC1A, TOMM20, and Sod2. Furthermore, co-transplantation of hMSCs with sub-therapeutic islet numbers leads to long-term improvements in glucose regulation, with UC-hMSCs showing better short-term efficacy (100% of diabetic mice receiving islets with UC-hMSCs recovered their blood glucose levels back to normal at 4 weeks post-transplantation, vs. 80% of those transplanted with BM-hMSCs, 60% with AD-hMSCs, and 16% for islets alone). These findings highlight the potential of hMSC-therapies for islet transplantation, underscoring the need to select the optimal MSC source to maximize the therapeutic outcome of transplanted islets.