Vascularization of PLGA-based bio-artificial beds by hypoxia-preconditioned mesenchymal stem cells for subcutaneous xenogeneic islet transplantation

Background: Subcutaneous tissue is an attractive extra-hepatic heterotopic site for islet transplantation; however, poor oxygen tension and blood supply during early engraftment of implanted islets have limited the use of this site in clinical applications. Methods: This study investigated the vascularization potential of hypoxia-preconditioned mesenchymal stem cells (3% O ₂ ; hypo-MSCs) in PLGA-based bio-artificial beds for subsequent subcutaneous islet transplantation. Sheet-typed polymeric PLGA scaffolds coated with hypo-MSCs or normo-MSCs (MSCs cultured under normoxia conditions, 21% O ₂ ) were implanted subcutaneously in mice. Results: Compared to normo-MSCs, hypo-MSCs significantly enhanced vasculogenesis, both on the interior and exterior surfaces of the implanted PLGA devices, which peaked 4 weeks after implantation. Further, infusion of porcine islets inside the prevascularized PLGA bed restored normal glycemic control in 6 of 6 STZ-induced diabetic mice. The mass of the marginal islet was approximately 2000 IEQs, which is comparable to that required for the renal subcapsular space, a highly vascularized site. Conclusions: Therefore, PLGA-based bio-artificial devices prevascularized with hypo-MSCs could be a useful modality for successful subcutaneous islet transplantation, which is of high clinical relevance.