Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle

TLDR

Transplanting pancreatic islets into the liver for type 1 diabetes often fails long‑term due to poor revascularization. The study aimed to assess striated muscle as an angiogenic site for islet transplantation and to develop a clinically applicable experimental model. Islets were implanted into mouse and human muscle, with revascularization assessed by intravital/confocal microscopy and MRI, while neutropenic mice received alloxan‑induced diabetes. Muscle‑engrafted islets revascularized comparably to native pancreas, required neutrophils, restored function and cured diabetic mice, and similar perfusion was observed in autotransplanted patients.

Abstract

Curing type 1 diabetes by transplanting pancreatic islets into the liver is associated with poor long-term outcome and graft failure at least partly due to inadequate graft revascularization. The aim of the current study was to evaluate striated muscle as a potential angiogenic site for islet transplantation.The current study presents a new experimental model that is found to be applicable to clinical islet transplantation. Islets were implanted into striated muscle and intraislet vascular density and blood flow were visualized with intravital and confocal microscopy in mice and by magnetic resonance imaging in three autotransplanted pancreatectomized patients. Mice were rendered neutropenic by repeated injections of Gr-1 antibody, and diabetes was induced by alloxan treatment.Contrary to liver-engrafted islets, islets transplanted to mouse muscle were revascularized with vessel densities and blood flow entirely comparable with those of islets within intact pancreas. Initiation of islet revascularization at the muscular site was dependent on neutrophils, and the function of islets transplanted to muscle was proven by curing diabetic mice. The experimental data were confirmed in autotransplanted patients where higher plasma volumes were measured in islets engrafted in forearm muscle compared with adjacent muscle tissue through high-resolution magnetic resonance imaging.This study presents a novel paradigm in islet transplantation whereby recruited neutrophils are crucial for the functionally restored intraislet blood perfusion following transplantation to striated muscle under experimental and clinical situations.