Intrasplenic Transplantation of Islets With a Platelet-Shielding System Restores Glycemic Control

Intraportal islet transplantation to treat insulin-dependent diabetes has been clinically validated. However, the hypoxic environment and sinusoidal architecture of the liver are unsuitable for the long-term survival of transplanted islets, leading to the loss of therapeutic effects within 1 year. The spleen has oxygen levels that meet islet needs, but intense instant blood-mediated inflammatory reactions (IBMIRs) and low extracellular matrix (ECM) concentrations hinder islet engraftment and survival. In this study, we developed constructs of islets encapsulated by hepatocytes and fibroblasts. The hepatocytes and fibroblasts create a protective coating that reduces IBMIRs because of the low expression of von Willebrand factor in hepatocytes and supports normal islet survival through ECM production by fibroblasts. These constructs can be easily injected into the mouse spleen. The hepatocyte–fibroblast encapsulation significantly reduces islet mortality during the posttransplantation stress period, enabling rapid engraftment and vascularization in the spleen. The high-oxygen environment of the spleen then supports long-term (>1 year) islet survival and sustained glycemic regulation. Additionally, this method significantly lowers the critical islet dose required for transplantation. The live cell–shielding strategy developed in this study represents a novel approach in islet transplantation and functional regeneration, demonstrating promising clinical potential. ARTICLE HIGHLIGHTS Instant blood-mediated inflammatory reactions (IBMIRs) and low extracellular matrix (ECM) concentrations hinder islet implantation and survival in the spleen. Islets were encapsulated in hepatocytes and fibroblasts. The low expression of von Willebrand factor in hepatocytes enables them to form a protective coating with fibroblasts. This coating reduces IBMIRs and supports islet survival through ECM production by fibroblasts. The hepatocyte–fibroblast encapsulation significantly reduces islet mortality during the posttransplantation stress period, enabling rapid engraftment and vascularization in the spleen.