Intrasplenic Transplantation of Islets with a Platelet Shielding System Restores Glycemic Control

Intraportal islet transplantation for treating insulin-dependent diabetes mellitus 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 a year. The spleen has oxygen levels that meet islet needs, but intense instant blood-mediated inflammatory reactions (IBMIR) 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 IBMIR due to the low expression of von Willebrand factor (vWF) 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 post-transplantation stress period, enabling rapid engraftment and vascularization in the spleen. The spleen's high-oxygen environment then supports long-term (over one 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 for islet transplantation and functional regeneration, demonstrating promising clinical potential.