Surface Modification of Islets With L-DOPA-KF7 Enhances Islet Survival by Inhibiting IBMIR in Intrahepatic Islet Transplantation.

Abstract

Intrahepatic islet transplantation is followed by islet loss due to the instant blood-mediated inflammatory response (IBMIR) in which platelet activation plays a key role. The KEATSTF-fragment (KF7), a newly discovered platelet inhibitor that interferes with the formation of the 14-3-3ζ-c-Src-integrin-β3 complex, holds significant potential in inhibiting IBMIR without causing significant bleeding. This study introduces a novel surface modification technique using 3,4-dihydroxy-l-phenylalanine (L-DOPA) conjugated with KF7 to enhance the engraftment of transplanted islets in a syngeneic marginal mass model. KF7 loaded with L-DOPA (L-DOPA-KF7) formed a protective coating on the surface of islets without interfering with their viability and functionality. Islets coated with L-DOPA-KF7 restored normoglycemia in diabetic mice, and survival time was significantly longer compared with the control group. Transplantation of L-DOPA-KF7-coated islets was associated with reduced blood clot formation and decreased infiltration of CD11b+ cells and platelets. In conclusion, a composite L-DOPA-KF7 coating significantly prolongs the survival of transplanted islets by providing a robust IBMIR isolation barrier, thereby enhancing the overall success of islet transplantation in preclinical models. KEATSTF-fragment (KF7), an inhibitor of 14-3-3ζ-c-Src-integrin-β3 complex, effectively suppresses the instant blood-mediated inflammatory response by reducing thrombosis without increasing the risk of bleeding. The dopamine precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) can simply bind to the surface of islets without affecting cell viability or functionality, thus providing potential opportunities for clinical applications. A composite L-DOPA-KF7 coating effectively inhibited infiltration of platelets and CD11+ cells, thereby enhancing the efficacy of islet transplantation.