Targeted Inhibition of MEGF10-Mediated Astrogliosis Reduces Glial Scar Formation and Promotes Neurofunction Recovery in Mice After Stroke.

Abstract

The formation of glial scar at the chronic stage of neurological disease is mainly attributed to the activation and proliferation of astrocytes, termed astrogliosis. It is documented that astrogliosis-induced glial scar formation following stroke severely impairs neurological recovery. However, the mechanisms underlying astrogliosis remain poorly understood. Herein, we discovered that knockdown of MEGF10, a well-known phagocytic receptor that mediates astrocyte-dependent synapse engulfment, caused G1 phase arrest in astrocytes and downregulated cell cycle-related genes, leading to reduced astrocyte proliferation and activation. Genetic deletion of MEGF10 in astrocytes reduced astrocyte proliferation and activation, glial scar formation, and extracellular matrix deposition, subsequentially decreased brain atrophy and promoted neurofunction recovery of mice after stroke. Leveraging on these findings, we further developed a clinically applicable lipid nanoparticle (LNP) system with good biocompatibility, capable of targeted delivery of MEGF10 siRNA to astrocytes. Injecting these LNPs effectively reduced astrocyte proliferation and activation, minimized glial scar formation, and enhanced neurobehavioral recovery of mice after stroke. Our study unveils a previously unrecognized role of MEGF10 in regulating astrogliosis and provides a clinically translatable strategy for targeted modulating glial scar formation and promoting neurofunction recovery after stroke, suggesting that targeting MEGF10 may represent a new therapeutic approach for treating stroke.