Intercellular Communication Compensates Intracellular Proliferative Signal Deficit during Liver Regeneration

Abstract

AbstractIt remains to be determined how cells strive to proliferate under proliferative signal deficit. Herein we report that with impaired RTK-Shp2-Ras-Erk signaling, heterogenous hepatocytes formed clusters to divide during liver regeneration. These hepatocytes were characterized by upregulated CD133 while negative for other progenitor cell markers. Pharmaceutical inhibition of proliferative signaling also induced CD133 expression in various cell types, suggesting a common mechanism of stress response. Super-resolution and electron microscopy localized CD133 on intracellular vesicles that apparently migrate between cells. Isolated CD133+vesicles were enriched with mitogenic mRNAs rather than miRNAs. Single-cell RNA sequencing revealed lower intracellular diversity (entropy) of mitogenic mRNAs in Shp2-deficient cells, which could be remedied by intercellular mRNA exchanges between CD133+cells. CD133-deficient cells were more sensitive to proliferative signal inhibition in livers and intestinal organoids. These data suggest a mechanism of intercellular communication to offset intracellular signal deficit in hepatocytes and other cell types.