CD133+ Intercellsome Mediates Direct Cell-Cell Communication to Offset Intracellular Signal Deficit

CD133 (prominin 1) is widely viewed as a cancer stem cell marker, in association with drug resistance and cancer recurrence. Herein we report that in response to defective RTK-Shp2-Ras-Erk signaling, heterogeneous hepatocytes with upregulated CD133 clustered to proliferate during liver regeneration. Similarly, pharmaceutical inhibition of proliferative signaling induced CD133 expression transiently in various cancer cell types of different tissue origins, indicating an inherent mechanism of drug resistance. Although previously known as a cell surface protein, super-resolution and electron microscopy localized CD133 mainly on intracellular vesicles trafficking between cells directly, which we name “intercellsome”. Overexpression of CD133 altered trafficking and morphology of intercellsomes, and isolated CD133+ intercellsomes were enriched with immediate early gene (IEG) transcripts. Single-cell RNA sequencing revealed lower intracellular diversity (entropy) of IEG transcripts in proliferative signal-deficient cells, which was 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 identify a long-sought CD133 function and a new mechanism of intercellular communication for cell proliferation under stress in healthy and cancer cells. ### Competing Interest Statement The authors have declared no competing interest.