CD133 (prominin 1) is widely viewed as a cancer stem cell marker in association with drug resistance and cancer recurrence. Herein, we report that with impaired RTK-Shp2-Ras-Erk signaling, heterogenous hepatocytes form clusters that manage to divide during mouse liver regeneration. These hepatocytes are characterized by upregulated CD133 while negative for other progenitor cell markers. Pharmaceutical inhibition of proliferative signaling also induced CD133 expression in various cancer cell types from multiple animal species, suggesting an inherent and common mechanism of stress response. Super-resolution and electron microscopy localize CD133 on intracellular vesicles that apparently migrate between cells, which we name 'intercellsome.' Isolated CD133+ intercellsomes are enriched with mRNAs rather than miRNAs. Single-cell RNA sequencing reveals lower intracellular diversity (entropy) of mitogenic mRNAs in Shp2-deficient cells, which may be remedied by intercellular mRNA exchanges between CD133+ cells. CD133-deficient cells are more sensitive to proliferative signal inhibition in livers and intestinal organoids. These data suggest a mechanism of intercellular communication to compensate for intracellular signal deficit in various cell types.
Keywords: CD133; Liver regeneration; Shp2/Ptpn11; cancer biology; cell biology; drug resistance; human; intercellular communication; mouse; vesicle trafficking.
The liver is an important metabolic organ that is responsible for digesting nutrients. Over time, it can become damaged by the toxins it receives from food and drink, as well as during infections. Thankfully, cells in the liver can divide and replace the parts that have become harmed allowing the organ to continue carrying out its vital role in the body. Experiments in mice have identified various genes and proteins involved in regenerating the liver. This includes the protein Shp2 which instructs liver cells to divide. However, scientists have found mice lacking the gene for Shp2 could still repair their livers. But how exactly these genetically modified mice were able to do this remained unclear. To investigate, Kaneko et al. examined the shape and size of cells in the livers of mice lacking Shp2. This revealed clusters of dividing cells that could still repair the liver that contained abundant amounts of a protein called CD133. The CD133 molecules resided in very small vesicles about 50 to 150 nm in width which Kaneko et al. named ‘intercellsomes’ because they could move from one liver cell to the next. Further experiments revealed that the intercellsomes contained important materials essential for cell division, making them distinct from other well-known vesicles. These newly discovered structures may allow liver cells to share replication signals with other cells that may be struggling to divide during liver regeneration. CD133 is also present in cancer cells that are resistant to treatment and can multiply under stress. Kaneko et al. found that treating various types of tumor cells with drugs that inhibit proliferation led to an increase in CD133. This suggests that some cancer cells may use the intercellsome mechanism to keep dividing following treatment, potentially resulting in a relapse of the malignant disease. Taken together, this study hints at the existence of a previously unknown communication system that helps cells to divide when their replication is inhibited. Further experiments are needed to see if this mechanism is widely employed by various cell types, how exactly the CD133 vesicles migrate between cells, and if intercellsomes carry out any other roles.
© 2023, Kaneko et al.