Proliferation maintains the undifferentiated status of stem cells: The role of the planarian cell cycle regulator Cdh1

The coincidence of cell cycle exit and differentiation has been described in a wide variety of stem cells and organisms for decades, but the causal relationship is still unclear due to the complicated regulation of the cell cycle. Here, we used the planarian Dugesia japonica since they may possess a simple cell cycle regulation in which Cdh1 is one of the factors responsible for exiting the cell cycle. When cdh1 was functionally inhibited, the planarians could not maintain their tissue homeostasis and could not regenerate their missing body parts. While the knockdown of cdh1 caused pronounced accumulation of the stem cells, the progenitor and differentiated cells were decreased. Further analyses indicated that the stem cells with cdh1 knockdown did not undergo differentiation even though they received ERK signaling activation as an induction signal. These results suggested that stem cells could not acquire differentiation competence without cell cycle exit. Thus, we propose that cell cycle regulation determines the differentiation competence and that cell cycle exit to G0 enables stem cells to undergo differentiation. [Display omitted] •As a homolog causing cell cycle exit, cdh1 was found but not CKIs in planarians.•The knockdown of cdh1 caused disruption of tissue homeostasis and regeneration.•The stem cells with cdh1 knockdown could not undergo differentiation.•Stem cells with cell cycle progression may persist their undifferentiated state.•Cell cycle exit to G0 may dictate stem cells to undergo differentiation.