De novo generation of somatic stem cells by YAP
We recently reported that expression of YAP into terminally differentiated cells explanted from distinct tissues induces cells with functional and molecular attributes of their corresponding tissue-specific stem cells (SCs) that can be expanded ex-vivo (Panciera et al., 2016). We dubbed these cells as YAP-induced SCs, or ySCs. Differentiated mammary gland, neuronal, and pancreatic exocrine cells (see Figure), identified using a combination of cell sorting and lineage tracing approaches, efficiently convert to proliferating cells with properties of stem/progenitor cells of their respective tissues after YAP induction. YAP-induced mammary stem/progenitor cells show molecular and functional properties similar to endogenous MaSCs, including organoid formation and mammary gland reconstitution after transplantation. The ySC state can be transmitted through cell generations without need of continuous expression of ectopic YAP/TAZ, indicating that a transient activation of ectopic YAP or TAZ is sufficient to induce a heritable self-renewing state. Differently from iPSCs or other reprogramming efforts, ySCs preserve memory of the tissue of origin, expanding the current reprogramming paradigms by focusing on somatic stem cell generation from related cells of the same lineage. As YAP/TAZ function is also important for self-renewal of endogenous stem cells in culture, our findings have implications for understanding the molecular determinants of the somatic stem cell state, of physiological cell plasticity and for regenerative medicine applications.
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