YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration.
Larsen, Hjalte L
Rundsten, Carsten F
Johansen, Jens V
Schweiger, Pawel J
Cell stem cell
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Yui, S., Azzolin, L., Maimets, M., Pedersen, M. T., Fordham, R., Hansen, S. L., Larsen, H. L., et al. (2018). YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration.. Cell stem cell, 22 (1), 35-49.e7. https://doi.org/10.1016/j.stem.2017.11.001
Tissue regeneration requires dynamic cellular adaptation to the wound environment. It is currently unclear how this is orchestrated at the cellular level and how cell fate is affected by severe tissue damage. Here, we dissect cell fate transitions during colonic regeneration in a mouse DSS colitis model and demonstrate that the epithelium is transiently reprogrammed into a primitive state. This is characterized by de novo expression of fetal markers as well as suppression of markers for adult stem and differentiated cells. The fate change is orchestrated by remodeling the extracellular matrix (ECM), increased FAK/Src signaling and ultimately YAP/TAZ activation. In a defined cell culture system recapitulating the ECM remodeling observed in vivo, we show that a collagen 3D matrix supplemented with Wnt ligands is sufficient to sustain endogenous YAP/TAZ and induce conversion of cell fate. This provides a simple model for tissue regeneration, implicating cellular reprogramming as an essential element.
Intestinal Mucosa, Extracellular Matrix, Fetus, Animals, Mice, Inbred C57BL, Humans, Adaptor Proteins, Signal Transducing, Cell Cycle Proteins, Phosphoproteins, Regeneration, Signal Transduction, Mechanotransduction, Cellular, Transcription, Genetic, Transcriptional Activation, Cellular Reprogramming, Biomarkers
This work was supported by Worldwide Cancer Research (13-1216 to KBJ), Lundbeck Foundation (R105-A9755 to KBJ), the Danish Cancer Society (R56-A2907 and R124-A7724 to KBJ), the Carlsberg Foundation (to KBJ), EMBO Young Investigator programme (to KBJ), AIRC Special Program Molecular Clinical Oncology ‘‘5 per mille’’ (to SP), an AIRC PI-Grant (to SP), Epigenetics Flagship projects (CNR-Miur grants. to SP), the DFF mobilix programme (to SY), Marie Curie fellowship programme (SY and JG), Foundation of Aase and Ejnar Danielsen (OHN), Axel Muusfeldts Foundation (OHN), The Ragnar Söderberg Foundation (CDM). This project has received funding from the European Union’s Horizon 2020 research and innovation programme (grant agreements STEMHEALTH ERCCoG682665 and INTENS 668294 to KBJ and DENOVOSTEM No. 670126 to SP).
European Commission Horizon 2020 (H2020) Societal Challenges (668294-2 INTENS)
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External DOI: https://doi.org/10.1016/j.stem.2017.11.001
This record's URL: https://www.repository.cam.ac.uk/handle/1810/271769
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: http://creativecommons.org/licenses/by-nc-nd/4.0/
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