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Cell Stem Cell. 2018 Jan 4;22(1):35-49.e7. doi: 10.1016/j.stem.2017.11.001. Epub 2017 Dec 14.

YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration.

Author information

1
BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen N, Denmark.
2
Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy.
3
Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
4
Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark.
5
Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University, 223 81 Lund, Sweden.
6
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo 113-8519, Japan.
7
Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy. Electronic address: piccolo@biouni.pd.it.
8
BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen N, Denmark; Novo Nordisk Foundation Center for Stem Cell Research, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark. Electronic address: kim.jensen@bric.ku.dk.

Abstract

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 dextran sulfate sodium (DSS) colitis model, and we 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 extracellular matrix 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.

KEYWORDS:

YAP/TAZ; intestinal stem cells; mechano-sensing; regeneration; reprogramming

PMID:
29249464
PMCID:
PMC5766831
DOI:
10.1016/j.stem.2017.11.001
[Indexed for MEDLINE]
Free PMC Article

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