PT  - JOURNAL ARTICLE
AU  - Martijn AJ Koppens
AU  - Hayley Davis
AU  - Gabriel N Valbuena
AU  - Eoghan J Mulholland
AU  - Nadia Nasreddin
AU  - Mathilde Colombe
AU  - Agne Antanaviciute
AU  - Sujata Biswas
AU  - Matthias Friedrich
AU  - Lennard Lee
AU  - Oxford IBD cohort investigators
AU  - Lai Mun Wang
AU  - Viktor H Koelzer
AU  - James E East
AU  - Alison Simmons
AU  - Douglas J Winton
AU  - Simon J Leedham
TI  - BMP pathway antagonism by <em>Grem1</em> regulates epithelial cell fate in intestinal regeneration
AID  - 10.1101/2021.01.06.425570
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.06.425570
4099  - http://biorxiv.org/content/early/2021/01/07/2021.01.06.425570.short
4100  - http://biorxiv.org/content/early/2021/01/07/2021.01.06.425570.full
AB  - In the intestine, the homeostatic effect of Bone Morphogenetic Protein (BMP) on cell fate has predominantly been inferred through pathway inactivation. Here, we assessed the impact of autocrine Bmp4 expression on secretory cell fate. Ligand exposure reduced proliferation, expedited terminal differentiation, abrogated long-term secretory cell survival and prevented dedifferentiation. As stem cell plasticity is required for regenerative adaptive reprogramming, we spatiotemporally mapped and functionally explored BMP’s role in epithelial restitution. Following ulceration, physiological attenuation of BMP signalling arose through upregulation of the secreted antagonist, Grem1, from topographically distinct populations of stromal cells. Concomitant expression supported functional compensation, following Grem1 deletion from tissue-resident fibroblasts. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory, but functionally sub-maximal, as regeneration was impaired or enhanced by epithelial overexpression of Bmp4 or Grem1 respectively. Mechanistically, Bmp4 abrogated regenerative stem cell reprogramming, despite a convergent impact of YAP/TAZ on cell fate in remodelled wounds.Competing Interest StatementSJL has received grant income from UCB. VHK has served as an invited speaker on behalf of Indica Labs.