RT Journal Article SR Electronic T1 BMP pathway antagonism by Grem1 regulates epithelial cell fate in intestinal regeneration JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.01.06.425570 DO 10.1101/2021.01.06.425570 A1 Martijn AJ Koppens A1 Hayley Davis A1 Gabriel N Valbuena A1 Eoghan J Mulholland A1 Nadia Nasreddin A1 Mathilde Colombe A1 Agne Antanaviciute A1 Sujata Biswas A1 Matthias Friedrich A1 Lennard Lee A1 Oxford IBD cohort investigators A1 Lai Mun Wang A1 Viktor H Koelzer A1 James E East A1 Alison Simmons A1 Douglas J Winton A1 Simon J Leedham YR 2021 UL http://biorxiv.org/content/early/2021/01/07/2021.01.06.425570.abstract 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.