BMP pathway antagonism by Grem1 regulates epithelial cell fate in intestinal regeneration

Background and aims: In homeostasis, intestinal cell fate is controlled by balanced gradients of morphogen signalling. The Bone Morphogenetic Protein (BMP) pathway has a physiological, pro-differentiation role, predominantly inferred through previous experimental pathway inactivation. Intestinal regeneration is underpinned by dedifferentiation and cell plasticity, but the signalling pathways that regulate this adaptive reprogramming are not well understood. We assessed the BMP signalling landscape, and investigated the impact and therapeutic potential, of pathway manipulation in homeostasis and regeneration. Methods: A novel mouse model was generated to assess the effect of autocrine Bmp4 ligand on individual secretory cell fate. We spatiotemporally mapped BMP signalling in mouse and human regenerating intestine. Transgenic models were used to explore the functional impact of pathway manipulation on stem cell fate and intestinal regeneration. Results: In homeostasis, ligand exposure reduced proliferation, expedited terminal differentiation, abrogated secretory cell survival and prevented dedifferentiation. Following ulceration, physiological attenuation of BMP signalling arose through upregulation of the secreted antagonist, Grem1, from topographically distinct populations of fibroblasts. Concomitant expression supported functional compensation following Grem1 deletion from tissue-resident cells. 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. Conclusions: BMP signalling prevents epithelial de-differentiation, and pathway attenuation, through stromal Grem1 upregulation, was required for adaptive reprogramming in intestinal regeneration. This intercompartmental antagonism was functionally sub-maximal, raising the possibility of therapeutic pathway manipulation in Inflammatory Bowel Disease.</p