Bone Morphogenetic Protein Pathway Antagonism by Grem1 Regulates Epithelial Cell Fate in Intestinal Regeneration

BACKGROUND & AIMS In homeostasis, intestinal cell fate is controlled by balanced gradients of morphogen signaling. The bone morphogenetic protein (BMP) pathway has a physiological, prodifferentiation role, predominantly inferred through previous experimental pathway inactivation. Intestinal regeneration is underpinned by dedifferentiation and cell plasticity, but the signaling pathways that regulate this adaptive reprogramming are not well understood. We assessed the BMP signaling 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 the autocrine Bmp4 ligand on individual secretory cell fate. We spatiotemporally mapped BMP signaling 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. After ulceration, physiological attenuation of BMP signaling arose through upregulation of the secreted antagonist Grem1 from topographically distinct populations of fibroblasts. Concomitant expression supported functional compensation after Grem1 deletion from tissue-resident cells. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory but functionally submaximal, because 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 remodeled wounds. CONCLUSIONS BMP signaling prevents epithelial dedifferentiation, and pathway attenuation through stromal Grem1 upregulation was required for adaptive reprogramming in intestinal regeneration. This intercompartmental antagonism was functionally submaximal, raising the possibility of therapeutic pathway manipulation in inflammatory bowel disease

Gustatory evoked potentials and cerebral control of food intake in obese subjects (PEGASE study)

National audienc

Extracellular matrix orchestration of tissue remodelling in the chronically inflamed mouse colon

Background & Aims: Chronic inflammatory illnesses are debilitating and recurrent conditions associated with significant co-morbidities, including an increased risk of developing cancer. Extensive tissue remodelling is a hallmark of such illnesses, and is both a consequence and a mediator of disease progression. Despite previous characterisation of epithelial and stromal remodelling during Inflammatory Bowel Disease, a complete understanding of its impact on disease progression is still lacking. Methods: A comprehensive proteomic pipeline using data-independent acquisition was applied to decellularized colon samples from the Muc2KO mouse model of colitis, for an in- depth characterisation of extracellular matrix remodelling. Unique proteomic profiles of the matrisomal landscape were extracted from pre- and pathological colitis. Integration of proteomics and transcriptomics datasets extracted from the same murine model produced network maps describing the orchestrating role of matrisomal proteins in tissue remodelling during the progression of colitis. Results: The in-depth proteomic workflow used here allowed the addition of 34 proteins to the known colon matrisomal signature. Protein signatures of pre- and pathological colitic states were extracted, differentiating the two states by expression of small leucine rich proteoglycans. We outlined the role of this class and other matrisomal proteins in tissue remodelling during colitis, as well as the potential for co-ordinated regulation of cell types by matrisomal ligands. Conclusion: Our work highlights a central role for matrisomal proteins in tissue remodelling during colitis and defines orchestrating nodes that can be exploited in selection of therapeutic targets