Recent studies have identified FoxL1⁺-telocytes (TC^FoxL1+) as key players in gut epithelial-mesenchymal interactions which can determine the colonic microenvironment. Bone morphogenetic protein signaling disruption in TC^FoxL1+ alters the physical and cellular microenvironment and leads to colon pathophysiology. This suggests a role for TC^FoxL1+ in stromagenesis, but it is hard to identify the specific contribution of TC^FoxL1+ when analyzing whole tissue profiling studies. We performed ex vivo deconstruction of control and BmpR1a^△FoxL1+ colon samples, isolated the mesenchyme-enriched fractions, and determined the protein composition of the in vivo extracellular matrix (ECM) to analyze microenvironment variation. Matrisomic analysis of mesenchyme fractions revealed modulations in ECM proteins with functions associated with innate immunity, epithelial wound healing, and the collagen network. These results show that TC^FoxL1+ is critical in orchestrating the biodynamics of the colon ECM. TC^FoxL1+ disfunction reprograms the gut's microenvironment and drives the intestinal epithelium toward colonic pathologies. SIGNIFICANCE: In this study, the method that was elected to isolate ECM proteins might not encompass the full extent of ECM proteins in a tissue, due to the protocol chosen, as this protocol by Naba et al., targets more the insoluble part of the matrisome and eliminates the more soluble components in the first steps. However, this ECM-enrichment strategy represents an improvement and interesting avenue to study ECM proteins in the colon compared to total tissue analysis with a background of abundant cellular protein. Thus, the matrisomic approach presented in this study, and its target validation delivered a broader evaluation of the matrix remodeling occurring in the colonic sub-epithelial mesenchyme of the BmpR1a^△FoxL1+ mouse model.

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