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Dynamic Reprogramming of Stromal Pdgfra-expressing cells during WNT-Mediated Transformation of the Intestinal Epithelium - Figure 3J

ABSTRACT: Stromal fibroblasts of the mesenchyme regulate critical signaling gradients along the crypt-villus axis1 and provide a niche that supports intestinal stem cells in the intestine. Here we report that Pdgfra-expressing fibroblasts secrete ligands that promote a fetal-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Using a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations, we revealed a dynamic reprogramming of Pdgfra+ fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFB signaling is notably induced in Pdgfra+ fibroblasts in the presence of oncogenic epithelium, and TGFB was essential to sustain fetal-like growth of organoids ex vivo. Genetic reduction of Cdx2 in the β-catenin mutant epithelium elevated the fetal-like transcriptome and accelerated WNT-dependent onset of oncogenic transformation of the tissue in vivo. These results demonstrate that Pdgfra+ fibroblasts are activated during WNT-driven oncogenesis to promote a fetal-like state in the epithelium that precedes and facilitates formation of tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE289318 | GEO | 2026/02/19

REPOSITORIES: GEO

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Project description:During organogenesis of the intestine, reciprocal crosstalk between the endodermally-derived epithelium and the underlying mesenchyme is required for regional patterning and proper differentiation. Though both of these tissue layers participate in patterning, the mesenchyme is thought to play a prominant role in the determination of epithelial phenotype during development and in adult life. However, the molecular basis of this instructional dominance is unclear. In fact, surprisingly little is known about the cellular origins of many of the critical signaling molecules and the gene transcriptional events that they impact. Here, we profile genes that are expressed in separated mesenchymal and epithelial compartments of the perinatal mouse intestine. The data indicate that the vast majority of soluble modulators of signaling pathways such as Hedgehog, Bmp, Wnt, Fgf and Igf are expressed predominantly or exclusively by the mesenchyme, accounting for its ability to dominate instructional crosstalk. We also catalog the most highly enriched transcription factors in both compartments and find evidence for a major role for Hnf4alpha and Hnf4 gamma in the regulation of epithelial genes. Finally, we find that while epithelially enriched genes tend to be highly tissue-restricted in their expression, mesenchymally-enriched genes tend to be broadly expressed in multiple tissues. Thus, the unique tissue-specific signature that characterizes the intestinal epithelium is instructed and supported by a mesenchyme that itself expresses genes that are largely non-tissue specific. Experiment Overall Design: Mouse small intestine (E18.5) is separated to epithelium and mesenchyme. Total RNA is extracted from epithelium and mesenchyme. There are 6 samples in this microarray experiment: 3 for epithelium and 3 for mesenchyme. Samples are hybridized the affymetrix Mouse Genome 430 2.0 Array. We compare the gene expression between epithelium and mesenchyme to study the gene expression profiles in these two compartments.

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Dynamic Reprogramming of Stromal Pdgfra-expressing cells during WNT-Mediated Transformation of the Intestinal Epithelium - Figure 3J

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