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OSKM-induced epithelial cells of mouse intestine [scRNA-seq]

ABSTRACT: Tissue regeneration after injury is thought to involve the dedifferentiation of somatic cells, which is often understood as evidence for natural adaptative reprogramming in vivo. In the intestinal epithelium, acute tissue damage triggers the rapid emergence of injury-responsive cells with fetal-like characteristics, a sign of dedifferentiation. However, there is no direct evidence that tissue regeneration involves a shared molecular mechanism with direct cellular reprogramming. It is also not known whether dedifferentiation shares a single (de)differentiation pathway or consists of multiple parallel routes between adult and fetal states. Here, we induced dedifferentiation of intestinal epithelial cells by forced partial reprogramming in vivo using the “Yamanaka factors” (Oct4, Sox2, Klf4 and c-Myc: OSKM). The induced dedifferentiation showed shared molecular features of intestinal regeneration, with rapid transition from homeostatic intestinal cell types to injury-responsive-like cells sharing a common gene signature of revival stem cells and atrophy-induced villus epithelial cells. When applied to intestinal organoids, induced dedifferentiation allowed the organoids to adopt fetal characteristics ex vivo, suggesting a direct effect on the intestinal epithelium. In vivo, induced dedifferentiation promoted regeneration from acute tissue injury caused by ionizing radiation (IR) via the formation of injury-responsive-like cells. Taken together, in the intestinal epithelium, in vivo reprogramming shares the same molecular pathway as damage-induced tissue regeneration and facilitates the repair process.

ORGANISM(S): Mus musculus

PROVIDER: GSE237173 | GEO | 2023/11/26

REPOSITORIES: GEO

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OSKM-induced mouse intestinal organoids [RNAseq_Dox]

Project description:Tissue regeneration after injury is thought to involve the dedifferentiation of somatic cells, which is often understood as evidence for natural adaptative reprogramming in vivo. In the intestinal epithelium, acute tissue damage triggers the rapid emergence of injury-responsive cells with fetal-like characteristics, a sign of dedifferentiation. However, there is no direct evidence that tissue regeneration involves a shared molecular mechanism with direct cellular reprogramming. It is also not known whether dedifferentiation shares a single (de)differentiation pathway or consists of multiple parallel routes between adult and fetal states. Here, we induced dedifferentiation of intestinal epithelial cells by forced partial reprogramming in vivo using the “Yamanaka factors” (Oct4, Sox2, Klf4 and c-Myc: OSKM). The induced dedifferentiation showed shared molecular features of intestinal regeneration, with rapid transition from homeostatic intestinal cell types to injury-responsive-like cells sharing a common gene signature of revival stem cells and atrophy-induced villus epithelial cells. When applied to intestinal organoids, induced dedifferentiation allowed the organoids to adopt fetal characteristics ex vivo, suggesting a direct effect on the intestinal epithelium. In vivo, induced dedifferentiation promoted regeneration from acute tissue injury caused by ionizing radiation (IR) via the formation of injury-responsive-like cells. Taken together, in the intestinal epithelium, in vivo reprogramming shares the same molecular pathway as damage-induced tissue regeneration and facilitates the repair process.

2023-11-26 | GSE237172 | GEO

Partial in vivo reprogramming enables injury-free intestinal regeneration via autonomous Ptgs1 induction [RNAseq_Fetal]

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2023-11-26 | GSE238056 | GEO

Partial in vivo reprogramming enables injury-free intestinal regeneration via autonomous Ptgs1 induction [RNAseq_IR]

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Smooth muscle-specific MMP17 (MT4-MMP) defines the intestinal ECM niche

Project description:Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle may have. Here, we show that smooth muscle is the dominant supplier of BMP antagonists, which are niche factors that are essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors can render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we provide evidence that MMP17 affects intestinal epithelial reprogramming indirectly by cleaving the matricellular protein PERIOSTIN, which itself is able to activate YAP. Together, we identify an important signaling axis that firmly establishes a role for smooth muscle as a modulator of intestinal epithelial regeneration and the intestinal stem cell niche.

2021-11-02 | PXD025770 | Pride

Smooth muscle-specific MMP17 (MT4-MMP) defines the intestinal ECM niche

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Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease

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Establishment of intestinal organoid cultures modeling injuryassociated epithelial regeneration [scRNA-seq]

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Establishment of intestinal organoid cultures modeling injuryassociated epithelial regeneration [ChIP-seq]

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BRB-seq data of murine intestinal organoids treated with 100ng/ml of Egf, Ereg or Nrg1 ligand for 24 h

Project description:Regeneration of the intestinal epithelium is a dynamic process requiring a transient Yap-dependent reprogramming of the epithelium into a fetal-like state. Adjacent stroma, including subepithelial fibroblasts, are believed to coordinate the process, but mechanisms are not well understood. Here, we identify Neuregulin 1 (NRG1) and Epiregulin (EREG) as fibroblast-derived EGF ligands in colon and intestine which are induced during regeneration and capable of supporting the growth of the intestinal epithelium. While EREG stimulated intestinal organoid growth similarly to EGF, NRG1 increased de novo crypt formation. The goal of this experiment was to observe the differences in gene expression profile of stromal-derived EGF ligands EREG and NRG1 on intestinal organoids compared to traditional used EGF. Organoids were derived from intestinal crypts of a WT mice C57BL/6J. To exclude the size differences observed in long term cultures of EREG and NRG1, we first cultured the organoids for three days in normal ENR media, removed exogenous EGF for 24h and added EGF, EREG or NRG1 to the culture medium for 24 hours prior to the RNA isolation. NRG1 treated organoids acquired a fetal/regenerative transcriptome including activation of the Yap pathway and induction of epithelial EGF ligand Ereg and Amphiregulin (Areg) expression, highlighting the dynamic orchestration of the EGF signaling during regeneration.

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