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

ABSTRACT: Tissue regeneration after injury involves the dedifferentiation of somatic cells, a natural adaptive reprogramming that leads to the emergence of injury-responsive cells with fetal-like characteristics. However, there is no direct evidence that adaptive reprogramming involves a shared molecular mechanism with direct cellular reprogramming. Here, we induced dedifferentiation of intestinal epithelial cells using OSKM (Oct4, Sox2, Klf4, and c-Myc) in vivo. The OSKM-induced forced dedifferentiation showed similar molecular features of intestinal regeneration, including a transition from homeostatic cell types to injury-responsive-like cell types. These injury-responsive-like cells, sharing gene signatures of revival stem cells and atrophy-induced villus epithelial cells, actively assisted tissue regeneration following damage. In contrast to normal intestinal regeneration involving Ptgs2 induction, the OSKM promotes autonomous production of prostaglandin E2 via epithelial Ptgs1 expression. These results indicate prostaglandin synthesis is a common mechanism for intestinal regeneration, but involves a different enzyme when partial reprogramming is applied to the intestinal epithelium.

ORGANISM(S): Mus musculus

PROVIDER: GSE238055 | GEO | 2023/11/26

REPOSITORIES: GEO

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

Project description:Tissue regeneration after injury involves the dedifferentiation of somatic cells, a natural adaptive reprogramming that leads to the emergence of injury-responsive cells with fetal-like characteristics. However, there is no direct evidence that adaptive reprogramming involves a shared molecular mechanism with direct cellular reprogramming. Here, we induced dedifferentiation of intestinal epithelial cells using OSKM (Oct4, Sox2, Klf4, and c-Myc) in vivo. The OSKM-induced forced dedifferentiation showed similar molecular features of intestinal regeneration, including a transition from homeostatic cell types to injury-responsive-like cell types. These injury-responsive-like cells, sharing gene signatures of revival stem cells and atrophy-induced villus epithelial cells, actively assisted tissue regeneration following damage. In contrast to normal intestinal regeneration involving Ptgs2 induction, the OSKM promotes autonomous production of prostaglandin E2 via epithelial Ptgs1 expression. These results indicate prostaglandin synthesis is a common mechanism for intestinal regeneration, but involves a different enzyme when partial reprogramming is applied to the intestinal epithelium.

2023-11-26 | GSE238056 | GEO

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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.

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

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