4.6 Article

Prenatal stress induces changes in PAR2-and M3-dependent regulation of colon primitive cells

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00061.2022

Keywords

intestinal stem cells; M3; PAR2; prenatal stress; sexual dimorphism

Funding

  1. Agence Nationale de la Recherche (ANR)
  2. region Occitanie
  3. Bettencourt-Schueller Foundation
  4. Fondation pour la Recherche Medicale (FRM)
  5. Region Occitanie PyreneesMediterranee

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Prenatal stress negatively impacts the proliferation and differentiation of intestinal stem cells and progenitors. This effect is mediated by the activation of protease-activated receptor 2 (PAR2) and muscarinic receptor 3 (M3) in a sexually dimorphic manner. In males, prenatal stress reinforces the negative control on cell proliferation and differentiation, while in females, it induces a switch in regulation leading to a resistant and proliferative phenotype of progenitors.
Prenatal stress is associated with a high risk of developing adult intestinal pathologies, such as irritable bowel syndrome, chronic inflammation, and cancer. Although epithelial stem cells and progenitors have been implicated in intestinal pathophysiology, how prenatal stress could impact their functions is still unknown. We have investigated the proliferative and differentiation capacities of primitive cells using epithelial crypts isolated from colons of adult male and female mice whose mothers have been stressed during late gestation. Our results show that stem cell/progenitor proliferation and differentiation in vitro are negatively impacted by prenatal stress in male progeny. This is promoted by a reinforcement of the negative proliferative/differentiation control by the protease-activated receptor 2 (PAR2) and the muscarinic receptor 3 (M3), two G protein-coupled receptors present in the crypt. Conversely, prenatal stress does not change in vitro proliferation of colon primitive cells in female progeny. Importantly, this maintenance is associated with a functional switch in the M3 negative control of colonoid growth, becoming proliferative after prenatal stress. In addition, the proliferative role of PAR2 specific to females is maintained under prenatal stress, even though PAR2-targeted stress signals Dusp6 and activated GSK3 beta are increased, reaching the levels of males. An epithelial serine protease could play a critical role in the activation of the survival kinase GSK3 beta in colonoids from prenatally stressed female progeny. Altogether, our results show that following prenatal stress, colon primitive cells cope with stress through sexually dimorphic mechanisms that could pave the way to dysregulated crypt regeneration and intestinal pathologies. NEW & NOTEWORTHY Primitive cells isolated from mouse colon following prenatal stress and exposed to additional stress conditions such as in vitro culture, present sexually dimorphic mechanisms based on PAR2- and M3-dependent regulation of proliferation and differentiation. Whereas prenatal stress reinforces the physiological negative control exerted by PAR2 and M3 in crypts from males, in females, it induces a switch in M3- and PAR2-dependent regulation leading to a resistant and proliferative phenotype of progenitor.

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