Abstract
BackgroundSexual dimorphism in biological responses is a critical knowledge for therapeutic proposals. However, gender differences in intestinal stem cell physiology have been poorly studied. Given the important role of the protease-activated receptor PAR2 in the control of colon epithelial primitive cells and cell cycle genes, we have performed a sex-based comparison of its expression and of the effects of PAR2 activation or knockout on cell proliferation and survival functions.MethodsEpithelial primitive cells isolated from colons from male and female mice were cultured as colonoids, and their number and size were measured. PAR2 activation was triggered by the addition of SLIGRL agonist peptide in the culture medium. PAR2-deficient mice were used to study the impact of PAR2 expression on colon epithelial cell culture and gene expression.ResultsColonoids from female mice were more abundant and larger compared to males, and these differences were further increased after PAR2 activation by specific PAR2 agonist peptide. The proliferation of male epithelial cells was lower compared to females but was specifically increased in PAR2 knockout male cells. PAR2 expression was higher in male colon cells compared to females and controlled the gene expression and activation of key negative signals of the primitive cell proliferation. This PAR2-dependent brake on the proliferation of male colon primitive cells was correlated with stress resistance.ConclusionsAltogether, these data demonstrate that there is a sexual dimorphism in the PAR2-dependent regulation of primitive cells of the colon crypt.
Highlights
Sexual dimorphism in biological responses is a critical knowledge for therapeutic proposals
Since we have previously shown that PAR2 plays a critical role in the control of intestinal stem cells (ISC) proliferation [7], we investigated the role of PAR2 in the proliferation of colon primitive cells from male and female mice
In agreement with our previous results, we measured a decrease in the number and size of colonoids from male mice treated by Altogether, these data show that the growth of colon primitive cells is sexually dimorphic and that PAR2 activation further increases this difference
Summary
Sexual dimorphism in biological responses is a critical knowledge for therapeutic proposals. Downstream of integrin engagement, Aktdependent pathways were shown to control the survival of male leukemic stem cells, whereas opposite GSK3βdependent pathways were required for females. This sexual dimorphism influenced stem cell clonogenicity capacities and resistance to chemotherapy [4]. The dependency on either GSK3 or Akt pathways was switched in normal adherent male and female hematopoietic stem cells, respectively. This indicates the occurrence of plasticity in these sex-related signaling pathways [4]
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