Sexual dimorphism in PAR2-dependent regulation of primitive colonic cells

Noguerol, Julie; Roustan, Pierre-Jean; N’Taye, Mikael; Delcombel, Léo; Rolland, Corinne; Guiraud, Laura; Sagnat, David; Edir, Anissa; Bonnart, Chrystelle; Denadai‐Souza, Alexandre; Deraison, Céline; Vergnolle, Nathalie; Racaud‐Sultan, Claire

doi:10.1186/s13293-019-0262-6

Cited by 5 publications

(14 citation statements)

References 32 publications

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“…Importantly, as for hematopoietic stem cells, a sexual dimorphism in PAR 2 -dependent GSK3β activation in colon stem cells has been observed [ 47 ]. The PAR 2 /GSK3β pathway has been triggered in colon progenitors from male mice, whereas females have displayed a PAR 2 /AKT pathway.…”

Section: Gsk3β In the Colon Crypt: Role And Controls By Proteases mentioning

confidence: 99%

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Racaud‐Sultan

Vergnolle

2021

Cells

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In adult stem cells, Glycogen Synthase Kinase 3β (GSK3β) is at the crossroad of signaling pathways controlling survival, proliferation, adhesion and differentiation. The microenvironment plays a key role in the regulation of these cell functions and we have demonstrated that the GSK3β activity is strongly dependent on the engagement of integrins and protease-activated receptors (PARs). Downstream of the integrin α5β1 or PAR2 activation, a molecular complex is organized around the scaffolding proteins RACK1 and β-arrestin-2 respectively, containing the phosphatase PP2A responsible for GSK3β activation. As a consequence, a quiescent stem cell phenotype is established with high capacities to face apoptotic and metabolic stresses. A protective role of GSK3β has been found for hematopoietic and intestinal stem cells. Latters survived to de-adhesion through PAR2 activation, whereas formers were protected from cytotoxicity through α5β1 engagement. However, a prolonged activation of GSK3β promoted a defect in epithelial regeneration and a resistance to chemotherapy of leukemic cells, paving the way to chronic inflammatory diseases and to cancer resurgence, respectively. In both cases, a sexual dimorphism was measured in GSK3β-dependent cellular functions. GSK3β activity is a key marker for inflammatory and cancer diseases allowing adjusted therapy to sex, age and metabolic status of patients.

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Section: Gsk3β In the Colon Crypt: Role And Controls By Proteases mentioning

confidence: 99%

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Racaud‐Sultan

Vergnolle

2021

Cells

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“…All pharmacological tools were added to the colonoids every 2 days from D0 of the culture. Note that our previous ( 9 , 21 ) or preliminary experiments have shown that the control peptide with reversed sequence of SLIGRL and final concentration of DMSO (1 × 10 −4 %) did not modify colonoid growth/survival.…”

Section: Methodsmentioning

confidence: 77%

“…Due to the roles of PAR2 and GSK3β in the control of proliferation and differentiation of colon primitive cells ( 9 , 21 , 25 ), we have investigated the gene expression of a panel of factors implicated in these functions and potentially linked to a PAR2-dependent regulation. Under PS (Stress), the expression of Muc2 and Chga (but not Ngn3 and Dclk1 ) was downregulated, arguing in favor of a reinforcement of the GSK3β-dependent anti-secretory pathway ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Berger

Guiraud

Dumas

et al. 2022

American Journal of Physiology-Gastrointestinal and Liver Physi

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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 following prenatal stress. Additionally, the proliferative role of PAR2 specific to females is maintained under prenatal stress, even though PAR2-targeted stress signals Dusp6 and activated GSK3β are increased, reaching the levels of males. An epithelial serine protease could play a critical role in the activation of the survival kinase GSK3β 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.

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“…PAR2 expression was higher in db/db compared to that in db + mice. PAR2 controls and activates critical negative signaling molecule gene expressions involved in primitive cell proliferation [ 42 ]. In addition, PAR2 signaling activation exerts a pivotal role in hepatic insulin resistance that subsequently leads to systemic steatosis in obesity [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Lipid Accumulation through PAR2 Signaling in Diabetic Male Mice

Kim

Bang

et al. 2021

Endocrinol Metab

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Background Protease-activated protein-2 (PAR2) has been reported to regulate hepatic insulin resistance condition in type 2 diabetes mice. However, the mechanism of lipid metabolism through PAR2 in obesity mice have not yet been examined. In liver, Forkhead box O1 (FoxO1) activity induces peroxisome proliferator-activated receptor γ (PPARγ), leading to accumulation of lipids and hyperlipidemia. Hyperlipidemia significantly influence hepatic steatoses, but the mechanisms underlying PAR2 signaling are complex and have not yet been elucidated. Methods To examine the modulatory action of FoxO1 and its altered interaction with PPARγ, we utilized db/db mice and PAR2-knockout (KO) mice administered with high-fat diet (HFD). Results Here, we demonstrated that PAR2 was overexpressed and regulated downstream gene expressions in db/db but not in db + mice. The interaction between PAR2/β-arrestin and Akt was also greater in db/db mice. The Akt inhibition increased FoxO1 activity and subsequently PPARγ gene in the livers that led to hepatic lipid accumulation. Our data showed that FoxO1 was negatively controlled by Akt signaling and consequently, the activity of a major lipogenesis-associated transcription factors such as PPARγ increased, leading to hepatic lipid accumulation through the PAR2 pathway under hyperglycemic conditions in mice. Furthermore, the association between PPARγ and FoxO1 was increased in hepatic steatosis condition in db/db mice. However, HFD-fed PAR2-KO mice showed suppressed FoxO1-induced hepatic lipid accumulation compared with HFD-fed control groups. Conclusion Collectively, our results provide evidence that the interaction of FoxO1 with PPARγ promotes hepatic steatosis in mice. This might be due to defects in PAR2/β-arrestin-mediated Akt signaling in diabetic and HFD-fed mice.

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Sexual dimorphism in PAR2-dependent regulation of primitive colonic cells

Cited by 5 publications

References 32 publications

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

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

Mechanism of Lipid Accumulation through PAR2 Signaling in Diabetic Male Mice

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