Activation of G protein–coupled estrogen receptor protects intestine from ischemia/reperfusion injury in mice by protecting the crypt cell proliferation

2019 ◽  
Vol 133 (3) ◽  
pp. 449-464 ◽  
Author(s):  
Shiquan Chai ◽  
Kaixuan Liu ◽  
Wanbing Feng ◽  
Tiantian Liu ◽  
Qian Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Estrogen Receptor ◽  
G Protein ◽  
Ischemia Reperfusion ◽  
Inos Expression ◽  
Crypt Cell ◽  
Clinical Event ◽  
Crypt Cell Proliferation ◽  
G Protein Coupled

AbstractThe intestinal ischemia/reperfusion (I/R) injury is a common clinical event related with high mortality in patients undergoing surgery or trauma. Estrogen exerts salutary effect on intestinal I/R injury, but the receptor type is not totally understood. We aimed to identify whether the G protein–coupled estrogen receptor (GPER) could protect the intestine against I/R injury and explored the mechanism. Adult male C57BL/6 mice were subjected to intestinal I/R injury by clamping (45 min) of the superior mesenteric artery followed by 4 h of intestinal reperfusion. Our results revealed that the selective GPER blocker abolished the protective effect of estrogen on intestinal I/R injury. Selective GPER agonist G-1 significantly alleviated I/R-induced intestinal mucosal damage, neutrophil infiltration, up-regulation of TNF-α and cyclooxygenase-2 (Cox-2) expression, and restored impaired intestinal barrier function. G-1 could ameliorate the impaired crypt cell proliferation ability induced by I/R and restore the decrease in villus height and crypt depth. The up-regulation of inducible nitric oxide synthase (iNOS) expression after I/R treatment was attenuated by G-1 administration. Moreover, selective iNOS inhibitor had a similar effect with G-1 on promoting the proliferation of crypt cells in the intestinal I/R model. Both GPER and iNOS were expressed in leucine-rich repeat containing G-protein coupled receptor 5 (Lgr5) positive stem cells in crypt. Together, these findings demonstrate that GPER activation can prompt epithelial cell repair following intestinal injury, which occurred at least in part by inhibiting the iNOS expression in intestinal stem cells (ISCs). GPER may be a novel therapeutic target for intestinal I/R injury.

scholarly journals G Protein-Coupled Estrogen Receptor Mediates Cell Proliferation through the cAMP/PKA/CREB Pathway in Murine Bone Marrow Mesenchymal Stem Cells

2020 ◽  
Vol 21 (18) ◽  
pp. 6490
Author(s):  
Shu-Chun Chuang ◽  
Chung-Hwan Chen ◽  
Ya-Shuan Chou ◽  
Mei-Ling Ho ◽  
Je-Ken Chang
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
Estrogen Receptor ◽  
Estrogen Receptors ◽  
G Protein ◽  
Neonatal Rat ◽  
Cell Counts ◽  
G Protein Coupled ◽  
Creb Pathway

Estrogen is an important hormone to regulate skeletal physiology via estrogen receptors. The traditional estrogen receptors are ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ. Moreover, G protein-coupled estrogen receptor-1 (GPER-1) was reported as a membrane receptor for estrogen in recent years. However, whether GPER-1 regulated osteogenic cell biology on skeletal system is still unclear. GPER-1 is expressed in growth plate abundantly before puberty but decreased abruptly since the very late stage of puberty in humans. It indicates GPER-1 might play an important role in skeletal growth regulation. GPER-1 expression has been confirmed in osteoblasts, osteocytes and chondrocytes, but its expression in mesenchymal stem cells (MSCs) has not been confirmed. In this study, we hypothesized that GPER-1 is expressed in bone MSCs (BMSC) and enhances BMSC proliferation. The cultured tibiae of neonatal rat and murine BMSCs were tested in our study. GPER-1-specific agonist (G-1) and antagonist (G-15), and GPER-1 siRNA (siGPER-1) were used to evaluate the downstream signaling pathway and cell proliferation. Our results revealed BrdU-positive cell counts were higher in cultured tibiae in the G-1 group. The G-1 also enhanced the cell viability and proliferation, whereas G-15 and siGPER-1 reduced these activities. The cAMP and phosphorylation of CREB were enhanced by G-1 but inhibited by G-15. We further demonstrated that GPER-1 mediates BMSC proliferation via the cAMP/PKA/p-CREB pathway and subsequently upregulates cell cycle regulators, cyclin D1/cyclin-dependent kinase (CDK) 6 and cyclin E1/CDK2 complex. The present study is the first to report that GPER-1 mediates BMSC proliferation. This finding indicates that GPER-1 mediated signaling positively regulates BMSC proliferation and may provide novel insights into addressing estrogen-mediated bone development.

scholarly journals SAT-LB035 The G Protein-Coupled Estrogen Receptor GPER Plays a Dominant Role in Human Islet Cell Proliferation upon High Glucose

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Sigal Shaklai ◽  
Meital Grafi-Cohen ◽  
Orli Sharon ◽  
Gabi Shefer ◽  
Dalia Somjen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
G Protein ◽  
High Glucose ◽  
Islet Cell ◽  
Dominant Role ◽  
Human Islet ◽  
G Protein Coupled

scholarly journals The murine intestinal stem cells are highly sensitive to the modulation of the T3/TRα1-dependent pathway

Development ◽  
2021 ◽  
pp. dev.194357
Author(s):  
Matthias Godart ◽  
Carla Frau ◽  
Diana Farhat ◽  
Maria Virginia Giolito ◽  
Catherine Jamard ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Ex Vivo ◽  
Cell Activity ◽  
Crypt Cell ◽  
Intestinal Stem Cells ◽  
Gut Development ◽  
Crypt Cell Proliferation ◽  
Depth Analysis

The thyroid hormone T3 and its nuclear receptor TRα1 control gut development and homeostasis through the modulation of intestinal crypt cell proliferation. Despite increasing data, in depth analysis on their specific action on intestinal stem cells is lacking.By using ex vivo 3D organoid cultures and molecular approaches we observed early responses to T3 involving the T3-metabolizing enzyme Dio1 and the transporter Mct10, accompanied by a complex response of stem cell- and progenitor-enriched genes. Interestingly, specific TRα1 loss-of-function (inducible or constitutive) was responsible for low ex vivo organoid development and impaired stem cell activity. T3-treatment of animals in vivo not only confirmed the positive action of this hormone on crypt cell proliferation but also demonstrated its key action in modulating i) the number of the stem cells, ii) the expression of their specific markers and iii) the commitment of progenitors into lineage-specific differentiation.In conclusion, T3 treatment or TRα1 modulation has a rapid and strong effect on intestinal stem cells, broadening our perspectives in the study of T3/TRα1-dependent signaling in these cells.

Abstract 1305: Activation of G-protein coupled estrogen receptor (GPER) inhibits ELT-3 uterine leiomyoma cell proliferation.

2013 ◽  
Author(s):  
Maryann Castillo ◽  
Angelique M. Wimbley ◽  
Jacob J. Mayfield ◽  
Jenifer C. Lascano ◽  
Kevin D. Houston
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
G Protein ◽  
Uterine Leiomyoma ◽  
G Protein Coupled

scholarly journals Low Doses of Bisphenol A Promote Human Seminoma Cell Proliferation by Activating PKA and PKG via a Membrane G-Protein–Coupled Estrogen Receptor

2009 ◽  
Vol 117 (7) ◽  
pp. 1053-1058 ◽  
Author(s):  
Adil Bouskine ◽  
Marielle Nebout ◽  
Françoise Brücker-Davis ◽  
Mohamed Benahmed ◽  
Patrick Fenichel
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Bisphenol A ◽  
G Protein ◽  
Low Doses ◽  
G Protein Coupled

scholarly journals G Protein-Coupled Estrogen Receptor 1 Mediates Acute Estrogen-Induced Cardioprotection via MEK/ERK/GSK-3β Pathway after Ischemia/Reperfusion

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0135988 ◽  
Author(s):  
Mohammad E. Kabir ◽  
Harpreet Singh ◽  
Rong Lu ◽  
Bjorn Olde ◽  
L. M. Fredrik Leeb-Lundberg ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Ischemia Reperfusion ◽  
Gsk 3Β ◽  
G Protein Coupled ◽  
Estrogen Receptor 1

scholarly journals Activation of G protein coupled estrogen receptor prevents chemotherapy-induced intestinal mucositis by inhibiting the DNA damage in crypt cell in an extracellular signal-regulated kinase 1- and 2- dependent manner

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Guanyu Chen ◽  
Honghui Zeng ◽  
Xinyun Li ◽  
Jianbo Liu ◽  
Zhao Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Estrogen Receptor ◽  
G Protein ◽  
Cyclin B1 ◽  
Crypt Cell ◽  
Mucosal Barrier ◽  
Dependent Manner ◽  
Intestinal Mucositis ◽  
G Protein Coupled

AbstractChemotherapy-induced intestinal mucositis (CIM) is a common adverse reaction to antineoplastic treatment with few appropriate, specific interventions. We aimed to identify the role of the G protein coupled estrogen receptor (GPER) in CIM and its mechanism. Adult male C57BL/6 mice were intraperitoneally injected with 5-fluorouracil to establish the CIM model. The selective GPER agonist G-1 significantly inhibited weight loss and histological damage in CIM mice and restored mucosal barrier dysfunction, including improving the expression of ZO-1, increasing the number of goblet cells, and decreasing mucosal permeability. Moreover, G-1 treatment did not alter the antitumor effect of 5-fluorouracil. In the CIM model, G-1 therapy reduced the expression of proapoptotic protein and cyclin D1 and cyclin B1, reversed the changes in the number of TUNEL+ cells, Ki67+ and bromodeoxyuridine+ cells in crypts. The selective GPER antagonist G15 eliminated all of the above effects caused by G-1 on CIM, and application of G15 alone increased the severity of CIM. GPER was predominantly expressed in ileal crypts, and G-1 inhibited the DNA damage induced by 5-fluorouracil in vivo and vitro, as confirmed by the decrease in the number of γH2AX+ cells in the crypts and the comet assay results. Referring to the data from GEO dataset we verified GPER activation restored ERK1/2 activity in CIM and 5-fluorouracil-treated IEC-6 cells. Once the effects of G-1 on ERK1/2 activity were abolished with the ERK1/2 inhibitor PD0325901, the effects of G-1 on DNA damage both in vivo and in vitro were eliminated. Correspondingly, all of the manifestations of G-1 protection against CIM were inhibited by PD0325901, such as body weight and histological changes, the mucosal barrier, the apoptosis and proliferation of crypt cells. In conclusion, GPER activation prevents CIM by inhibiting crypt cell DNA damage in an ERK1/2-dependent manner, suggesting GPER might be a target preventing CIM.

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