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We tested the effect of chronic GPER activation on ISCs of ovariectomized (OVX) mice by injection of the selective GPER agonist G-1 for 28 days, or G-1 stimulation of organoids derived from crypts of OVX mice. G-1 up-regulated crypt depth, the number of Ki67+, bromodeoxyuridine+ cells and Olfm4+ ISCs, and the expression of ISCs marker genes (Lgr5, Olfm4 and Axin2). G-1 administration promoted organoid growth, increased the number of EdU+ cells per organoid and protein expression of Cyclin D1 and cyclin B1 in organoids. After G-1 treatment in vivo or in vitro, Paneth cell\u2013derived Wnt3, Wnt3 effector \u03b2-catenin and Wnt target genes c-Myc and Cyclin D1 increased in ileum or organoids. Once blocking the secretion of Wnt3 from Paneth cells, the effects of G-1 on organoids growth, ISCs marker genes and Wnt\/\u03b2-catenin signaling were abolished. G-1 did not affect the number of Paneth cells in ex vivo organoids, while activated Mmp7\/cryptdin program in Paneth cells, promoted their maturation, and increased the expression of lysozyme protein. G-1 pretreatment in OVX mice inhibited radiation-induced ISCs proliferation injury and enhanced the resistance of mice to intestinal injury. In conclusion, chronic GPER activation prompted the Wnt3 synthesis in Paneth cells, thus increased the proliferation of ISCs via activation of Wnt3\/\u03b2-catenin signaling in OVX mice.<\/jats:p>","DOI":"10.1042\/cs20220392","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T10:08:54Z","timestamp":1670839734000},"page":"109-127","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chronic GPER activation prompted the proliferation of ileal stem cell in ovariectomized mice depending on Paneth cell\u2013derived Wnt3"],"prefix":"10.1042","volume":"137","author":[{"given":"Jianbo","family":"Liu","sequence":"first","affiliation":[{"name":"1Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaixuan","family":"Liu","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiquan","family":"Chai","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China"},{"name":"2Department of Anesthesiology, Shangrao People\u2019s Hospital, Jiangxi, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Runze","family":"Xu","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yundi","family":"Zhang","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuanglian","family":"Wang","sequence":"additional","affiliation":[{"name":"3Science and Technology Innovation Center, Shandong First Medical University, Jinan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8615-3897","authenticated-orcid":false,"given":"Chuanyong","family":"Liu","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2341-3460","authenticated-orcid":false,"given":"Bing","family":"Xue","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2023,1,5]]},"reference":[{"key":"2023010508104490600_B1","doi-asserted-by":"publisher","first-page":"e1003731","DOI":"10.1371\/journal.pmed.1003731","article-title":"Menopausal hormone therapy and women's health: An umbrella review","volume":"18","author":"Zhang","year":"2021","journal-title":"PLoS Med."},{"key":"2023010508104490600_B2","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s11883-020-00854-8","article-title":"Menopausal hormone therapy: a comprehensive review","volume":"22","author":"Lundberg","year":"2020","journal-title":"Curr. 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