{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T14:24:17Z","timestamp":1777386257036,"version":"3.51.4"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T00:00:00Z","timestamp":1650499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The National Natural Science Foundation of China\/Research Grants Council Joint Research Scheme","award":["N_HKU 732\/20"],"award-info":[{"award-number":["N_HKU 732\/20"]}]},{"name":"Shenzhen Knowledge Innovation Programme of the Shenzhen Science and Technology Innovation Commission","award":["JCYJ20180508153031952"],"award-info":[{"award-number":["JCYJ20180508153031952"]}]},{"name":"The Hong Kong University Shenzhen Hospital Scientific Research Training Plan","award":["HKUSZH20192003"],"award-info":[{"award-number":["HKUSZH20192003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human endometrium is an incredibly dynamic tissue undergoing cyclic regeneration and shedding during a woman\u2019s reproductive life. Endometrial mesenchymal stromal\/stem-like cells (eMSC) contribute to this process. A hypoxic niche with low oxygen levels has been reported in multiple somatic stem cell types. However, the knowledge of hypoxia on eMSC remains limited. In mice, stromal stem\/progenitor cells can be identified by the label-retaining technique. We examined the relationship between the label-retaining stromal cells (LRSC) and hypoxia during tissue breakdown in a mouse model of simulated menses. Our results demonstrated that LRSC resided in a hypoxic microenvironment during endometrial breakdown and early repair. Immunofluorescence staining revealed that the hypoxic-located LRSC underwent proliferation and was highly colocalized with Notch1. In vitro studies illustrated that hypoxia activated Notch signaling in eMSC, leading to enhanced self-renewal, clonogenicity and proliferation of cells. More importantly, HIF-1\u03b1 played an essential role in the hypoxia-mediated maintenance of eMSC through the activation of Notch signaling. In conclusion, our findings show that some endometrial stem\/progenitor cells reside in a hypoxic niche during menstruation, and hypoxia can regulate the self-renewal activity of eMSC via Notch signaling.<\/jats:p>","DOI":"10.3390\/ijms23094613","type":"journal-article","created":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T05:07:22Z","timestamp":1650604042000},"page":"4613","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Hypoxia Regulates the Self-Renewal of Endometrial Mesenchymal Stromal\/Stem-like Cells via Notch Signaling"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-8697","authenticated-orcid":false,"given":"Sisi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China"},{"name":"Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8276-0868","authenticated-orcid":false,"given":"Rachel W.S.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China"},{"name":"Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7688-4557","authenticated-orcid":false,"given":"Ernest H.Y.","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China"},{"name":"Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William S.B.","family":"Yeung","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China"},{"name":"Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nri.2017.53","article-title":"Adult haematopoietic stem cell niches","volume":"17","author":"Crane","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.stem.2020.06.013","article-title":"Cell-by-Cell Deconstruction of Stem Cell Niches","volume":"27","author":"Tikhonova","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.stem.2010.07.007","article-title":"Oxygen in stem cell biology: A critical component of the stem cell niche","volume":"7","author":"Mohyeldin","year":"2010","journal-title":"Cell Stem Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/978-1-62703-508-8_17","article-title":"Hypoxia and visualization of the stem cell niche","volume":"1035","author":"Dalloul","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1002\/stem.96","article-title":"Low oxygen enhances primitive and definitive neural stem cell colony formation by inhibiting distinct cell death pathways","volume":"27","author":"Clarke","year":"2009","journal-title":"Stem Cells"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/jcp.21908","article-title":"The hematopoietic stem cell niche: Low in oxygen but a nice place to be","volume":"222","author":"Eliasson","year":"2010","journal-title":"J. Cell. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/j.1365-2184.2009.00621.x","article-title":"Impact of oxygen environment on mesenchymal stem cell expansion and chondrogenic differentiation","volume":"42","author":"Krinner","year":"2009","journal-title":"Cell Prolif."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1242\/dev.079665","article-title":"Hypoxia promotes satellite cell self-renewal and enhances the efficiency of myoblast transplantation","volume":"139","author":"Liu","year":"2012","journal-title":"Development"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"17254","DOI":"10.1002\/jcp.28342","article-title":"Hypoxia enhances buffalo adipose-derived mesenchymal stem cells proliferation, stemness, and reprogramming into induced pluripotent stem cells","volume":"234","author":"Deng","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"dev199577","DOI":"10.1242\/dev.199577","article-title":"Cyclical endometrial repair and regeneration","volume":"148","author":"Salamonsen","year":"2021","journal-title":"Development"},{"key":"ref_11","first-page":"137","article-title":"Endometrial stem\/progenitor cells: The first 10 years","volume":"22","author":"Gargett","year":"2016","journal-title":"Hum. Reprod. Update"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.1093\/humrep\/dem265","article-title":"Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium","volume":"22","author":"Schwab","year":"2007","journal-title":"Hum. Reprod."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/0002-9378(78)90119-9","article-title":"Menstruation in intraocular endometrial transplants in the Rhesus monkey","volume":"131","author":"Markee","year":"1978","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"F1","DOI":"10.1530\/REP-20-0268","article-title":"Hypoxia and Reproductive Health: The presence and role of hypoxia in the endometrium","volume":"161","author":"Kershaw","year":"2021","journal-title":"Reproduction"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41467-017-02375-6","article-title":"Hypoxia and hypoxia inducible factor-1\u03b1 are required for normal endometrial repair during menstruation","volume":"9","author":"Maybin","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1530\/REP-18-0562","article-title":"Hypoxia: Involved but not essential for endometrial breakdown in mouse menstural-like model","volume":"159","author":"Chen","year":"2020","journal-title":"Reproduction"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3711","DOI":"10.1096\/fj.13-232074","article-title":"Hypoxia is not required for human endometrial breakdown or repair in a xenograft model of menstruation","volume":"27","author":"Coudyzer","year":"2013","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1089\/scd.2014.0225","article-title":"Label-retaining stromal cells in mouse endometrium awaken for expansion and repair after parturition","volume":"24","author":"Cao","year":"2015","journal-title":"Stem Cells Dev."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rudolph, M., D\u00f6cke, W.D., M\u00fcller, A., Menning, A., R\u00f6se, L., Zollner, T.M., and Gashaw, I. (2012). Induction of overt menstruation in intact mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032922"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/S0070-2153(10)92012-7","article-title":"Notch signaling in the regulation of stem cell self-renewal and differentiation","volume":"92","author":"Liu","year":"2010","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/cdd.2011.95","article-title":"HIF-1\u03b1 is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway","volume":"19","author":"Qiang","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1089\/scd.2013.0642","article-title":"Role of notch signaling in the maintenance of human mesenchymal stem cells under hypoxic conditions","volume":"23","author":"Moriyama","year":"2014","journal-title":"Stem Cells Dev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.devcel.2005.09.010","article-title":"Hypoxia requires notch signaling to maintain the undifferentiated cell state","volume":"9","author":"Gustafsson","year":"2005","journal-title":"Dev. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1016\/j.yexcr.2009.12.012","article-title":"Interactions between Notch- and hypoxia-induced transcriptomes in embryonic stem cells","volume":"316","author":"Main","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_25","first-page":"3765","article-title":"Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker","volume":"58","author":"Raleigh","year":"1998","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e1254","DOI":"10.21769\/BioProtoc.1254","article-title":"Hypoxia Studies with Pimonidazole in vivo","volume":"4","author":"Aguilera","year":"2014","journal-title":"Bio-Protocol"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/S1472-6483(10)61443-5","article-title":"Observations on intrauterine oxygen tension measured by fibre-optic microsensors","volume":"13","author":"Ottosen","year":"2006","journal-title":"Reprod. Biomed. Online"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1002\/stem.3070","article-title":"Myometrial Cells Stimulate Self-Renewal of Endometrial Mesenchymal Stem-Like Cells Through WNT5A\/\u03b2-Catenin Signaling","volume":"37","author":"Cao","year":"2019","journal-title":"Stem Cells"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1002\/cmdc.201900106","article-title":"Toward the Characterization of DAPT Interactions with \u03b3-Secretase","volume":"14","author":"Dominguez","year":"2019","journal-title":"ChemMedChem"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"pe33","DOI":"10.1126\/scisignal.2002277","article-title":"HIF takes it up a notch","volume":"4","author":"Johnson","year":"2011","journal-title":"Sci. Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1093\/humrep\/17.2.265","article-title":"Expression of hypoxia-inducible factors in human endometrium and suppression of matrix metalloproteinases under hypoxic conditions do not support a major role for hypoxia in regulating tissue breakdown at menstruation","volume":"17","author":"Zhang","year":"2002","journal-title":"Hum. Reprod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3571","DOI":"10.1096\/fj.08-111401","article-title":"VEGF blockade inhibits angiogenesis and reepithelialization of endometrium","volume":"22","author":"Fan","year":"2008","journal-title":"FASEB J."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cousins, F.L., Murray, A.A., Scanlon, J.P., and Saunders, P.T. (2016). Hypoxyprobe\u2122 reveals dynamic spatial and temporal changes in hypoxia in a mouse model of endometrial breakdown and repair. BMC Res. Notes, 9.","DOI":"10.1186\/s13104-016-1842-8"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e2002058","DOI":"10.1002\/adhm.202002058","article-title":"Discrepancies on the Role of Oxygen Gradient and Culture Condition on Mesenchymal Stem Cell Fate","volume":"10","author":"Samal","year":"2021","journal-title":"Adv. Healthc. Mater."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1126\/science.aba0629","article-title":"Airway stem cells sense hypoxia and differentiate into protective solitary neuroendocrine cells","volume":"371","author":"Shivaraju","year":"2021","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"771","DOI":"10.2217\/rme.13.71","article-title":"The role of hypoxia in stem cell potency and differentiation","volume":"8","author":"Hawkins","year":"2013","journal-title":"Regen. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.transci.2017.03.015","article-title":"The effect of hypoxia preconditioning on the neural and stemness genes expression profiling in human umbilical cord blood mesenchymal stem cells","volume":"56","author":"Kheirandish","year":"2017","journal-title":"Transfus. Apher. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"241","DOI":"10.5966\/sctm.2013-0079","article-title":"Human bone marrow-derived mesenchymal stem cells display enhanced clonogenicity but impaired differentiation with hypoxic preconditioning","volume":"3","author":"Boyette","year":"2014","journal-title":"Stem Cells Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1002\/cbin.10097","article-title":"Hypoxia preconditioned human adipose derived mesenchymal stem cells enhance angiogenic potential via secretion of increased VEGF and bFGF","volume":"37","author":"Liu","year":"2013","journal-title":"Cell Biol. Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1093\/humrep\/deaa379","article-title":"Markers of human endometrial hypoxia can be detected in vivo and ex vivo during physiological menstruation","volume":"36","author":"Reavey","year":"2021","journal-title":"Hum. Reprod."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4165","DOI":"10.21873\/anticanres.13575","article-title":"Hypoxia Up-regulates HIF Expression While Suppressing Cell Growth and NOTCH Activity in Leukaemia Cells","volume":"39","author":"Itoh","year":"2019","journal-title":"Anticancer. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.nbd.2013.10.009","article-title":"Evidence that collaboration between HIF-1\u03b1 and Notch-1 promotes neuronal cell death in ischemic stroke","volume":"62","author":"Cheng","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.neuroscience.2018.10.037","article-title":"HIF-1\u03b1 is Critical for the Activation of Notch Signaling in Neurogenesis During Acute Epilepsy","volume":"394","author":"Li","year":"2018","journal-title":"Neuroscience"},{"key":"ref_44","first-page":"575","article-title":"A new notch in the HIF belt: How hypoxia impacts differentiation","volume":"9","author":"Johnson","year":"2005","journal-title":"Dev. Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4613\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:58:27Z","timestamp":1760137107000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4613"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,21]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23094613"],"URL":"https:\/\/doi.org\/10.3390\/ijms23094613","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,21]]}}}