{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:48:24Z","timestamp":1790084904008,"version":"4.0.1"},"reference-count":55,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T00:00:00Z","timestamp":1586822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81490740"],"award-info":[{"award-number":["81490740"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81730040"],"award-info":[{"award-number":["81730040"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cell Proliferation"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>During human pregnancy, the endothelial cells of the uterine spiral arteries (SPA) are extensively replaced by a subtype of placental trophoblasts, endovascular extravillous trophoblasts (enEVTs), thus establishing a placental\u2010maternal circulation. On this pathway, foetus\u2010derived placental villi and enEVTs bath into the maternal blood that perfuses along SPA being not attacked by the maternal lymphocytes. We aimed to reveal the underlying mechanism of such immune tolerance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In situ hybridization, immunofluorescence, ELISA and FCM assay were performed to examine TGF\u2010\u03b21 expression and distribution of regulatory T cells (Tregs) along the placental\u2010maternal circulation route. The primary enEVTs, interstitial extravillous trophoblasts (iEVTs) and decidual endothelial cells (dECs) were purified by FACS, and their conditioned media were collected to treat na\u00efve CD4<jats:sup>+<\/jats:sup> T cells. Treg differentiation was measured by FLOW and CFSE assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that enEVTs but not iEVTs or dECs actively produced TGF\u2010\u03b21. The primary enEVTs significantly promoted na\u00efve CD4<jats:sup>+<\/jats:sup> T\u2010cell differentiation into immunosuppressive FOXP3<jats:sup>+<\/jats:sup> Tregs, and this effect was dependent on TGF\u2010\u03b21. In recurrent spontaneous abortion (RSA) patients, an evidently reduced proportion of TGF\u2010\u03b21\u2013producing enEVTs and their ability to educate Tregs differentiation were observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings demonstrate a unique immune\u2010regulatory characteristic of placental enEVTs to develop immune tolerance along the placental\u2010maternal circulation. New insights into the pathogenesis of RSA are also suggested.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cpr.12802","type":"journal-article","created":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T03:43:59Z","timestamp":1586922239000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Placental endovascular extravillous trophoblasts (enEVTs) educate maternal T\u2010cell differentiation along the maternal\u2010placental circulation"],"prefix":"10.1111","volume":"53","author":[{"given":"Yeling","family":"Ma","sequence":"first","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing China"},{"name":"University of Chinese Academy of Sciences Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing China"},{"name":"NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research) Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjie","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Peking University Third Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics The 306 Hospital of PLA Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Gu","sequence":"additional","affiliation":[{"name":"Second Hospital Affiliated to Tianjin Medical University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentong","family":"Jia","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing China"},{"name":"University of Chinese Academy of Sciences Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhilang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing China"},{"name":"University of Chinese Academy of Sciences Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feiyang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing China"},{"name":"University of Chinese Academy of Sciences Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010xia","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research) Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Peking University Third Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0352-1648","authenticated-orcid":false,"given":"Xuan","family":"Shao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing China"},{"name":"University of Chinese Academy of Sciences Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9448-7803","authenticated-orcid":false,"given":"Yan\u2010Ling","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing China"},{"name":"University of Chinese Academy of Sciences Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,14]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"667","article-title":"War and peace at the feto\u2010placental front line: recurrent spontaneous abortion","volume":"16","author":"De Carolis C","year":"2014","journal-title":"Isr Med Assoc J"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(88)90522-3"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-11-154"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0035-1554917"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.humrep.a138703"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/postgradmedj-2014-132672"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43998"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.11.018"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69204-0"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2014.06.013"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-007-0067-2"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmp004"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/2006"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.75"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.118.10858"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2011.01002.x"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2004.01869.x"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803177"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2007.03.037"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2010.11.007"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.2010.00921.x"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400498"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.04.012"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030152"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/318464"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1590\/1414-431x20176527"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.5582\/bst.2018.01012"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2010.05.002"},{"key":"e_1_2_9_30_1","first-page":"59","article-title":"Comparing serum levels of Th17 and Treg cytokines in women with unexplained recurrent spontaneous abortion and fertile women","volume":"15","author":"Roomandeh N","year":"2018","journal-title":"Iran J Immunol"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1479-828X.2006.00589.x"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2134"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17882"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2005.02.010"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2012.09.023"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.01.009"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/14.8.2131"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(98)80043-4"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0185(199607)245:3<525::AID-AR9>3.0.CO;2-Q"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0039.1997.tb02852.x"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2008.06.002"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12643"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1A0815-351R"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1053\/plac.2001.0686"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1507977112"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2016.23"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.066589"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611098104"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.8.5737"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1037"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2005.12.006"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-10-0294"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-016-1474-z"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1080\/00016340500501731"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1053\/plac.1999.0481"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrd.20061"}],"container-title":["Cell Proliferation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcpr.12802","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cpr.12802","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cpr.12802","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cpr.12802","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T03:23:43Z","timestamp":1693970623000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cpr.12802"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,14]]},"references-count":55,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,5]]}},"alternative-id":["10.1111\/cpr.12802"],"URL":"https:\/\/doi.org\/10.1111\/cpr.12802","archive":["Portico"],"relation":{},"ISSN":["0960-7722","1365-2184"],"issn-type":[{"value":"0960-7722","type":"print"},{"value":"1365-2184","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,14]]},"assertion":[{"value":"2020-01-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12802"}}