{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T15:47:54Z","timestamp":1788018474630,"version":"build-2784847793"},"reference-count":64,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T00:00:00Z","timestamp":1629331200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Endoplasmic reticulum (ER) stress promotes placental dysmorphogenesis and is associated with poor pregnancy outcomes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We show that unfolded protein response signalling pathways located in the ER drive differentiation of mouse trophoblast stem cells into trophoblast subtypes involved in development of the placental labyrinth zone and trophoblast invasion.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In a mouse model of chronic ER stress (<jats:italic>Eif2s1<\/jats:italic><jats:sup>tm1RjK<\/jats:sup>), higher ER stress in homozygous blastocysts is accompanied by reduced trophectoderm cell number and developmental delay and also is associated with an increased incidence of early pregnancy loss.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Administration of the chemical chaperone, tauroursodeoxycholic acid, to <jats:italic>Eif2s1<jats:sup>+\/<\/jats:sup><\/jats:italic><jats:sup>tm1RjK<\/jats:sup> heterozygous females during pregnancy alleviated ER stress in the mutant placenta, restored normal trophoblast populations and reduced the frequency of early pregnancy loss.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our results suggest that alleviation of intrauterine ER stress could provide a potential therapeutic target to improve pregnancy outcome in women with pre\u2010gestational metabolic or gynaecological conditions.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Women with pre\u2010gestational health conditions (e.g. obesity, diabetes) or gynaecological problems (e.g. endometriosis) are at increased risk of adverse pregnancy outcomes including miscarriage, pre\u2010eclampsia and fetal growth restriction. Increasing evidence suggests that unfavourable intrauterine conditions leading to poor implantation and\/or defective placentation are a possible causative factor. The endoplasmic reticulum (ER) unfolded protein response (UPR<jats:sup>ER<\/jats:sup>) signalling pathways are a convergence point of various physiological stress stimuli that can be triggered by an unfavourable intrauterine environment. Therefore, we explored the impact of ER stress on mouse trophoblast differentiation <jats:italic>in vitro<\/jats:italic>, mouse blastocyst formation and early placenta development in the <jats:italic>Eif2s1<\/jats:italic><jats:sup>tm1RjK<\/jats:sup> mutant mouse model of chronic ER stress. Chemically\u2010manipulated ER stress or activation of UPR<jats:sup>ER<\/jats:sup> pathways in a mouse trophoblast stem cell line promoted lineage\u2010specific differentiation. Co\u2010treatment with specific UPR<jats:sup>ER<\/jats:sup> pathway inhibitors rescued this effect. Although the inner cell mass was unaffected, the trophectoderm of homozygous <jats:italic>Eif2s1<\/jats:italic><jats:sup>tm1RjK<\/jats:sup> blastocysts exhibited ER stress associated with a reduced cell number. Furthermore, one\u2010third of <jats:italic>Eif2s1<\/jats:italic><jats:sup>tm1RjK<\/jats:sup> homozygous blastocysts exhibited severe developmental defects. We have previously reported a reduced trophoblast population and premature trophoblast differentiation in <jats:italic>Eif2s1<\/jats:italic><jats:sup>tm1RjK<\/jats:sup> homozygous placentas at mid\u2010gestation. Here, we demonstrate that treatment of <jats:italic>Eif2s1<\/jats:italic><jats:sup>+\/tm1RjK<\/jats:sup> heterozygous pregnant females with the chemical chaperone tauroursodeoxycholic acid alleviated ER stress, restored the trophoblast population and reduced the frequency of embryonic lethality. Our data suggest that therapeutic targeting of ER stress may improve pregnancy outcome in women with pre\u2010gestational metabolic or gynaecological conditions.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp281994","type":"journal-article","created":{"date-parts":[[2021,7,16]],"date-time":"2021-07-16T10:38:52Z","timestamp":1626431932000},"page":"4153-4181","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Excessive endoplasmic reticulum stress drives aberrant mouse trophoblast differentiation and placental development leading to pregnancy loss"],"prefix":"10.1113","volume":"599","author":[{"given":"Nadejda","family":"Capatina","sequence":"first","affiliation":[{"name":"Centre for Trophoblast Research Department of Physiology Development and Neuroscience University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Hemberger","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research Department of Physiology Development and Neuroscience University of Cambridge  Cambridge UK"},{"name":"Department of Biochemistry and Molecular Biology Cumming School of Medicine University of Calgary  Calgary AB Canada"},{"name":"Alberta Children's Hospital Research Institute University of Calgary  Calgary AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8677-4143","authenticated-orcid":false,"given":"Graham J.","family":"Burton","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research Department of Physiology Development and Neuroscience University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4496-2271","authenticated-orcid":false,"given":"Erica D.","family":"Watson","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research Department of Physiology Development and Neuroscience University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0869-7426","authenticated-orcid":false,"given":"Hong Wa","family":"Yung","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research Department of Physiology Development and Neuroscience University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,19]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gar076"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes2030420"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2010.08.009"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2017.06.007"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2008.11.003"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/der402"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-8-74"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11695-008-9424-z"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/jog.13799"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10815-007-9142-9"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1115623109"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/plac.2002.0887"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa4484"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.003798"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0902925106"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0226735"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.07.032"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12884-020-03481-y"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00375893"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.108.072546"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.02.031"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0903775106"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/2049-1891-3-7"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00428.2008"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2016.02.002"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2013.07.005"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.133462"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.21.7448-7459.2003"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2018.10.015"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.173"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00779-06"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/15.9.2011"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.3.736"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/289645"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0412.2003.00220.x"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1472-6483(10)60649-9"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1128294"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201642195"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpobgyn.2010.10.009"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.15550"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02597"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-12-0240"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1111726"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2199"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.017178"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/35003601"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.13920"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(01)00265-9"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1259"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2007.01.009"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-10-0461"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01801"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5396.2072"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e07-03-0275"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00001.2005"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2007.07.018"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.116.138412"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.113.113480"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-016-4040-2"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.071193"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4068"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.11.3864-3874.2002"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2012.12.011"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP281994","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP281994","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP281994","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T19:08:53Z","timestamp":1693336133000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP281994"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,19]]},"references-count":64,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2021,9]]}},"alternative-id":["10.1113\/JP281994"],"URL":"https:\/\/doi.org\/10.1113\/jp281994","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,19]]},"assertion":[{"value":"2021-06-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}