{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T04:55:45Z","timestamp":1783400145377,"version":"3.54.6"},"reference-count":63,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T00:00:00Z","timestamp":1695340800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Placental insufficiency disorders, including preeclampsia and intrauterine growth restriction, are major obstetric complications that can have devastating effects on both the mother and the fetus. These syndromes have underlying poor placental trophoblast cell invasion into uterine tissues. Placental invasion is controlled by many hormones and growth factors. Myostatin (MSTN) is a transforming growth factor\u2010\u03b2 superfamily member recognized for its important role in muscle growth control. MSTN has also been shown to be secreted and functioning in the placenta, and its serum and\/or placental levels were found to be upregulated in preeclampsia and intrauterine growth restriction. Considering that the mechanistic role of MSTN in placentation remains poorly understood, we hypothesized that MSTN uses ALK4\/5\u2010SMAD2\/3\/4 signaling to increase human trophoblast invasion through a group of epithelial\u2013mesenchymal transition genes including SERPINE2, PAI\u20101, and SOX4. mRNA sequencing of control and MSTN\u2010treated primary human trophoblast cells (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20095) yielded a total of 610 differentially expressed genes (false discovery rate\u2009&lt;0.05) of which 380 genes were upregulated and 230 were downregulated. These differentially expressed genes were highly enriched in epithelial\u2013mesenchymal transition genes, and a subset including SERPINE2, PAI\u20101, and SOX4 was investigated for its role in MSTN\u2010induced trophoblast cell invasion. We found that MSTN induced upregulation of SERPINE2 via ALK4\/5\u2010SMAD2\/3\/4 signaling; however, SMAD2 was not involved in MSTN\u2010induced PAI\u20101 upregulation. SOX4 was involved in MSTN\u2010induced upregulation of SERPINE2, but not PAI\u20101. Collectively, this study discovers novel molecular mechanisms of MSTN\u2010induced human trophoblast cell invasion and provides insight into the functional consequences of its dysregulation in placental insufficiency disorders.\n                  <\/jats:p>","DOI":"10.1096\/fj.202300740r","type":"journal-article","created":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T11:25:18Z","timestamp":1695381918000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Growth differentiation factor myostatin regulates epithelial\u2010mesenchymal transition genes and enhances invasion by increasing serine protease inhibitors E1 and E2 in human trophoblast cells"],"prefix":"10.1096","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6657-3034","authenticated-orcid":false,"given":"Faten F.","family":"AbdelHafez","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute University of British Columbia  Vancouver British Columbia Canada"},{"name":"Department of Obstetrics and Gynecology Assiut School of Medicine  Assiut Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0485-0366","authenticated-orcid":false,"given":"Christian","family":"Klausen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8789-6390","authenticated-orcid":false,"given":"Hua","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8306-2359","authenticated-orcid":false,"given":"Yuyin","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3152-3800","authenticated-orcid":false,"given":"Peter C. K.","family":"Leung","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,22]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03104-6"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpobgyn.2011.02.006"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0039-1695004"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1530\/ror.0.0040011"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1159\/000052971"},{"key":"e_1_2_11_7_1","volume-title":"Physiology, Plasminogen Activation","author":"Katz JM","year":"2022"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-68535-9"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2003-38897"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V69.2.460.460"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2006-7-5-216"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/1933719108314626"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-22711-5_11"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-9-106"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M007609200"},{"issue":"1","key":"e_1_2_11_16_1","first-page":"20","article-title":"Plasminogen activator inhibitor types 1 and 2 in human trophoblasts. PAI\u20101 is an immunocytochemical marker of invading trophoblasts","volume":"61","author":"Feinberg RF","year":"1989","journal-title":"Lab Invest"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000250831.52876.cb"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0041-1742082"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-2615"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2361"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1447-0756.2011.01823.x"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1177\/1933719115572482"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2014.11.006"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.573781"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-21-0197"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioab238"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-023-01107-2"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmaa028"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0143-4004(95)90100-0"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2012.016"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/30.1.207"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1993.1139"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2015.08.002"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.506"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.06.008"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202100925RR"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.24554"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2020.12.005"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0051136"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.768669"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-018-0165-y"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preghy.2018.02.009"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1651566"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-9-38"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2020.e04759"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioy042"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2018.7819"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-4573"},{"issue":"16","key":"e_1_2_11_50_1","first-page":"4945","article-title":"SERPINE2 (protease nexin I) promotes extracellular matrix production and local invasion of pancreatic tumors in vivo","volume":"63","author":"Buchholz M","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9378(94)70246-2"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)37610-0"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.21.13705"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0008-6363(01)00547-8"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-0876"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2017.06.002"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401994101"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.72073"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-191189"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.11.3091"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq466"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky755"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V84.1.143.143"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2020.11551"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202300740R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T19:37:47Z","timestamp":1761680267000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202300740R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,22]]},"references-count":63,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["10.1096\/fj.202300740R"],"URL":"https:\/\/doi.org\/10.1096\/fj.202300740r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,22]]},"assertion":[{"value":"2023-04-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e23204"}}