{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:51:43Z","timestamp":1792785103586,"version":"4.5.0"},"reference-count":86,"publisher":"Springer Science and Business Media LLC","issue":"18","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012756","name":"Lalor Foundation","doi-asserted-by":"publisher","award":["."],"award-info":[{"award-number":["."]}],"id":[{"id":"10.13039\/100012756","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012756","name":"Lalor Foundation","doi-asserted-by":"publisher","award":["."],"award-info":[{"award-number":["."]}],"id":[{"id":"10.13039\/100012756","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018524","name":"Kansas IDeA Network of Biomedical Research Excellence","doi-asserted-by":"publisher","award":["P20 GM103418"],"award-info":[{"award-number":["P20 GM103418"]}],"id":[{"id":"10.13039\/100018524","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018524","name":"Kansas IDeA Network of Biomedical Research Excellence","doi-asserted-by":"publisher","award":["P20 GM103418"],"award-info":[{"award-number":["P20 GM103418"]}],"id":[{"id":"10.13039\/100018524","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006937","name":"HHS | NIH | NICHD | National Center for Medical Rehabilitation Research","doi-asserted-by":"publisher","award":["HD115834"],"award-info":[{"award-number":["HD115834"]}],"id":[{"id":"10.13039\/100006937","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD104071"],"award-info":[{"award-number":["HD104071"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD020676"],"award-info":[{"award-number":["HD020676"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD105734"],"award-info":[{"award-number":["HD105734"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD112559"],"award-info":[{"award-number":["HD112559"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD112559"],"award-info":[{"award-number":["HD112559"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001864","name":"Sosland Foundation","doi-asserted-by":"publisher","award":["."],"award-info":[{"award-number":["."]}],"id":[{"id":"10.13039\/100001864","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Donald C. Johnson Research Endowment Fund","award":["."],"award-info":[{"award-number":["."]}]},{"name":"Program of the Joint Usage\/Research Center for Developmental Medicine and High Depth Omics, IMEG, Kumamoto University","id":[{"id":"https:\/\/ror.org\/02cgss904","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["EMBO Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The expansion and differentiation of trophoblast stem (TS) cells are critical for defining fundamental properties of the placenta. Specialized trophoblast cells called extravillous trophoblast (EVT) cells in human and invasive trophoblast cells in rat, exit the placenta, enter and transform the uterus. This includes the restructuring of uterine spiral arteries, essential for the transfer of nutrients to the fetus. Mechanisms governing invasive trophoblast cell differentiation remain poorly understood. Here, we investigate peroxisome proliferator-activated receptor gamma (PPARG) as a potential regulator of EVT\/invasive trophoblast cell development. In first trimester human placentas, PPARG is expressed in the EVT cell column and increases in amount as human TS cells differentiate into EVT cells. PPARG disruption impairs EVT cell differentiation and alters the expression of genes controlling EVT cell lineage development. Rat invasive trophoblast cells similarly express PPARG. Conditional inactivation of PPARG within rat invasive trophoblast cells establishes PPARG as an essential cell-autonomous regulator of invasive trophoblast cells in vivo. In conclusion, PPARG is a conserved regulator of placentation and is essential for directing trophoblast cell-guided uterine transformation.<\/jats:p>","DOI":"10.1038\/s44319-026-00896-0","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T12:58:11Z","timestamp":1787230691000},"page":"5341-5364","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PPARG directs trophoblast cell fate and establishment of the uterine-placental interface"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3540-4411","authenticated-orcid":false,"given":"Esteban M","family":"Dominguez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6810-6475","authenticated-orcid":false,"given":"Ayelen","family":"Moreno-Irusta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6742-4591","authenticated-orcid":false,"given":"Khursheed","family":"Iqbal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Finlinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Parrish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Okae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Arima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8726-9955","authenticated-orcid":false,"given":"Geetu","family":"Tuteja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7158-1592","authenticated-orcid":false,"given":"Michael J","family":"Soares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"896_CR1","doi-asserted-by":"publisher","unstructured":"Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM (2013) PPAR\u03b3 signaling and metabolism: the good, the bad and the future. Nat Med. https:\/\/doi.org\/10.1038\/nm.3159","DOI":"10.1038\/nm.3159"},{"key":"896_CR2","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/S0012-1606(03)00210-0","volume":"260","author":"R Ain","year":"2003","unstructured":"Ain R, Canham LN, Soares MJ (2003) Gestation stage-dependent intrauterine trophoblast cell invasion in the rat and mouse: novel endocrine phenotype and regulation. Dev Biol 260:176\u2013190","journal-title":"Dev Biol"},{"key":"896_CR3","first-page":"295","volume":"121","author":"R Ain","year":"2006","unstructured":"Ain R, Konno T, Canham LN, Soares MJ (2006) Phenotypic analysis of the rat placenta. Methods Mol Med 121:295\u2013313","journal-title":"Methods Mol Med"},{"key":"896_CR4","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.bbrc.2004.01.074","volume":"315","author":"R Asami-Miyagishi","year":"2004","unstructured":"Asami-Miyagishi R, Iseki S, Usui M, Uchida K, Kubo H, Morita I (2004) Expression and function of PPARgamma in rat placental development. Biochem Biophys Res Commun 315:497\u2013501","journal-title":"Biochem Biophys Res Commun"},{"key":"896_CR5","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1152\/physrev.00039.2024","volume":"105","author":"ILMH Aye","year":"2025","unstructured":"Aye ILMH, Tong S, Charnock-Jones DS, Smith GCS (2025) The human placenta and its role in reproductive outcomes revisited. Physiol Rev 105:2305\u20132376","journal-title":"Physiol Rev"},{"key":"896_CR6","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/S1097-2765(00)80209-9","volume":"4","author":"Y Barak","year":"1999","unstructured":"Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans RM (1999) PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 4:585\u2013595","journal-title":"Mol Cell"},{"key":"896_CR7","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1146\/annurev.med.53.082901.104018","volume":"53","author":"J Berger","year":"2002","unstructured":"Berger J, Moller DE (2002) The mechanisms of action of PPARs. Annu Rev Med 53:409\u2013435","journal-title":"Annu Rev Med"},{"key":"896_CR8","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.ajog.2010.08.009","volume":"204","author":"I Brosens","year":"2011","unstructured":"Brosens I, Pijnenborg R, Vercruysse L, Romero R (2011) The \u201cgreat obstetrical syndromes\u201d are associated with disorders of deep placentation. Am J Obstet Gynecol 204:193\u2013201","journal-title":"Am J Obstet Gynecol"},{"key":"896_CR9","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.ajog.2019.05.044","volume":"221","author":"I Brosens","year":"2019","unstructured":"Brosens I, Puttemans P, Benagiano G (2019) Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes. Am J Obstet Gynecol 221:437\u2013456","journal-title":"Am J Obstet Gynecol"},{"key":"896_CR10","first-page":"158","volume":"41","author":"K Calkins","year":"2011","unstructured":"Calkins K, Devaskar SU (2011) Fetal origins of adult disease. Curr Probl Pediatr Adolesc Health Care 41:158\u2013176","journal-title":"Curr Probl Pediatr Adolesc Health Care"},{"key":"896_CR11","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-2-46","volume":"2","author":"AM Carter","year":"2004","unstructured":"Carter AM, Enders AC (2004) Comparative aspects of trophoblast development and placentation. Reprod Biol Endocrinol 2:46","journal-title":"Reprod Biol Endocrinol"},{"key":"896_CR12","doi-asserted-by":"publisher","first-page":"E7212","DOI":"10.1073\/pnas.1612626113","volume":"113","author":"D Chakraborty","year":"2016","unstructured":"Chakraborty D, Cui W, Rosario GX, Scott RL, Dhakal P, Renaud SJ, Tachibana M, Rumi MAK, Mason CW, Krieg AJ et al (2016) HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia. Proc Natl Acad Sci USA 113:E7212\u2013E7221","journal-title":"Proc Natl Acad Sci USA"},{"key":"896_CR13","doi-asserted-by":"publisher","first-page":"16295","DOI":"10.1073\/pnas.1109478108","volume":"108","author":"D Chakraborty","year":"2011","unstructured":"Chakraborty D, Rumi MAK, Konno T, Soares MJ (2011) Natural killer cells direct hemochorial placentation by regulating hypoxia-inducible factor dependent trophoblast lineage decisions. Proc Natl Acad Sci USA 108:16295\u201316300","journal-title":"Proc Natl Acad Sci USA"},{"key":"896_CR14","doi-asserted-by":"publisher","first-page":"dev148932","DOI":"10.1242\/dev.148932","volume":"145","author":"W-L Chang","year":"2018","unstructured":"Chang W-L, Liu Y-W, Dang Y-L, Jiang X-X, Xu H, Huang X, Wang Y-L, Wang H, Zhu C, Xue L-Q et al (2018) PLAC8, a new marker for human interstitial extravillous trophoblast cells, promotes their invasion and migration. Development 145:dev148932","journal-title":"Development"},{"key":"896_CR15","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giab008","volume":"10","author":"P Danecek","year":"2021","unstructured":"Danecek P, Bonfield JK, Liddle J, Marshall J, Ohan V, Pollard MO, Whitwham A, Keane T, McCarthy SA, Davies RM et al (2021) Twelve years of SAMtools and BCFtools. GigaScience 10:giab008","journal-title":"GigaScience"},{"key":"896_CR16","doi-asserted-by":"publisher","first-page":"232","DOI":"10.2144\/000114548","volume":"62","author":"P Dhakal","year":"2017","unstructured":"Dhakal P, Soares MJ (2017) Single step PCR-based genetic sex determination for rat tissues and cells. Biotechniques 62:232\u2013233","journal-title":"Biotechniques"},{"key":"896_CR17","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.186471","volume":"10","author":"EM Dominguez","year":"2025","unstructured":"Dominguez EM, Moreno-Irusta A, Scott RL, Iqbal K, Soares MJ (2025) TFAP2C is a key regulator of intrauterine trophoblast cell invasion and deep hemochorial placentation. JCI Insight 10:e186471","journal-title":"JCI Insight"},{"key":"896_CR18","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1146\/annurev-immunol-032712-100003","volume":"31","author":"A Erlebacher","year":"2013","unstructured":"Erlebacher A (2013) Immunology of the maternal-fetal interface. Annu Rev Immunol 31:387\u2013411","journal-title":"Annu Rev Immunol"},{"key":"896_CR19","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.plipres.2005.12.002","volume":"45","author":"JN Feige","year":"2006","unstructured":"Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W (2006) From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res 45:120\u2013159","journal-title":"Prog Lipid Res"},{"key":"896_CR20","doi-asserted-by":"publisher","first-page":"S115","DOI":"10.1016\/j.ajog.2015.08.042","volume":"213","author":"SJ Fisher","year":"2015","unstructured":"Fisher SJ (2015) Why is placentation abnormal in preeclampsia?. Am J Obstet Gynecol 213:S115\u2013S122","journal-title":"Am J Obstet Gynecol"},{"key":"896_CR21","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.jri.2011.05.003","volume":"90","author":"T Fournier","year":"2011","unstructured":"Fournier T, Guibourdenche J, Handschuh K, Tsatsaris V, Rauwel B, Davrinche C, Evain-Brion D (2011) PPAR\u03b3 and human trophoblast differentiation. J Reprod Immunol 90:41\u201349","journal-title":"J Reprod Immunol"},{"key":"896_CR22","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.placenta.2006.04.009","volume":"28","author":"T Fournier","year":"2007","unstructured":"Fournier T, Tsatsaris V, Handschuh K, Evain-Brion D (2007) PPARs and the placenta. Placenta 28:65\u201376","journal-title":"Placenta"},{"key":"896_CR23","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1053\/plac.2001.0738","volume":"23","author":"P Georgiades","year":"2002","unstructured":"Georgiades P, Ferguson-Smith AC, Burton GJ (2002) Comparative developmental anatomy of the murine and human definitive placentae. Placenta 23:3\u201319","journal-title":"Placenta"},{"key":"896_CR24","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1056\/NEJMra0708473","volume":"359","author":"PD Gluckman","year":"2008","unstructured":"Gluckman PD, Hanson MA, Cooper C, Thornburg KL (2008) Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359:61\u201373","journal-title":"N Engl J Med"},{"key":"896_CR25","doi-asserted-by":"publisher","first-page":"gkaf669","DOI":"10.1093\/nar\/gkaf669","volume":"53","author":"Q Guo","year":"2025","unstructured":"Guo Q, Choi J, Lee M, Kim J (2025) PPARG-centric transcriptional re-wiring during differentiation of human trophoblast stem cells into extravillous trophoblasts. Nucleic Acids Res 53:gkaf669","journal-title":"Nucleic Acids Res"},{"key":"896_CR26","doi-asserted-by":"publisher","first-page":"S93","DOI":"10.1016\/j.placenta.2009.12.012","volume":"31","author":"LK Harris","year":"2010","unstructured":"Harris LK (2010) Review: trophoblast-vascular cell interactions in early pregnancy: how to remodel a vessel. Placenta 31:S93\u2013S98","journal-title":"Placenta"},{"key":"896_CR27","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.ajog.2019.07.010","volume":"221","author":"LK Harris","year":"2019","unstructured":"Harris LK, Benagiano M, D\u2019Elios MM, Brosens I, Benagiano G (2019) Placental bed research: II. Functional and immunological investigations of the placental bed. Am J Obstet Gynecol 221:457\u2013469","journal-title":"Am J Obstet Gynecol"},{"key":"896_CR28","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1016\/j.molcel.2010.05.004","volume":"38","author":"S Heinz","year":"2010","unstructured":"Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38:576\u2013589","journal-title":"Mol Cell"},{"key":"896_CR29","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1002\/dvdy.10291","volume":"227","author":"M Hemberger","year":"2003","unstructured":"Hemberger M, Nozaki T, Masutani M, Cross JC (2003) Differential expression of angiogenic and vasodilatory factors by invasive trophoblast giant cells depending on depth of invasion. Dev Dyn 227:185\u2013191","journal-title":"Dev Dyn"},{"key":"896_CR30","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.placenta.2009.12.009","volume":"31","author":"SJ Holdsworth-Carson","year":"2010","unstructured":"Holdsworth-Carson SJ, Lim R, Mitton A, Whitehead C, Rice GE, Permezel M, Lappas M (2010) Peroxisome proliferator-activated receptors are altered in pathologies of the human placenta: gestational diabetes mellitus, intrauterine growth restriction and preeclampsia. Placenta 31:222\u2013229","journal-title":"Placenta"},{"key":"896_CR31","doi-asserted-by":"publisher","first-page":"dev202239","DOI":"10.1242\/dev.202239","volume":"151","author":"K Iqbal","year":"2024","unstructured":"Iqbal K, Dominguez EM, Nixon B, Moreno-Irusta A, Crnkovich B, Scott RL, Vu HTH, Tuteja G, Vivian JL, Soares MJ (2024) Conditionally mutant animal model for investigating the invasive trophoblast cell lineage. Development 151:dev202239","journal-title":"Development"},{"key":"896_CR32","doi-asserted-by":"publisher","first-page":"e2203071119","DOI":"10.1073\/pnas.2203071119","volume":"119","author":"MJ Jeyarajah","year":"2022","unstructured":"Jeyarajah MJ, Jaju Bhattad G, Kelly RD, Baines KJ, Jaremek A, Yang F-HP, Okae H, Arima T, Dumeaux V, Renaud SJ (2022) The multifaceted role of GCM1 during trophoblast differentiation in the human placenta. Proc Natl Acad Sci USA 119:e2203071119","journal-title":"Proc Natl Acad Sci USA"},{"key":"896_CR33","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3109\/19396368.2014.991881","volume":"61","author":"L Kadam","year":"2015","unstructured":"Kadam L, Kohan-Ghadr HR, Drewlo S (2015) The balancing act \u2013 PPAR-\u03b3\u2019s roles at the maternal-fetal interface. Syst Biol Reprod Med 61:65\u201371","journal-title":"Syst Biol Reprod Med"},{"key":"896_CR34","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1016\/j.stem.2022.04.004","volume":"29","author":"RM Karvas","year":"2022","unstructured":"Karvas RM, Khan SA, Verma S, Yin Y, Kulkarni D, Dong C, Park K, Chew B, Sane E, Fischer LA et al (2022) Stem-cell-derived trophoblast organoids model human placental development and susceptibility to emerging pathogens. Cell Stem Cell 29:810\u2013825.e8","journal-title":"Cell Stem Cell"},{"key":"896_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1095\/biolreprod.102.014977","volume":"69","author":"P Kaufmann","year":"2003","unstructured":"Kaufmann P, Black S, Huppertz B (2003) Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 69:1\u20137","journal-title":"Biol Reprod"},{"key":"896_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45669-2","volume":"15","author":"M Kim","year":"2024","unstructured":"Kim M, Jang YJ, Lee M, Guo Q, Son AJ, Kakkad NA, Roland AB, Lee B-K, Kim J (2024) The transcriptional regulatory network modulating human trophoblast stem cells to extravillous trophoblast differentiation. Nat Commun 15:1285","journal-title":"Nat Commun"},{"key":"896_CR37","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/S1097-2765(00)80210-5","volume":"4","author":"N Kubota","year":"1999","unstructured":"Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Satoh S, Nakano R, Ishii C, Sugiyama T et al (1999) PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 4:597\u2013609","journal-title":"Mol Cell"},{"key":"896_CR38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2213622120","volume":"120","author":"M Kuna","year":"2023","unstructured":"Kuna M, Dhakal P, Iqbal K, Dominguez EM, Kent LN, Muto M, Moreno-Irusta A, Kozai K, Varberg KM, Okae H et al (2023) CITED2 is a conserved regulator of the uterine\u2013placental interface. Proc Natl Acad Sci USA 120:e2213622120","journal-title":"Proc Natl Acad Sci USA"},{"key":"896_CR39","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows\u2013Wheeler transform. Bioinformatics 25:1754\u20131760","journal-title":"Bioinformatics"},{"key":"896_CR40","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1038\/s41422-018-0066-y","volume":"28","author":"Y Liu","year":"2018","unstructured":"Liu Y, Fan X, Wang R, Lu X, Dang Y-L, Wang H, Lin H-Y, Zhu C, Ge H, Cross JC et al (2018) Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta. Cell Res 28:819\u2013832","journal-title":"Cell Res"},{"key":"896_CR41","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1146\/annurev-cellbio-100814-125620","volume":"31","author":"E Maltepe","year":"2015","unstructured":"Maltepe E, Fisher SJ (2015) Placenta: the forgotten organ. Annu Rev Cell Dev Biol 31:523\u2013552","journal-title":"Annu Rev Cell Dev Biol"},{"key":"896_CR42","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nbt.1630","volume":"28","author":"CY McLean","year":"2010","unstructured":"McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, Wenger AM, Bejerano G (2010) GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol 28:495\u2013501","journal-title":"Nat Biotechnol"},{"key":"896_CR43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2426385122","volume":"122","author":"G Meinhardt","year":"2025","unstructured":"Meinhardt G, Waldh\u00e4usl H, Lackner AI, W\u00e4chter J, Maxian T, H\u00f6bler A-L, Vondra S, Kunihs V, Saleh L, Haslinger P et al (2025) The multifaceted roles of the transcriptional coactivator TAZ in extravillous trophoblast development of the human placenta. Proc Natl Acad Sci USA 122:e2426385122","journal-title":"Proc Natl Acad Sci USA"},{"key":"896_CR44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2529836123","volume":"123","author":"A Moreno-Irusta","year":"2026","unstructured":"Moreno-Irusta A, Basu MK, Dominguez EM, Chen TS, Smith SH, Varberg KM, Okae H, Arima T, Soares MJ (2026a) Developmental landmarks and cellular transitions during extravillous trophoblast cell differentiation. Proc Natl Acad Sci USA 123:e2529836123","journal-title":"Proc Natl Acad Sci USA"},{"key":"896_CR45","doi-asserted-by":"publisher","DOI":"10.1242\/dev.205290","volume":"153","author":"A Moreno-Irusta","year":"2026","unstructured":"Moreno-Irusta A, Urosevic J, Iqbal K, Seetharam AS, Nteeba J, Scott RL, Kuna M, Muto M, Kozai K, Celic A et al (2026b) Fundamental and unique roles of PLAC1 in the regulation of rat and human trophoblast cell development. Development 153:dev205290","journal-title":"Development"},{"key":"896_CR46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2111267118","volume":"118","author":"M Muto","year":"2021","unstructured":"Muto M, Chakraborty D, Varberg KM, Moreno-Irusta A, Iqbal K, Scott RL, McNally RP, Choudhury RH, Aplin JD, Okae H et al (2021) Intersection of regulatory pathways controlling hemostasis and hemochorial placentation. Proc Natl Acad Sci USA 118:e2111267118","journal-title":"Proc Natl Acad Sci USA"},{"key":"896_CR47","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.stem.2017.11.004","volume":"22","author":"H Okae","year":"2018","unstructured":"Okae H, Toh H, Sato T, Hiura H, Takahashi S, Shirane K, Kabayama Y, Suyama M, Sasaki H, Arima T (2018) Derivation of human trophoblast stem cells. Cell Stem Cell 22:50\u201363.e6","journal-title":"Cell Stem Cell"},{"key":"896_CR48","doi-asserted-by":"publisher","first-page":"e8055","DOI":"10.1371\/journal.pone.0008055","volume":"4","author":"MM Parast","year":"2009","unstructured":"Parast MM, Yu H, Ciric A, Salata MW, Davis V, Milstone DS (2009) PPAR\u03b3 regulates trophoblast proliferation and promotes labyrinthine trilineage differentiation. PLoS One 4:e8055","journal-title":"PLoS One"},{"key":"896_CR49","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1093\/carcin\/bgg074","volume":"24","author":"L Pavan","year":"2003","unstructured":"Pavan L, Tarrade A, Hermouet A, Delouis C, Titeux M, Vidaud M, Th\u00e9rond P, Evain-Brion D, Fournier T (2003) Human invasive trophoblasts transformed with simian virus 40 provide a new tool to study the role of PPAR\u03b3 in cell invasion process. Carcinogenesis 24:1325\u20131336","journal-title":"Carcinogenesis"},{"key":"896_CR50","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/S0143-4004(81)80042-2","volume":"2","author":"R Pijnenborg","year":"1981","unstructured":"Pijnenborg R, Robertson WB, Brosens I, Dixon G (1981) Review article: trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta 2:71\u201391","journal-title":"Placenta"},{"key":"896_CR51","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/j.placenta.2005.12.006","volume":"27","author":"R Pijnenborg","year":"2006","unstructured":"Pijnenborg R, Vercruysse L, Hanssens M (2006) The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 27:939\u2013958","journal-title":"Placenta"},{"key":"896_CR52","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1093\/bioinformatics\/btq033","volume":"26","author":"AR Quinlan","year":"2010","unstructured":"Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26:841\u2013842","journal-title":"Bioinformatics"},{"key":"896_CR53","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.ydbio.2014.01.015","volume":"387","author":"A Rai","year":"2014","unstructured":"Rai A, Cross JC (2014) Development of the hemochorial maternal vascular spaces in the placenta through endothelial and vasculogenic mimicry. Dev Biol 387:131\u2013141","journal-title":"Dev Biol"},{"key":"896_CR54","doi-asserted-by":"publisher","first-page":"W160","DOI":"10.1093\/nar\/gkw257","volume":"44","author":"F Ram\u00edrez","year":"2016","unstructured":"Ram\u00edrez F, Ryan DP, Gr\u00fcning B, Bhardwaj V, Kilpert F, Richter AS, Heyne S, D\u00fcndar F, Manke T (2016) deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res 44:W160\u2013W165","journal-title":"Nucleic Acids Res"},{"key":"896_CR55","doi-asserted-by":"publisher","first-page":"R91","DOI":"10.1530\/REP-14-0271","volume":"149","author":"MT R\u00e4tsep","year":"2015","unstructured":"R\u00e4tsep MT, Felker AM, Kay VR, Tolusso L, Hofmann AP, Croy BA (2015) Uterine natural killer cells: supervisors of vasculature construction in early decidua basalis. Reproduction 149:R91\u2013R102","journal-title":"Reproduction"},{"key":"896_CR56","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1095\/biolreprod.116.142752","volume":"96","author":"SJ Renaud","year":"2017","unstructured":"Renaud SJ, Scott RL, Chakraborty D, Rumi MAK, Soares MJ (2017) Natural killer-cell deficiency alters placental development in rats. Biol Reprod 96:145\u2013158","journal-title":"Biol Reprod"},{"key":"896_CR57","doi-asserted-by":"publisher","first-page":"R179","DOI":"10.1530\/REP-16-0325","volume":"152","author":"RM Roberts","year":"2016","unstructured":"Roberts RM, Green JA, Schulz LC (2016) The evolution of the placenta. Reproduction 152:R179\u2013R189","journal-title":"Reproduction"},{"key":"896_CR58","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1016\/j.jsgi.2005.03.004","volume":"12","author":"VA Rodie","year":"2005","unstructured":"Rodie VA, Young A, Jordan F, Sattar N, Greer IA, Freeman DJ (2005) Human placental peroxisome proliferator-activated receptor delta and gamma expression in healthy pregnancy and in preeclampsia and intrauterine growth restriction. J Soc Gynecol Investig 12:320\u2013329","journal-title":"J Soc Gynecol Investig"},{"key":"896_CR59","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.ydbio.2007.12.007","volume":"314","author":"GX Rosario","year":"2008","unstructured":"Rosario GX, Konno T, Soares MJ (2008) Maternal hypoxia activates endovascular trophoblast cell invasion. Dev Biol 314:362\u2013375","journal-title":"Dev Biol"},{"key":"896_CR60","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1016\/j.tips.2015.06.010","volume":"36","author":"S Sauer","year":"2015","unstructured":"Sauer S (2015) Ligands for the nuclear peroxisome proliferator-activated receptor gamma. Trends Pharmacol Sci 36:688\u2013704","journal-title":"Trends Pharmacol Sci"},{"key":"896_CR61","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.mce.2006.02.009","volume":"249","author":"WT Schaiff","year":"2006","unstructured":"Schaiff WT, Barak Y, Sadovsky Y (2006) The pleiotropic function of PPAR\u03b3 in the placenta. Mol Cell Endocrinol 249:10\u201315","journal-title":"Mol Cell Endocrinol"},{"key":"896_CR62","doi-asserted-by":"publisher","first-page":"4267","DOI":"10.1210\/jc.2004-2265","volume":"90","author":"WT Schaiff","year":"2005","unstructured":"Schaiff WT, Bildirici I, Cheong M, Chern PL, Nelson DM, Sadovsky Y (2005) Peroxisome proliferator-activated receptor-gamma and retinoid X receptor signaling regulate fatty acid uptake by primary human placental trophoblasts. J Clin Endocrinol Metab 90:4267\u20134275","journal-title":"J Clin Endocrinol Metab"},{"key":"896_CR63","first-page":"3874","volume":"85","author":"WT Schaiff","year":"2000","unstructured":"Schaiff WT, Carlson MG, Smith SD, Levy R, Nelson DM, Sadovsky Y (2000) Peroxisome proliferator-activated receptor-gamma modulates differentiation of human trophoblast in a ligand-specific manner. J Clin Endocrinol Metab 85:3874\u20133881","journal-title":"J Clin Endocrinol Metab"},{"key":"896_CR64","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2210633119","volume":"119","author":"RL Scott","year":"2022","unstructured":"Scott RL, Vu HTH, Jain A, Iqbal K, Tuteja G, Soares MJ (2022) Conservation at the uterine\u2013placental interface. Proc Natl Acad Sci USA 119:e2210633119","journal-title":"Proc Natl Acad Sci USA"},{"key":"896_CR65","unstructured":"Scott RL, Vu HTH, Jain A, Iqbal K, Tuteja G. Soares MJ (2022) Gene expression omnibus GSE206086. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE206086"},{"key":"896_CR66","doi-asserted-by":"publisher","first-page":"10661","DOI":"10.1128\/MCB.24.24.10661-10669.2004","volume":"24","author":"T Shalom-Barak","year":"2004","unstructured":"Shalom-Barak T, Nicholas JM, Wang Y, Zhang X, Ong ES, Young TH, Gendler SJ, Evans RM, Barak Y (2004) Peroxisome proliferator-activated receptor gamma controls Muc1 transcription in trophoblasts. Mol Cell Biol 24:10661\u201310669","journal-title":"Mol Cell Biol"},{"key":"896_CR67","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2311372120","volume":"120","author":"T Shimizu","year":"2023","unstructured":"Shimizu T, Oike A, Kobayashi EH, Sekiya A, Kobayashi N, Shibata S, Hamada H, Saito M, Yaegashi N, Suyama M et al (2023) CRISPR screening in human trophoblast stem cells reveals both shared and distinct aspects of human and mouse placental development. Proc Natl Acad Sci USA 120:e2311372120","journal-title":"Proc Natl Acad Sci USA"},{"key":"896_CR68","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2403003121","volume":"121","author":"V Shukla","year":"2024","unstructured":"Shukla V, Moreno-Irusta A, Varberg KM, Kuna M, Iqbal K, Galligos AM, Aplin JD, Choudhury RH, Okae H, Arima T et al (2024) NOTUM-mediated WNT silencing drives extravillous trophoblast cell lineage development. Proc Natl Acad Sci USA 121:e2403003121","journal-title":"Proc Natl Acad Sci USA"},{"key":"896_CR69","doi-asserted-by":"publisher","first-page":"2947","DOI":"10.3390\/ijms23062947","volume":"23","author":"V Shukla","year":"2022","unstructured":"Shukla V, Soares MJ (2022) Modeling trophoblast cell-guided uterine spiral artery transformation in the rat. Int J Mol Sci 23:2947","journal-title":"Int J Mol Sci"},{"key":"896_CR70","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.placenta.2011.11.026","volume":"33","author":"MJ Soares","year":"2012","unstructured":"Soares MJ, Chakraborty D, Karim Rumi MA, Konno T, Renaud SJ (2012) Rat placentation: an experimental model for investigating the hemochorial maternal-fetal interface. Placenta 33:233\u2013243","journal-title":"Placenta"},{"key":"896_CR71","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1093\/biolre\/ioy049","volume":"99","author":"MJ Soares","year":"2018","unstructured":"Soares MJ, Varberg KM, Iqbal K (2018) Hemochorial placentation: development, function, and adaptations. Biol Reprod 99:196\u2013211","journal-title":"Biol Reprod"},{"key":"896_CR72","first-page":"5017","volume":"86","author":"A Tarrade","year":"2001","unstructured":"Tarrade A (2001) PPAR \/RXR heterodimers control human trophoblast invasion. J Clin Endocrinol Metab 86:5017\u20135024","journal-title":"J Clin Endocrinol Metab"},{"key":"896_CR73","doi-asserted-by":"publisher","first-page":"4504","DOI":"10.1210\/endo.142.10.8448","volume":"142","author":"A Tarrade","year":"2001","unstructured":"Tarrade A, Schoonjans K, Guibourdenche J, Bidart JM, Vidaud M, Auwerx J, Rochette-Egly C, Evain-Brion D (2001) PPAR\u03b3\/RXR\u03b1 heterodimers are involved in human cg\u03b2 synthesis and human trophoblast differentiation. Endocrinology 142:4504\u20134514","journal-title":"Endocrinology"},{"key":"896_CR74","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40424-5","volume":"14","author":"KM Varberg","year":"2023","unstructured":"Varberg KM, Dominguez EM, Koseva B, Varberg JM, McNally RP, Moreno-Irusta A, Wesley ER, Iqbal K, Cheung WA, Schwendinger-Schreck C et al (2023) Extravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape. Nat Commun 14:4826","journal-title":"Nat Commun"},{"key":"896_CR75","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2016517118","volume":"118","author":"KM Varberg","year":"2021","unstructured":"Varberg KM, Iqbal K, Muto M, Simon ME, Scott RL, Kozai K, Choudhury RH, Aplin JD, Biswell R, Gibson M et al (2021) ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development. Proc Natl Acad Sci USA 118:e2016517118","journal-title":"Proc Natl Acad Sci USA"},{"key":"896_CR76","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1080\/19336918.2015.1089376","volume":"10","author":"P Velicky","year":"2015","unstructured":"Velicky P, Kn\u00f6fler M, Pollheimer J (2015) Function and control of human invasive trophoblast subtypes: intrinsic vs. maternal control. Cell Adh Migr 10:154\u2013162","journal-title":"Cell Adh Migr"},{"key":"896_CR77","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41586-018-0698-6","volume":"563","author":"R Vento-Tormo","year":"2018","unstructured":"Vento-Tormo R, Efremova M, Botting RA, Turco MY, Vento-Tormo M, Meyer KB, Park J-E, Stephenson E, Pola\u0144ski K, Goncalves A et al (2018) Single-cell reconstruction of the early maternal-fetal interface in humans. Nature 563:347\u2013353","journal-title":"Nature"},{"key":"896_CR78","doi-asserted-by":"publisher","first-page":"dev201826","DOI":"10.1242\/dev.201826","volume":"150","author":"HTH Vu","year":"2023","unstructured":"Vu HTH, Scott RL, Iqbal K, Soares MJ, Tuteja G (2023) Core conserved transcriptional regulatory networks define the invasive trophoblast cell lineage. Development 150:dev201826","journal-title":"Development"},{"key":"896_CR79","unstructured":"Vu HTH, Scott RL, Iqbal K, Soares MJ, Tuteja G (2023) Gene expression omnibus GSE227943. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE227943"},{"key":"896_CR80","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1210\/jc.2004-0849","volume":"90","author":"LL Waite","year":"2005","unstructured":"Waite LL, Louie RE, Taylor RN (2005) Circulating Activators of peroxisome proliferator-activated receptors are reduced in preeclamptic pregnancy. J Clin Endocrinol Metab 90:620\u2013626","journal-title":"J Clin Endocrinol Metab"},{"key":"896_CR81","first-page":"3808","volume":"85","author":"LL Waite","year":"2000","unstructured":"Waite LL, Person EC, Zhou Y, Lim KH, Scanlan TS, Taylor RN (2000) Placental peroxisome proliferator-activated receptor-gamma is up-regulated by pregnancy serum. J Clin Endocrinol Metab 85:3808\u20133814","journal-title":"J Clin Endocrinol Metab"},{"key":"896_CR82","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29312-6","volume":"13","author":"L-J Wang","year":"2022","unstructured":"Wang L-J, Chen C-P, Lee Y-S, Ng P-S, Chang G-D, Pao Y-H, Lo H-F, Peng C-H, Cheong M-L, Chen H (2022) Functional antagonism between \u0394Np63\u03b1 and GCM1 regulates human trophoblast stemness and differentiation. Nat Commun 13:1626","journal-title":"Nat Commun"},{"key":"896_CR83","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1677\/joe.0.1790335","volume":"179","author":"DO Wiemers","year":"2003","unstructured":"Wiemers DO, Ain R, Ohboshi S, Soares MJ (2003) Migratory trophoblast cells express a newly identified member of the prolactin gene family. J Endocrinol 179:335\u2013346","journal-title":"J Endocrinol"},{"key":"896_CR84","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1016\/j.bbrc.2018.10.139","volume":"506","author":"J Xie","year":"2018","unstructured":"Xie J, Xu Y, Wan L, Wang P, Wang M, Dong M (2018) Involvement of follistatin-like 3 in preeclampsia. Biochem Biophys Res Commun 506:692\u2013697","journal-title":"Biochem Biophys Res Commun"},{"key":"896_CR85","volume":"5","author":"G Yu","year":"2024","unstructured":"Yu G (2024) Thirteen years of clusterProfiler. Innovation 5:100722","journal-title":"Innovation"},{"key":"896_CR86","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137","volume":"9","author":"Y Zhang","year":"2008","unstructured":"Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nusbaum C, Myers RM, Brown M, Li W et al (2008) Model-based analysis of ChIP-seq (MACS). Gen Biol 9:R137","journal-title":"Gen Biol"}],"container-title":["EMBO Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1038\/s44319-026-00896-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1038\/s44319-026-00896-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1038\/s44319-026-00896-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:33:09Z","timestamp":1790145189000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1038\/s44319-026-00896-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":86,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9,23]]}},"alternative-id":["896"],"URL":"https:\/\/doi.org\/10.1038\/s44319-026-00896-0","relation":{},"ISSN":["1469-3178"],"issn-type":[{"value":"1469-3178","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]},"assertion":[{"value":"13 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 August 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}]}}