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Side-population cells possess progenitor properties. Recent human trophoblast side-population isolation identified enrichment of 8 specific genes (<jats:italic>CXCL8, ELL2, GATA6, HK2, HLA-DPB1, INTS6, SERPINE3<\/jats:italic> and <jats:italic>UPP1<\/jats:italic>) (Gamage et al. 2020, <jats:italic>Stem Cell Rev Rep<\/jats:italic>). We characterised these trophoblast side-population markers in human placenta and in placental insufficiency disorders: preeclampsia and fetal growth restriction (FGR). Trophoblast side-population markers localised to mononuclear trophoblasts lining the placental villous basement membrane in preterm control, preeclamptic and FGR placental sections (<jats:italic>n<\/jats:italic>\u2009=\u20093, panel of 3 markers\/serial section). Analysis of single-cell transcriptomics of an organoid human trophoblast stem cell (hTSC) to extravillous trophoblast (EVT) differentiation model (Shannon et al. 2022, <jats:italic>Development<\/jats:italic>) identified that all side-population genes were enriched in mononuclear trophoblast and trophoblasts committed to differentiation under hTSC culture conditions. <jats:italic>In vitro<\/jats:italic> validation via 96\u00a0h time course hTSC differentiation to EVTs or syncytiotrophoblasts (<jats:italic>n<\/jats:italic>\u2009=\u20095) demonstrated <jats:italic>ELL2<\/jats:italic> and <jats:italic>HK2<\/jats:italic> increased with differentiation (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0024, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0039 respectively). <jats:italic>CXCL8<\/jats:italic> and <jats:italic>HLA-DPB1<\/jats:italic> were downregulated (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.030, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.011 respectively). <jats:italic>GATA6<\/jats:italic> and <jats:italic>INTS6<\/jats:italic> increased with EVT differentiation only, and <jats:italic>UPP1<\/jats:italic> reduced with syncytialisation. <jats:italic>SERPINE3<\/jats:italic> was undetectable. Trophoblast side-population marker mRNA was measured in human placentas (&lt;\u200934-weeks\u2019 gestation; <jats:italic>n<\/jats:italic>\u2009=\u200978 preeclampsia, <jats:italic>n<\/jats:italic>\u2009=\u200930 FGR, and <jats:italic>n<\/jats:italic>\u2009=\u200918 gestation-matched controls). <jats:italic>ELL2, HK2<\/jats:italic> and <jats:italic>CXCL8<\/jats:italic> were elevated in preeclamptic (<jats:italic>p<\/jats:italic>\u2009=\u20090.0006, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001, <jats:italic>p<\/jats:italic>\u2009=\u20090.0335 respectively) and FGR placentas (<jats:italic>p<\/jats:italic>\u2009=\u20090.0065, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001, <jats:italic>p<\/jats:italic>\u2009=\u20090.0001 respectively) versus controls. Placental <jats:italic>GATA6<\/jats:italic> was reduced in pregnancies with preeclampsia and FGR (<jats:italic>p<\/jats:italic>\u2009=\u20090.0014, <jats:italic>p<\/jats:italic>\u2009=\u20090.0146 respectively).\u00a0Placental <jats:italic>INTS6<\/jats:italic> was reduced with FGR only (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). This study identified the localisation of a unique trophoblast subset enriched for side-population markers. Aberrant expression of some side-population markers may indicate disruptions to unique trophoblast subtypes in placental insufficiency.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s12015-024-10764-w","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T08:01:46Z","timestamp":1721376106000},"page":"1954-1970","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Trophoblast Side-Population Markers are Dysregulated in Preeclampsia and Fetal Growth Restriction"],"prefix":"10.1007","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4131-0008","authenticated-orcid":false,"given":"Georgia P.","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunhild","family":"Hartmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Simmons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Ellis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Nonn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Cannon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuong-Vi","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy A.","family":"Bartho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie J.","family":"Hannan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tu\u2019uhevaha J.","family":"Kaitu\u2019u-Lino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,19]]},"reference":[{"issue":"1","key":"10764_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejogrb.2013.05.005","volume":"170","author":"E Abalos","year":"2013","unstructured":"Abalos, E., Cuesta, C., Grosso, A. 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