• Cindrova-Davies, T. & Sferruzzi-Perri, A. N. Human placental development and function. Semin. Cell Dev. Biol. 131, 66–77 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Burton, G. J. & Fowden, A. L. The placenta: a multifaceted, transient organ. Philos. Trans. R. Soc. B 370, 20140066 (2015).

    Article 

    Google Scholar
     

  • Smith, G. C. S. First-trimester determination of complications of late pregnancy. JAMA 303, 561–562 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Brosens, I., Pijnenborg, R., Vercruysse, L. & Romero, R. The ‘great obstetrical syndromes’ are associated with disorders of deep placentation. Am. J. Obstet. Gynecol. 204, 193–201 (2011). This study coined the phrase ‘great obstetrical syndromes’, which describe pregnancy complications rooted in deficient trophoblast invasion.

    Article 
    PubMed 

    Google Scholar
     

  • Hamilton, W. J. & Boyd, J. D. Development of the human placenta in the first three months of gestation. J. Anat. 94, 297–328 (1960).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hertig, A. T., Rock, J. & Adams, E. C. A description of 34 human ova within the first 17 days of development. Am. J. Anat. 98, 435–493 (1956).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Pijnenborg, R., Dixon, G., Robertson, W. B. & Brosens, I. Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy. Placenta 1, 3–19 (1980).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Burton, G. J., Jauniaux, E. & Watson, A. L. Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited. Am. J. Obstet. Gynecol. 181, 718–724 (1999).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Armingol, E., Officer, A., Harismendy, O. & Lewis, N. E. Deciphering cell-cell interactions and communication from gene expression. Nat. Rev. Genet. 22, 71–88 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Suryawanshi, H. et al. A single-cell survey of the human first-trimester placenta and decidua. Sci. Adv. 4, eaau4788 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Vento-Tormo, R. et al. Single-cell reconstruction of the early maternal-fetal interface in humans. Nature 563, 347–353 (2018). This study was among the first to use single-cell transcriptomics to elucidate the cellular composition and interactions at the placental–decidual interface in early human pregnancy, identifying distinct immune cell subtypes (uNK1–uNK3 and uM1–uM3) and their predicted communication with trophoblast.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Tsang, J. C. H. et al. Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics. Proc. Natl Acad. Sci. USA 114, E7786–E7795 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Pique-Regi, R. et al. Single cell transcriptional signatures of the human placenta in term and preterm parturition. eLife 8, e52004 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Garcia-Flores, V. et al. Deciphering maternal-fetal cross-talk in the human placenta during parturition using single-cell RNA sequencing. Sci. Transl. Med. 16, eadh8335 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Liu, Y. et al. Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta. Cell Res. 28, 819–832 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Arutyunyan, A. et al. Spatial multiomics map of trophoblast development in early pregnancy. Nature 616, 143–151 (2023). This study presents a spatial multiomics dataset of implantation sites in early human pregnancy, uncovering the full trajectory of trophoblast differentiation and associated regulatory mechanisms.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Greenbaum, S. et al. A spatially resolved timeline of the human maternal-fetal interface. Nature 619, 595–605 (2023). This study used spatial proteomics and transcriptomics to profile the human placental–decidual interface across gestation, characterizing the cellular composition and interactions underlying both SAR and gestational progression.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Ounadjela, J. R. et al. Spatial multiomic landscape of the human placenta at molecular resolution. Nat. Med. 30, 3495–3508 (2024). This study provided a spatial reference of chromatin accessibility landscapes within first-trimester human placental villi at single-cell resolution, identifying genes under complex enhancer control (that is, domains of regulatory chromatin) and localizing them to discrete niches in the villi.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wang, C. et al. Single-cell spatiotemporal dissection of the human maternal-fetal interface. Nature 653, 167–179 (2026). This study surveyed the human maternal–fetal interface across gestation, combining spatial transcriptomics and paired single-nucleus and chromatin accessibility profiling to identify and characterize new trophoblast, decidual stromal and decidual endothelial cell states.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Okae, H. et al. Derivation of human trophoblast stem cells. Cell Stem Cell 22, 50–63.e6 (2018).  This landmark study derived hTSCs for the first time from both primary human placental villi and human blastocysts, and established robust protocols for their differentiation into SCTs and EVTs.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Haider, S. et al. Self-renewing trophoblast organoids recapitulate the developmental program of the early human placenta. Stem Cell Rep. 11, 537–551 (2018). 

    Article 
    CAS 

    Google Scholar
     

  • Turco, M. Y. et al. Trophoblast organoids as a model for maternal-fetal interactions during human placentation. Nature 564, 263–267 (2018). This study provided one of the first robust protocols for deriving primary human trophoblast organoids and their subsequent differentiation into trophoblast subtypes (EVT).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Horii, M. et al. Modeling preeclampsia using human induced pluripotent stem cells. Sci. Rep. 11, 5877 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hori, T. et al. Trophoblast stem cell-based organoid models of the human placental barrier. Nat. Commun. 15, 962 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Dong, C. et al. A genome-wide CRISPR-Cas9 knockout screen identifies essential and growth-restricting genes in human trophoblast stem cells. Nat. Commun. 13, 2548 (2022). This study used a CRISPR–Cas9-based screen in hTSCs to identify key regulators of trophoblast proliferation.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Muter, J., Lynch, V. J., McCoy, R. C. & Brosens, J. J. Human embryo implantation. Development 150, dev201507 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Turco, M. Y. & Moffett, A. Development of the human placenta. Development 146, dev163428 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Knöfler, M. et al. Human placenta and trophoblast development: key molecular mechanisms and model systems. Cell. Mol. Life Sci. 76, 3479–3496 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Molè, M. A., Weberling, A. & Zernicka-Goetz, M. Comparative analysis of human and mouse development: from zygote to pre-gastrulation. Curr. Top. Dev. Biol. 136, 113–138 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Burton, G. J., Watson, A. L., Hempstock, J., Skepper, J. N. & Jauniaux, E. Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. J. Clin. Endocrinol. Metab. 87, 2954–2959 (2002).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Demir, R. et al. Sequential expression of VEGF and its receptors in human placental villi during very early pregnancy: differences between placental vasculogenesis and angiogenesis. Placenta 25, 560–572 (2004).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kayisli, U. A. et al. Spatial and temporal distribution of Tie-1 and Tie-2 during very early development of the human placenta. Placenta 27, 648–659 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Aplin, J. D. et al. Hemangioblastic foci in human first trimester placenta: distribution and gestational profile. Placenta 36, 1069–1077 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Huppertz, B. & Borges, M. Placenta trophoblast fusion. Methods Mol. Biol. 475, 135–147 (2008).

    Article 
    PubMed 

    Google Scholar
     

  • Baergen, R. N., Burton, G. J. & Kaplan, C. G. (eds). Benirschke’s Pathology of the Human Placenta https://doi.org/10.1007/978-3-030-84725-8 (Springer, 2021).

  • Burton, G. J. & Jauniaux, E. The cytotrophoblastic shell and complications of pregnancy. Placenta 60, 134–139 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Boyd, J. D. & Hamilton, W. J. Growth of placenta. In The Human Placenta 136–139 (Palgrave Macmillan, 1970).

  • Hustin, J. & Schaaps, J. P. Echographic [corrected] and anatomic studies of the maternotrophoblastic border during the first trimester of pregnancy. Am. J. Obstet. Gynecol. 157, 162–168 (1987).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Pijnenborg, R., Vercruysse, L. & Hanssens, M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 27, 939–958 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kam, E. P., Gardner, L., Loke, Y. W. & King, A. The role of trophoblast in the physiological change in decidual spiral arteries. Hum. Reprod. 14, 2131–2138 (1999).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Burton, G. J., Woods, A. W., Jauniaux, E. & Kingdom, J. C. P. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta 30, 473–482 (2009).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Jones, C. J. P. & Aplin, J. D. A re-examination of the origins of placental bed giant cells. Placenta 114, 39–41 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • al-Lamki, R. S., Skepper, J. N. & Burton, G. J. Are human placental bed giant cells merely aggregates of small mononuclear trophoblast cells? An ultrastructural and immunocytochemical study. Hum. Reprod. 14, 496–504 (1999).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Castellucci, M., Kosanke, G., Verdenelli, F., Huppertz, B. & Kaufmann, P. Villous sprouting: fundamental mechanisms of human placental development. Hum. Reprod. Update 6, 485–494 (2000).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Petropoulos, S. et al. Single-cell RNA-seq reveals lineage and X chromosome dynamics in human preimplantation embryos. Cell 165, 1012–1026 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Yanagida, A. et al. Naive stem cell blastocyst model captures human embryo lineage segregation. Cell Stem Cell 28, 1016–1022.e4 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Meistermann, D. et al. Integrated pseudotime analysis of human pre-implantation embryo single-cell transcriptomes reveals the dynamics of lineage specification. Cell Stem Cell 28, 1625–1640.e6 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Xiang, L. et al. A developmental landscape of 3D-cultured human pre-gastrulation embryos. Nature 577, 537–542 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zhao, C. et al. A comprehensive human embryo reference tool using single-cell RNA-sequencing data. Nat. Methods 22, 193–206 (2025). This is an integrated reference dataset for human embryo development spanning pre-implantation to post-implantation stages.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Saha, B. et al. TEAD4 ensures postimplantation development by promoting trophoblast self-renewal: an implication in early human pregnancy loss. Proc. Natl Acad. Sci. USA 117, 17864–17875 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Meinhardt, G. et al. Pivotal role of the transcriptional co-activator YAP in trophoblast stemness of the developing human placenta. Proc. Natl Acad. Sci. USA 117, 13562–13570 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Papuchova, H. & Latos, P. A. Transcription factor networks in trophoblast development. Cell. Mol. Life Sci. 79, 337 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Aplin, J. D. & Jones, C. J. P. Cell dynamics in human villous trophoblast. Hum. Reprod. Update 27, 904–922 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Ng, R. K. et al. Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5. Nat. Cell Biol. 10, 1280–1290 (2008).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hemberger, M., Udayashankar, R., Tesar, P., Moore, H. & Burton, G. J. ELF5-enforced transcriptional networks define an epigenetically regulated trophoblast stem cell compartment in the human placenta. Hum. Mol. Genet. 19, 2456–2467 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Soncin, F. et al. Comparative analysis of mouse and human placentae across gestation reveals species-specific regulators of placental development. Development 145, dev156273 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Calderon, R. I. et al. VGLL1 contributes to both the transcriptome and epigenome of the developing trophoblast compartment. Proc. Natl Acad. Sci. USA 122, e2508432122 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Gerri, C. et al. Initiation of a conserved trophectoderm program in human, cow and mouse embryos. Nature 587, 443–447 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hornbachner, R. et al. MSX2 safeguards syncytiotrophoblast fate of human trophoblast stem cells. Proc. Natl Acad. Sci. USA 118, e2105130118 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Li, Y., Moretto-Zita, M., Leon-Garcia, S. & Parast, M. M. P63 inhibits extravillous trophoblast migration and maintains cells in a cytotrophoblast stem cell-like state. Am. J. Pathol. 184, 3332–3343 (2014).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Li, W.-F. et al. The transcription factor PBX3 promotes tumor cell growth through transcriptional suppression of the tumor suppressor p53. Acta Pharmacol. Sin. 42, 1888–1899 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Costa, M. A. The endocrine function of human placenta: an overview. Reprod. Biomed. Online 32, 14–43 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Renaud, S. J. & Jeyarajah, M. J. How trophoblasts fuse: an in-depth look into placental syncytiotrophoblast formation. Cell. Mol. Life Sci. 79, 433 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Burton, G. J. & Watson, A. L. The structure of the human placenta: implications for initiating and defending against virus infections. Rev. Med. Virol. 7, 219–228 (1997).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Wang, M. et al. Single-nucleus multi-omic profiling of human placental syncytiotrophoblasts identifies cellular trajectories during pregnancy. Nat. Genet. 56, 294–305 (2024). This study used single-nucleus transcriptomics and chromatin accessibility profiling to characterize distinct SCT subtype transitions, and associated regulatory programmes, across human pregnancy.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Petrany, M. J. et al. Single-nucleus RNA-seq identifies transcriptional heterogeneity in multinucleated skeletal myofibers. Nat. Commun. 11, 6374 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Chuong, E. B., Rumi, M. A. K., Soares, M. J. & Baker, J. C. Endogenous retroviruses function as species-specific enhancer elements in the placenta. Nat. Genet. 45, 325–329 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Todd, C. D., Deniz, Ö, Taylor, D. & Branco, M. R. Functional evaluation of transposable elements as enhancers in mouse embryonic and trophoblast stem cells. eLife 8, e44344 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Frost, J. M. et al. Regulation of human trophoblast gene expression by endogenous retroviruses. Nat. Struct. Mol. Biol. 30, 527–538 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Fueyo, R. et al. A human-specific regulatory mechanism revealed in a pre-implantation model. Nature 647, 238–247 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Anwar, R. et al. ERV3-MLT1 provides cis-regulatory elements for human placental functioning and are commonly dysregulated in human-specific preeclampsia. Genome Biol. 26, 364 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Keighley, L. M., Lynch-Sutherland, C. F., Almomani, S. N., Eccles, M. R. & Macaulay, E. C. Unveiling the hidden players: the crucial role of transposable elements in the placenta and their potential contribution to pre-eclampsia. Placenta 141, 57–64 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Štafl, K. et al. Receptor usage of Syncytin-1: ASCT2, but not ASCT1, is a functional receptor and effector of cell fusion in the human placenta. Proc. Natl Acad. Sci. USA 121, e2407519121 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Soygur, B. & Sati, L. The role of syncytins in human reproduction and reproductive organ cancers. Reproduction 152, R167–R178 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Cesana, M. et al. TFEB controls syncytiotrophoblast formation and hormone production in placenta. Cell Death Differ. 31, 1439–1451 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zheng, W. et al. TFEB safeguards trophoblast syncytialization in humans and mice. Proc. Natl Acad. Sci. USA 121, e2404062121 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Liang, C.-Y. et al. GCM1 regulation of the expression of syncytin 2 and its cognate receptor MFSD2A in human placenta. Biol. Reprod. 83, 387–395 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Karlsson, M. et al. A single-cell type transcriptomics map of human tissues. Sci. Adv. 7, eabh2169 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Cinkornpumin, J. K. et al. Hypoxia and loss of GCM1 expression prevent differentiation and contact inhibition in human trophoblast stem cells. Stem Cell Rep. 20, 102481 (2025).

    Article 
    CAS 

    Google Scholar
     

  • Genbacev, O., Zhou, Y., Ludlow, J. W. & Fisher, S. J. Regulation of human placental development by oxygen tension. Science 277, 1669–1672 (1997).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Burton, G. J., Cindrova-Davies, T., Yung, H. W. & Jauniaux, E. Hypoxia and reproductive health: oxygen and development of the human placenta. Reproduction 161, F53–F65 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kopriva, S. E., Chiasson, V. L., Mitchell, B. M. & Chatterjee, P. TLR3-induced placental miR-210 down-regulates the STAT6/interleukin-4 pathway. PLoS ONE 8, e67760 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Monget, P. & Oxvig, C. PAPP-A and the IGF system. Ann. Endocrinol. 77, 90–96 (2016).

    Article 

    Google Scholar
     

  • Cristodoro, M. et al. First trimester placental biomarkers for pregnancy outcomes. Int. J. Mol. Sci. 25, 6136 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Mayhew, T. M. A stereological perspective on placental morphology in normal and complicated pregnancies. J. Anat. 215, 77–90 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Männik, J., Vaas, P., Rull, K., Teesalu, P. & Laan, M. Differential placental expression profile of human Growth Hormone/Chorionic Somatomammotropin genes in pregnancies with pre-eclampsia and gestational diabetes mellitus. Mol. Cell. Endocrinol. 355, 180–187 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Männik, J. et al. Differential expression profile of growth hormone/chorionic somatomammotropin genes in placenta of small- and large-for-gestational-age newborns. J. Clin. Endocrinol. Metab. 95, 2433–2442 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Freemark, M. Regulation of maternal metabolism by pituitary and placental hormones: roles in fetal development and metabolic programming. Horm. Res. 65, 41–49 (2006).

    PubMed 
    CAS 

    Google Scholar
     

  • Napso, T., Yong, H. E. J., Lopez-Tello, J. & Sferruzzi-Perri, A. N. The role of placental hormones in mediating maternal adaptations to support pregnancy and lactation. Front. Physiol. 9, 1091 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Walker, V. The molecular biology of placental transport of calcium to the human foetus. Int. J. Mol. Sci. 26, 383 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Loukeris, K., Sela, R. & Baergen, R. N. Syncytial knots as a reflection of placental maturity: reference values for 20 to 40 weeks’ gestational age. Pediatr. Dev. Pathol. 13, 305–309 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Fogarty, N. M. E., Ferguson-Smith, A. C. & Burton, G. J. Syncytial knots (Tenney-Parker changes) in the human placenta: evidence of loss of transcriptional activity and oxidative damage. Am. J. Pathol. 183, 144–152 (2013).

    Article 
    PubMed 

    Google Scholar
     

  • Bierens, J. et al. Imaging and quantification of placental terminal villi microvasculature and nuclear characteristics in preeclampsia. Eur. J. Obstet. Gynecol. Reprod. Biol. 308, 181–189 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Luo, Y. et al. Clinical and pathological characteristics of gestational diabetes mellitus with different insulin resistance. J. Diabetes Complications 38, 108796 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Bhanarkar, U. & Potdar, P. A cross-sectional study comparing placental characteristics in pregnancy-induced hypertension and sickle cell anaemia. Cureus 16, e70034 (2024).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Barak, Y. et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol. Cell 4, 585–595 (1999).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Ruebner, M. et al. Regulation of the human endogenous retroviral Syncytin-1 and cell-cell fusion by the nuclear hormone receptors PPARγ/RXRα in placentogenesis. J. Cell. Biochem. 113, 2383–2396 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Armistead, B. et al. Induction of the PPARγ (peroxisome proliferator-activated receptor γ)-GCM1 (glial cell missing 1) syncytialization axis reduces sFLT1 (soluble fms-like tyrosine kinase 1) in the preeclamptic placenta. Hypertension 78, 230–240 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Chen, Z. et al. PPARγ stimulates expression of L-type amino acid and taurine transporters in human placentas: the evidence of PPARγ regulating fetal growth. Sci. Rep. 5, 12650 (2015).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Gaccioli, F. et al. Expression and functional characterisation of System L amino acid transporters in the human term placenta. Reprod. Biol. Endocrinol. 13, 57 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ohgaki, R. et al. Essential roles of L-type amino acid transporter 1 in syncytiotrophoblast development by presenting fusogenic 4F2hc. Mol. Cell. Biol. 37, e00427–16 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kudo, Y., Boyd, C. A. R., Millo, J., Sargent, I. L. & Redman, C. W. G. Manipulation of CD98 expression affects both trophoblast cell fusion and amino acid transport activity during syncytialization of human placental BeWo cells. J. Physiol. 550, 3–9 (2003).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • He, P. et al. Reduced expression of 11β-hydroxysteroid dehydrogenase type 2 in preeclamptic placentas is associated with decreased PPARγ but increased PPARα expression. Endocrinology 155, 299–309 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Granitzer, S. et al. LAT1-NRF2 axis controls sFlt-1/PlGF imbalance and oxidative stress in preeclampsia. Nat. Commun. 16, 9112 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Guo, Q., Choi, J., Lee, M. & Kim, J. PPARG-centric transcriptional re-wiring during differentiation of human trophoblast stem cells into extravillous trophoblasts. Nucleic Acids Res. 53, gkaf669 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Keenen, M. M. et al. Comparative analysis of the syncytiotrophoblast in placenta tissue and trophoblast organoids using snRNA sequencing. eLife 13, RP101170 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pierleoni, C., Castellucci, M., Kaufmann, P., Lund, L. R. & Schnack Nielsen, B. Urokinase receptor is up-regulated in endothelial cells and macrophages associated with fibrinoid deposits in the human placenta. Placenta 24, 677–685 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Thomas, J. R. et al. Phenotypic and functional characterization of first-trimester human placental macrophages, Hofbauer cells. J. Exp. Med. 218, e20200891 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Jauniaux, E. & Jurkovic, D. Placenta accreta: pathogenesis of a 20th century iatrogenic uterine disease. Placenta 33, 244–251 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Garrido-Gomez, T. et al. Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology. Proc. Natl Acad. Sci. USA 114, E8468–E8477 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Lee, C. Q. E. et al. Integrin α2 marks a niche of trophoblast progenitor cells in first trimester human placenta. Development 145, dev162305 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Damsky, C. H. et al. Integrin switching regulates normal trophoblast invasion. Development 120, 3657–3666 (1994).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Dietrich, B., Haider, S., Meinhardt, G., Pollheimer, J. & Knöfler, M. WNT and NOTCH signaling in human trophoblast development and differentiation. Cell. Mol. Life Sci. 79, 292 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Haider, S. et al. Notch1 controls development of the extravillous trophoblast lineage in the human placenta. Proc. Natl Acad. Sci. USA 113, E7710–E7719 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Meinhardt, G. et al. The multifaceted roles of the transcriptional coactivator TAZ in extravillous trophoblast development of the human placenta. Proc. Natl Acad. Sci. USA 122, e2426385122 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Gu, B. et al. The TEA domain transcription factors TEAD1 and TEAD3 and WNT signaling determine HLA-G expression in human extravillous trophoblasts. Proc. Natl Acad. Sci. USA 122, e2425339122 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Ghosh, A. et al. The GATA transcriptional program dictates cell fate equilibrium to establish the maternal-fetal exchange interface and fetal development. Proc. Natl Acad. Sci. USA 121, e2310502121 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Varberg, K. M. et al. Extravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape. Nat. Commun. 14, 4826 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kim, M. et al. The transcriptional regulatory network modulating human trophoblast stem cells to extravillous trophoblast differentiation. Nat. Commun. 15, 1285 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Shukla, V. et al. NOTUM-mediated WNT silencing drives extravillous trophoblast cell lineage development. Proc. Natl Acad. Sci. USA 121, e2403003121 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kakugawa, S. et al. Notum deacylates Wnt proteins to suppress signalling activity. Nature 519, 187–192 (2015).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Dietrich, B. et al. NOTCH3 signalling controls human trophoblast stem cell expansion and differentiation. Development 150, dev202152 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178–196 (2014).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Haider, S. et al. Transforming growth factor-β signaling governs the differentiation program of extravillous trophoblasts in the developing human placenta. Proc. Natl Acad. Sci. USA 119, e2120667119 (2022). This study explores the role of TGFβ signalling in generating higher-fidelity invasive EVTs in vitro.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Perez-Garcia, V. et al. BAP1/ASXL complex modulation regulates epithelial-mesenchymal transition during trophoblast differentiation and invasion. eLife 10, e63254 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Thompson, E. W. et al. EMT and cancer: what clinicians should know. Nat. Rev. Clin. Oncol. 22, 711–733 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Zhang, D. et al. ASCL2 induces an immune excluded microenvironment by activating cancer-associated fibroblasts in microsatellite stable colorectal cancer. Oncogene 42, 2841–2853 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kong, S.-Y. et al. The ELK3-GATA3 axis orchestrates invasion and metastasis of breast cancer cells in vitro and in vivo. Oncotarget 7, 65137–65146 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He, Y. et al. EGFR-ERK induced activation of GRHL1 promotes cell cycle progression by up-regulating cell cycle related genes in lung cancer. Cell Death Dis. 12, 430 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Wakeland, A. K. et al. Hypoxia directs human extravillous trophoblast differentiation in a hypoxia-inducible factor-dependent manner. Am. J. Pathol. 187, 767–780 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Treissman, J. et al. Low oxygen enhances trophoblast column growth by potentiating differentiation of the extravillous lineage and promoting LOX activity. Development 147, dev181263 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zhou, Y. et al. LIMK1 regulates human trophoblast invasion/differentiation and is down-regulated in preeclampsia. Am. J. Pathol. 184, 3321–3331 (2014).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Genbacev, O., Joslin, R., Damsky, C. H., Polliotti, B. M. & Fisher, S. J. Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. J. Clin. Invest. 97, 540–550 (1996).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Cowden Dahl, K. D. et al. Hypoxia-inducible factors 1alpha and 2alpha regulate trophoblast differentiation. Mol. Cell. Biol. 25, 10479–10491 (2005).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Maltepe, E. et al. Hypoxia-inducible factor-dependent histone deacetylase activity determines stem cell fate in the placenta. Development 132, 3393–3403 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Pijnenborg, R. & Vercruysse, L. Animal models of deep trophoblast invasion. In Placental Bed Disorders (eds Pijnenborg, R. et al.) 127–139 https://doi.org/10.1017/cbo9780511750847.014 (Cambridge Univ. Press, 2010).

  • Renaud, S. J., Kubota, K., Rumi, M. A. K. & Soares, M. J. The FOS transcription factor family differentially controls trophoblast migration and invasion. J. Biol. Chem. 289, 5025–5039 (2014).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Moffett, A. & Shreeve, N. Local immune recognition of trophoblast in early human pregnancy: controversies and questions. Nat. Rev. Immunol. 23, 222–235 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Papuchova, H. et al. Three types of HLA-G+ extravillous trophoblasts that have distinct immune regulatory properties. Proc. Natl Acad. Sci. USA 117, 15772–15777 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Brosens, I., Robertson, W. B. & Dixon, H. G. The physiological response of the vessels of the placental bed to normal pregnancy. J. Pathol. Bacteriol. 93, 569–579 (1967).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Wiedemann, E. et al. Regulation of endothelial migration and proliferation by ephrin-A1. Cell. Signal. 29, 84–95 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Jerafi-Vider, A. et al. VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells. Cell Rep. 35, 109255 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Fagiani, E. & Christofori, G. Angiopoietins in angiogenesis. Cancer Lett. 328, 18–26 (2013).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Gonçalves Silva, I. et al. The Tim-3-galectin-9 secretory pathway is involved in the immune escape of human acute myeloid leukemia cells. eBioMedicine 22, 44–57 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wilkens, J. et al. Uterine NK cells regulate endometrial bleeding in women and are suppressed by the progesterone receptor modulator asoprisnil. J. Immunol. 191, 2226–2235 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Choudhury, R. H. et al. Decidual leucocytes infiltrating human spiral arterioles are rich source of matrix metalloproteinases and degrade extracellular matrix in vitro and in situ. Am. J. Reprod. Immunol. 81, e13054 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Hazan, A. D. et al. Vascular-leukocyte interactions: mechanisms of human decidual spiral artery remodeling in vitro. Am. J. Pathol. 177, 1017–1030 (2010).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Robson, A. et al. Uterine natural killer cells initiate spiral artery remodeling in human pregnancy. FASEB J. 26, 4876–4885 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Fraser, R., Whitley, G. S. J., Thilaganathan, B. & Cartwright, J. E. Decidual natural killer cells regulate vessel stability: implications for impaired spiral artery remodelling. J. Reprod. Immunol. 110, 54–60 (2015).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Puig-Gámez, M., Van Attekum, M., Theis, T., Dick, A. & Park, J. E. Transcriptional signature of rapidly responding NK cells reveals S1P5 and CXCR4 as anti-tumor response disruptors. Sci. Rep. 15, 10769 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, E. et al. CXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis. Nat. Commun. 16, 4854 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Solano, M. E. Decidual immune cells: guardians of human pregnancies. Best Pract. Res. Clin. Obstet. Gynaecol. 60, 3–16 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Vondra, S. et al. The human placenta shapes the phenotype of decidual macrophages. Cell Rep. 42, 112285 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Huhn, O. et al. Distinctive phenotypes and functions of innate lymphoid cells in human decidua during early pregnancy. Nat. Commun. 11, 381 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hiby, S. E. et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J. Exp. Med. 200, 957–965 (2004). This haplotype association study linked maternal KIR genotype AA, when paired with fetal HLA-C2, with a higher risk of pre-eclampsia.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hamilton, G. S., Lysiak, J. J., Watson, A. J. & Lala, P. K. Effects of colony stimulating factor-1 on human extravillous trophoblast growth and invasion. J. Endocrinol. 159, 69–77 (1998).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Sato, Y. et al. Trophoblasts acquire a chemokine receptor, CCR1, as they differentiate towards invasive phenotype. Development 130, 5519–5532 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Li, Q. et al. Human uterine natural killer cells regulate differentiation of extravillous trophoblast early in pregnancy. Cell Stem Cell 31, 181–195.e9 (2024). This study functionally validated the role of uNK-derived cytokines in modulating trophoblast invasion.

    Article 
    PubMed 

    Google Scholar
     

  • Hegde, U. C. Immunomodulation of the mother during pregnancy. Med. Hypotheses 35, 159–164 (1991).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Li, W.-X., Xu, X.-H. & Jin, L.-P. Regulation of the innate immune cells during pregnancy: an immune checkpoint perspective. J. Cell. Mol. Med. 25, 10362–10375 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Deer, E. et al. The role of immune cells and mediators in preeclampsia. Nat. Rev. Nephrol. 19, 257–270 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Arenas-Hernandez, M. et al. Effector and activated T cells induce preterm labor and birth that is prevented by treatment with progesterone. J. Immunol. 202, 2585–2608 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Cai, J. & Li, Q. Mendelian randomization analysis of the causal links between immune cells, metabolites, and ectopic pregnancy. Eur. J. Obstet. Gynecol. Reprod. Biol. 316, 114797 (2026).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Apps, R. et al. Human leucocyte antigen (HLA) expression of primary trophoblast cells and placental cell lines, determined using single antigen beads to characterize allotype specificities of anti-HLA antibodies. Immunology 127, 26–39 (2009).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Lee, C. Q. E. et al. What is trophoblast? A combination of criteria define human first-trimester trophoblast. Stem Cell Rep. 6, 257–272 (2016). This paper proposed a framework consisting of four criteria that together define the identity of first-trimester human trophoblasts.

    Article 
    CAS 

    Google Scholar
     

  • Petroff, M. G. et al. B7 family molecules are favorably positioned at the human maternal-fetal interface. Biol. Reprod. 68, 1496–1504 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kovats, S. et al. A class I antigen, HLA-G, expressed in human trophoblasts. Science 248, 220–223 (1990).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • King, A. et al. HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells. Eur. J. Immunol. 30, 1623–1631 (2000).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Loke, Y. W. & King, A. Immunology of implantation. Baillieres Best Pract. Res. Clin. Obstet. Gynaecol. 14, 827–837 (2000).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Apps, R., Gardner, L., Sharkey, A. M., Holmes, N. & Moffett, A. A homodimeric complex of HLA-G on normal trophoblast cells modulates antigen-presenting cells via LILRB1. Eur. J. Immunol. 37, 1924–1937 (2007).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • King, A., Birkby, C. & Loke, Y. W. Early human decidual cells exhibit NK activity against the K562 cell line but not against first trimester trophoblast. Cell. Immunol. 118, 337–344 (1989).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Pitts, H. A. et al. SPINK2 protein expression is an independent adverse prognostic marker in AML and is potentially implicated in the regulation of ferroptosis and immune response. Int. J. Mol. Sci. 24, 9696 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Han, P.-F. et al. Annexin A1 involved in the regulation of inflammation and cell signaling pathways. Chin. J. Traumatol. 23, 96–101 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Takenaka, M. C., Robson, S. & Quintana, F. J. Regulation of the T cell response by CD39. Trends Immunol. 37, 427–439 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Bouariu, A., Panaitescu, A. M. & Nicolaides, K. H. First trimester prediction of adverse pregnancy outcomes-identifying pregnancies at risk from as early as 11-13 weeks. Medicina 58, 332 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dimitriadis, E. et al. Pre-eclampsia. Nat. Rev. Dis. Primers 9, 8 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Chappell, L. C., Cluver, C. A., Kingdom, J. & Tong, S. Pre-eclampsia. Lancet 398, 341–354 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Hiby, S. E. et al. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum. Reprod. 23, 972–976 (2008).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Hiby, S. E. et al. Maternal KIR in combination with paternal HLA-C2 regulate human birth weight. J. Immunol. 192, 5069–5073 (2014).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Tyrmi, J. S. et al. Genetic risk factors associated with preeclampsia and hypertensive disorders of pregnancy. JAMA Cardiol. 8, 674–683 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pujol Gualdo, N. et al. Atlas of genetic and phenotypic associations across 42 female reproductive health diagnoses. Nat. Med. 31, 1626–1634 (2025). This study provided a meta-analysis of GWAS results for various reproductive disorders, describing genetic risk factors implicated in reproductive development and function.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Manokhina, I., Wilson, S. L. & Robinson, W. P. Noninvasive nucleic acid-based approaches to monitor placental health and predict pregnancy-related complications. Am. J. Obstet. Gynecol. 213, S197–S206 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Moufarrej, M. N. et al. Early prediction of preeclampsia in pregnancy with cell-free RNA. Nature 602, 689–694 (2022). This study identified cell-free RNA signatures that may serve as early predictors of pre-eclampsia.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • De Borre, M. et al. Cell-free DNA methylome analysis for early preeclampsia prediction. Nat. Med. 29, 2206–2215 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Adil, M. et al. Preeclampsia risk prediction from prenatal cell-free DNA screening. Nat. Med. 31, 1312–1318 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Elovitz, M. A. et al. Molecular subtyping of hypertensive disorders of pregnancy. Nat. Commun. 16, 2948 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111, 649–658 (2003).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Levine, R. J. et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672–683 (2004).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zeisler, H. et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N. Engl. J. Med. 374, 13–22 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Miller, J. J. et al. Clinical validation of the sFlt-1:PlGF ratio as a biomarker for preeclampsia diagnosis in a high-risk obstetrics unit. J. Appl. Lab. Med. 8, 457–468 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Gaccioli, F., Lager, S., Sovio, U., Charnock-Jones, D. S. & Smith, G. C. S. The pregnancy outcome prediction (POP) study: investigating the relationship between serial prenatal ultrasonography, biomarkers, placental phenotype and adverse pregnancy outcomes. Placenta 59, S17–S25 (2017).

    Article 
    PubMed Central 

    Google Scholar
     

  • Kariori, M., Katsi, V. & Tsioufis, C. Late vs early preeclampsia. Int. J. Mol. Sci. 26, 11091 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hiby, S. E. et al. Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J. Clin. Invest. 120, 4102–4110 (2010).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Gil Laborda, R. et al. Centromeric AA motif in KIR as an optimal surrogate marker for precision definition of alloimmune reproductive failure. Sci. Rep. 14, 3354 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Xiong, S. et al. Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation. J. Clin. Invest. 123, 4264–4272 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kennedy, P. R. et al. Activating KIR2DS4 is expressed by uterine NK cells and contributes to successful pregnancy. J. Immunol. 197, 4292–4300 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Redman, C. W. G., Staff, A. C. & Roberts, J. M. Syncytiotrophoblast stress in preeclampsia: the convergence point for multiple pathways. Am. J. Obstet. Gynecol. 226, S907–S927 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Guller, S. Role of the syncytium in placenta-mediated complications of preeclampsia. Thromb. Res. 124, 389–392 (2009).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Aplin, J. D., Myers, J. E., Timms, K. & Westwood, M. Tracking placental development in health and disease. Nat. Rev. Endocrinol. 16, 479–494 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • McGinnis, R. et al. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. Nat. Genet. 49, 1255–1260 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Mack, J. A. et al. Genetic variants associated with preeclampsia and maternal serum sFLT1 levels. Hypertension 82, 839–848 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Admati, I. et al. Two distinct molecular faces of preeclampsia revealed by single-cell transcriptomics. Med 4, 687–709.e7 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Granger, J. P., Alexander, B. T., Llinas, M. T., Bennett, W. A. & Khalil, R. A. Pathophysiology of preeclampsia: linking placental ischemia/hypoxia with microvascular dysfunction. Microcirculation 9, 147–160 (2002).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Li, H., Gu, B., Zhang, Y., Lewis, D. F. & Wang, Y. Hypoxia-induced increase in soluble Flt-1 production correlates with enhanced oxidative stress in trophoblast cells from the human placenta. Placenta 26, 210–217 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Fuenzalida, B. et al. Primary human trophoblasts mimic the preeclampsia phenotype after acute hypoxia-reoxygenation insult. Cells 11, 1898 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Ma, J. et al. The diversity of trophoblast cells and niches of placenta accreta spectrum disorders revealed by single-cell RNA sequencing. Front. Cell Dev. Biol. 10, 1044198 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Afshar, Y. et al. Placenta accreta spectrum disorder at single-cell resolution: a loss of boundary limits in the decidua and endothelium. Am. J. Obstet. Gynecol. 230, 443.e1–443.e18 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Ji, K. et al. Single-cell and spatial transcriptomics reveal alterations in trophoblasts at invasion sites and disturbed myometrial immune microenvironment in placenta accreta spectrum disorders. Biomark. Res. 12, 55 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gingrich, J., Ticiani, E. & Veiga-Lopez, A. Placenta disrupted: endocrine disrupting chemicals and pregnancy. Trends Endocrinol. Metab. 31, 508–524 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Mathiesen, L., Sandal, D., Hammer, I. E. M., Styrishave, B. & Knudsen, L. E. Models of endocrine-disrupting effects: human placental steroidogenesis. Basic Clin. Pharmacol. Toxicol. 137, e70073 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Armingol, E. et al. Atlas-scale metabolic activities inferred from single-cell and spatial transcriptomics. Preprint at bioRxiv https://doi.org/10.1101/2025.05.09.653038 (2025).

  • Wagner, A. et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 184, 4168–4185.e21 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Maizels, R. J. & Briscoe, J. Gene regulatory networks: from correlative models to causal explanations. Nat. Rev. Genet. 27, 485–498 (2026).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Karvas, R. M. et al. Stem-cell-derived trophoblast organoids model human placental development and susceptibility to emerging pathogens. Cell Stem Cell 29, 810–825.e8 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Schwarz, L. C. et al. A blastocyst-derived in vitro model of the human chorion. Preprint at bioRxiv https://doi.org/10.1101/2025.08.06.668884 (2025).

  • Shannon, M. J. et al. Single-cell assessment of primary and stem cell-derived human trophoblast organoids as placenta-modeling platforms. Dev. Cell 59, 776–792.e11 (2024). This study benchmarks trophoblast organoid models from different origins (stem cells versus primary) using single-cell transcriptomics.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Sheridan, M. A. et al. Characterization of primary models of human trophoblast. Development 148, dev199749 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hoo, R. et al. Acute response to pathogens in the early human placenta at single-cell resolution. Cell Syst. 15, 425–444.e9 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Turco, M. Y. et al. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat. Cell Biol. 19, 568–577 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Boretto, M. et al. Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability. Development 144, 1775–1786 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Boretto, M. et al. Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening. Nat. Cell Biol. 21, 1041–1051 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Gnecco, J. S. et al. Organoid co-culture model of the human endometrium in a fully synthetic extracellular matrix enables the study of epithelial-stromal crosstalk. Med 4, 554–579.e9 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Rawlings, T. M. et al. Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids. eLife 10, e69603 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Yu, L. et al. Large-scale production of human blastoids amenable to modeling blastocyst development and maternal-fetal cross talk. Cell Stem Cell 30, 1246–1261.e9 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kagawa, H. et al. Human blastoids model blastocyst development and implantation. Nature 601, 600–605 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Shibata, S. et al. Modeling embryo-endometrial interface recapitulating human embryo implantation. Sci. Adv. 10, eadi4819 (2024). This study developed a multicellular in vitro 3D platform encompassing endometrial epithelial, stromal and endothelial compartments that recapitulate key stages of human embryo implantation.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Molè, M. A. et al. Modeling human embryo implantation in vitro. Cell 189, 87–105.e28 (2026). This study recently developed a bi-compartmentalized scaffold containing endometrial epithelial and stromal cells that resemble key features of endometrial tissue architecture (for example, invaginating glands), which is permissive to human embryo implantation.

    Article 
    PubMed 

    Google Scholar
     

  • Li, Q. et al. A 3D in vitro model for studying human implantation and implantation failure. Cell 189, 70–86.e20 (2026).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Liu, L. et al. Modeling post-implantation stages of human development into early organogenesis with stem-cell-derived peri-gastruloids. Cell 186, 3776–3792.e16 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Simoni, M. K. et al. Type I interferon exposure of an implantation-on-a-chip device alters invasive extravillous trophoblast function. Cell Rep. Med. 6, 101991 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Park, J. Y. et al. A microphysiological model of human trophoblast invasion during implantation. Nat. Commun. 13, 1252 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kim, S. W., Genceroglu, A. & Kim, J. Patient-specific trophoblast stem cells for placental medicine. Trends Mol. Med. https://doi.org/10.1016/j.molmed.2026.02.009 (2026).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pacesa, M., Pelea, O. & Jinek, M. Past, present, and future of CRISPR genome editing technologies. Cell 187, 1076–1100 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Shimizu, T. et al. 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 (2023). The second CRISPR–Cas9-based screen in hTSCs, identifying key regulators driving the acquisition of specific trophoblast fates (SCT and EVT).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Rood, J. E. et al. The Human Cell Atlas from a cell census to a unified foundation model. Nature 637, 1065–1071 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Bahrami, M., Richter, T., Schmacke, N. A., Egea Lavandera, A. & Theis, F. J. From modality-specific to compositional foundation models for cell biology. Cell Syst. 17, 101534 (2026).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Cui, H. et al. Towards multimodal foundation models in molecular cell biology. Nature 640, 623–633 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Genbacev, O., Schubach, S. A. & Miller, R. K. Villous culture of first trimester human placenta-model to study extravillous trophoblast (EVT) differentiation. Placenta 13, 439–461 (1992).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Newby, D., Marks, L., Cousins, F., Duffie, E. & Lyall, F. Villous explant culture: characterization and evaluation of a model to study trophoblast invasion. Hypertens. Pregnancy 24, 75–91 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Sooranna, S. R., Oteng-Ntim, E., Meah, R., Ryder, T. A. & Bajoria, R. Characterization of human placental explants: morphological, biochemical and physiological studies using first and third trimester placenta. Hum. Reprod. 14, 536–541 (1999).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • James, J. L., Stone, P. R. & Chamley, L. W. Cytotrophoblast differentiation in the first trimester of pregnancy: evidence for separate progenitors of extravillous trophoblasts and syncytiotrophoblast. Reproduction 130, 95–103 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Seeho, S. K. M., Park, J. H., Rowe, J., Morris, J. M. & Gallery, E. D. M. Villous explant culture using early gestation tissue from ongoing pregnancies with known normal outcomes: the effect of oxygen on trophoblast outgrowth and migration. Hum. Reprod. 23, 1170–1179 (2008).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Miller, R. K. et al. Human placental explants in culture: approaches and assessments. Placenta 26, 439–448 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Li, X., Li, Z.-H., Wang, Y.-X. & Liu, T.-H. A comprehensive review of human trophoblast fusion models: recent developments and challenges. Cell Death Discov. 9, 372 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kliman, H. J., Nestler, J. E., Sermasi, E., Sanger, J. M. & Strauss, J. F. 3rd. Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology 118, 1567–1582 (1986).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zhou, Y. et al. Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J. Clin. Invest. 99, 2139–2151 (1997).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Douglas, G. C. & King, B. F. Isolation of pure villous cytotrophoblast from term human placenta using immunomagnetic microspheres. J. Immunol. Methods 119, 259–268 (1989).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Librach, C. L. et al. 92-kD type IV collagenase mediates invasion of human cytotrophoblasts. J. Cell Biol. 113, 437–449 (1991).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Pattillo, R. A., Gey, G. O., Delfs, E. & Mattingly, R. F. Human hormone production in vitro. Science 159, 1467–1469 (1968).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Pattillo, R. A. et al. The hormone-synthesizing trophoblastic cell in vitro: a model for cancer research and placental hormone synthesis. Ann. N. Y. Acad. Sci. 172, 288–298 (1971).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kohler, P. O. & Bridson, W. E. Isolation of hormone-producing clonal lines of human choriocarcinoma. J. Clin. Endocrinol. Metab. 32, 683–687 (1971).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Rothbauer, M. et al. A comparative study of five physiological key parameters between four different human trophoblast-derived cell lines. Sci. Rep. 7, 5892 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McConkey, C. A. et al. A three-dimensional culture system recapitulates placental syncytiotrophoblast development and microbial resistance. Sci. Adv. 2, e1501462 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pastuschek, J. et al. Molecular characteristics of established trophoblast-derived cell lines. Placenta 108, 122–133 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Yin, E. & Esbin, M. N. Optimized CRISPR-based knockout in BeWo cells. Placenta 166, 71–76 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Graham, C. H. et al. Establishment and characterization of first trimester human trophoblast cells with extended lifespan. Exp. Cell Res. 206, 204–211 (1993).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Hannan, N. J., Paiva, P., Dimitriadis, E. & Salamonsen, L. A. Models for study of human embryo implantation: choice of cell lines? Biol. Reprod. 82, 235–245 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kilburn, B. A. et al. Extracellular matrix composition and hypoxia regulate the expression of HLA-G and integrins in a human trophoblast cell line. Biol. Reprod. 62, 739–747 (2000).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • LaMarca, H. L. et al. Three-dimensional growth of extravillous cytotrophoblasts promotes differentiation and invasion. Placenta 26, 709–720 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Abou-Kheir, W., Barrak, J., Hadadeh, O. & Daoud, G. HTR-8/SVneo cell line contains a mixed population of cells. Placenta 50, 1–7 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Chen, Y., Siriwardena, D., Penfold, C., Pavlinek, A. & Boroviak, T. E. An integrated atlas of human placental development delineates essential regulators of trophoblast stem cells. Development 149, dev200171 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Lea, G. et al. Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome. Cell Stem Cell 32, 276–292.e9 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Shannon, M. J. et al. Cell trajectory modeling identifies a primitive trophoblast state defined by BCAM enrichment. Development 149, dev199840 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Varberg, K. M. et al. Leveraging chorionic villus biopsies for the derivation of patient-specific trophoblast stem cells. Commun. Biol. 8, 964 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wang, L.-J. et al. Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation. Nat. Commun. 13, 1626 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Karakis, V., Britt, J. W., Jabeen, M., San Miguel, A. & Rao, B. M. Derivation of human trophoblast stem cells from placentas at birth. J. Biol. Chem. 301, 108505 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Naama, M. et al. Pluripotency-independent induction of human trophoblast stem cells from fibroblasts. Nat. Commun. 14, 3359 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Dong, C. et al. Derivation of trophoblast stem cells from naïve human pluripotent stem cells. eLife 9, e52504 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Castel, G. et al. Induction of human trophoblast stem cells from somatic cells and pluripotent stem cells. Cell Rep. 33, 108419 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Cinkornpumin, J. K. et al. Naive human embryonic stem cells can give rise to cells with a trophoblast-like transcriptome and methylome. Stem Cell Rep. 15, 198–213 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Io, S. et al. Capturing human trophoblast development with naive pluripotent stem cells in vitro. Cell Stem Cell 28, 1023–1039.e13 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Morey, R. et al. iPSC-based modeling of preeclampsia identifies epigenetic defects in extravillous trophoblast differentiation. iScience 27, 109569 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Liu, X. et al. Reprogramming roadmap reveals route to human induced trophoblast stem cells. Nature 586, 101–107 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Yang, L., Liang, P., Yang, H. & Coyne, C. B. Trophoblast organoids with physiological polarity model placental structure and function. J. Cell Sci. 137, jcs261528 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Smith, S. D., Dunk, C. E., Aplin, J. D., Harris, L. K. & Jones, R. L. Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am. J. Pathol. 174, 1959–1971 (2009).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Vandereyken, K., Sifrim, A., Thienpont, B. & Voet, T. Methods and applications for single-cell and spatial multi-omics. Nat. Rev. Genet. 24, 494–515 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Navin, N. et al. Tumour evolution inferred by single-cell sequencing. Nature 472, 90–94 (2011).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Goltsev, Y. et al. Deep profiling of mouse splenic architecture with CODEX multiplexed imaging. Cell 174, 968–981.e15 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Marco Salas, S. et al. Optimizing Xenium In Situ data utility by quality assessment and best-practice analysis workflows. Nat. Methods 22, 813–823 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Rodriques, S. G. et al. Slide-seq: a scalable technology for measuring genome-wide expression at high spatial resolution. Science 363, 1463–1467 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Stickels, R. R. et al. Highly sensitive spatial transcriptomics at near-cellular resolution with Slide-seqV2. Nat. Biotechnol. 39, 313–319 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Russell, A. J. C. et al. Slide-tags enables single-nucleus barcoding for multimodal spatial genomics. Nature 625, 101–109 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Oliveira, M. F. de et al. High-definition spatial transcriptomic profiling of immune cell populations in colorectal cancer. Nat. Genet. 57, 1512–1523 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zhou, F. et al. Reconstituting the transcriptome and DNA methylome landscapes of human implantation. Nature 572, 660–664 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Wang, Y. et al. A single-cell characterization of human post-implantation embryos cultured in vitro delineates morphogenesis in primary syncytialization. Front. Cell Dev. Biol. 10, 835445 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • d’Hauterive, S. P. et al. Human chorionic gonadotropin and early embryogenesis: review. Int. J. Mol. Sci. 23, 1380 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, P. J. & Liu, D. R. Prime editing for precise and highly versatile genome manipulation. Nat. Rev. Genet. 24, 161–177 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Wang, T., Wei, J. J., Sabatini, D. M. & Lander, E. S. Genetic screens in human cells using the CRISPR-Cas9 system. Science 343, 80–84 (2014).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Shalem, O. et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84–87 (2014).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kampmann, M. CRISPRi and CRISPRa screens in mammalian cells for precision biology and medicine. ACS Chem. Biol. 13, 406–416 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar