{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T04:19:43Z","timestamp":1788754783305,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Amsterdam Reproduction and Development Research Institute","award":["2022.01.006"],"award-info":[{"award-number":["2022.01.006"]}]},{"name":"Amsterdam Reproduction and Development Research Institute","award":["EINF-10239"],"award-info":[{"award-number":["EINF-10239"]}]},{"name":"SURF Cooperative","award":["2022.01.006"],"award-info":[{"award-number":["2022.01.006"]}]},{"name":"SURF Cooperative","award":["EINF-10239"],"award-info":[{"award-number":["EINF-10239"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Placentation disorders, including severe preeclampsia and fetal growth restriction, have their origins in early pregnancy, whereas symptoms typically present later on. To investigate the pathogenesis of these diseases, there is a need for a reliable in vitro model system of early placenta development with known pregnancy outcomes. Therefore, we optimized the generation of human induced trophoblast stem cells (iTSCs) from term umbilical cord, enabling non-invasive collection of patient-derived material immediately after birth. Using a direct reprogramming approach previously described for dermal fibroblasts, we investigated the effects of three supplements (A-485, BMP4, and EPZ-6438) to assess their potential to enhance iTSC induction. The generated iTSCs fulfilled the criteria for bona fide first-trimester trophoblasts and exhibited key functional capacities, including long-term self-renewal, differentiation into hormone-producing syncytiotrophoblasts and invasive extravillous trophoblasts, and the formation of organoids. Furthermore, transcriptomic analysis revealed high similarity between the generated iTSCs and trophoblast stem cells derived from first-trimester placental tissue. The supplements did not improve the generation of iTSCs. In conclusion, we successfully generated bona fide iTSCs from term umbilical cord using a direct reprogramming approach, providing a robust and clinically relevant model to study early placentation mechanisms in patient-derived trophoblasts.<\/jats:p>","DOI":"10.3390\/ijms26010271","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T10:17:40Z","timestamp":1735640260000},"page":"271","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Generation of Bona Fide Human Induced Trophoblast Stem Cells by Direct Reprogramming of Term Umbilical Cord Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2810-9968","authenticated-orcid":false,"given":"A. Jantine","family":"van Voorden","sequence":"first","affiliation":[{"name":"Reproductive Biology Laboratory, Amsterdam University Medical Center Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Reproduction and Development Research Institute, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souad","family":"Boussata","sequence":"additional","affiliation":[{"name":"Reproductive Biology Laboratory, Amsterdam University Medical Center Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Reproduction and Development Research Institute, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remco","family":"Keijser","sequence":"additional","affiliation":[{"name":"Reproductive Biology Laboratory, Amsterdam University Medical Center Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Reproduction and Development Research Institute, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marloes","family":"Vermij","sequence":"additional","affiliation":[{"name":"Reproductive Biology Laboratory, Amsterdam University Medical Center Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Reproduction and Development Research Institute, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8218-5015","authenticated-orcid":false,"given":"Muriel K.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Reproductive Biology Laboratory, Amsterdam University Medical Center Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Reproduction and Development Research Institute, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7243-2115","authenticated-orcid":false,"given":"Wessel","family":"Ganzevoort","sequence":"additional","affiliation":[{"name":"Amsterdam Reproduction and Development Research Institute, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Obstetrics and Gynaecology, Amsterdam University Medical Center Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2155-725X","authenticated-orcid":false,"given":"Gijs B.","family":"Afink","sequence":"additional","affiliation":[{"name":"Reproductive Biology Laboratory, Amsterdam University Medical Center Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Reproduction and Development Research Institute, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.stem.2017.11.004","article-title":"Derivation of human trophoblast stem cells","volume":"22","author":"Okae","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41586-018-0753-3","article-title":"Trophoblast organoids as a model for maternal-fetal interactions during human placentation","volume":"564","author":"Turco","year":"2018","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.stemcr.2018.07.004","article-title":"Self-renewing trophoblast organoids recapitulate the developmental program of the early human placenta","volume":"11","author":"Haider","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"l2381","DOI":"10.1136\/bmj.l2381","article-title":"Pre-eclampsia: Pathophysiology and clinical implications","volume":"366","author":"Burton","year":"2019","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.placenta.2020.05.003","article-title":"The placenta in fetal growth restriction: What is going wrong?","volume":"96","author":"Sun","year":"2020","journal-title":"Placenta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1186\/s13287-019-1339-1","article-title":"Establishment of human trophoblast stem cells from human induced pluripotent stem cell-derived cystic cells under micromesh culture","volume":"10","author":"Li","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e52504","DOI":"10.7554\/eLife.52504","article-title":"Derivation of trophoblast stem cells from naive human pluripotent stem cells","volume":"9","author":"Dong","year":"2020","journal-title":"eLife"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.stemcr.2020.06.003","article-title":"Naive human embryonic stem cells can give rise to cells with a trophoblast-like transcriptome and methylome","volume":"15","author":"Cinkornpumin","year":"2020","journal-title":"Stem Cell Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41586-020-2734-6","article-title":"Reprogramming roadmap reveals route to human induced trophoblast stem cells","volume":"586","author":"Liu","year":"2020","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"108419","DOI":"10.1016\/j.celrep.2020.108419","article-title":"Induction of human trophoblast stem cells from somatic cells and pluripotent stem cells","volume":"33","author":"Castel","year":"2020","journal-title":"Cell Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mischler, A., Karakis, V., Mahinthakumar, J., Carberry, C.K., San Miguel, A., Rager, J.E., Fry, R.C., and Rao, B.M. (2021). Two distinct trophectoderm lineage stem cells from human pluripotent stem cells. J. Biol. Chem., 296.","DOI":"10.1016\/j.jbc.2021.100386"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.stem.2021.03.013","article-title":"Capturing human trophoblast development with naive pluripotent stem cells in vitro","volume":"28","author":"Io","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.stem.2021.02.025","article-title":"Human naive epiblast cells possess unrestricted lineage potential","volume":"28","author":"Guo","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"102507","DOI":"10.1016\/j.scr.2021.102507","article-title":"Establishment of human induced trophoblast stem-like cells from term villous cytotrophoblasts","volume":"56","author":"Bai","year":"2021","journal-title":"Stem Cell Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"eabf4416","DOI":"10.1126\/sciadv.abf4416","article-title":"Efficient derivation of human trophoblast stem cells from primed pluripotent stem cells","volume":"7","author":"Wei","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2115709119","DOI":"10.1073\/pnas.2115709119","article-title":"Induction of human trophoblast stem-like cells from primed pluripotent stem cells","volume":"119","author":"Jang","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1016\/j.stemcr.2022.09.008","article-title":"Human primed and naive PSCs are both able to differentiate into trophoblast stem cells","volume":"17","author":"Viukov","year":"2022","journal-title":"Stem Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.stem.2022.04.004","article-title":"Stem-cell-derived trophoblast organoids model human placental development and susceptibility to emerging pathogens","volume":"29","author":"Karvas","year":"2022","journal-title":"Cell Stem Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/j.stemcr.2022.04.013","article-title":"Derivation of functional trophoblast stem cells from primed human pluripotent stem cells","volume":"17","author":"Soncin","year":"2022","journal-title":"Stem Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1038\/s41556-022-00932-w","article-title":"Integrated multi-omics reveal polycomb repressive complex 2 restricts human trophoblast induction","volume":"24","author":"Zijlmans","year":"2022","journal-title":"Nat. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1038\/s41596-022-00742-2","article-title":"Establishment of human induced trophoblast stem cells via reprogramming of fibroblasts","volume":"17","author":"Tan","year":"2022","journal-title":"Nat. Protoc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3359","DOI":"10.1038\/s41467-023-39104-1","article-title":"Pluripotency-independent induction of human trophoblast stem cells from fibroblasts","volume":"14","author":"Naama","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tietze, E., Barbosa, A.R., Araujo, B., Euclydes, V., Spiegelberg, B., Cho, H.J., Lee, Y.K., Wang, Y., McCord, A., and Lorenzetti, A. (2024). Human archetypal pluripotent stem cells differentiate into trophoblast stem cells via endogenous BMP5\/7 induction without transitioning through naive state. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-53381-w"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"109569","DOI":"10.1016\/j.isci.2024.109569","article-title":"iPSC-based modeling of preeclampsia identifies epigenetic defects in extravillous differentiation","volume":"27","author":"Morey","year":"2024","journal-title":"iScience"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1093\/biolre\/ioab080","article-title":"Modeling human peri-implantation placental development and function","volume":"105","author":"Zhou","year":"2021","journal-title":"Biol. Reprod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1007\/s00018-022-04549-y","article-title":"Accessing the human trophoblast stem cell state from pluripotent and somatic cells","volume":"79","author":"Karvas","year":"2022","journal-title":"Cell Mol. Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.placenta.2022.10.011","article-title":"Modeling placental development and disease using human pluripotent stem cells","volume":"141","author":"Morey","year":"2023","journal-title":"Placenta"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Karakis, V., Britt, J.W., Jabeen, M., Miguel, A.S., and Rao, B.M. (2024). Derivation of human trophoblast stem cells from placentas at birth. bioRxiv.","DOI":"10.1101\/2024.05.01.592064"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/s41586-021-03345-1","article-title":"Inherent mosaicism and extensive mutation of human placentas","volume":"592","author":"Coorens","year":"2021","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.1152\/physrev.00001.2023","article-title":"The placenta: Epigenetic insights into trophoblast developmental models of a generation-bridging organ with long-lasting impact on lifelong health","volume":"103","author":"Hemberger","year":"2023","journal-title":"Physiol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/s41589-019-0264-z","article-title":"Bromodomain inhibition of the coactivators CBP\/EP300 facilitate cellular reprogramming","volume":"15","author":"Ebrahimi","year":"2019","journal-title":"Nat. Chem. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e2217405120","DOI":"10.1073\/pnas.2217405120","article-title":"EP300 facilitates human trophoblast stem cell differentiation","volume":"120","author":"Keijser","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s00018-022-04478-w","article-title":"The role of BMP4 signaling in trophoblast emergence from pluripotency","volume":"79","author":"Roberts","year":"2022","journal-title":"Cell Mol. Life Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/s41556-022-00916-w","article-title":"Polycomb repressive complex 2 shields naive human pluripotent cells from trophectoderm differentiation","volume":"24","author":"Kumar","year":"2022","journal-title":"Nat. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.stemcr.2016.01.006","article-title":"What is trophoblast? A combination of criteria define human first-trimester trophoblast","volume":"6","author":"Lee","year":"2016","journal-title":"Stem Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"26606","DOI":"10.1073\/pnas.1916019116","article-title":"Loss of p57KIP2 expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells","volume":"116","author":"Takahashi","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","unstructured":"Atlas, H.P. (2024, November 11). The Trophoblast Cell-Specific Proteome, Available online: https:\/\/www.proteinatlas.org\/humanproteome\/single+cell\/single+cell+type\/trophoblast+cells."},{"key":"ref_38","unstructured":"Atlas, H.P. (2024, November 11). The Placenta-Specific Proteome, Available online: https:\/\/www.proteinatlas.org\/humanproteome\/tissue\/placenta."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"E3882","DOI":"10.1073\/pnas.1604747113","article-title":"Human pluripotent stem cells as a model of trophoblast differentiation in both normal development and disease","volume":"113","author":"Horii","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4336","DOI":"10.1073\/pnas.1816150116","article-title":"Early onset preeclampsia in a model for human placental trophoblast","volume":"116","author":"Sheridan","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1093\/biolre\/ioy070","article-title":"Specification of trophoblast from embryonic stem cells exposed to BMP4","volume":"99","author":"Roberts","year":"2018","journal-title":"Biol. Reprod."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Horii, M., Morey, R., Bui, T., Touma, O., Nelson, K.K., Cho, H.Y., Rishik, H., Laurent, L.C., and Parast, M.M. (2021). Modeling preeclampsia using human induced pluripotent stem cells. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-85230-5"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.stem.2016.01.019","article-title":"Naive human pluripotent cells feature a methylation landscape devoid of blastocyst or germline memory","volume":"18","author":"Pastor","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.stem.2016.06.011","article-title":"Molecular criteria for defining the naive human pluripotent state","volume":"19","author":"Theunissen","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.cell.2015.06.016","article-title":"Integrative analyses of human reprogramming reveal dynamic nature of induced pluripotency","volume":"162","author":"Cacchiarelli","year":"2015","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"eaba1190","DOI":"10.1126\/sciadv.aba1190","article-title":"Diversification of reprogramming trajectories revealed by parallel single-cell transcriptome and chromatin accessibility sequencing","volume":"6","author":"Xing","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1038\/s41586-023-06424-7","article-title":"Transient naive reprogramming corrects hiPS cells functionally and epigenetically","volume":"620","author":"Buckberry","year":"2023","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Mallona, I., Diez-Villanueva, A., and Peinado, M.A. (2014). Methylation plotter: A web tool for dynamic visualization of DNA methylation data. Source Code Biol. Med., 9.","DOI":"10.1186\/1751-0473-9-11"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/271\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:57:37Z","timestamp":1760115457000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/271"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,31]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ijms26010271"],"URL":"https:\/\/doi.org\/10.3390\/ijms26010271","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,31]]}}}