{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:43:16Z","timestamp":1787654596261,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T00:00:00Z","timestamp":1618185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["669622"],"award-info":[{"award-number":["669622"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["SAF2017-82613-R"],"award-info":[{"award-number":["SAF2017-82613-R"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Pluripotent stem cells can be stabilized in vitro at different developmental states by the use of specific chemicals and soluble factors. The na\u00efve and primed states are the best characterized pluripotency states. Na\u00efve pluripotent stem cells (PSCs) correspond to the early pre-implantation blastocyst and, in mice, constitute the optimal starting state for subsequent developmental applications. However, the stabilization of human na\u00efve PSCs remains challenging because, after short-term culture, most current methods result in karyotypic abnormalities, aberrant DNA methylation patterns, loss of imprinting and severely compromised developmental potency. We have recently developed a novel method to induce and stabilize na\u00efve human PSCs that consists in the simple addition of a chemical inhibitor for the closely related CDK8 and CDK19 kinases (CDK8\/19i). Long-term cultured CDK8\/19i-na\u00efve human PSCs preserve their normal karyotype and do not show widespread DNA demethylation. Here, we investigate the long-term stability of allele-specific methylation at imprinted loci and the differentiation potency of CDK8\/19i-na\u00efve human PSCs. We report that long-term cultured CDK8\/19i-na\u00efve human PSCs retain the imprinting profile of their parental primed cells, and imprints are further retained upon differentiation in the context of teratoma formation. We have also tested the capacity of long-term cultured CDK8\/19i-na\u00efve human PSCs to differentiate into primordial germ cell (PGC)-like cells (PGCLCs) and trophoblast stem cells (TSCs), two cell types that are accessible from the na\u00efve state. Interestingly, long-term cultured CDK8\/19i-na\u00efve human PSCs differentiated into PGCLCs with a similar efficiency to their primed counterparts. Also, long-term cultured CDK8\/19i-na\u00efve human PSCs were able to differentiate into TSCs, a transition that was not possible for primed PSCs. We conclude that inhibition of CDK8\/19 stabilizes human PSCs in a functional na\u00efve state that preserves imprinting and potency over long-term culture.<\/jats:p>","DOI":"10.3390\/cells10040876","type":"journal-article","created":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T11:05:06Z","timestamp":1618225506000},"page":"876","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Stability of Imprinting and Differentiation Capacity in Na\u00efve Human Cells Induced by Chemical Inhibition of CDK8 and CDK19"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9003-1323","authenticated-orcid":false,"given":"Raquel","family":"Bernad","sequence":"first","affiliation":[{"name":"Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cian J.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2736-5758","authenticated-orcid":false,"given":"Rocio G.","family":"Urdinguio","sequence":"additional","affiliation":[{"name":"Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Cancer Epigenetics and Nanomedicine Laboratory, 33940 El Entrego, Spain"},{"name":"Health Research Institute of Asturias (ISPA), 33011 Oviedo, Spain"},{"name":"Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006 Oviedo, Spain"},{"name":"Rare Diseases CIBER (CIBERER), 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8045-320X","authenticated-orcid":false,"given":"Camille","family":"Stephan-Otto Attolini","sequence":"additional","affiliation":[{"name":"Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario F.","family":"Fraga","sequence":"additional","affiliation":[{"name":"Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Cancer Epigenetics and Nanomedicine Laboratory, 33940 El Entrego, Spain"},{"name":"Health Research Institute of Asturias (ISPA), 33011 Oviedo, Spain"},{"name":"Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006 Oviedo, Spain"},{"name":"Rare Diseases CIBER (CIBERER), 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7177-9312","authenticated-orcid":false,"given":"Manuel","family":"Serrano","sequence":"additional","affiliation":[{"name":"Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain"},{"name":"Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/ncb2965","article-title":"The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification","volume":"16","author":"Boroviak","year":"2014","journal-title":"Nat. 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