{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T10:04:48Z","timestamp":1784282688656,"version":"3.55.0"},"reference-count":19,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002855","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFA1105402"],"award-info":[{"award-number":["2022YFA1105402"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"publisher","award":["YQ2024C002"],"award-info":[{"award-number":["YQ2024C002"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Understanding how pluripotency regulatory networks evolve across mammals remains a central question in developmental and stem cell biology. While rodent models have defined the canonical core circuitry of pluripotency, the extent to which these regulatory hierarchies are conserved in large mammals is unclear. Here, we provide evidence that SOX15 contributes to the species-specific regulatory network as a modulator that sustains pluripotency and preserves functional differentiation capacity in porcine embryo-derived stem cells. Comparative sequence analysis revealed strong conservation of the SOX15 HMG domain across mammals, yet promoter divergence suggested lineage-specific regulatory evolution. Transcriptomic profiling demonstrated that, unlike in mice, SOX15 is robustly upregulated from the 2-cell stage and remains highly expressed in the porcine epiblast, coinciding with key windows of pluripotency establishment. In porcine embryo-derived stem cells, stable SOX15 knockdown resulted in reduced colony integrity, diminished alkaline phosphatase activity, impaired proliferation, and downregulation of core pluripotency genes, including OCT4 and NANOG. Furthermore, loss of SOX15 disrupts embryoid body formation and abolishes teratoma-forming capacity in vivo. This deficit likely reflects impaired pluripotency, but may also be attributed to compromised cell survival or proliferative fitness following transplantation. Notably, comparable perturbations in mouse models do not produce equivalent phenotypes, underscoring a lineage-dependent functional divergence. Together, our findings suggest that SOX15 contributes to the support of the porcine pluripotency network, and hint at evolutionary plasticity in the hierarchical architecture of mammalian pluripotency. These findings move beyond the rodent-centric paradigm and offer a refined perspective on the evolutionary plasticity of pluripotency networks, highlighting SOX15 as a pivotal lineage-specialized node governing naive pluripotency in large mammals. Notably, these inferences are based on functional perturbation using a single validated miRNAi construct; definitive confirmation of SOX15-specific causality will require future orthogonal validation via independent knockdown sequences, CRISPR interference, or RNAi-resistant rescue experiments.<\/jats:p>","DOI":"10.3390\/cells15141283","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:00:52Z","timestamp":1784278852000},"page":"1283","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SOX15 Contributes to the Maintenance of Pluripotency in Porcine Embryonic Stem Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"Chenghe","family":"Jian","sequence":"first","affiliation":[{"name":"College of Life Science, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjiao","family":"Lv","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Cellular and Genetics Engineering of Heilongjiang Province, Northeast Agricultural University, No. 59 Mucai Street, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Cellular and Genetics Engineering of Heilongjiang Province, Northeast Agricultural University, No. 59 Mucai Street, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxing","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Life Science, Northeast Agricultural University, Harbin 150030, China"},{"name":"Key Laboratory of Animal Cellular and Genetics Engineering of Heilongjiang Province, Northeast Agricultural University, No. 59 Mucai Street, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Du","sequence":"additional","affiliation":[{"name":"College of Life Science, Northeast Agricultural University, Harbin 150030, China"},{"name":"Key Laboratory of Animal Cellular and Genetics Engineering of Heilongjiang Province, Northeast Agricultural University, No. 59 Mucai Street, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyang","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Life Science, Northeast Agricultural University, Harbin 150030, China"},{"name":"Key Laboratory of Animal Cellular and Genetics Engineering of Heilongjiang Province, Northeast Agricultural University, No. 59 Mucai Street, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhan","family":"Su","sequence":"additional","affiliation":[{"name":"College of Life Science, Northeast Agricultural University, Harbin 150030, China"},{"name":"Key Laboratory of Animal Cellular and Genetics Engineering of Heilongjiang Province, Northeast Agricultural University, No. 59 Mucai Street, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6128-6378","authenticated-orcid":false,"given":"Jun","family":"Song","sequence":"additional","affiliation":[{"name":"College of Life Science, Northeast Agricultural University, Harbin 150030, China"},{"name":"Key Laboratory of Animal Cellular and Genetics Engineering of Heilongjiang Province, Northeast Agricultural University, No. 59 Mucai Street, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingsheng","family":"Yan","sequence":"additional","affiliation":[{"name":"College of Life Science, Northeast Agricultural University, Harbin 150030, China"},{"name":"Key Laboratory of Animal Cellular and Genetics Engineering of Heilongjiang Province, Northeast Agricultural University, No. 59 Mucai Street, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9199-6493","authenticated-orcid":false,"given":"Zhonghua","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Life Science, Northeast Agricultural University, Harbin 150030, China"},{"name":"Key Laboratory of Animal Cellular and Genetics Engineering of Heilongjiang Province, Northeast Agricultural University, No. 59 Mucai Street, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1089\/scd.2014.0297","article-title":"The SOX Transcription Factors as Key Players in Pluripotent Stem Cells","volume":"23","author":"Abdelalim","year":"2014","journal-title":"Stem Cells Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1101\/gad.224503","article-title":"Multipotent Cell Lineages in Early Mouse Development Depend on SOX2 Function","volume":"17","author":"Avilion","year":"2003","journal-title":"Genes Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eadi5516","DOI":"10.1126\/science.adi5516","article-title":"Multifaceted SOX2-Chromatin Interaction Underpins Pluripotency Progression in Early Embryos","volume":"382","author":"Li","year":"2023","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4933","DOI":"10.1093\/nar\/gks153","article-title":"Deciphering the Sox-Oct Partner Code by Quantitative Cooperativity Measurements","volume":"40","author":"Ng","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.cell.2008.02.039","article-title":"An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells","volume":"132","author":"Kim","year":"2008","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors","volume":"126","author":"Takahashi","year":"2006","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.stem.2013.05.010","article-title":"Klf4 Organizes Long-Range Chromosomal Interactions with the Oct4 Locus in Reprogramming and Pluripotency","volume":"13","author":"Wei","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1007\/s12015-021-10239-2","article-title":"C-MYC Triggers Lipid Remodelling During Early Somatic Cell Reprogramming to Pluripotency","volume":"17","author":"Prieto","year":"2021","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1152\/physrev.00046.2011","article-title":"Stem Cell Factor Receptor\/c-Kit: From Basic Science to Clinical Implications","volume":"92","author":"Lennartsson","year":"2012","journal-title":"Physiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1016\/j.biocel.2006.12.005","article-title":"C-Kit\u2014A Hematopoietic Cell Essential Receptor Tyrosine Kinase","volume":"39","author":"Edling","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1093\/nar\/21.7.1669","article-title":"Sox 15, a Novel Member of the Murine Sox Family of HMG Box Transcription Factors","volume":"21","author":"Clevers","year":"1993","journal-title":"Nucl. Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.biocel.2009.10.023","article-title":"Function and Molecular Evolution of Mammalian Sox15, a Singleton in the SoxG Group of Transcription Factors","volume":"42","author":"Ito","year":"2010","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"24371","DOI":"10.1074\/jbc.M501423200","article-title":"Differential Roles for Sox15 and Sox2 in Transcriptional Control in Mouse Embryonic Stem Cells","volume":"280","author":"Maruyama","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8428","DOI":"10.1128\/MCB.24.19.8428-8436.2004","article-title":"Sox15 Is Required for Skeletal Muscle Regeneration","volume":"24","author":"Lee","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/s41467-019-08387-8","article-title":"Pluripotency and X Chromosome Dynamics Revealed in Pig Pre-Gastrulating Embryos by Single Cell Analysis","volume":"10","author":"Sang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1007\/s12015-013-9485-9","article-title":"Comparative Gene Expression Signature of Pig, Human and Mouse Induced Pluripotent Stem Cell Lines Reveals Insight into Pig Pluripotency Gene Networks","volume":"10","author":"Liu","year":"2014","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1093\/stmcls\/sxac034","article-title":"Porcine Pluripotent Stem Cells Established from LCDM Medium with Characteristics Differ from Human and Mouse Extended Pluripotent Stem Cells","volume":"40","author":"Yu","year":"2022","journal-title":"Stem Cells"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"39974","DOI":"10.1038\/s41598-025-23723-3","article-title":"Selectively Inhibition of MAPK Pathway Showed Positive Effects on Porcine Embryo-Derived Stem Cells Pluripotency","volume":"15","author":"Yu","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"116385","DOI":"10.1016\/j.celrep.2025.116385","article-title":"LEUTX and OTX2 Orchestrate Totipotency-to-Pluripotency Transitions and Heterogeneity in pEPSCs","volume":"44","author":"Wu","year":"2025","journal-title":"Cell Rep."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1283\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:20:17Z","timestamp":1784280017000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1283"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":19,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cells15141283"],"URL":"https:\/\/doi.org\/10.3390\/cells15141283","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]}}}