{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T06:44:58Z","timestamp":1776840298838,"version":"3.51.2"},"reference-count":143,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["PID 2021-127493OB-C21"],"award-info":[{"award-number":["PID 2021-127493OB-C21"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background and Objective<\/jats:title>\n                    <jats:p>\n                      Uterine leiomyomas may arise from somatic stem or progenitor cells, leading to abnormal activation, proliferation, and clonal expansion. In organ cultures of myometrium and leiomyoma, differentiated cells decline after 7\u00a0days, whereas resident stem cells may persist within their niches and subsequently become activated, proliferate, and repopulate tissue slices. This study investigated gene expression programs that regulate the proliferation and differentiation of myometrial and\n                      <jats:italic>MED12<\/jats:italic>\n                      -mutant leiomyoma stem cells during long-term organ culture.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Comparison of normal and tumor tissues at baseline and after culture revealed several fibroid transcriptional signatures that were preserved during prolonged\n                      <jats:italic>ex vivo<\/jats:italic>\n                      culture. The\n                      <jats:italic>MED12<\/jats:italic>\n                      mutation persisted in the repopulated fibroid slices, supporting the hypothesis that fibroids originate from stem or progenitor cells harboring\n                      <jats:italic>MED12<\/jats:italic>\n                      mutation. Both tissues activated hypoxia and stemness-associated programs, including robust induction of\n                      <jats:italic>HMGA1<\/jats:italic>\n                      ,\n                      <jats:italic>HMGA2<\/jats:italic>\n                      , and\n                      <jats:italic>PLAG1<\/jats:italic>\n                      . Myometrium induced KITLG\/KIT expression, a limited number of CD49b (ITGA2)-stem-positive and Ki67-positive proliferating cells, indicating restrained proliferation, likely mediated by upregulation of\n                      <jats:italic>ITGA2-AS1<\/jats:italic>\n                      . Additionally, myometrial slice cultures were enriched for immune and endothelial\/vascular programs, including several SOX family members. In contrast, leiomyoma cultures exhibited widespread CD24\/CD73 expression, focal CD49b clusters, high Ki67 positivity, metabolic reprogramming toward complex carbohydrate degradation, SLC-mediated transport, and a low-PLIN2\/high-ACLY signature. Uterine leiomyoma cultures repressed genes involved in vascular homeostasis (e.g.,\n                      <jats:italic>PLPP3<\/jats:italic>\n                      ) and preferentially activated pathways related to smooth muscle excitability and vesicle secretion. Extracellular matrix (ECM) remodeling was strongly pro-fibrotic in leiomyomas, with significant upregulation of several TGFB-regulated and related genes, a disrupted balance of KLF regulators, including loss of the anti-fibrotic repressor\n                      <jats:italic>KLF10<\/jats:italic>\n                      and induction of the pro-fibrotic\n                      <jats:italic>KLF5<\/jats:italic>\n                      factor, and broad upregulation of integrins. Differential expression of multiple HOX genes further distinguished ECM regulation between tissues. From niche survival to pro-fibrotic expansion, the study delineates checkpoints primed for intervention, highlighting potential therapeutic opportunities targeting profibrotic signaling, metabolic dependencies, and integrin-mediated ECM interactions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Long-term organ culture recapitulates key molecular features of fibroids and reveals tissue-specific mechanisms governing stem cell activation and differentiation. These findings identify potential therapeutic opportunities and establish long-term organ culture as a robust, physiologically relevant platform for investigating normal and tumor biology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1804196","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T05:47:42Z","timestamp":1776836862000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Stem cell activation in organ culture reveals novel transcriptional programs underlying metabolic, fibrotic, vascular, and immune dysregulation in uterine leiomyomas"],"prefix":"10.3389","volume":"14","author":[{"given":"Paula","family":"V\u00e1zquez","sequence":"first","affiliation":[{"name":"Molecular Bases of Neoplasms Group (MOLNEO), Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL)","place":["La Laguna, Tenerife, Spain"]},{"name":"Institute of Tropical Diseases and Public Health of the Canary Islands (IUETSPC)","place":["Tenerife, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Salas","sequence":"additional","affiliation":[{"name":"Canary Islands Health Research Institute Foundation (FIICS), University Hospital of Gran Canaria Dr. Negr\u00edn","place":["Las Palmas, Spain"]},{"name":"Canary Islands Health Research Institute (IISC)","place":["Tenerife, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Beltr\u00e1n-Flores","sequence":"additional","affiliation":[{"name":"Molecular Bases of Neoplasms Group (MOLNEO), Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL)","place":["La Laguna, Tenerife, Spain"]},{"name":"Institute of Tropical Diseases and Public Health of the Canary Islands (IUETSPC)","place":["Tenerife, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco","family":"Montes de Oca","sequence":"additional","affiliation":[{"name":"Hospital Quir\u00f3nsalud Tenerife","place":["Santa Cruz de Tenerife, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Araceli","family":"Delgado","sequence":"additional","affiliation":[{"name":"Canary Islands Health Research Institute (IISC)","place":["Tenerife, Spain"]},{"name":"Department of Chemical Engineering and Pharmaceutical Technology, Universidad de La Laguna","place":["La Laguna, Tenerife, Spain"]},{"name":"Institute of Biomedical Technologies (ITB), Universidad de La Laguna","place":["La Laguna, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa A.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Molecular Bases of Neoplasms Group (MOLNEO), Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL)","place":["La Laguna, Tenerife, Spain"]},{"name":"Institute of Tropical Diseases and Public Health of the Canary Islands (IUETSPC)","place":["Tenerife, Spain"]},{"name":"Canary Islands Health Research Institute (IISC)","place":["Tenerife, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1093\/molehr\/3.8.685","article-title":"Expression of the fibroblast growth factor receptor in women with leiomyomas and abnormal uterine bleeding","volume":"3","author":"Anania","year":"1997","journal-title":"Mol. 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