{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T19:24:59Z","timestamp":1765567499072,"version":"3.48.0"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004761","name":"the Natural Science Foundation of Hunan Province","doi-asserted-by":"crossref","award":["2023JJ40964"],"award-info":[{"award-number":["2023JJ40964"]}],"id":[{"id":"10.13039\/501100004761","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cellular senescence plays a critical role in regulating angiogenesis. While UTX has been implicated in vascular regeneration following spinal cord injury (SCI), its underlying mechanisms remain incompletely understood. This study investigates how senescence mediates UTX-regulated vascular responses after SCI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We assessed p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      (a senescence marker) and UTX expression in spinal cord endothelial cells at 3, 5, 7 and 14 days post-SCI. By breeding UTX\n                      <jats:sup>flox\/flox<\/jats:sup>\n                      mice with heterozygous Tek-Cre mice, we generated endothelial-specific UTX knockout mice. Cellular senescence and proliferation were evaluated in primary spinal cord microvascular endothelial cells (SCMVECs). RNA sequencing and chromatin immunoprecipitation (ChIP)-seq were performed to identify UTX target genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      UTX and p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      expression were both elevated post-SCI in a time-dependent manner. UTX deletion reduced endothelial senescence and enhanced proliferation both in vivo and in vitro. RNA-seq and ChIP-seq identified Top2\u03b2 as a direct transcriptional target of UTX, negatively regulated through promoter binding. These findings were validated by ChIP-qPCR, western blotting, and immunofluorescence. Knockdown of Top2\u03b2 reversed the anti-senescence and pro-proliferative effects induced by UTX deletion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>UTX deletion attenuates vascular endothelial senescence and promotes angiogenesis after SCI by upregulating Top2\u03b2 expression. This newly defined UTX\/Top2\u03b2 axis regulates vascular regeneration and represents a potential therapeutic target for promoting vascular repair following SCI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0338326","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T18:29:46Z","timestamp":1765564186000},"page":"e0338326","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["UTX\/Top2\u03b2 axis mediated spinal cord microvascular endothelial cells senescence exacerbates spinal cord injury"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3857-4763","authenticated-orcid":true,"given":"Dongliang","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yudong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianding","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianzhong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"issue":"1","key":"pone.0338326.ref001","doi-asserted-by":"crossref","first-page":"153","DOI":"10.14336\/AD.2023.0512","article-title":"Chondroitin Sulfate Proteoglycans Revisited: Its Mechanism of Generation and Action for Spinal Cord Injury","volume":"15","author":"R Yang","year":"2024","journal-title":"Aging Dis"},{"issue":"11","key":"pone.0338326.ref002","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.4103\/NRR.NRR-D-23-01505","article-title":"Advances in spinal cord injury: insights from non-human primates","volume":"19","author":"G Poulen","year":"2024","journal-title":"Neural Regen Res"},{"issue":"11","key":"pone.0338326.ref003","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/S1474-4422(23)00287-9","article-title":"Global, regional, and national burden of spinal cord injury, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019","volume":"22","year":"2023","journal-title":"Lancet Neurol"},{"issue":"1","key":"pone.0338326.ref004","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1007\/s10143-024-02372-6","article-title":"An updated systematic review of neuroprotective agents in the treatment of spinal cord injury","volume":"47","author":"I Serag","year":"2024","journal-title":"Neurosurg Rev"},{"key":"pone.0338326.ref005","doi-asserted-by":"crossref","first-page":"720938","DOI":"10.3389\/fncel.2021.720938","article-title":"Fibrotic Scar After Spinal Cord Injury: Crosstalk With Other Cells, Cellular Origin, Function, and Mechanism","volume":"15","author":"Z Li","year":"2021","journal-title":"Front Cell Neurosci"},{"issue":"6","key":"pone.0338326.ref006","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1089\/neu.2013.3034","article-title":"Characterization of vascular disruption and blood-spinal cord barrier permeability following traumatic spinal cord injury","volume":"31","author":"SA Figley","year":"2014","journal-title":"J Neurotrauma"},{"key":"pone.0338326.ref007","doi-asserted-by":"crossref","first-page":"17018","DOI":"10.1038\/nrdp.2017.18","article-title":"Traumatic spinal cord injury","volume":"3","author":"CS Ahuja","year":"2017","journal-title":"Nat Rev Dis Primers"},{"issue":"4","key":"pone.0338326.ref008","doi-asserted-by":"crossref","first-page":"790","DOI":"10.4103\/1673-5374.353485","article-title":"Pathophysiological mechanisms of chronic compressive spinal cord injury due to vascular events","volume":"18","author":"Z-X Ren","year":"2023","journal-title":"Neural Regen Res"},{"issue":"1","key":"pone.0338326.ref009","first-page":"9","article-title":"Molecular Mechanisms in the Vascular and Nervous Systems following Traumatic Spinal Cord Injury","volume":"13","author":"S Li","year":"2022","journal-title":"Life (Basel)"},{"issue":"5","key":"pone.0338326.ref010","article-title":"Angiogenesis in Spinal Cord Injury: Progress and Treatment","volume":"14","author":"K Tsivelekas","year":"2022","journal-title":"Cureus"},{"issue":"4","key":"pone.0338326.ref011","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.cell.2019.10.005","article-title":"Cellular Senescence: Defining a Path Forward","volume":"179","author":"V Gorgoulis","year":"2019","journal-title":"Cell"},{"issue":"12","key":"pone.0338326.ref012","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3390\/genes8120343","article-title":"Epigenetic Basis of Cellular Senescence and Its Implications in Aging","volume":"8","author":"T Nacarelli","year":"2017","journal-title":"Genes (Basel)"},{"issue":"12","key":"pone.0338326.ref013","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1038\/nm.4000","article-title":"Cellular senescence in aging and age-related disease: from mechanisms to therapy","volume":"21","author":"BG Childs","year":"2015","journal-title":"Nat Med"},{"issue":"18","key":"pone.0338326.ref014","doi-asserted-by":"crossref","first-page":"4411","DOI":"10.3390\/ijms20184411","article-title":"Vascular Endothelial Cell Biology: An Update","volume":"20","author":"A Kr\u00fcger-Genge","year":"2019","journal-title":"Int J Mol Sci"},{"key":"pone.0338326.ref015","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.mad.2016.05.003","article-title":"Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases","volume":"159","author":"C Regina","year":"2016","journal-title":"Mech Ageing Dev"},{"issue":"1","key":"pone.0338326.ref016","doi-asserted-by":"crossref","DOI":"10.1111\/acel.13988","article-title":"Senescent cells at the crossroads of aging, disease, and tissue homeostasis","volume":"23","author":"C Kuehnemann","year":"2024","journal-title":"Aging Cell"},{"issue":"6","key":"pone.0338326.ref017","doi-asserted-by":"crossref","first-page":"103582","DOI":"10.1016\/j.drudis.2023.103582","article-title":"Senolytics: Opening avenues in drug discovery to find novel therapeutics for Parkinson\u2019s Disease","volume":"28","author":"V Kakoty","year":"2023","journal-title":"Drug Discov Today"},{"issue":"5","key":"pone.0338326.ref018","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41574-020-0335-y","article-title":"The role of cellular senescence in ageing and endocrine disease","volume":"16","author":"S Khosla","year":"2020","journal-title":"Nat Rev Endocrinol"},{"issue":"10","key":"pone.0338326.ref019","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/s41581-022-00601-z","article-title":"Cellular senescence: the good, the bad and the unknown","volume":"18","author":"W Huang","year":"2022","journal-title":"Nat Rev Nephrol"},{"issue":"6","key":"pone.0338326.ref020","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1111\/acel.12518","article-title":"Small molecule compounds that induce cellular senescence","volume":"15","author":"NV Petrova","year":"2016","journal-title":"Aging Cell"},{"issue":"3","key":"pone.0338326.ref021","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1002\/ijc.32116","article-title":"The histone demethylase UTX\/KDM6A in cancer: Progress and puzzles","volume":"145","author":"WA Schulz","year":"2019","journal-title":"Int J Cancer"},{"issue":"12","key":"pone.0338326.ref022","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1016\/j.ymthe.2019.08.009","article-title":"UTX\/KDM6A Deletion Promotes Recovery of Spinal Cord Injury by Epigenetically Regulating Vascular Regeneration","volume":"27","author":"S Ni","year":"2019","journal-title":"Mol Ther"},{"key":"pone.0338326.ref023","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.omtm.2020.12.004","article-title":"UTX\/KDM6A deletion promotes the recovery of spinal cord injury by epigenetically triggering intrinsic neural regeneration","volume":"20","author":"Z Guo","year":"2020","journal-title":"Mol Ther Methods Clin Dev"},{"issue":"6","key":"pone.0338326.ref024","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/s41419-022-04985-5","article-title":"Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration","volume":"13","author":"W-S Lian","year":"2022","journal-title":"Cell Death Dis"},{"key":"pone.0338326.ref025","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.jneuroim.2006.05.012","article-title":"Isolation and culture of microvascular endothelial cells from murine spinal cord","volume":"177","author":"S Ge","year":"2006","journal-title":"J Neuroimmunol"},{"key":"pone.0338326.ref026","doi-asserted-by":"crossref","first-page":"631500","DOI":"10.3389\/fphys.2021.631500","article-title":"Revascularization after traumatic spinal cord injury","volume":"12","author":"C Yao","year":"2021","journal-title":"Front Physiol"},{"issue":"11","key":"pone.0338326.ref027","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1038\/jcbfm.2008.76","article-title":"Transcriptomic screening of microvascular endothelial cells implicates novel molecular regulators of vascular dysfunction after spinal cord injury","volume":"28","author":"RL Benton","year":"2008","journal-title":"J Cereb Blood Flow Metab"},{"issue":"2","key":"pone.0338326.ref028","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.bbrc.2010.07.061","article-title":"The tumor suppressor Rb and its related Rbl2 genes are regulated by Utx histone demethylase","volume":"399","author":"M Terashima","year":"2010","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0338326.ref029","first-page":"36","article-title":"Microvascular endothelial cells derived from spinal cord promote spinal cord injury repair","volume":"29","author":"Z You","year":"2023","journal-title":"Bioact Mater"},{"issue":"23","key":"pone.0338326.ref030","doi-asserted-by":"crossref","first-page":"9459","DOI":"10.1073\/pnas.0900222106","article-title":"Quantitative analysis by in vivo imaging of the dynamics of vascular and axonal networks in injured mouse spinal cord","volume":"106","author":"C Dray","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pone.0338326.ref031","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13148-024-01665-3","article-title":"Targeting histone demethylases JMJD3 and UTX: selenium as a potential therapeutic agent for cervical cancer","volume":"16","author":"D Chen","year":"2024","journal-title":"Clin Epigenetics"},{"issue":"21","key":"pone.0338326.ref032","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1161\/CIRCULATIONAHA.119.040125","article-title":"Transient p53-Mediated Regenerative Senescence in the Injured Heart","volume":"139","author":"R Sarig","year":"2019","journal-title":"Circulation"},{"issue":"1","key":"pone.0338326.ref033","doi-asserted-by":"crossref","DOI":"10.1111\/acel.13052","article-title":"Cell senescence contributes to tissue regeneration in zebrafish","volume":"19","author":"S Da Silva-\u00c1lvarez","year":"2020","journal-title":"Aging Cell"},{"issue":"2","key":"pone.0338326.ref034","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1152\/physrev.00020.2018","article-title":"Cellular Senescence: Aging, Cancer, and Injury","volume":"99","author":"A Calcinotto","year":"2019","journal-title":"Physiol Rev"},{"key":"pone.0338326.ref035","doi-asserted-by":"crossref","first-page":"102273","DOI":"10.1016\/j.arr.2024.102273","article-title":"Understanding the intricacies of cellular senescence in atherosclerosis: Mechanisms and therapeutic implications","volume":"96","author":"I Ali","year":"2024","journal-title":"Ageing Res Rev"},{"key":"pone.0338326.ref036","doi-asserted-by":"crossref","first-page":"103208","DOI":"10.1016\/j.redox.2024.103208","article-title":"Interactions between oxidative stress and senescence in cancer: Mechanisms, therapeutic implications, and future perspectives","volume":"73","author":"D Li","year":"2024","journal-title":"Redox Biol"},{"issue":"6","key":"pone.0338326.ref037","article-title":"Endothelial-specific telomerase inactivation causes telomere-independent cell senescence and multi-organ dysfunction characteristic of aging","volume":"23","author":"Z Gao","year":"2024","journal-title":"Aging Cell"},{"issue":"2","key":"pone.0338326.ref038","doi-asserted-by":"crossref","DOI":"10.1093\/gerona\/glad194","article-title":"Counteracting Age-Related Netrin-1 Signaling Insufficiency Ameliorates Endothelial Cell Senescence and Angiogenesis Impairment","volume":"79","author":"Z Yang","year":"2024","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"pone.0338326.ref039","doi-asserted-by":"crossref","first-page":"853688","DOI":"10.3389\/fcell.2022.853688","article-title":"Elimination of Senescent Cells by Senolytics Facilitates Bony Endplate Microvessel Formation and Mitigates Disc Degeneration in Aged Mice","volume":"10","author":"B Chen","year":"2022","journal-title":"Front Cell Dev Biol"},{"issue":"7411","key":"pone.0338326.ref040","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nature11272","article-title":"The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming","volume":"488","author":"AA Mansour","year":"2012","journal-title":"Nature"},{"issue":"2","key":"pone.0338326.ref041","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cmet.2011.07.001","article-title":"Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin\/IGF-1 signaling pathway","volume":"14","author":"C Jin","year":"2011","journal-title":"Cell Metab"},{"issue":"7","key":"pone.0338326.ref042","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.3390\/cancers12071745","article-title":"Cancer Stem Cell-Inducing Media Activates Senescence Reprogramming in Fibroblasts","volume":"12","author":"PM Perrigue","year":"2020","journal-title":"Cancers (Basel)"},{"issue":"2","key":"pone.0338326.ref043","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.molcel.2012.06.010","article-title":"Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation","volume":"47","author":"T Chandra","year":"2012","journal-title":"Mol Cell"},{"issue":"16","key":"pone.0338326.ref044","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1101\/gad.223834.113","article-title":"Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape","volume":"27","author":"PP Shah","year":"2013","journal-title":"Genes Dev"},{"key":"pone.0338326.ref045","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.abb.2017.06.021","article-title":"Topoisomerase II\u03b2 and its role in different biological contexts","volume":"633","author":"VS Bollimpelli","year":"2017","journal-title":"Arch Biochem Biophys"},{"issue":"16","key":"pone.0338326.ref046","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1119798109","article-title":"Target genes of Topoisomerase II\u03b2 regulate neuronal survival and are defined by their chromatin state","volume":"109","author":"VK Tiwari","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"pone.0338326.ref047","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1016\/j.tiv.2010.08.003","article-title":"Cultured cerebellar granule neurons as an in vitro aging model: topoisomerase II\u03b2 as an additional biomarker in DNA repair and aging","volume":"24","author":"MU Bhanu","year":"2010","journal-title":"Toxicol In Vitro"},{"issue":"6","key":"pone.0338326.ref048","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0230-6","article-title":"The cancer driver genes IDH1\/2, JARID1C\/ KDM5C, and UTX\/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism","volume":"51","author":"S Chang","year":"2019","journal-title":"Exp Mol Med"},{"key":"pone.0338326.ref049","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.gde.2016.03.010","article-title":"Histone demethylases in physiology and cancer: a tale of two enzymes, JMJD3 and UTX","volume":"36","author":"KM Arcipowski","year":"2016","journal-title":"Curr Opin Genet Dev"},{"issue":"1","key":"pone.0338326.ref050","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s13072-020-00359-3","article-title":"UTX\/KDM6A suppresses AP-1 and a gliogenesis program during neural differentiation of human pluripotent stem cells","volume":"13","author":"B Xu","year":"2020","journal-title":"Epigenetics Chromatin"},{"issue":"3","key":"pone.0338326.ref051","doi-asserted-by":"crossref","first-page":"341","DOI":"10.21147\/j.issn.1000-9604.2024.03.09","article-title":"Unraveling links between aging, circadian rhythm and cancer: Insights from evidence-based analysis","volume":"36","author":"D Feng","year":"2024","journal-title":"Chin J Cancer Res"},{"key":"pone.0338326.ref052","first-page":"0612","article-title":"The Common Hallmarks and Interconnected Pathways of Aging, Circadian Rhythms, and Cancer: Implications for Therapeutic Strategies","volume":"8","author":"J Wang","year":"2025","journal-title":"Research (Wash D C)"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0338326","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T18:29:52Z","timestamp":1765564192000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0338326"}},"subtitle":[],"editor":[{"given":"Hualin","family":"Fu","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,12]]},"references-count":52,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,12]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0338326","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,12]]}}}