{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:55:33Z","timestamp":1790574933571,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U24A20659"],"award-info":[{"award-number":["U24A20659"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Cellular senescence is a fundamental hallmark of aging and represents a major barrier to the scalable and reproducible application of mesenchymal stromal cell (MSC)\u2010derived small extracellular vesicles (sEVs). Senescent human umbilical cord mesenchymal stromal cells (hUCMSCs) exhibit impaired proliferative capacity, disrupted mitochondrial homeostasis, and altered secretory phenotypes, which may compromise the biological activity and therapeutic reliability of sEVs. Here, we investigated whether overexpression of human telomerase reverse transcriptase (hTERT) attenuates senescence\u2010associated deterioration and stabilizes sEV functional properties. Late\u2010passage hUCMSCs displayed canonical senescence features and mitochondrial dysfunction, all of which were markedly alleviated by hTERT expression. Functionally, sEVs derived from senescent cells exhibited impaired immunomodulatory activity, whereas sEVs from hTERT\u2010expressing cells largely restored this function. Mechanistically, senescence was associated with altered sEV cargo, including enrichment of miR\u2010217\u20105p, which contributed to diminished immunomodulatory potency, at least in part through modulation of SIRT1\u2010associated inflammatory signaling in recipient macrophages. Proteomic profiling further showed that H11\u2010sEVs retained a young\u2010like protein cargo profile, particularly for proteins associated with immune and inflammatory regulation. In parallel, sEVs from all three groups retained primordial follicle\u2010activating capacity, consistent with the broad retention of PI3K\u2010Akt pathway\u2010related proteins in their proteomic profiles and PI3K\u2010Akt pathway activation in ovarian tissues. In aged female mice, H11\u2010sEVs exhibited young\u2010like ovarian protective activity. Collectively, these findings demonstrate that hTERT uncouples cellular senescence from sEV functional decline, supporting the development of potency\u2010stabilized sEV sources for aging\u2010related and regenerative applications and providing insight into the biological roles of senescent cell\u2010derived sEVs.<\/jats:p>","DOI":"10.1111\/acel.70681","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:24:49Z","timestamp":1787315089000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>hTERT<\/scp>\n                    Immortalization Stabilizes Human Umbilical Cord\n                    <scp>MSCs<\/scp>\n                    and Maintains Their Small Extracellular Vesicles With Preserved Immunomodulatory Activity and Primordial Follicle\u2010Activating Capacity"],"prefix":"10.1111","volume":"25","author":[{"given":"Yating","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University  Nanjing Jiangsu P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Tian","sequence":"additional","affiliation":[{"name":"The Center for Clinical Reproductive Medicine, State Key Laboratory of Reproductive Medicine and Offspring Health The First Affiliated Hospital of Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University  Nanjing Jiangsu P. R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feiyang","family":"Diao","sequence":"additional","affiliation":[{"name":"The Center for Clinical Reproductive Medicine, State Key Laboratory of Reproductive Medicine and Offspring Health The First Affiliated Hospital of Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8692-4981","authenticated-orcid":false,"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University  Nanjing Jiangsu P. R. China"},{"name":"Changzhou Medical Center Nanjing Medical University  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241612594"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.2779"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287\u2010025\u201004610\u20100"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep43923"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202413759"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aam7828"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2016.5169"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.727"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287\u2010018\u20100791\u20107"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10522\u2010025\u201010290\u20103"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.4014\/jmb.2310.10035"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010022\u201005034\u2010x"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.18915"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2017.2912"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/9291013"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1042\/cbi20110350"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010024\u201003914\u20101"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2012.0222"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.70029"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287\u2010021\u201002222\u2010y"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.109.864629"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1080\/20013078.2020.1725285"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365\u20102141.2003.04217.x"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1284"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes14122155"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/496218"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.206292"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.269"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207651"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11071168"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/35036093"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287\u2010020\u201001881\u20107"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2025.04.034"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287\u2010025\u201004743\u20102"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/5584_2018_235"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002213"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2020.111263"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2021.09.021"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/stcltm\/szac004"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.955175"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252413562"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00068"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.02.003"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010024\u201005094\u2010x"}],"container-title":["Aging 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