{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:29:50Z","timestamp":1791386990769,"version":"4.3.3"},"reference-count":46,"publisher":"American Society for Clinical Investigation","issue":"18","license":[{"start":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T00:00:00Z","timestamp":1600300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NIAID","award":["R01AI121147"],"award-info":[{"award-number":["R01AI121147"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,17]]},"abstract":"<jats:p>\n                    Age-associated systemic, chronic inflammation is partially attributed to increased self-autoreactivity, resulting from disruption of central tolerance in the aged, involuted thymus. This involution causally results from gradually decreased expression of the transcription factor\n                    <jats:italic>FOXN1<\/jats:italic>\n                    in thymic epithelial cells (TECs), whereas exogenous\n                    <jats:italic>FOXN1<\/jats:italic>\n                    in TECs can partially rescue age-related thymic involution. TECs induced from\n                    <jats:italic>FOXN1<\/jats:italic>\n                    -overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule, and intrathymic injection of naturally young TECs can lead to middle-aged thymus regrowth. Therefore, as a thymic rejuvenation strategy, we extended these 2 findings by combining them with 2 types of promoter-driven (\n                    <jats:italic>Rosa26<\/jats:italic>\n                    CreER\n                    <jats:sup>T<\/jats:sup>\n                    and\n                    <jats:italic>FoxN1<\/jats:italic>\n                    Cre) Cre-mediated\n                    <jats:italic>FOXN1<\/jats:italic>\n                    -reprogrammed embryonic fibroblasts (FREFs). We engrafted these FREFs directly into the aged murine thymus. We found substantial regrowth of the native aged thymus with rejuvenated architecture and function in both males and females, exhibiting increased thymopoiesis and reinforced thymocyte negative selection, along with reduced senescent T cells and autoreactive T cell\u2013mediated inflammation in old mice. Therefore, this approach has preclinical significance and presents a strategy to potentially rescue decreased thymopoiesis and perturbed negative selection to substantially, albeit partially, restore defective central tolerance and reduce subclinical autoimmune symptoms in elderly people.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.140313","type":"journal-article","created":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T12:01:56Z","timestamp":1597320116000},"source":"Crossref","is-referenced-by-count":42,"title":["Thymic rejuvenation via FOXN1-reprogrammed embryonic fibroblasts (FREFs) to counteract age-related inflammation"],"prefix":"10.1172","volume":"5","author":[{"given":"Jiyoung","family":"Oh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weikan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3326-4753","authenticated-orcid":true,"given":"Dong-Ming","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2020,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2009.05.023"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glu057"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2010.03.003"},{"key":"B4","article-title":"Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes?","volume":"8","author":"Fulop","year":"2017","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-012-0970-0"},{"issue":"3","key":"B6","first-page":"248","article-title":"Age-related disruption of steady-state thymic medulla provokes autoimmune phenotype via perturbing negative selection","volume":"3","author":"Xia","year":"2012","journal-title":"Aging Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500082"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1714478115"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1385\/IR:36:1:221"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0601040103"},{"key":"B11","doi-asserted-by":"crossref","DOI":"10.1186\/s12979-020-0173-8","article-title":"Contributions of age-related thymic involution to immunosenescence and inflammaging","volume":"17","author":"Thomas","year":"2020","journal-title":"Immun Ageing"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-121808-102144"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2018.09.003"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0083-6"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.2003352"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2010.00559.x"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502010"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxf042"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646553"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1403158"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3023"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1242\/dev.103614"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-342097"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-08-043794"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-04-149435"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-05-1657"},{"issue":"19","key":"B27","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.aal2736","article-title":"Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration","volume":"3","author":"Wertheimer","year":"2018","journal-title":"Sci Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/science.1218004"},{"key":"B29","doi-asserted-by":"crossref","unstructured":"Wang W, et al. 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