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While research has long focused on how antigen\u2010presenting cells shape the T cell repertoire, recent discoveries unveil a far richer cellular landscape that challenges long\u2010held views of thymus structure and function. This review traces the history of early thymic reconstitution assays, the paradigm of clonal stem cells and serial transplantation, assessing evidence for \u201cstemness\u201d within the thymus. A key focus is the paradox that an involuting thymus retains cells able to expand in culture and reconstitute organ function. We differentiate embryonic\/fetal thymus development from postnatal homeostasis, emphasizing how the potency of epithelial progenitor\/stem cells shifts with age or upon injury. The role of mesenchymal\/interstitial cells and the extracellular milieu is considered alongside advances in organ reconstruction. We outline major unsolved questions in the field: thymus regeneration after childhood; the minimal components required to generate functional na\u00efve T cells outside the body; and the potential of next\u2010generation humanized mouse models to interrogate immune tolerance and novel immunotherapies. We argue that thymus research is entering a new era, one in which understanding and harnessing thymus regenerative potential could yield transformative advances in both basic science and clinical applications.<\/jats:p>","DOI":"10.1111\/imr.70110","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T06:45:26Z","timestamp":1771224326000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Thymus Regeneration Paradox: The Search for Stemness in an Involuting Organ"],"prefix":"10.1111","volume":"338","author":[{"given":"Roberta","family":"Ragazzini","sequence":"first","affiliation":[{"name":"Epithelial Stem Cell Biology &amp; Regenerative Medicine Laboratory The Francis Crick Institute  London UK"},{"name":"Institute of Immunity &amp; Transplantation, Division of Infection &amp; Immunity UCL  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9655-3766","authenticated-orcid":false,"given":"Paola","family":"Bonfanti","sequence":"additional","affiliation":[{"name":"Epithelial Stem Cell Biology &amp; Regenerative Medicine Laboratory The Francis Crick Institute  London UK"},{"name":"Institute of Immunity &amp; Transplantation, Division of Infection &amp; Immunity UCL  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,15]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12220"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.01.037"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.2741\/3896"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4684-9066-4_42"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0171-2985(84)80142-4"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12893-021-01048-y"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.2214\/ajr.149.2.269"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199501193320303"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00005-017-0462-x"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646309"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2834"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.2001.01212.x"},{"issue":"3","key":"e_1_2_13_14_1","first-page":"307","article-title":"Changes in the Weight of the Thymus After Birth and in Pregnancy in Mice","volume":"101","author":"Endo T.","year":"1998","journal-title":"Research Communications in Molecular Pathology and Pharmacology"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202100543"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2007.10.007"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo.142.3.8032"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.114.1_Part_2.452"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.40.4.429"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(61)90693-6"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/191248a0"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.141.3586.1193"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0016672300010168"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(54)90169-X"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1699-0463.1974.tb03853.x"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1699-0463.1973.tb00479.x"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09269"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20140047"},{"issue":"2","key":"e_1_2_13_29_1","first-page":"322","article-title":"Generation of T\u2010Cell Function in Organ Culture of Foetal Mouse Thymus. 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