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Here, a chemically defined reprogramming strategy is developed that enables efficient conversion of adult human AT2 cells into a highly expandable alveolar progenitor\u2010like state that, at late passages, closely resembles primitive lung bud tip epithelium. These progenitor cells robustly self\u2010organize into three\u2010dimensional alveolar progenitor\u2010like organoids (APLOs), which can be further efficiently differentiated into mature alveolar\u2010like organoids (ALOs). In vitro, ALOs serve as a physiologically relevant platform for modeling influenza A virus (IAV) infection and mounting innate immune responses characterized by interferon signaling, thereby enabling mechanistic studies of viral pathogenesis and host defense. In vivo, following intratracheal transplantation into lung\u2010injured mice, APLO\u2010derived cells exhibit stable engraftment and differentiate into alveolar epithelial lineages, leading to improvement in pulmonary function. In summary, this study establishes an adult\u2010derived, expandable alveolar progenitor platform generated through chemical reprogramming that recapitulates key aspects of alveolar development, disease modeling, and regenerative potential.<\/jats:p>","DOI":"10.1002\/advs.77773","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T15:50:51Z","timestamp":1791129051000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endowing Flexibility of Alveolar Type II Cells to Recapitulate Development From Lung Bud to Alveoli"],"prefix":"10.1002","author":[{"given":"Hongqian","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine Key Laboratory of Anesthesiology (Shanghai Jiao Tong University) Ministry of Education  Shanghai China"},{"name":"Shanghai Engineering Research Center of Peri\u2010operative Organ Support and Function Preservation (20DZ2254200)  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine Key Laboratory of Anesthesiology (Shanghai Jiao Tong University) Ministry of Education  Shanghai China"},{"name":"Shanghai Engineering Research Center of Peri\u2010operative Organ Support and Function Preservation (20DZ2254200)  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6863-2608","authenticated-orcid":false,"given":"Lujia","family":"Sun","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Infectious Disease and Biosecurity Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS) School of Basic Medical Sciences Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery 905 Hospital of People's Liberation Army Navy  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Li","sequence":"additional","affiliation":[{"name":"Celliver Biotechnology Inc.  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