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Here, utilizing human pluripotent stem cell-derived lung organoids embedded in stiffness-tunable hydrogels as an in vitro model, we show ECM stiffness governs region-specific epithelial differentiation. Stepwise softening of ECM stiffness yields airway organoids with proximal-to-distal airway epithelial compositions and biomimetic physiological functions. During alveolar differentiation, increased stiffness promotes alveolar type 2 (AT2) and type 1 (AT1) maturation and drives AT2-to-AT1 transition. Furthermore, RNA sequencing reveals ECM stiffness regulates epithelial fates primarily through mechanotransduction pathways. Finally, these organoids reproduce the infection tropisms of SARS-CoV-2 variants. Together, this research elucidates ECM stiffness as a critical determinant of epithelial cell fate specification and region-specific lung organoid generation, which offers a valuable in vitro model for studying region-specific lung development, diseases pathogenesis, and drug screening.<\/jats:p>","DOI":"10.1038\/s41467-026-75663-9","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T06:53:50Z","timestamp":1784271230000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extracellular matrix stiffness directs region-specific lung epithelial differentiation revealed by hPSC-derived lung organoids"],"prefix":"10.1038","volume":"17","author":[{"given":"Zhiying","family":"Liao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4647-6541","authenticated-orcid":false,"given":"Hao","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengrui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runxi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruihao","family":"Lan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5153-0007","authenticated-orcid":false,"given":"Zonghong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangping","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7316-6894","authenticated-orcid":false,"given":"Xuepeng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2515-5589","authenticated-orcid":false,"given":"Jincun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5371-7943","authenticated-orcid":false,"given":"Huisheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"75663_CR1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adj7615","volume":"386","author":"MB Baghdadi","year":"2024","unstructured":"Baghdadi, M. 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