GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE293nnn/GSE293170/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE293170GEOGSEfalseExtracellular stiffness regulates site-specific lung development [AWO]Extracellular matrix (ECM) stiffness plays a crucial role in regulating cell fate and maturation, but its influence on lung development is limited known. Here we utilized stiffness-tunable gelatin methacryloyl (GelMA) hydrogels to investigate how ECM stiffness influences site-specific lung development in a stem cell-derived lung organoid model. We found increased stiffness promoted NKX2-1+ lung progenitor cells (LPCs) generation. In airway organoids (hAWOs), stiff hydrogels directed proximal airway differentiation enriched with goblet, ciliated, and basal cells; whereas the decreased stiffness favored emergence of secretory cells in the proximal-distal transition zone and distal airway. In alveolar organoids (hALOs), increased stiffness enhanced AT2 and AT1 cells transition. Moreover, infection assays with Omicron BA.1.1 and Delta variants recapitulated the proximal-to-distal tropism of SARS-CoV-2 in the lung. Transcriptomic sequencing revealed ECM stiffness regulates lung development via Hippo, TGF-β, HIF and Wnt pathways. These findings advance mechanism understanding of ECM stiffness on lung development and provide a novel mechanical regulation for generating site-specific lung organoids.2026/06/02GSE293170GSM8877764GSM8877765GSM887776334284293170Homo sapiens