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Updated: Aug 6, 2026
Generation of 3D Whole Lung Organoids from Induced Pluripotent Stem Cells for Modeling Lung Developmental Biology and Disease
Published on: April 12, 2021
Extracellular matrix stiffness directs region-specific lung epithelial differentiation revealed by hPSC-derived lung
Zhiying Liao1, Hao Meng2, Junjie Lv1,3
1School of Biomedical Engineering, Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou, China.
Abstract:
Regional epithelial lineages of the human respiratory system reside within an extracellular matrix (ECM) whose mechanics vary along the airway-alveolar axis, yet how ECM stiffness directs epithelial fates remains unclear. 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.
