Defining signals that promote human alveolar type I differentiation

Am J Physiol Lung Cell Mol Physiol. 2024 Feb 13. doi: 10.1152/ajplung.00191.2023. Online ahead of print.ABSTRACTAlveolar type I (ATI) cells cover >95% of the lung's distal surface and facilitate gas exchange through their exceptionally thin shape. ATI cells in vivo are replenished by alveolar type II cell division and differentiation, but a detailed understanding of ATI biology has been hampered by the challenges in direct isolation of these cell due to their fragility, and incomplete understanding of the signaling interactions that promote differentiation of ATII to ATI cells. Here we explored the signals that maintain ATII versus promote ATI fates in 3D organoid cultures, and developed a human alveolar type I differentiation medium (hATIDM) suitable for generating ATI cells from either mixed distal human lung cells or purified ATII cells. This media adds bone morphogenetic protein 4 (BMP4) and removes epidermal growth factor (EGF), Wnt agonist CHIR99021, and transforming growth factor-beta (TGF-beta) inhibitor SB431542 from previously developed alveolar organoid culture media. We demonstrate that BMP4 promotes expression of the ATI marker gene AGER whereas CHIR99021 and SB431542 maintain expression of the ATII marker gene SFTPC. The human ATI spheroids generated with hATIDM express multiple molecular and morphological features reminiscent of human ATI cells. Our results demonstrate that signaling interactions among BMP, TGF-beta and Wnt signaling pathways in alveolar sph...
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Source Type: research