title: The development and plasticity of alveolar type 1 cells.
abstract: Alveolar type 1 (AT1) cells cover >95% of the gas exchange surface and are extremely thin to facilitate passive gas diffusion. The development of these highly specialized cells and its coordination with the formation of the honeycomb-like alveolar structure are poorly understood. Using new marker-based stereology and single-cell imaging methods, we show that AT1 cells in the mouse lung form expansive thin cellular extensions via a non-proliferative two-step process while retaining cellular plasticity. In the flattening step, AT1 cells undergo molecular specification and remodel cell junctions while remaining connected to their epithelial neighbors. In the folding step, AT1 cells increase in size by more than 10-fold and undergo cellular morphogenesis that matches capillary and secondary septa formation, resulting in a single AT1 cell spanning multiple alveoli. Furthermore, AT1 cells are an unexpected source of VEGFA and their normal development is required for alveolar angiogenesis. Notably, a majority of AT1 cells proliferate upon ectopic SOX2 expression and undergo stage-dependent cell fate reprogramming. These results provide evidence that AT1 cells have both structural and signaling roles in alveolar maturation and can exit their terminally differentiated non-proliferative state. Our findings suggest that AT1 cells might be a new target in the pathogenesis and treatment of lung diseases associated with premature birth.
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Belinda J
authors.initials: BJ
authors.lastname: Hernandez
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Martinez Alanis
authors.affiliation: University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico 00927.
authors.forename: Odemaris
authors.initials: O
authors.lastname: Narvaez del Pilar
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA Tecnologico de Monterrey - Escuela de Medicina, Monterrey 64710, Mexico.
authors.forename: Lisandra
authors.initials: L
authors.lastname: Vila-Ellis
authors.affiliation: Department of Orthopedics, Kyoto University, Sakyo, Kyoto 606-8507, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Evans
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Ostrin
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA Center for Stem Cells and Developmental Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA jchen16@mdanderson.org.
authors.forename: Jichao
authors.initials: J
authors.lastname: Chen
mesh_terms: D056809:Alveolar Epithelial Cells / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation; D000066670:Cell Plasticity / Q000502:physiology*; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology; D021621:Imaging, Three-Dimensional; D017404:In Situ Hybridization, Fluorescence; D008171:Lung Diseases / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000196:embryology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: Alveolar angiogenesis; Cell plasticity; Lung development