Multi-apical polarity of alveolar stem cells and their dynamics during lung development and regeneration
Arvind Konkimalla,
Satoshi Konishi,
Yoshihiko Kobayashi,
Preetish Kadur Lakshminarasimha Murthy,
Lauren Macadlo,
Ananya Mukherjee,
Zachary Elmore,
So-Jin Kim,
Ann Marie Pendergast,
Patty J. Lee,
Aravind Asokan,
Lars Knudsen,
Jose Javier Bravo-Cordero,
Aleksandra Tata,
Purushothama Rao Tata
Affiliations
Arvind Konkimalla
Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA; Medical Scientist Training Program, Duke University School of Medicine, Durham, NC 27710, USA
Satoshi Konishi
Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
Yoshihiko Kobayashi
Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
Preetish Kadur Lakshminarasimha Murthy
Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
Lauren Macadlo
Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
Ananya Mukherjee
Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Zachary Elmore
Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA
So-Jin Kim
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine and the Durham Veterans Administration Medical Center, Durham, NC 27710, USA
Ann Marie Pendergast
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
Patty J. Lee
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine and the Durham Veterans Administration Medical Center, Durham, NC 27710, USA
Aravind Asokan
Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Biomedical Engineering, Regeneration Next, Duke University, Durham, NC 27710, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27710, USA
Lars Knudsen
Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover 30625, Germany
Jose Javier Bravo-Cordero
Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Aleksandra Tata
Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA; Corresponding author
Purushothama Rao Tata
Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine and the Durham Veterans Administration Medical Center, Durham, NC 27710, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC 27710, USA; Duke Regeneration Center, Duke University, Durham, NC 27710, USA; Corresponding author
Summary: Epithelial cells of diverse tissues are characterized by the presence of a single apical domain. In the lung, electron microscopy studies have suggested that alveolar type-2 epithelial cells (AT2s) en face multiple alveolar sacs. However, apical and basolateral organization of the AT2s and their establishment during development and remodeling after injury repair remain unknown. Thick tissue imaging and electron microscopy revealed that a single AT2 can have multiple apical domains that enface multiple alveoli. AT2s gradually establish multi-apical domains post-natally, and they are maintained throughout life. Lineage tracing, live imaging, and selective cell ablation revealed that AT2s dynamically reorganize multi-apical domains during injury repair. Single-cell transcriptome signatures of residual AT2s revealed changes in cytoskeleton and cell migration. Significantly, cigarette smoke and oncogene activation lead to dysregulation of multi-apical domains. We propose that the multi-apical domains of AT2s enable them to be poised to support the regeneration of a large array of alveolar sacs.
