title: Combinations of differentiation markers distinguish subpopulations of alveolar epithelial cells in adult lung.
abstract: Distal lung epithelium is maintained by proliferation of alveolar type II (AT2) cells and, for some daughter AT2 cells, transdifferentiation into alveolar type I (AT1) cells. We investigated if subpopulations of alveolar epithelial cells (AEC) exist that represent various stages in transdifferentiation from AT2 to AT1 cell phenotypes in normal adult lung and if they can be identified using combinations of cell-specific markers. Immunofluorescence microscopy showed that, in distal rat and mouse lungs, ∼ 20-30% of NKX2.1(+) (or thyroid transcription factor 1(+)) cells did not colocalize with pro-surfactant protein C (pro-SP-C), a highly specific AT2 cell marker. In distal rat lung, NKX2.1(+) cells coexpressed either pro-SP-C or the AT1 cell marker homeodomain only protein x (HOPX). Not all HOPX(+) cells colocalize with the AT1 cell marker aquaporin 5 (AQP5), and some AQP5(+) cells were NKX2.1(+). HOPX was expressed earlier than AQP5 during transdifferentiation in rat AEC primary culture, with robust expression of both by day 7. We speculate that NKX2.1 and pro-SP-C colocalize in AT2 cells, NKX2.1 and HOPX or AQP5 colocalize in intermediate or transitional cells, and HOPX and AQP5 are expressed without NKX2.1 in AT1 cells. These findings suggest marked heterogeneity among cells previously identified as exclusively AT1 or AT2 cells, implying the presence of subpopulations of intermediate or transitional AEC in normal adult lung.
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Will Rogers Institute Pulmonary Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Janice M
authors.identifier: http://orcid.org/0000-0002-4166-6197
authors.initials: JM
authors.lastname: Liebler
authors.affiliation: Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California; Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California; and.
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Marconett
authors.affiliation: Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Juul
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Will Rogers Institute Pulmonary Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Will Rogers Institute Pulmonary Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Yixin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Will Rogers Institute Pulmonary Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Per
authors.initials: P
authors.lastname: Flodby
authors.affiliation: Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California; Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California; and.
authors.forename: Ite A
authors.initials: IA
authors.lastname: Laird-Offringa
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, and Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Will Rogers Institute Pulmonary Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California; bzhou@usc.edu.
authors.forename: Beiyun
authors.initials: B
authors.lastname: Zhou
mesh_terms: D000375:Aging; D056809:Alveolar Epithelial Cells / Q000166:cytology*; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D054338:Cell Transdifferentiation / Q000502:physiology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D011650:Pulmonary Alveoli / Q000166:cytology*; D051381:Rats
chemical_list: D000943:Antigens, Differentiation
keywords: NKX2.1; alveolar epithelial type I cell; alveolar epithelial type II cell; aquaporin-5; homeodomain only protein x; intermediate cells; transdifferentiation