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Am J Physiol Lung Cell Mol Physiol. 2016 Jan 15;310(2):L114-20. doi: 10.1152/ajplung.00337.2015. Epub 2015 Nov 6.

Combinations of differentiation markers distinguish subpopulations of alveolar epithelial cells in adult lung.

Author information

1
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;
2
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.
3
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California;
4
Division of Newborn Medicine, Department of Pediatrics, and Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
5
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.

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.

KEYWORDS:

NKX2.1; alveolar epithelial type I cell; alveolar epithelial type II cell; aquaporin-5; homeodomain only protein x; intermediate cells; transdifferentiation

PMID:
26545903
PMCID:
PMC4719049
DOI:
10.1152/ajplung.00337.2015
[Indexed for MEDLINE]
Free PMC Article

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