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Deletion of Pten Expands Lung Epithelial Progenitor Pools and Confers Resistance to Airway Injury

¹ Department of Pediatrics, Division of Neonatology, Women's and Children's Hospital, USC Keck School of Medicine; ² Developmental Biology Program, Division of Surgery, Saban Research Institute of Children's Hospital Los Angeles; ³ Department of Pediatrics, Division of Neonatology and Developmental Biology, David Geffen School of Medicine UCLA; ⁴ Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Southern California, Los Angeles, California; ⁵ Department of Psychiatry, Weill Cornell Medical College, New York, New York; and ⁶ Department of Pediatrics, Division of Cell Biology, National Jewish Health, Denver, Colorado

Correspondence and requests for reprints should be addressed to Dr. Parviz Minoo, Ph.D., General Lab Building, Women's and Children's Hospital, 1801 E. Marengo Street, Los Angeles, CA 90033. E-mail: minoo{at}usc.edu

Rationale: Pten is a tumor-suppressor gene involved in stem cell homeostasis and tumorigenesis. In mouse, Pten expression is ubiquitous and begins as early as 7 days of gestation. Pten^–/– mouse embryos die early during gestation indicating a critical role for Pten in embryonic development.

Objectives: To test the role of Pten in lung development and injury.

Methods: We conditionally deleted Pten throughout the lung epithelium by crossing Pten^flox/flox with Nkx2.1-cre driver mice. The resulting Pten^Nkx2.1-cre mutants were analyzed for lung defects and response to injury.

Measurements and Main Results: Pten^Nkx2.1-cre embryonic lungs showed airway epithelial hyperplasia with no branching abnormalities. In adult mice, Pten^Nkx2.1-cre lungs exhibit increased progenitor cell pools composed of basal cells in the trachea, CGRP/CC10 double-positive neuroendocrine cells in the bronchi, and CC10/SPC double-positive cells at the bronchioalveolar duct junctions. Pten deletion affected differentiation of various lung epithelial cell lineages, with a decreased number of terminally differentiated cells. Over time, Pten^Nxk2.1-cre epithelial cells residing in the bronchioalveolar duct junctions underwent proliferation and formed uniform masses, supporting the concept that the cells residing in this distal niche may also be the source of procarcinogenic stem cells. Finally, increased progenitor cells in all the lung compartments conferred an overall selective advantage to naphthalene injury compared with wild-type control mice.

Conclusions: Pten has a pivotal role in lung stem cell homeostasis, cell differentiation, and consequently resistance to lung injury.

Key Words: Pten • lung progenitor cells • injury

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject PTEN is a well-known tumor suppressor that plays a key role in stem cell homeostasis in multiple organs, including the lung. The role of PTEN in lung injury and repair has not been studied yet. What This Study Adds to the Field This study demonstrates that lung epithelial-specific deletion of Pten leads to the expansion of epithelial progenitor cells and allows increased protection as well as regeneration of the airways after injury.