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Published ahead of print on July 2, 2009, doi:10.1164/rccm.200901-0100OC

Am. J. Respir. Crit. Care Med., Volume 180, Number 8, October 2009, 701-712

A more recent version of this article appeared on October 15, 2009
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Submitted on January 19, 2009
Accepted on July 1, 2009

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

Caterina Tiozzo1, Stijn De Langhe2, Mingke Yu1, Vedang A. Londhe3, Gianni Carraro4, Min Li1, Changgong Li1, Yiming Xing1, Stewart Anderson5, Zea Borok6, Saverio Bellusci4, and Parviz Minoo1*

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

* To whom correspondence should be addressed. 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. Objective: To test the role of Pten in lung development and injury, we conditionally deleted Pten throughout the lung epithelium by crossing Ptenflox/flox with Nkx2.1-cre driver mice. The resulting PtenNkx2.1-cre mutants were analyzed for lung defects and response to injury. Results: PtenNkx2.1-cre embryonic lungs showed airway epithelial hyperplasia with no branching abnormalities. In adult mice, PtenNkx2.1-cre lungs exhibit increased progenitor cell pools comprised 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 (BADJ). Pten deletion impacted differentiation of various lung epithelial cell lineages, with decreased number of terminally differentiated cells. Over time, PtenNxk2.1-cre epithelial cells residing in the BADJ underwent proliferation and formed uniform masses, supporting the concept that the cells residing in this distal niche may also be the source of pro-carcinogenic "stem" cells. Finally, increased progenitor cells in all the lung compartments conferred an overall selective advantage to naphthalene injury compared to 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






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