TY - JOUR
T1 - Deletion of Pten expands lung epithelial progenitor pools and confers resistance to airway injury
AU - Tiozzo, Caterina
AU - De Langhe, Stijn
AU - Yu, Mingke
AU - Londhe, Vedang A.
AU - Carraro, Gianni
AU - Li, Min
AU - Li, Changgong
AU - Xing, Yiming
AU - Anderson, Stewart
AU - Borok, Zea
AU - Bellusci, Saverio
AU - Minoo, Parviz
PY - 2009/10/15
Y1 - 2009/10/15
N2 - 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: PtenNkx2.1-cre embryonic lungs showed airway epithelial hyperplasia with no branching abnormalities. In adult mice, PtenNkx2.1-cre lungs exhibit increasedprogenitor 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, PtenNxk2.1-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.
AB - 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: PtenNkx2.1-cre embryonic lungs showed airway epithelial hyperplasia with no branching abnormalities. In adult mice, PtenNkx2.1-cre lungs exhibit increasedprogenitor 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, PtenNxk2.1-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.
KW - Injury
KW - Lung progenitor cells
KW - Pten
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U2 - 10.1164/rccm.200901-0100OC
DO - 10.1164/rccm.200901-0100OC
M3 - Article
C2 - 19574443
AN - SCOPUS:70349861927
SN - 1073-449X
VL - 180
SP - 701
EP - 712
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 8
ER -