TY - JOUR
T1 - Alveolar progenitor and stem cells in lung development, renewal and cancer
AU - Desai, Tushar J.
AU - Brownfield, Douglas G.
AU - Krasnow, Mark A.
N1 - Funding Information:
Author Contributions T.J.D. conducted the experiments except the gene expression profiling and AT2 cell cultures, which were done by D.G.B.; T.J.D., D.G.B. and M.A.K. conceived the experiments, analysed the data and wrote the manuscript. This work was supported by a Parker B. Francis Foundation Fellowship and NIH 5KO8HL084095 Award (T.J.D.), NIH T32HD007249 (D.G.B.), and an NHLBI U01HL099995 Progenitor Cell Biology Consortium grant (M.A.K.). M.A.K. is an investigator of the Howard Hughes Medical Institute.
PY - 2014
Y1 - 2014
N2 - Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal. This stem-cell function is broadly activated by AT1 injury, and AT2 self-renewal is selectively induced by EGFR (epidermal growth factor receptor) ligands in vitro and oncogenic Kras(G12D) in vivo, efficiently generating multifocal, clonal adenomas. Thus, there is a switch after birth, when AT2 cells function as stem cells that contribute to alveolar renewal, repair and cancer. We propose that local signals regulate AT2 stem-cell activity: a signal transduced by EGFR-KRAS controls self-renewal and is hijacked during oncogenesis, whereas another signal controls reprogramming to AT1 fate.
AB - Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal. This stem-cell function is broadly activated by AT1 injury, and AT2 self-renewal is selectively induced by EGFR (epidermal growth factor receptor) ligands in vitro and oncogenic Kras(G12D) in vivo, efficiently generating multifocal, clonal adenomas. Thus, there is a switch after birth, when AT2 cells function as stem cells that contribute to alveolar renewal, repair and cancer. We propose that local signals regulate AT2 stem-cell activity: a signal transduced by EGFR-KRAS controls self-renewal and is hijacked during oncogenesis, whereas another signal controls reprogramming to AT1 fate.
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U2 - 10.1038/nature12930
DO - 10.1038/nature12930
M3 - Article
C2 - 24499815
AN - SCOPUS:84896319764
SN - 0028-0836
VL - 507
SP - 190
EP - 194
JO - Nature
JF - Nature
IS - 7491
ER -