title: Integrin α6β4 identifies human distal lung epithelial progenitor cells with potential as a cell-based therapy for cystic fibrosis lung disease.
abstract: To develop stem/progenitor cell-based therapy for cystic fibrosis (CF) lung disease, it is first necessary to identify markers of human lung epithelial progenitor/stem cells and to better understand the potential for differentiation into distinct lineages. Here we investigated integrin α6β4 as an epithelial progenitor cell marker in the human distal lung. We identified a subpopulation of α6β4(+) cells that localized in distal small airways and alveolar walls and were devoid of pro-surfactant protein C expression. The α6β4(+) epithelial cells demonstrated key properties of stem cells ex vivo as compared to α6β4(-) epithelial cells, including higher colony forming efficiency, expression of stem cell-specific transcription factor Nanog, and the potential to differentiate into multiple distinct lineages including basal and Clara cells. Co-culture of α6β4(+) epithelial cells with endothelial cells enhanced proliferation. We identified a subset of adeno-associated virus (AAVs) serotypes, AAV2 and AAV8, capable of transducing α6β4(+) cells. In addition, reconstitution of bronchi epithelial cells from CF patients with only 5% normal α6β4(+) epithelial cells significantly rescued defects in Cl(-) transport. Therefore, targeting the α6β4(+) epithelial population via either gene delivery or progenitor cell-based reconstitution represents a potential new strategy to treat CF lung disease.
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Nathan
authors.initials: N
authors.lastname: Rossen
authors.affiliation: Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Sinn
authors.affiliation: Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Hornick
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Steines
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Karp
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Ernst
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Adam
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Moninger
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Dana N
authors.initials: DN
authors.lastname: Levasseur
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
mesh_terms: D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000229:Dependovirus; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D039161:Integrin alpha6beta4 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic
chemical_list: D039161:Integrin alpha6beta4