Integrin α6β4 Identifies Human Distal Lung Epithelial Progenitor Cells with Potential as a Cell-Based Therapy for Cystic Fibrosis Lung Disease

Xiaopeng Li; Nathan Rossen; Patrick L Sinn; Andrew L Hornick; Benjamin R Steines; Philip H Karp; Sarah E Ernst; Ryan J Adam; Thomas O Moninger; Dana N Levasseur; Joseph Zabner

doi:10.1371/journal.pone.0083624

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Integrin α6β4 Identifies Human Distal Lung Epithelial Progenitor Cells with Potential as a Cell-Based Therapy for Cystic Fibrosis Lung Disease

Journal article

Open access

Peer reviewed

Integrin α6β4 Identifies Human Distal Lung Epithelial Progenitor Cells with Potential as a Cell-Based Therapy for Cystic Fibrosis Lung Disease

Xiaopeng Li, Nathan Rossen, Patrick L Sinn, Andrew L Hornick, Benjamin R Steines, Philip H Karp, Sarah E Ernst, Ryan J Adam, Thomas O Moninger, Dana N Levasseur, …

PloS one, Vol.8(12), e83624

2013

DOI: 10.1371/journal.pone.0083624

PMCID: PMC3861522

PMID: 24349537

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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.

Cystic Fibrosis - therapy

Genetic Therapy

Lung - pathology

Epithelial Cells - metabolism

Transduction, Genetic

Cystic Fibrosis - metabolism

Humans

Integrin alpha6beta4 - genetics

Cells, Cultured

Cystic Fibrosis - pathology

Epithelial Cells - pathology

Male

Dependovirus

Stem Cells - metabolism

Respiratory Mucosa - pathology

Cystic Fibrosis - genetics

Stem Cells - pathology

Female

Lung - metabolism

Respiratory Mucosa - metabolism

Integrin alpha6beta4 - metabolism

Details

Title: Subtitle: Integrin α6β4 Identifies Human Distal Lung Epithelial Progenitor Cells with Potential as a Cell-Based Therapy for Cystic Fibrosis Lung Disease
Creators: Xiaopeng Li - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Nathan Rossen - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Patrick L Sinn - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Andrew L Hornick - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Benjamin R Steines - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Philip H Karp - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Sarah E Ernst - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Ryan J Adam - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Thomas O Moninger - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Dana N Levasseur - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Joseph Zabner - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Resource Type: Journal article
Publication Details: PloS one, Vol.8(12), e83624
DOI: 10.1371/journal.pone.0083624
PMID: 24349537
PMCID: PMC3861522
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science
Grant note: P30 ES005605 / NIEHS NIH HHS P01 HL091842 / NHLBI NIH HHS R01 HL105821 / NHLBI NIH HHS T32 HL007638 / NHLBI NIH HHS HL091842 / NHLBI NIH HHS HL51670 / NHLBI NIH HHS P01 HL051670 / NHLBI NIH HHS P30 DK054759 / NIDDK NIH HHS HL07638-24 / NHLBI NIH HHS DK54759 / NIDDK NIH HHS
Language: English
Date published: 2013
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Occupational and Environmental Health; Stead Family Department of Pediatrics; Internal Medicine
Record Identifier: 9984093337102771

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