Rare SOX2+ Airway Progenitor Cells Generate KRT5+ Cells that Repopulate Damaged Alveolar Parenchyma following Influenza Virus Infection

• Published in: Stem cell reports 2016-11, Vol.7 (5), p.817-825
• Main Authors: Ray, Samriddha, Chiba, Norika, Yao, Changfu, Guan, Xiangrong, McConnell, Alicia M., Brockway, Brian, Que, Loretta, McQualter, Jonathan L., Stripp, Barry R.
• Format: Article
• Language: English
• Subjects: Alveolar Epithelial Cells - cytology; Alveolar Epithelial Cells - metabolism; Alveolar Epithelial Cells - virology; Animals; Biomarkers; Cell Differentiation; Cell Lineage; Cell Self Renewal - genetics; Influenza A Virus, H1N1 Subtype; influenza virus; keratin 5; Keratin-5 - metabolism; lung injury; lung repair; Mice; Mice, Transgenic; Models, Biological; Orthomyxoviridae Infections - genetics; Orthomyxoviridae Infections - metabolism; Orthomyxoviridae Infections - pathology; Orthomyxoviridae Infections - virology; progenitor cells; Respiratory Mucosa - cytology; Respiratory Mucosa - metabolism; Respiratory Mucosa - virology; SCGB1A1 lineage; SOX2 lineage; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Stem Cells - cytology; Stem Cells - metabolism; wound repair
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2016.09.010

Recent studies have implicated keratin 5 (KRT5)+ cells in repopulation of damaged lung tissue following severe H1N1 influenza virus infection. However, the origins of the cells repopulating the injured alveolar region remain controversial. We sought to determine the cellular dynamics of lung repair following influenza infection and define whether nascent KRT5+ cells repopulating alveolar epithelium were derived from pre-existing alveolar or airway progenitor cells. We found that the wound-healing response begins with proliferation of SOX2+ SCGB1A1− KRT5− progenitor cells in airways. These cells generate nascent KRT5+ cells as an early response to airway injury and yield progeny that colonize damaged alveolar parenchyma. Moreover, we show that local alveolar progenitors do not contribute to nascent KRT5+ cells after injury. Repopulation of injured airway and alveolar regions leads to proximalization of distal airways by pseudostratified epithelium and of alveoli by airway-derived epithelial cells that lack the normal characteristics of mature airway or alveolar epithelium. [Display omitted] •Influenza induces KRT5+ cell appearance in remodeled distal lung epithelium•Alveolar progenitor cells do not contribute to nascent KRT5+ cells•Multiple airway progenitor cells give rise to nascent KRT5+ cells in airways•SOX2 lineage-labeled cells are the major cellular source of nascent KRT5+ cells Stripp and colleagues report that H1N1 influenza virus infection in mice induces distal lung epithelial remodeling marked by the appearance of nascent KRT5+ cells in injured airways and alveoli. Rather than pre-existing basal, club, and alveolar progenitor cells, they traced the cellular origin of these nascent KRT5+ cells to a population of airway-resident SOX2+ Lin− progenitor cells.