The role of pulmonary mesenchymal cells in airway epithelium regeneration during injury repair

BACKGROUND: The airways of mammalian lung are lined with highly specialized cell types that are the target of airborne toxicants and injury. Several epithelial cell types and bone marrow-derived mesenchymal stem cells have been identified to serve as stem cells during injury repair. However, the contributions of endogenous mesenchymal cells to recruitment, expansion or differentiation of stem cells, and repair and reestablishment of the normal composition of airway epithelium following injury have not been addressed. METHODS: The role of mouse pulmonary mesenchymal cells was investigated by lineage tracing using Dermo1-Cre; ROSA(mTmG) mice. In experimental models of lung injury by lipopolysaccharide and naphthalene, GFP-labeled Dermo1(+) mesenchymal cells were traced during injury repair. In vitro lung explant culture treated with or without lipopolysaccharide was also used to verify in vivo data. RESULTS: During injury repair, a subgroup of GFP-labeled Dermo1(+) mesenchymal cells were found to contribute to normal repair of the airway epithelium and differentiated into Club cells, ciliated cells, and goblet cells. In Club cell-specific naphthalene injury model, the process of Dermo1(+) stem cell regenerating epithelial cells was dissected. The Dermo1(+) stem cells was migrated into the airway epithelium layer sooner after injury, and sequentially differentiated transitionally to epithelial stem cells, such as neuroendocrine cells, and finally to newly differentiated Club cells, ciliated cells, and goblet cells in injury repair. CONCLUSION: In this study, a population of Dermo1(+) mesenchymal stem cell was identified to serve as stem cells in airway epithelial cell regeneration during injury repair. The Dermo1(+) mesenchymal stem cell differentiated into epithelial stem cells before reestablishing various epithelial cells. These findings have implications for understanding the regulation of lung repair and the potential for usage of mesenchymal stem cells in therapeutic strategies for lung diseases.