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Identification of a Repair-Supportive Mesenchymal Cell Population during Airway Epithelial Regeneration.

ABSTRACT: Tissue regeneration requires coordinated and dynamic remodeling of stem and progenitor cells and the surrounding niche. Although the plasticity of epithelial cells has been well explored in many tissues, the dynamic changes occurring in niche cells remain elusive. Here, we show that, during lung repair after naphthalene injury, a population of PDGFRα⁺ cells emerges in the non-cartilaginous conducting airway niche, which is normally populated by airway smooth muscle cells (ASMCs). This cell population, which we term "repair-supportive mesenchymal cells" (RSMCs), is distinct from conventional ASMCs, which have previously been shown to contribute to epithelial repair. Gene expression analysis on sorted lineage-labeled cells shows that RSMCs express low levels of ASMC markers, but high levels of the pro-regenerative marker Fgf10. Organoid co-cultures demonstrate an enhanced ability for RSMCs in supporting club-cell growth. Our study highlights the dynamics of mesenchymal cells in the airway niche and has implications for chronic airway-injury-associated diseases.

SUBMITTER: Moiseenko A

PROVIDER: S-EPMC8363050 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Identification of a Repair-Supportive Mesenchymal Cell Population during Airway Epithelial Regeneration.

Moiseenko Alena A Vazquez-Armendariz Ana Ivonne AI Kheirollahi Vahid V Chu Xuran X Tata Aleksandra A Rivetti Stefano S Günther Stefan S Lebrigand Kevin K Herold Susanne S Braun Thomas T Mari Bernard B De Langhe Stijn S Kwapiszewska Grazyna G Günther Andreas A Chen Chengshui C Seeger Werner W Tata Purushothama Rao PR Zhang Jin-San JS Bellusci Saverio S El Agha Elie E

Cell reports 20201201 12

Tissue regeneration requires coordinated and dynamic remodeling of stem and progenitor cells and the surrounding niche. Although the plasticity of epithelial cells has been well explored in many tissues, the dynamic changes occurring in niche cells remain elusive. Here, we show that, during lung repair after naphthalene injury, a population of PDGFRα<sup>+</sup> cells emerges in the non-cartilaginous conducting airway niche, which is normally populated by airway smooth muscle cells (ASMCs). This ...[more]

PMID: 33357434

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Project description:Repair-supportive mesenchymal cells (RSMCs) have been recently reported in the context of naphthalene (NA)-induced airway injury and regeneration. These cells transiently express smooth muscle actin (Acta2) and are enriched with platelet-derived growth factor receptor alpha (Pdgfra) and fibroblast growth factor 10 (Fgf10) expression. Genetic deletion of Ctnnb1 (gene coding for beta catenin) or Fgf10 in these cells using the Acta2-Cre-ERT2 driver line after injury (defined as NA-Tam condition; Tam refers to tamoxifen) led to impaired repair of the airway epithelium. In this study, we demonstrate that RSMCs are mostly captured using the Acta2-Cre-ERT2 driver when labeling occurs after (NA-Tam condition) rather than before injury (Tam-NA condition), and that their expansion occurs mostly between days 3 and 7 following NA treatment. Previous studies have shown that lineage-traced peribronchial GLI1+ cells are transiently amplified after NA injury. Here, we report that Gli1 expression is enriched in RSMCs. Using lineage tracing with Gli1Cre-ERT2 mice combined with genetic inactivation of Fgf10, we show that GLI1+ cells with Fgf10 deletion fail to amplify around the injured airways, thus resulting in impaired airway epithelial repair. Interestingly, Fgf10 expression is not upregulated in GLI1+ cells following NA treatment, suggesting that epithelial repair is mostly due to the increased number of Fgf10-expressing GLI1+ cells. Co-culture of SCGB1A1+ cells with GLI1+ cells isolated from non-injured or injured lungs showed that GLI1+ cells from these two conditions are similarly capable of supporting bronchiolar organoid (or bronchiolosphere) formation. Single-cell RNA sequencing on sorted lineage-labeled cells showed that the RSMC signature resembles that of alveolar fibroblasts. Altogether, our study provides strong evidence for the involvement of mesenchymal progenitors in airway epithelial regeneration and highlights the critical role played by Fgf10-expressing GLI1+ cells in this context.

Project description:BackgroundThe 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.MethodsThe role of mouse pulmonary mesenchymal cells was investigated by lineage tracing using Dermo1-Cre; ROSAmTmG 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.ResultsDuring 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.ConclusionIn 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.

Dataset Information

Identification of a Repair-Supportive Mesenchymal Cell Population during Airway Epithelial Regeneration.

Publications

Identification of a Repair-Supportive Mesenchymal Cell Population during Airway Epithelial Regeneration.

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