mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline

• Published in: Nature communications 2020-11, Vol.11 (1), p.5640-5640, Article 5640
• Main Authors: Obraztsova, Kseniya, Basil, Maria C., Rue, Ryan, Sivakumar, Aravind, Lin, Susan M., Mukhitov, Alexander R., Gritsiuta, Andrei I., Evans, Jilly F., Kopp, Meghan, Katzen, Jeremy, Robichaud, Annette, Atochina-Vasserman, Elena N., Li, Shanru, Carl, Justine, Babu, Apoorva, Morley, Michael P., Cantu, Edward, Beers, Michael F., Frank, David B., Morrisey, Edward E., Krymskaya, Vera P.
• Format: Article
• Language: English
• Subjects: 14/1; 14/19; 14/35; 14/63; 38/22; 38/39; 38/47; 38/77; 38/90; 38/91; 631/136/1425; 631/80/304; 64/110; 64/60; 82/29; 82/51; Age; Age composition; Age Factors; Aged; Alveoli; Animals; Crosstalk; Deactivation; Female; Gene expression; Gene sequencing; Genotype & phenotype; Humanities and Social Sciences; Humans; Inactivation; Lung - drug effects; Lung - metabolism; Lung - physiopathology; Lung diseases; Lymphangioleiomyomatosis - drug therapy; Lymphangioleiomyomatosis - genetics; Lymphangioleiomyomatosis - metabolism; Lymphangioleiomyomatosis - physiopathology; Male; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mesenchyme; Mesoderm - drug effects; Mesoderm - metabolism; Mice; multidisciplinary; Mutation; Phenotypes; Pulmonary functions; Rapamycin; Respiratory function; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Sex; Sex Factors; Signal transduction; Signaling; Sirolimus - administration & dosage; Structure-function relationships; Suppressors; TOR protein; Tuberous sclerosis; Tuberous Sclerosis Complex 2 Protein - genetics; Tuberous Sclerosis Complex 2 Protein - metabolism; Wnt protein; Wnt Signaling Pathway
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18979-4

Lymphangioleiomyomatosis (LAM) is a rare fatal cystic lung disease due to bi-allelic inactivating mutations in tuberous sclerosis complex (TSC1/TSC2) genes coding for suppressors of the mechanistic target of rapamycin complex 1 (mTORC1). The origin of LAM cells is still unknown. Here, we profile a LAM lung compared to an age- and sex-matched healthy control lung as a hypothesis-generating approach to identify cell subtypes that are specific to LAM. Our single-cell RNA sequencing (scRNA-seq) analysis reveals novel mesenchymal and transitional alveolar epithelial states unique to LAM lung. This analysis identifies a mesenchymal cell hub coordinating the LAM disease phenotype. Mesenchymal-restricted deletion of Tsc2 in the mouse lung produces a mTORC1-driven pulmonary phenotype, with a progressive disruption of alveolar structure, a decline in pulmonary function, increase of rapamycin-sensitive expression of WNT ligands, and profound female-specific changes in mesenchymal and epithelial lung cell gene expression. Genetic inactivation of WNT signaling reverses age-dependent changes of mTORC1-driven lung phenotype, but WNT activation alone in lung mesenchyme is not sufficient for the development of mouse LAM-like phenotype. The alterations in gene expression are driven by distinctive crosstalk between mesenchymal and epithelial subsets of cells observed in mesenchymal Tsc2 -deficient lungs. This study identifies sex- and age-specific gene changes in the mTORC1-activated lung mesenchyme and establishes the importance of the WNT signaling pathway in the mTORC1-driven lung phenotype. The cellular origins of lymphangioleiomyomatosis (LAM), a rare fatal lung disease, are poorly understood. Here the authors identify a mesenchymal cell hub coordinating the LAM phenotype and develop a LAM mouse model where they investigate the co-operative dysregulation of mTORC1 and WNT growth pathways in the sex- and age-specific changes leading to structural and functional decline.