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• W3095718278 abstract "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." @default.
• W3095718278 created "2020-11-09" @default.
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• W3095718278 date "2020-11-06" @default.
• W3095718278 modified "2023-10-16" @default.
• W3095718278 title "mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline" @default.
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• W3095718278 doi "https://doi.org/10.1038/s41467-020-18979-4" @default.
• W3095718278 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7648630" @default.
• W3095718278 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33159078" @default.
• W3095718278 hasPublicationYear "2020" @default.
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