Single Cell Transcriptomic Analysis Identifies a Unique Pulmonary Lymphangioleiomyomatosis Cell.

RATIONALE Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive age women associated with mutations in tuberous sclerosis complex (TSC) genes. LAM causes cystic remodeling of the lung and progressive respiratory failure. The sources and cellular characteristics of LAM cells underlying disease pathogenesis remain elusive. OBJECTIVES Identification and characterization of LAM cells in human lung and uterus using single cell approach. METHODS Single cell/nuclei RNA sequencing on LAM (n=4) and control (n=7) lungs, immunofluorescence confocal microscopy, ELISA, and aptamer proteomics were used to identify and validate LAMCORE cells and secreted biomarkers, predict cellular origins, define molecular and cellular networks in LAM. MEASUREMENTS AND MAIN RESULTS A unique cell type termed LAMCORE was identified, which was distinct from, but closely related to, lung mesenchymal cells. LAMCORE cells expressing signature genes included known LAM markers such as PMEL, FIGF, CTSK and MLANA, and novel biomarkers validated by aptamer screening, ELISA, and immunofluorescence microscopy. LAM cells in lung and uterus are morphologically indistinguishable and share similar gene expression profiles and biallelic TSC2 mutations, supporting a potential uterine origin for the LAMCORE cell. Effects of LAM on resident pulmonary cell types indicated recruitment and activation of lymphatic endothelial cells. CONCLUSION A unique population of LAMCORE cells was identified in lung and uterus of LAM patients, sharing close transcriptomic identity. LAM cell selective markers, secreted biomarkers, and the predicted cellular molecular features provide new insights into the signaling and transcriptional programs which may serve as diagnostic markers and therapeutic targets to influence the pathogenesis of LAM.