Single-Cell Transcriptomic Analysis Identifies a Unique Pulmonary Lymphangioleiomyomatosis Cell.

Area of Science:

• Pulmonary Medicine
• Oncology
• Genetics

Background:

• Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease affecting women of reproductive age.
• LAM is characterized by cystic lung remodeling and progressive respiratory failure, linked to tuberous sclerosis complex gene mutations.
• The cellular origin and characteristics of LAM cells remain poorly understood.

Purpose of the Study:

• To identify and characterize LAM cells in human lung and uterus using a single-cell approach.
• To elucidate the cellular origins and molecular networks involved in LAM pathogenesis.
• To discover novel biomarkers for LAM diagnosis and potential therapeutic targets.

Main Methods:

• Single-cell and single-nuclei RNA sequencing of LAM and control lung tissues.
• Immunofluorescence confocal microscopy, ELISA, and aptamer proteomics for biomarker validation.
• Analysis of gene expression profiles and mutations (TSC2) in LAM cells from lung and uterus.

Main Results:

• A distinct cell type, termed LAMCORE, was identified, closely related to lung mesenchymal cells.
• LAMCORE cells express known LAM markers (PMEL, FIGF, CTSK, MLANA) and novel validated biomarkers.
• LAM cells in lung and uterus exhibit similar gene expression and biallelic TSC2 mutations, suggesting a potential uterine origin.

Conclusions:

• A unique LAMCORE cell population with shared transcriptomic identity was discovered in both lung and uterus of LAM patients.
• Novel LAM cell-selective and secreted biomarkers were identified.
• These findings provide critical insights into LAM pathogenesis, offering potential diagnostic markers and therapeutic targets.