Single-Cell Transcriptomic Analysis Identifies a Unique Pulmonary Lymphangioleiomyomatosis Cell

Guo, Minzhe; Yu, Jane; Perl, Anne‐Karina T.; Wikenheiser-Brokamp, Kathryn A.; Riccetti, Matthew; Zhang, Erik Y.; Sudha, Parvathi; Adam, Mike; Potter, Andrew; Kopras, E.J.-A.; Γιαννίκου, Κρινιώ; Potter, S. Steven; Sherman, Sue; Hammes, Stephen R.; Kwiatkowski, David J.; Whitsett, Jeffrey A.; McCormack, Francis X.; Xu, Yan

doi:10.1164/rccm.201912-2445oc

Cited by 74 publications

(136 citation statements)

References 61 publications

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“…LAM lesions also stain positively for melanocytic markers detected with HMB45 3,4 , chemoattractant proteins CCL2 and CXCL12 14 the lymphangiogenic factor VEGFD 15 , and also contain activated fibroblasts 16 . However, the origin or the evolution of the "bona fide" cell of disease origin in LAM is hotly debated [17][18][19] .…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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“…The characteristics of LAM-LECs (T) strongly indicate that the phenotype of LAM-associated LECs differs from that of LECs in normal lung tissues. This idea is supported by a recent study using single cell sequence analysis, which revealed that the gene expression of LECs in LAM-affected lung tissues is distinct from that in normal lung tissues 19 . The functions of LECs may be altered in the pathological microenvironment of LAM lungs and still be conserved in vitro, with enhanced growth and migration potential and expression of VEGFR-3 and integrin α9.…”

Section: Discussionmentioning

confidence: 69%

Isolation and Characterisation of Lymphatic Endothelial Cells from Lung Tissues Affected by Lymphangioleiomyomatosis

Nishino

Yoshimatsu

Muramatsu

et al. 2021

Preprint

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Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, however, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. In this study, human primary-cultured LECs were obtained both from LAM-affected lung tissues (LAM-LECs) and normal lung tissues (control LECs) using fluorescence-activated cell sorting (FACS). We found that LAM-LECs had significantly higher ability of proliferation and migration compared to control LECs. VEGF-D significantly promoted migration of LECs but not proliferation of LECs in vitro. cDNA microarray and FACS analysis revealed the expression of vascular endothelial growth factor receptor (VEGFR)-3 and integrin α9 were elevated in LAM-LECs. Inhibition of VEGFR-3 suppressed proliferation and migration of LECs, and blockade of integrin α9 reduced VEGF-D-induced migration of LECs. Our data uncovered the distinct features of LAM-associated LECs, increased proliferation and migration, which may be due to higher expression of VEGFR-3 and integrin α9. Furthermore, we also found VEGF-D/VEGFR-3 and VEGF-D/ integrin α9 signaling play an important role in LAM-associated lymphangiogenesis.

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“…In this issue of the Journal, Guo et al (1) use state-of-the-art single cell techniques to provide insights into lymphangioleiomyomatosis (LAM), a rare multisystem disease primarily affecting women, which is characterized by cystic destruction of the lungs, kidney angiomyolipomas, and/or lymphatic involvement (2) It is important to plumb the depths of pathways implicated in LAM pathogenesis to determine druggable targets. The data on the LAM CORE cell, its gene expression pattern, and its effect on its microenvironment were generated with the input of only three LAM lungs due to the difficulty of obtaining fresh tissue samples.…”

mentioning

confidence: 99%

“…In this issue of the Journal , Guo and colleagues (pp. 1373–1387 ) ( 1 ) use state-of-the-art single-cell techniques to provide insights into lymphangioleiomyomatosis (LAM), a rare multisystem disease primarily affecting women, which is characterized by cystic destruction of the lungs, kidney angiomyolipomas, and/or lymphatic involvement ( 2 ). LAM can occur sporadically or in conjunction with tuberous sclerosis complex (TSC), an autosomal-dominant disorder characterized by hamartomatous growths in the central nervous system, skin, heart, liver, and eyes.…”

mentioning

confidence: 99%

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Needle in the Haystack: Finding the Elusive Lymphangioleiomyomatosis Cell

Steagall

Moss

2020

Am J Respir Crit Care Med

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Single-Cell Transcriptomic Analysis Identifies a Unique Pulmonary Lymphangioleiomyomatosis Cell

Cited by 74 publications

References 61 publications

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

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

Isolation and Characterisation of Lymphatic Endothelial Cells from Lung Tissues Affected by Lymphangioleiomyomatosis

Needle in the Haystack: Finding the Elusive Lymphangioleiomyomatosis Cell

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