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Identification of the Lymphangioleiomyomatosis Cell and Its Uterine Origin

71 Pages Posted: 1 Oct 2019 Publication Status: Review Complete

See all articles by Minzhe Guo

Minzhe Guo

Cincinnati Children's Hospital Medical Center - The Perinatal Institute

Jane J. Yu

University of Cincinnati

Anne Karina Perl

Cincinnati Children's Hospital Medical Center - The Perinatal Institute

Kathryn A. Wikenheiser-Brokamp

Cincinnati Children's Hospital Medical Center - The Perinatal Institute

Matt Riccetti

Cincinnati Children's Hospital Medical Center - The Perinatal Institute

Erik Y. Zhang

University of Cincinnati

Parvathi Sudha

Cincinnati Children's Hospital Medical Center - The Perinatal Institute

Mike Adam

Cincinnati Children's Hospital Medical Center - Division of Developmental Biology

Andrew Potter

Cincinnati Children's Hospital Medical Center - Division of Developmental Biology

Elizabeth J. Kopras

University of Cincinnati

Krinio Giannikou

Brigham and Women’s Hospital - Department of Medicine

S. Steven Potter

Cincinnati Children's Hospital Medical Center - Division of Developmental Biology

Sue Sherman

The LAM Foundation

Stephen R. Hammes

University of Rochester

David J. Kwiatkowski

Harvard University - Department of Medicine

Jeffrey A. Whitsett

Cincinnati Children's Hospital Medical Center - The Perinatal Institute

Francis X. McCormack

University of Cincinnati

Yan Xu

Cincinnati Children's Hospital Medical Center - The Perinatal Institute

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Abstract

Lymphangioleiomyomatosis (LAM) is a metastasizing neoplasm of reproductive age women that causes cystic lung remodeling and progressive respiratory failure. The source of LAM cells that invade the lung and the reasons that LAM targets women have remained elusive. We employed single cell and single nuclei RNA sequencing on LAM lesions within explanted LAM lungs, known to contain smooth muscle like cells bearing mTOR activating mutations in TSC1 or TSC2, and identified a unique population of cells that were readily distinguished from those of endogenous lung cells. LAM CORE cells shared closest transcriptomic similarity to normal uterus and neural crest. Immunofluorescence microscopy demonstrated the expression of LAMCORE cell signature genes within LAM lesions in both lung and uterus. Serum aptamer proteomics and ELISA identified biomarkers predicted to be secreted by LAM CORE cells. Single cell transcriptomics strongly supports a uterine neural crest origin of LAM CORE cells; providing insights into disease pathogenesis and informing future treatment strategies for LAM.

Keywords: lymphangioleiomyomatosis, lung, single cell analysis, origin, uterus

Suggested Citation

Guo, Minzhe and Yu, Jane J. and Perl, Anne Karina and Wikenheiser-Brokamp, Kathryn A. and Riccetti, Matt and Zhang, Erik Y. and Sudha, Parvathi and Adam, Mike and Potter, Andrew and Kopras, Elizabeth J. and Giannikou, Krinio and Potter, S. Steven and Sherman, Sue and Hammes, Stephen R. and Kwiatkowski, David J. and Whitsett, Jeffrey A. and McCormack, Francis X. and Xu, Yan, Identification of the Lymphangioleiomyomatosis Cell and Its Uterine Origin (September 30, 2019). Available at SSRN: https://ssrn.com/abstract=3461777 or http://dx.doi.org/10.2139/ssrn.3461777
This version of the paper has not been formally peer reviewed.

Minzhe Guo

Cincinnati Children's Hospital Medical Center - The Perinatal Institute ( email )

United States

Jane J. Yu

University of Cincinnati

Cincinnati, OH 45221-0389
United States

Anne Karina Perl

Cincinnati Children's Hospital Medical Center - The Perinatal Institute ( email )

United States

Kathryn A. Wikenheiser-Brokamp

Cincinnati Children's Hospital Medical Center - The Perinatal Institute ( email )

United States

Matt Riccetti

Cincinnati Children's Hospital Medical Center - The Perinatal Institute ( email )

United States

Erik Y. Zhang

University of Cincinnati

Cincinnati, OH 45221-0389
United States

Parvathi Sudha

Cincinnati Children's Hospital Medical Center - The Perinatal Institute ( email )

United States

Mike Adam

Cincinnati Children's Hospital Medical Center - Division of Developmental Biology ( email )

3333 Burnet Avenue
Cincinnati, OH 45229-3026
United States

Andrew Potter

Cincinnati Children's Hospital Medical Center - Division of Developmental Biology

3333 Burnet Avenue
Cincinnati, OH 45229-3026
United States

Elizabeth J. Kopras

University of Cincinnati ( email )

Cincinnati, OH 45221-0389
United States

Krinio Giannikou

Brigham and Women’s Hospital - Department of Medicine ( email )

Boston, MA 02115
United States

S. Steven Potter

Cincinnati Children's Hospital Medical Center - Division of Developmental Biology ( email )

3333 Burnet Avenue
Cincinnati, OH 45229-3026
United States

Sue Sherman

The LAM Foundation ( email )

United States

Stephen R. Hammes

University of Rochester ( email )

300 Crittenden Blvd.
Rochester, NY 14627
United States

David J. Kwiatkowski

Harvard University - Department of Medicine ( email )

Boston, Massachusetts
United States

Jeffrey A. Whitsett

Cincinnati Children's Hospital Medical Center - The Perinatal Institute ( email )

United States

Francis X. McCormack

University of Cincinnati ( email )

Cincinnati, OH 45221-0389
United States

Yan Xu (Contact Author)

Cincinnati Children's Hospital Medical Center - The Perinatal Institute ( email )

United States

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