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| Status |
Public on Jan 25, 2024 |
| Title |
Hyperactive mTORC1 in Lung Mesenchyme Induces Endothelial Cell Dysfunction and Pulmonary Vascular Remodeling |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of LAM patients develops pulmonary vascular remodeling and pulmonary hypertension. To model LAM disease, we utilized an mTORC1 gain-of-function mouse model with a Tsc2 knock-out (Tsc2KO) specific to lung mesenchyme (Tbx4LME-CreTsc2fl/fl), similar to the mesenchyme specific genetic alterations seen in human disease. As early as 8 weeks of age, ECs from Tbx4LME-CreTsc2fl/fl mice exhibited marked transcriptomic changes despite absence of morphological changes to the distal lung microvasculature. In contrast, 1 year old Tbx4LME-CreTsc2fl/fl mice spontaneously developed pulmonary vascular remodeling with increased medial thickness. We subsequently performed single cell RNA-sequencing of 1 year old mouse lung and identified paracrine ligands originating from Tsc2KO mesenchyme impacting arterial endothelial cells. These cells contained transcriptionally altered genes including those in pathways associated with blood vessel remodeling, highlighting the pathogenic importance of the mesenchymal-endothelial cell axis.
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| Overall design |
Whole murine lung single cells suspension in one year Tbx4Tsc2 WT and KO; samples were CD45 depleted with 10% spiked back into CD45- fractions and then loaded on 10x genomic platform for single cell RNA sequencing
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| Contributor(s) |
Lin S, Krymskaya V, Babu A |
| Citation(s) |
38127441 |
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| Submission date |
Dec 07, 2023 |
| Last update date |
Feb 26, 2024 |
| Contact name |
Apoorva Babu |
| Organization name |
University of Pennsylvania
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| Department |
Cardiovascular Institute
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| Street address |
SCTR, 3400 Civic Center Blvd
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| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA1049848 |
