RT Journal Article
SR Electronic
T1 Single-Cell Analysis Reveals Distinct Immune and Smooth Muscle Cell Populations that Contribute to Chronic Thromboembolic Pulmonary Hypertension
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.26.477878
DO 10.1101/2022.01.26.477878
A1 Gayathri Viswanathan
A1 Hélène Fradin Kirshner
A1 Nour Nazo
A1 Asvin Ganapathi
A1 Ian Cummings
A1 Anmol Warman
A1 Susana Almeida-Peters
A1 John Haney
A1 David Corcoran
A1 Yen-Rei Yu
A1 Sudarshan Rajagopal
YR 2022
UL http://biorxiv.org/content/early/2022/01/28/2022.01.26.477878.abstract
AB Chronic thromboembolic pulmonary hypertension (CTEPH) is a sequelae of acute pulmonary embolism (PE) in which the PE remodels into a chronic scar in the pulmonary arteries. This results in vascular obstruction, small vessel arteriopathy and pulmonary hypertension. Our current understanding of CTEPH pathobiology is primarily derived from cell-based studies limited by the use of specific cell markers or phenotypic modulation in cell culture. Here we used single cell RNA sequencing (scRNAseq) of tissue removed at the time of pulmonary thromboendarterectomy (PTE) surgery to identify the multiple cell types, including macrophages, T cells, and smooth muscle cells, that comprise CTEPH thrombus. Notably, multiple macrophage subclusters were identified but broadly split into two categories, with the larger group characterized by an upregulation of inflammatory signaling predicted to promote pulmonary vascular remodeling. Both CD4+ and CD8+ T cells were identified and likely contribute to chronic inflammation in CTEPH. Smooth muscle cells were a heterogeneous population, with a cluster of myofibroblasts that express markers of fibrosis and are predicted to arise from other smooth muscle cell clusters based on pseudotime analysis. Additionally, cultured endothelial, smooth muscle and myofibroblast cells isolated from CTEPH thrombus have distinct phenotypes from control cells with regards to angiogenic potential and rates of proliferation and apoptosis. Lastly, our analysis identified protease-activated receptor 1 (PAR1) as a potential therapeutic target that links thrombosis to chronic PE in CTEPH, with PAR1 inhibition decreasing smooth muscle cell and myofibroblast proliferation and migration. These findings suggest a model for CTEPH similar to atherosclerosis, with chronic inflammation promoted by macrophages and T cells driving vascular remodeling through smooth muscle cell modulation, and suggest new approaches for pharmacologically targeting this disease.Competing Interest StatementThe authors have declared no competing interest.