GSE210248
Gene expression profile at single cell level of human pulmonary arteries (PA) of healthy and Pulmonary hypertension affected lungs and murine PA exposed to normoxia and hypoxia
A central feature of progressive vascular remodeling is altered smooth muscle cell (SMC) homeostasis; however, the understanding of how different cell populations contribute to this process is limited. Here, we utilized single cell RNA sequencing to provide insight into cellular composition changes within isolated pulmonary arteries (PA) from pulmonary arterial hypertension (PAH) and donor lungs. Our results revealed that remodeling skewed the balanced communication network between immune and structural cells, in particular SMC. Comparative analysis with murine PA showed that human PA harbor heterogeneous SMC populations with an abundant intermediary cluster displaying a gradient transition between SMC and adventitial fibroblasts. Transcriptionally distinct SMC populations were enriched in specific biological processes and could be distinguished into four major clusters: oxygen sensing (enriched in pericytes), contractile, synthetic and fibroblast-like. End-stage remodeling was associated with phenotypic shift of pre-existing SMC populations and accumulation of synthetic SMC in neointima. Distinctly regulated genes in clusters built non-redundant regulatory hubs encompassing stress response and differentiation regulators. The current study provides a blueprint of cellular and molecular changes on a single cell level that are defining pathological vascular remodeling process. Overall design: Using droplet-based single cell RNA sequencing we analyzed 3 pulmonary arteries (PA) from lungs affected with pulmonary arterial hypertension (PAH) against PA from 3 healthy controls. Clustering, dimensionality reduction, trajectory inference and pseudotime, as well as transcription factor analyses were performed and select marker gene were examined for specific segregation of PA media layer using immunofluorescence in both the conditions. Validation of human findings was also performed in a mouse animal model of pulmonary hypertension (PH)