Adventitial fibroblasts direct smooth muscle cell-state transition in pulmonary vascular disease

Abstract

Pulmonary vascular remodeling is a progressive pathological process characterized by functional alterations within pulmonary artery smooth muscle cells (PASMC) and adventitial fibroblasts (PAAF). Mechanisms driving the transition to a diseased phenotype remain elusive. Utilizing a combination of transcriptomic and proteomic profiling, along with phenotyping of source-matched cells from healthy controls and individuals with idiopathic pulmonary arterial hypertension (IPAH), our investigation uncovered that while PASMC and PAAF retained their original cellular identities, they acquired distinct disease-associated states. Though both cell types exhibited reduced mitochondrial content and hyperpolarization, IPAH-PASMC displayed heightened glycosaminoglycan production and downregulation of contractile machinery, contrasting a hyperproliferative phenotype of IPAH-PAAF. We elucidated the involvement of cellular crosstalk in regulating cell state dynamics and identified pentraxin-3 and hepatocyte growth factor as modulators of PASMC phenotypic transition orchestrated by PAAF. Our findings contribute to a deeper understanding of pulmonary vascular mesenchyme dynamics in disease pathogenesis.

Fibroblasts in Pulmonary Hypertension: Roles and Molecular Mechanisms

“…Ultimately, they concluded that the maintenance and cell-state transition of PASMCs is partly dependent on external cues provided by neighboring PAAFs using a source-matched PASMC and PAAF co-culture model. These results underscore the role of PAAFs as signaling hubs involved in orchestrating heterotypic-cell-state maintenance and transitions [ 102 ].…”

“…Crnkovic et al have reported that pulmonary vascular remodeling is associated with a skewed cellular communication on a single-cell level to define the pathological vascular remodeling process of PAH centered on PAAFs and SMCs [ 50 ]. Their most recent findings further uncovered cell-type-specific phenotypic shifts and identified PAAFs as a source of secreted factors that regulate the PASMC state [ 102 ]. In this study, Crnkovic and colleagues applied integrative omics and a network-based analysis combined with targeted phenotypic screens to identify common cell-type and cell-state distinct cellular behaviors and examined the bidirectional cell communication between source-matched human PASMCs and PAAFs from healthy controls and IPAH patients.…”