Myofibroblasts reduce angiogenesis and vasculogenesis in a vascularized microphysiological model of lung fibrosis

Abstract Lung fibrosis, characterized by chronic and progressive scarring, has no cure. Hallmarks are the accumulation of myofibroblasts and extracellular matrix, as well as vascular remodeling. The crosstalk between myofibroblasts and vasculature is poorly understood, with conflicting reports on whether angiogenesis and vessel density are increased or decreased in lung fibrosis. We developed a microphysiological system that recapitulates the pathophysiology of lung fibrosis and disentangles myofibroblast-vascular interactions. Lung myofibroblasts maintained their phenotype in 3D without exogenous TGF-β and displayed anti-angiogenic and anti-vasculogenic activities when cultured with endothelial cells in a microfluidic device. These effects, including decreased endothelial sprouting, altered vascular morphology, and increased vascular permeability, were mediated by increased TGF-β1 and reduced VEGF secretion. Pharmacological interventions targeting these cytokines restored vascular morphology and permeability, demonstrating the potential of this model to screen anti-fibrotic drugs. This system provides insights into myofibroblast-vascular crosstalk in lung fibrosis and offers a platform for therapeutic development. Competing Interest Statement RDK is a co-founder and a board member of AIM Biotech. He also has current research support from Boehringer-Ingelheim, Roche, Amgen, Takeda, Eisai, Visterra, Merck KgA, AbbVie, Daichi Sankyo, and Novartis. DAB reports personal fees from Qiagen, Exo Therapeutics, and Tango Biosciences; he is a Scientific Advisory Board Member/Co-Founder of XSphera Biosciences, and has received grants from Gilead, Novartis, BMS, and Lilly/Loxo Oncology. None of these activities are related to the content of this article.