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Secreted Factors From Proinflammatory Macrophages Promote an Osteoblast-Like Phenotype in Valvular Interstitial Cells
Journal article   Open access   Peer reviewed

Secreted Factors From Proinflammatory Macrophages Promote an Osteoblast-Like Phenotype in Valvular Interstitial Cells

Joseph C Grim, Brian A Aguado, Brandon J Vogt, Dilara Batan, Cassidy L Andrichik, Megan E Schroeder, Andrea Gonzalez-Rodriguez, F Max Yavitt, Robert M Weiss and Kristi S Anseth
Arteriosclerosis, thrombosis, and vascular biology, Vol.40(11), pp.e296-e308
11/2020
DOI: 10.1161/ATVBAHA.120.315261
PMCID: PMC7578003
PMID: 32938214
url
https://doi.org/10.1161/ATVBAHA.120.315261View
Published (Version of record) Open Access

Abstract

Resident valvular interstitial cells (VICs) activate to myofibroblasts during aortic valve stenosis progression, which further promotes fibrosis or even differentiate into osteoblast-like cells that can lead to calcification of valve tissue. Inflammation is a hallmark of aortic valve stenosis, so we aimed to determine proinflammatory cytokines secreted from M1 macrophages that give rise to a transient VIC phenotype that leads to calcification of valve tissue. Approach and Results: We designed hydrogel biomaterials as valve extracellular matrix mimics enabling the culture of VICs in either their quiescent fibroblast or activated myofibroblast phenotype in response to the local matrix stiffness. When VIC fibroblasts and myofibroblasts were treated with conditioned media from THP-1-derived M1 macrophages, we observed robust reduction of αSMA (alpha smooth muscle actin) expression, reduced stress fiber formation, and increased proliferation, suggesting a potent antifibrotic effect. We further identified TNF (tumor necrosis factor)-α and IL (interleukin)-1β as 2 cytokines in M1 media that cause the observed antifibrotic effect. After 7 days of culture in M1 conditioned media, VICs began differentiating into osteoblast-like cells, as measured by increased expression of RUNX2 (runt-related transcription factor 2) and osteopontin. We also identified and validated IL-6 as a critical mediator of the observed pro-osteogenic effect. Proinflammatory cytokines in M1 conditioned media inhibit myofibroblast activation in VICs (eg, TNF-α and IL-1β) and promote their osteogenic differentiation (eg, IL-6). Together, our work suggests inflammatory M1 macrophages may drive a myofibroblast-to-osteogenic intermediate VIC phenotype, which may mediate the switch from fibrosis to calcification during aortic valve stenosis progression.
 Animals Aortic Valve - metabolism Aortic Valve - pathology Aortic Valve Stenosis - metabolism Aortic Valve Stenosis - pathology Calcinosis - metabolism Calcinosis - pathology Cell Proliferation Cytokines - metabolism Extracellular Matrix - metabolism Fibrosis Humans Inflammation Mediators - metabolism Macrophages - metabolism Male Myofibroblasts - metabolism Myofibroblasts - pathology Osteoblasts - metabolism Osteoblasts - pathology Osteogenesis Paracrine Communication Phenotype Secretory Pathway Signal Transduction Sus scrofa THP-1 Cells

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