Cardiac Cell-to-Cell Communication Using Exosomes and Cytokines Regulated By Spectrin-Based Pathways

Abstract

Increased levels of cardiac fibrosis are characteristic remodeling responses to stress-induced conditions in cardiovascular diseases associated with cardiac dysfunction and arrhythmias. The stress-induced transition of resident/quiescent cardiac fibroblasts (CF) to an activated myofibroblast state displays increased proliferation, contractility, and deposition of extracellular matrix, all crucial steps in the fibrotic pathway. While the precise mechanism associated with this process remains unclear, our group has identified a novel βIV-spectrin/STAT3 complex in the heart crucial for the regulation of normal gene transcription and maintenance of the quiescent CF phenotype. Further, the complex plays a key role in regulating the cardiac-cell response to acute and chronic stress, however the upstream extracellular stress signals that lead to stress-induced βIV-spectrin dysfunction and successive CF activation remain unknown. This study explores the upstream extracellular stress signals associated with CF activation, using βIV-spectrin deficient mice. Specifically, primary mouse CFs from WT (control) and βIV-spectrin deficient (qv4J) species were isolated and cultured. Extracellular stress signals (i.e. exosomes and cytokines/chemokines) were examined. Finally, in-vitro assays (e.g. proliferation and collagen gel contractility) were performed to evaluate CF activity in response to the extracellular stress signals. We reported that WT CFs treated with qv4J conditioned media displayed higher rates of proliferation and contraction than CFs treated with control media. We also identified several cytokine/chemokine candidates that are involved in the CF activation pathway. The knowledge gained from this study will provide new insight into understanding the overall fibroblast biology, mechanisms of cardiac cell cross-talk, and for developing therapeutic strategies to target cardiac fibrosis.