Spectrin-Based Regulation of Cardiac Fibroblast Cell-Cell Communication

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 5; p. 748
• Main Authors: Nassal, Drew M, Shaheen, Rebecca, Patel, Nehal J, Yu, Jane, Leahy, Nick, Bibidakis, Dimitra, Parinandi, Narasimham L, Hund, Thomas J
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26-02-2023; MDPI
• Subjects: Biological control systems; cardiac fibroblast; Cell Communication; Cell culture; Cell interaction; Cell interactions; Cell research; cell-cell communication; Cells; Chemokines; Collagen; Communication; Communications networks; Culture media; Cytokines; Cytokines - metabolism; Cytoskeleton; Exosomes; Experiments; Extracellular matrix; Fibroblasts; Fibroblasts - metabolism; Fibrosis; Heart; Heart cells; Humans; Inflammation; Laboratory animals; Membrane proteins; Myocardium - metabolism; Paracrine signalling; Physiological aspects; Proteins; Signal transduction; Spectrin; Spectrin - metabolism; STAT3; Stat3 protein; United States; United States > US; spectrin; cell-cell communication; cardiac fibroblast; exosomes; STAT3
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12050748

Cardiac fibroblasts (CFs) maintain the fibrous extracellular matrix (ECM) that supports proper cardiac function. Cardiac injury induces a transition in the activity of CFs to promote cardiac fibrosis. CFs play a critical role in sensing local injury signals and coordinating the organ level response through paracrine communication to distal cells. However, the mechanisms by which CFs engage cell-cell communication networks in response to stress remain unknown. We tested a role for the action-associated cytoskeletal protein β
-spectrin in regulating CF paracrine signaling. Conditioned culture media (CCM) was collected from WT and β
-spectrin deficient (
) CFs. WT CFs treated with
CCM showed increased proliferation and collagen gel compaction compared to control. Consistent with the functional measurements,
CCM contained higher levels of pro-inflammatory and pro-fibrotic cytokines and increased concentration of small extracellular vesicles (30-150 nm diameter, exosomes). Treatment of WT CFs with exosomes isolated from
CCM induced a similar phenotypic change as that observed with complete CCM. Treatment of
CFs with an inhibitor of the β
-spectrin-associated transcription factor, STAT3, decreased the levels of both cytokines and exosomes in conditioned media. This study expands the role of the β
-spectrin/STAT3 complex in stress-induced regulation of CF paracrine signaling.