Preventing hypocontractility-induced fibroblast expansion alleviates dilated cardiomyopathy
Ross C. Bretherton, Isabella M. Reichardt, Kristin A. Zabrecky, Abigail Nagle, Logan R.J. Bailey, Darrian Bugg, Sasha Smolgovsky, Anne E. Gifford, Timothy S. McMillen, Alex J. Goldstein, Kristina B. Kooiker, Galina Flint, Amy Martinson, Jagdambika Gunaje, Franziska Koser, Elizabeth Plaster, Wolfgang A. Linke, Michael Regnier, Farid Moussavi‐Harami, Nathan J. Sniadecki, Cole A. DeForest, Jennifer Davis
Abstract
Cardiomyocyte hypocontractility underlies inherited dilated cardiomyopathy (DCM). Yet, whether fibroblasts modify DCM phenotypes remains unclear despite their regulation of fibrosis, which strongly predicts disease severity. Expression of a hypocontractility-linked sarcomeric variant in mice triggered cardiac fibroblast expansion from the de novo formation of hyperproliferative mechanosensitized fibroblast states, which occurred prior to eccentric myocyte remodeling. Initially, this fibroblast response reorganized fibrillar collagen and stiffened the myocardium, albeit without depositing fibrotic tissue. These adaptations coincided with heightened matrix-integrin receptor interactions and diastolic tension sensation at focal adhesions within fibroblasts. Targeted p38 deletion arrested these cardiac fibroblast responses in DCM mice, which prevented cardiomyocyte remodeling and improved contractility. p38-mediated fibroblast responses were essential regulators of DCM severity, marking a potential cellular target for therapeutic intervention.