Preventing hypocontractility-induced fibroblast expansion alleviates dilated cardiomyopathy

• 成果类型: Article
• 署名作者: Bretherton, Ross C.; Reichardt, Isabella M.; Zabrecky, Kristin A.; Nagle, Abigail; Bailey, Logan R. J.; Bugg, Darrian; Smolgovsky, Sasha; Gifford, Amy L.; Mcmillen, Timothy S.; Goldstein, Alex J.; Kooiker, Kristina B.; Flint, Galina V.; Martinson, Amy; Gunaje, Jagdambika; Koser, Franziska; Plaster, Elizabeth; Linke, Wolfgang A.; Regnier, Michael; Moussavi-Harami, Farid; Sniadecki, Nathan J.; Deforest, Cole A.; Davis, Jennifer
• 署名单位: University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Munster; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adv9157
• 发表日期: 2025-11-06
• 页码: eadv9157
• 关键词: mechanical-properties; extracellular-matrix; CARDIAC FIBROBLASTS; cell-fate; morphogenesis; tension; transitions; mutations; PATHWAY

摘要

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.