Multicellular Mechanoreciprocity in the Heart: Coordinated ECM Sensing and Remodeling by Cardiomyocytes, Fibroblasts, and Macrophages

The cardiac extracellular matrix (ECM) is a dynamic, mechanically active network continuously shaped and interpreted by cardiomyocytes, fibroblasts, and macrophages. Interdependent mechanosensing, force transmission, and ECM remodeling functions create multicellular feedback loops that control tissue stiffness, alignment, maturation, and fibrotic remodeling. Together, these biomechanical processes create reciprocal signaling pathways in which cellular behavior modifies the ECM while the ECM’s mechanics concurrently shape cellular phenotype and function. This review explores cell–ECM mechanoreciprocity, a physiologic framework that unifies cell-sensing mechanotransduction, mechano-electrical coupling, and ECM-based biochemical signaling with cell-driven ECM remodeling. We propose three interconnected feedback loops that integrate biochemical and mechanical cues across cell types: load amplification, structural alignment, and immune regulation. We discuss how advanced two- and three-dimensional engineered cardiac systems incorporating tunable and dynamic mechanical cues can be used to model these interactions. We address the limitations of existing experimental platforms and the need for better models to fully recapitulate in vivo complexities. Understanding and recreating these reciprocal mechanical interactions will provide essential frameworks for disease modeling and therapeutic development while reducing reliance on in vivo studies.