The human myocardium is a mechanically active tissue typified by the anisotropic organization of cells and extracellular matrix (ECM). Upon injury, the composition of the myocardium changes, resulting in disruption of tissue organization and loss of coordinated contraction. Understanding how anisotropic organization in the adult myocardium is shaped and disrupted by environmental cues is thus critical, not only for unravelling the processes taking place during disease progression, but also for developing regenerative strategies to recover tissue function. Here, we decoupled in vitro the two major physical cues that are inherent in the myocardium: structural ECM and mechanical strain. We show that patterned ECM proteins control the orientation of the two main cell types in the myocardium: human cardiac fibroblasts (cFBs) and cardiomyocytes (hiPSC-CMs), despite their different mechanosensing machinery. Uniaxial cyclic strain, mimicking the local anisotropic deformation of the myocardium, did not affect hiPSC-CMs orientation. It did however induce a reorientation of cFBs, perpendicular to the strain direction, albeit this strain-avoidance response was overruled in the presence of anisotropic structural cues. These findings reveal that the mechanoresponsiveness of cFBs may be a critical handle in controlling myocardial tissue structure and function. To test this, we co-cultured hiPSC-CMs and cFBs in varying cell ratios to reconstruct normal and pathological myocardium. Contrary to the hiPSC-CM monoculture, the co-cultures adopted an anisotropic organization under uniaxial cyclic strain, regardless of the cell ratio. Together, these results identify the cFBs as a therapeutic target to mechanically restore structural organization of the tissue in cardiac regenerative therapies.
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