Uniaxial cyclic strain to restore the anisotropy of cardiac cells and ECM in 2D and 3D in vitro models of myocardial infarction

The human myocardium is a mechanically active tissue typified by its anisotropic organization of cells and extracellular matrix. Upon injury, the myocardium undergoes dramatic alterations, resulting in disruption of anisotropy and loss of coordinated contraction. Moreover, loss of anisotropic organization hampers the differentiation, matrix production, and mechanotransduction of resident and newly injected cardiac cells. Therefore, restoring the anisotropic organization in the injured myocardium could greatly benefit myocardial regeneration.
In this project, we studied the effect of mechanical and structural cues, inspired by myocardial biology, on the organization of cardiac cells. We showed that uniaxial cyclic strain, mimicking the local deformation of cardiac beating, led to anisotropic organization of cardiac fibroblasts (cFBs), but not of cardiomyocytes (hiPSC-CMs). Next, we reconstructed the cellular compositions of normal and pathological myocardium using co-cultures with varying cell ratios. Surprisingly, contrary to the response of the hiPSC-CM monoculture, the co-cultures adopted an anisotropic organization under uniaxial cyclic strain, regardless of the co-culture composition. These data suggest that the mechanoresponsiveness of cFBs may be critical in determining myocardial tissue structure and function.
To further investigate the relevance of these mechanical and structural cues in vivo, we developed 3D myocardial micro-tissues, consisting of cell-laden collagen I/Matrigel constructs within flexible micropillars. Using this model, we successfully imposed mechanical constraints to tune the degree of microtissue organization and allow measurement of tissue contraction. We will discuss how uniaxial cyclic strain can be used to induce anisotropy in a 3D myocardial micro-tissue and how this effects tissue contraction and function.