Abstract
Cardiac regeneration post-injury is a tantalizing feature of many lower vertebrates such as fishes and urodeles, but absent in adult humans. Restoration of pumping function is a key endpoint of cardiac regeneration, but very little is known about the biomechanical remodeling process. Here, we quantify and compare the evolution of cellular composition and mechanical stiffness of the zebrafish ventricular myocardium during maturation and following cryoinjury during regeneration to better understand the dynamics of biomechanical remodeling during these two processes. With increasing age, normal myocardial trabecular density and cardiomyocyte fraction increased, while non-myocyte cell fractions decreased. Cell density remained constant during maturation. Cardiomyocyte sarcomeres shortened to a minimum reached at 7.5 months of age, but lengthened with additional age. Concomitantly, ventricular wall stiffness increased up until 7.5 months before plateauing with additional age. Endothelial, myofibroblast/smooth muscle, and cardiomyocyte cell fractions were disrupted following cryoinjury, but were progressively restored to age-specific natural norms by 35 days post infarct (DPI). Infarcted myocardium stiffened immediately following cryoinjury and was a 100-fold greater than non-infarcted tissue by 3 DPI. By 14 DPI, stiffness of the infarcted myocardium had fallen below that of 0 DPI and had completely normalized by 35 DPI. Interestingly, cardiomyocyte sarcomere length increased until 14 DPI, but subsequently shortened to lengths below age-specific natural norms, indicating recovery from a volume overloaded condition. These observations are consistent with the view that regenerating myocardium requires biomechanical stimulation (e.g. strain) to rescue from a volume overloaded condition. Intriguingly, the biomechanical progression of the infarcted adult myocardial wall mirrors that of normal remodeling during aging. The biomechanical progression of the infarcted myocardium targets the values of age-specific norms despite a large divergence in initial conditions. These findings identify a novel biomechanical control of heart regeneration that may orchestrate cellular and tissue level remodeling responses.
Highlights
The inability of the adult human heart to regenerate myocardium remains a persistent clinical challenge in managing depressed cardiac function and pathological ventricular remodeling following myocardial infarction (MI)
The bulk stiffness of the ventricular myocardium can be attributed to the stiffness of the individual tissue components, tissue composition, and degree of mechanical coupling; they include stiffness of individuals cells and extracellular matrix (ECM) protein structures, cell and ECM composition, cell-cell and cell-ECM mechanical coupling and ECM cross-linking
Changes in any of these components can lead to changes in the mechanical stiffness of the ventricular myocardium
Summary
The inability of the adult human heart to regenerate myocardium remains a persistent clinical challenge in managing depressed cardiac function and pathological ventricular remodeling following myocardial infarction (MI). The mechanical properties of ECM have been shown to direct differentiation of mesenchymal stem cells into specific lineages[4] and has been shown to be important in the maturation of embryonic cardiomyocytes[5] In the latter, Engler et al demonstrated that pliable substrates resembling the mechanical microenvironment of the developing heart supported myofibril formation and spontaneous beating of embryonic cardiomyocytes. An alternative, unexplored approach is to study the biomechanics of infarct remodeling in an animal model capable of cardiac regeneration We believe that such an approach can aid in improving cardiomyocyte viability and function following cardiac cell therapy and provide an important comparative biological paradigm. Cryoinjury, a technique for inducing localized MI by cooling a region of myocardium to sub-zero centigrade, has been utilized as a method to better recapitulate the inflammation and wound healing process exhibited by human hearts following MI because surgical coronary occlusion is not possible in the adult zebrafish[9,13]
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