Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance

Abstract

Cellular therapy for myocardial injury has improved ventricular function in both animal and clinical studies, though the mechanism of benefit is unclear. This study was undertaken to examine the effects of cellular injection after infarction on myocardial elasticity. Coronary artery ligation of Lewis rats was followed by direct injection of human mesenchymal stem cells (MSCs) into the acutely ischemic myocardium. Two weeks postinfarct, myocardial elasticity was mapped by atomic force microscopy. MSC-injected hearts near the infarct region were twofold stiffer than myocardium from noninfarcted animals but softer than myocardium from vehicle-treated infarcted animals. After 8 wk, the following variables were evaluated: MSC engraftment and left ventricular geometry by histological methods, cardiac function with a pressure-volume conductance catheter, myocardial fibrosis by Masson Trichrome staining, vascularity by immunohistochemistry, and apoptosis by TdT-mediated dUTP nick-end labeling assay. The human cells engrafted and expressed a cardiomyocyte protein but stopped short of full differentiation and did not stimulate significant angiogenesis. MSC-injected hearts showed significantly less fibrosis than controls, as well as less left ventricular dilation, reduced apoptosis, increased myocardial thickness, and preservation of systolic and diastolic cardiac function. In summary, MSC injection after myocardial infarction did not regenerate contracting cardiomyocytes but reduced the stiffness of the subsequent scar and attenuated postinfarction remodeling, preserving some cardiac function. Improving scarred heart muscle compliance could be a functional benefit of cellular cardiomyoplasty.

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

“…Our stretched tissues exhibited reduced systolic stress, suggesting that excessive stretch affects myocyte shortening, but not relaxation. One potential explanation is that pathological hypertrophy and heart failure are also associated with increased fibrosis, which stiffens the cellular microenvironment (52). These pathological changes in compliance likely impede myocyte relaxation and could be essential to diastolic dysfunction.…”

Fibroblast proliferation alters cardiac excitation conduction and contraction: a computational study

“…This process is strongly correlated with atrial and ventricular tachyarrhythmias and sudden cardiac death (John et al, 2004;Assomull et al, 2006;Pellman et al, 2010). The elastic modulus rises from (18±2) kPa in the normal heart muscle of non-infarcted animals to (55±15) kPa in significant fibroblast proliferous muscle of infarcted animals, an almost three-fold increase (Berry et al, 2006). Therefore, the functional roles of the fibroblasts in cardiac electrical and mechanical activities have attracted increasing interest, and have been explored in experimental studies (Miragoli et al, 2007;Zlochiver et al, 2008) and computational models (MacCannell et al, 2007;Tanaka et al, 2007;Jacquemet and Henriquez, 2008;Zlochiver et al, 2008;Sachse et al, 2009).…”

Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics

“…However, matrix stiffening is more relevant for many biological events, including tissue development, wound healing and disease progression, such as fibrosis and tumour formation. For instance, fibrous scar tissue that develops after myocardial infarction is much stiffer than normal myocardium [17][18][19] , and mesenchymal stem cells (MSCs) differentiate down an osteogenic lineage and produce markers of bone when injected into infarct tissue in mice 20 . Recent evidence also suggests that matrix stiffening, which is generally regarded as an outcome of disease, may be a contributing factor in disease development.…”