Development of high fidelity cardiac tissue engineering platforms by biophysical signaling: in vitro models and in vivo repair

Cardiovascular disease (CVD) is broadly characterized by a loss of global function, exacerbated by a very limited ability for the heart to regenerate itself following injury. CVD remains the leading cause of death in the United States and the leading citation in hospital discharges. The overall concept of this dissertation is to investigate the use of biophysical signals that drive physiologic maturation of myocardium, and lead to its deterioration in disease. By incorporating biophysical signaling into cardiac tissue engineering methods, the aim is to generate high fidelity engineered platforms for cell delivery and maturation of surrogate muscle, while understanding the cues that lead to pathological cell fate in disease. The first part of this thesis describes the development of a composite scaffold, derived from human myocardium, to use as a delivery platform of mesenchymal stem cells to the heart. Through biochemical signaling, we are able to modulate MSC phenotype, and propose a mechanism through which angio- and arteriogenesis of the heart leading to global functional improvements, following myocardial infarction, may be attributed. We further demonstrate cardioprotection of host myocardium in a setting of acute injury by exploiting non-invasive radioimaging techniques. The mechanism through which we can attribute cell mobilization to the infarct bed is further explored in patient-derived myocardium, to understand how this pathway remains relevant in chronic heart failure. The second focus of the thesis is the use of electro-mechanical stimulation to generate high fidelity Engineered Heart Muscle (EHM). We report that electro-mechanical stimulation of EHM at near-physiologic frequency leads to development and maturation of Calcium handling and the T- tubular network, as well as improved functionality and positive force frequency relationship. Lastly, we return to human myocardium as platform understand regulation of cardiomyocyte function by the extracellular matrix. Here, we seek to understand how the ECM from different disease states (eg. non-diseased, ischemic, non-ischemic) affects cell phenotype. Specifically, can bona fide engineered myocardium successfully integrate and remodel diseased ECM? Using stem cell derived cardiomyocytes and patient-derived decellularized myocardium to generated engineered myocardium (hhEMs), we report that hhEMs mimic native myogenic expression patterns representative of their failing- and non-failing heart tissue