Myocardial infarction often induces a period of left ventricular (LV) remodeling. When LV remodeling occurs, an initial period of hemodynamic stability is followed by the development of LV dysfunction that may result in congestive heart failure (CHF). The molecular and cellular basis for the progressive heart failure is the result of the inability of damaged and apoptotic myocytes to be replaced. Although there are a significant number of reports in recent literature on cellular therapy for myocardial repair using different type of stem cells, the low engraftment rate, as well as the low cardiomyocytes regeneration are the major problems in cardiac cell therapy. The proposed studies will utilize pre differentiated myocytes and vascular cells derived from human induced pluripotent stem cells (hiPSCs) in a porcine model of postinfarction LV remodeling with immune suppression that we have previously demonstrated to be very relevant to human clinical cardiac regenerative therapies. Here we will pursue the following specific aims.
Specific Aim 1 : To use submicron 3D printing to fabricate ECM-based hydrogels based on the distribution of ECM in the native myocardium to generate a myocardial tissue equivalent with enhanced function of iPSC-derived tri-lineage cardiac cell types.
Specific Aim 2 : Using the recently established T1-nom P-31 magnetization saturation transfer (MST) and 2D chemical shifting imaging (2D-CSI) methods to examine whether the myocardial ATP flux rate via both CK and ATPase are most severely altered in the periscar border zone subendocardial layers (ENDO) of infarcted hearts. The severity of the decrease in ATP production capacity via CK and ATPase in ENDO of the infarcted heart is linearly related to the severity of the LV dysfunction.
Specific Aim 3 : To examine whether the functional beneficial effects of transplantation of the novel ECM tissue equivalent using human iPSC-CM, -endothelial cells (EC) and ?smooth muscle cells (SMC) are accompanied by enhanced retention and integration of transplanted cells to the myocardium and associated reduction of LV wall stress, which in turn results in improvement of myocardial ATP production reserve via both CK and ATPase in the ENDO of infarcted hearts. The results of these studies may lead to better diagnostic and therapeutic modalities for acute myocardial infarction.
The proposed studies will utilize human myocardial tissue equivalent (hMTE) with pre differentiated myocytes and vascular progenitor cells derived from human cardiac induced pluripotent stem cells (hciPSCs) in a porcine model of postinfarction LV remodeling with immune suppression that we have previously demonstrated to be very relevant to human clinical cardiac regenerative therapies. Using the recently established T1-nom P-31 and double magnetization saturation transfer (MST) and 2D chemical shifting imaging (2D-CSI) methods, we will examine whether the myocardial ATP flux rate via both CK and ATPase are most severely altered in the periscar border zone subendocardial layers (ENDO) of infarcted hearts, and whether the hMTE transplantation can result in the improvement of myocardial perfusion, metabolism and contractile function of failing heart.
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