Cellular transplantation has emerged as a therapeutic approach to restore lost systolic function to the diseased heart. To date, cellular engraftment approaches have utilized a variety of donor cell types (namely, fetal cardiomyocytes, embryonic stem cell-derived cardiomyocytes, skeletal myoblasts, and adult stem cells). Although cell transfer resulted in an improvement of global cardiac function in a number of studies, in most instances the functional assays employed were unable to distinguish between direct contractions of the donor cells vs. a beneficial effect imparted upon the surviving host myocardium. Accordingly, we have implemented a novel, 2-photon laser scanning microscopy (TPLSM)-based imaging system to monitor cytosolic Ca2+ transients in donor and host cardiomyocytes in situ. This system allows us to assess the level of functional coupling of transplanted cells as well as their effects on the function of recipient cardiomyocytes. In this application we propose to investigate the functional consequences of engrafting 3 cell types that are currently being pursued experimentally and in some cases clinically.
Aim 1 will test the ability of fetal cardiomyocytes transplanted at the infarct border zone to functionally couple with the surviving host myocardium. We have recently demonstrated that, using TPLSM imaging of enhanced green fluorescent protein (EGFP)-expressing donor cells, fetal cardiomyocytes transplanted into normal mouse hearts are able to functionally couple with the host myocardium. We will transplant EGFP-expressing fetal cardiomyocytes to the infarct border zone and use TPLSM to determine the degree to which they are able to couple with the host myocardium.
Aim 2 will test the hypothesis that skeletal myoblasts can alter electrical properties of the bordering host cardiomyocytes following transplantation into normal or infarcted hearts. EGFP-expressing primary skeletal myoblasts will be transplanted and TPLSM will be used to determine if there is functional coupling between host cardiomyocytes and the skeletal myotubes, and if the presence of myotubes influences the function of bordering host cardiomyocytes.
Aim 3 will test the hypothesis that transplanted or mobilized adult stem cells have limited cardiomyogenic differentiation, but can alter the electrical properties of the bordering host cardiomyocytes in normal or infarcted hearts. We will utilize TPLSM and EGFP-expressing bone marrow progenitor cells to monitor the degree of differentiation and functional coupling following transplantation into normal or injured hearts, as well as after mobilization of progenitors following stable bone marrow transplant. In all aims, parallel echocardiographic studies will examine whether functional donor-host coupling as assessed with TPLSM imaging translates into improved global contractile activity of infarcted hearts following cellular transplantation. Additional studies examining the structural consequences of cell transplantation (i.e., angiogenesis, post infarct remodeling, and connexin distribution) will also be performed. The studies proposed here will address fundamental hypotheses regarding the fate of donor cells following cellular transplantation into normal and injured hearts.
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