Stem Cell Therapy and Postinfarction LV Remodeling

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DESCRIPTION (provided by applicant): Congestive heart failure has generally been considered an end-stage irreversible clinical condition for which medical management is principally to relieve symptoms and slow progression. Several exciting recent studies have shown that tissue specific stem cells may have the ability to generate cells of tissues from unrelated organs. Whether this unexpected plasticity constitutes "trans differentiation" or whether a small population of multi potent stem cells persists in post-natal tissues is not known. Recently, there is an increased volume of reports that cellular therapy improves LV function in murine hearts with myocardial infarction. However, the cell engraftment rate is usually low and ranges from 0.3%-3% depending upon the animal models and modes of the delivery. Hence, the majority of cells transplanted to the heart do not successfully engraft. Further, most engrafted cells do not differentiate into host cardiac cell phenotypes. Therefore, methods to enhance MSCs engraftment and increase their rates of proliferation and differentiation into functioning cardiomyocytes are urgently needed. Using bone marrow derived mesenchymal stem cells (MSC), this research proposal will examine the mechanisms of a possible cellular therapy for cardiac repair in a swine model of postinfarction LV remodeling. The functional consequences of stem cell transplantation on LV contractile function will be measured by cardiac MRI, myocardial energy metabolism and oxygenation levels measured by 31P- and 1H- MR spectroscopy, and myocardial maximum blood flow reserve by microspheres. The specific aims of this project are: SA1. To determine the efficacy of growth factor enhanced autologous MSCs transplantation at the time of infarction and whether short term beneficial effects are durable, i.e.. whether therapeutic effects present at 4 weeks will persist for -4 months post-transplantation . SA2. To determine if delayed, growth factor enhanced autologous MSCs transplantation (4 weeks post-Infarction) is more effective than transplantation at the time of infarction and whether the therapeutic effects of delayed transplantation are durable. SA3. To determine whether myocardial inlectlon a mixture of partially pre-differentiated cardlomvocvtes and endothelium (exposure to the respective differentiation protocols for 7 days before transplantation) plus growth ,' factors will have greater beneficial effects than injection of undifferentiated MSCs. SA4. To determine whether myocardial injection of banked alloqenic MSCs fplus growth factors) will have beneficial ! effects comparable to those of autoloqous MSCs. SA5. To determine whether transplantation of MSC in a thretf-dimensional porous biodegradable PEGvlated fibrin \ matrix that covalentlv binds the growth factors (HGF and IGF) will enhance the rate, of MSCs enqraftment. and therefore functional benefits.