One (1) of the leading causes of hospital admission and mortality in the patients is heart failure and current interventional techniques often fail to treat the underlying cause of pathogenesis. Prevention of LV remodeling after acute MI is important because it causes heart failure and poor prognosis. The proposed strategy is based on the principle to supplement the inadequate intrinsic repair mechanism of the heart through stem cell transplantation. A potential approach to achieve enhanced bone marrow-derived stem cells (BMSC) engraftment into the damaged myocardium is through mobilization of BMSC using hematopoietic growth factors. Various proof-of-concept studies in animals have shown the applicability of this approach using various myelosuppressive and chemotherapeutic agents and hematopoietic growth factors alone or in combination therapy. Recently, it has been reported that a pretreatment with cytokine(s), like G-CSF and SCF attenuates LV remodeling after MI. G-CSF also causes a marked increase in the release of hematopoietic stem cells (HSCs) into the peripheral blood circulation, a process termed mobilization. The goal of our study is to pharmacologically mobilize cells and improve hemodynamic parameters and global cardiac performance. Based on our preliminary data, we postulate that mobilization of BMSC by various combinations of cytokines provides more efficient egress of the cells from bone marrow and that this process is dependent on specific lineage BMSC and chemokine receptor (CXCR4). 4 hypotheses will be tested in a well-established murine model using broad multidisciplinary approaches that will encompass diverse techniques including biochemistry, integrative physiology, immunohistochemistry, gene therapy, pathology, flow cytometric analysis, pressure-volume relationship and confocal microscopy. Hypotheses to the tested are: Hypothesis 1: Systemic administration of either G-CSF with SCF, or G-CSF with FL is superior to the use of G-CSF alone. We will identify and quantify the subpopulation of BMSC mobilized by G-CSF, SCF and FL alone or through the synergistic interaction between these cytokines to achieve lineage specific mobilization. Hypothesis 2: Ex-vivo delivered G-CSF and SCF transfected BMSC at the site of myocardial injury may efficiently trigger further mobilization and homing of BMSC for cardiac repair. This is based on the fact that G-CSF is an effective chemoattractant for BMSC and enhances the infiltration of side population after MI in mice. Hypothesis 3: The un-mobilized and cytokine mobilized bone marrow cells differ in the expression of their surface marker proteins, and this difference contributes to their emigration and release from bone marrow cells """"""""niche"""""""". Hypothesis 4: Enhanced expression of CXCR4 receptor on BMSC accelerates their homing and survival in the infarcted myocardium. SDF-1 through its receptor CXCR-4 is believed to be superior in stem cell mobilization, angiogenesis and cell survival. This proposal is expected to yield novel information on various cytokine regimens to regenerate infarcted myocardium and the molecular mechanisms of HSC homing. The results of cytokine-mediated regeneration therapy may become a novel therapeutic strategy for MI. .
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