Abstract 303: Migration of Cardiac Progenitor Cells to the Scarred Infarcted Myocardium is Mediated by Matrix Metalloproteinases and Chemotactic Factors
Ischemic heart disease is characterized chronically by myocardial scarring, cavitary dilation and impaired ventricular performance. These alterations can only be reversed by replacing scarred tissue with functionally competent myocardium. Therefore, myocardial infarction was produced in rats and 20 days later animals were injected with cardiac progenitor cells (CPCs) or vehicle. To characterize the mechanisms of CPC invasion, the expression of MMPs and their inhibitors TIMPs was evaluated in healed infarcts 1–3 days after cell delivery. In the presence of CPCs, MMP-2, MMP-9 and MMP-14 were significantly increased and TIMP-4 was decreased. The activity of MMP-9 was 10-fold higher in CPC-treated than untreated infarcts. A cytokine array was then performed. In comparison with sham-operated rats, the scarred myocardium contained higher quantities of the cell adhesion molecule sICAM-1, the chemoattractant CXCL7, bFGF and TIMP-1. A similar analysis was also done shortly after infarction to establish whether the cytokine profile differed in chronic and acute infarcts. The acutely infarcted heart displayed a cytokine array that reflected an inflammatory response and tissue reaction to ischemic injury. SDF-1 content was higher in acute than chronic infarcts, favoring CPC migration shortly after ischemia. However, sICAM-1 and bFGF showed higher expression chronically facilitating homing of CPCs to the scar. sICAM-1, CXCL7 and TIMP-1 promoted CPC mobilization, endothelial cell migration and differentiation, and vessel formation within the scar. Finally, we tested whether the delivery of CPCs to the scar participated in the synthesis of soluble proteins which exerted an autocrine or paracrine effect on myocardial regeneration. CPCs attenuated, at least in part, the differences in cytokine profile with acute infarcts by increasing the quantities of LIX that is involved in stem cell maintenance and proliferation, and IP-10 that modulates vessel homeostasis and growth. Thus, CPCs synthesize and secrete MMPs and chronic myocardial infarcts lead to the expression of cytokines that create a favorable microenvironment for the activation, migration and growth of these cells. These two variables control the regenerative response of the pathologic heart.