Over one million Americans suffer a myocardial infarction (MI) each year. Although the majority of patients survive the initial event, the physiologic regeneration in the adult heart is grossly inadequate to compensate for the severe loss of myocardium. Thus, considerable effort of modern cardiology is dedicated to management of patients suffering from progression of heart failure. Controlled recruitment of cardiac progenitor cells for myocardial regeneration is a potentially powerful therapy for myocardial infarction and heart failure. A rigorous understanding of the molecular mechanisms that control the recruitment and migration of cardiac progenitors to the targeted tissues is absolutely essential for the success of any cell therapy, regardless of the progenitor type or delivery strategy used. Multipotent adult cardiac progenitors, characterized by the expression of early embryonic cardiac precursor genes in the absence of specific lineage markers, are an attractive target for therapeutic recruitment after MI. One possibility is that these adult cardiac progenitors represent a remnant of the multipotent cell population that has persisted in the heart throughout embryonic and postnatal development. By studying the behavior of clearly defined embryonic cardiac progenitor cells in response to specific chemotactic stimuli, we could potentially elucidate mechanisms involved in the activity of adult cardiac progenitor population and use this knowledge in the design of regenerative therapies. This proposal uses unique technological advances to rigorously investigate the migration and differentiation of embryonic cardiac progenitors, identified by the expression of Nkx2.5 gene, in the controlled chemotactic environment of microfluidic bioreactors. The Nkx2.5+ cardiac precursors differentiate into cardiomyocytes both during embryonic development and in the adult heart, and are capable of migration into infarcted myocardium during healing. The proposed experiments will involve both the isolated Nkx2.5+ embryonic cells and embryonic cardiac explants from the transgenic Nkx2.5 reporter mouse. Microfluidic devices allow precise control over the chemokine gradients, as well as real-time observation of cell migration, differentiation, and complex organization in the 3D environment of collagen gels. To study the migratory behavior and differentiation potential of Nkx2.5+ cardiac precursors, the stromal cell-derived factor-1 (SDF-1) is proposed as a candidate chemokine. The SDF-1 and its receptor, CXCR4, comprise the key axis for stem cell migration. In addition, co-culture experiments of Nkx2.5+ embryonic cells and endothelial cells are proposed to investigate the effect of microvascular structures on migration and organization of cardiac precursors. The insights from the proposed research are critically important to the design of successful cell therapies that aim to recruit cardiac progenitors for myocardial regeneration.
Regenerative cell therapies for patients suffering from heart failure are currently impeded by a lack of understanding of mechanisms involved in cell recruitment and migration into the target region. The proposed research uses rigorous approaches to investigate these mechanisms in cardiac progenitor cells, and may lead to the design of successful cell therapies.
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