The adult bone marrow is a major reservoir of multipotent stem/progenitor cells including hematopoietic stem cells (HSC), mesenchymal stem cells (MSC), and endothelial progenitor cells (EPC). The ability of HSC to regenerate hematopoietic tissue following myeloablative therapy is well documented and widely used in clinical practice. Emerging data suggest that stem cells in the bone marrow also may be able to regenerate damaged tissue in other organs, including liver and heart. However, repair of damaged tissue by endogenous stem cells may be limited by the rarity of stem cells in the circulation under basal conditions. To circumvent this limitation, the number of HSC, EPC and possibly MSC in the circulation can be dramatically increased or mobilized by treatment with various agents. Cytokine mobilization of bone marrow cells prior to myocardial infarction has been reported to improve survival and cardiac function in mice. Collectively, these data support the hypothesis that rapid mobilization of stem cells from the bone marrow to blood may enhance tissue regeneration following injury. HOWEVER, there are significant gaps in our knowledge of this process that should be addressed prior to the rational design of clinical trials. What are the optimal regimens to mobilize HSC, MSC, and EPC into the blood in a rapid yet sustained fashion? Can the initiation of stem cell mobilization after organ damage lead to significant tissue regeneration? If so, what are the cell types capable of mediating the most robust tissue repair, and what is the optimal time period following tissue injury to deliver these cells? To begin to answer these questions, we recently developed NOD/SCID/MPSVII mice. These mice are deficient in b-glucuronidase (GUSB), a ubiquitously expressed lysosomal enzyme. Importantly, sensitive and specific methods have been developed to detect GUSB-positive cells in these mice following transplantation. In the proposed studies, we will use this novel murine model to examine the stem cell-mediated repair of chemically damaged liver tissue and of cardiac tissue following myocardial infarction. The following specific aims are proposed. 1. Optimize mobilization regimens that lead to rapid and sustained increases in the number of circulating HSC, MSC, and EPC 2. Assess the efficacy of stem cell mobilization to mediate tissue regeneration in a novel murine model of acute liver injury. 3. Examine the efficacy of stem cell mobilization to mediate tissue regeneration in a murine model of acute myocardial infarction.
