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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073762-04
Application #
7083563
Study Section
Special Emphasis Panel (ZHL1-CSR-J (M2))
Program Officer
Thomas, John
Project Start
2003-07-01
Project End
2008-12-31
Budget Start
2006-07-01
Budget End
2008-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$526,086
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Gregory, Alyssa D; Capoccia, Benjamin J; Woloszynek, Jill R et al. (2010) Systemic levels of G-CSF and interleukin-6 determine the angiogenic potential of bone marrow resident monocytes. J Leukoc Biol 88:123-31
Capoccia, Benjamin J; Robson, Debra L; Levac, Krysta D et al. (2009) Revascularization of ischemic limbs after transplantation of human bone marrow cells with high aldehyde dehydrogenase activity. Blood 113:5340-51
Shaked, Yuval; Tang, Terence; Woloszynek, Jill et al. (2009) Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents. Cancer Res 69:7524-8
Capoccia, Benjamin J; Gregory, Alyssa D; Link, Daniel C (2008) Recruitment of the inflammatory subset of monocytes to sites of ischemia induces angiogenesis in a monocyte chemoattractant protein-1-dependent fashion. J Leukoc Biol 84:760-8
Shepherd, Rebecca M; Capoccia, Benjamin J; Devine, Steven M et al. (2006) Angiogenic cells can be rapidly mobilized and efficiently harvested from the blood following treatment with AMD3100. Blood 108:3662-7
Capoccia, Benjamin J; Shepherd, Rebecca M; Link, Daniel C (2006) G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism. Blood 108:2438-45
Guven, Hasan; Shepherd, Rebecca M; Bach, Richard G et al. (2006) The number of endothelial progenitor cell colonies in the blood is increased in patients with angiographically significant coronary artery disease. J Am Coll Cardiol 48:1579-87