This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cardiovascular disease is a leading cause of hospitalization and death in South Carolina. Cardiac ischemic injury results myocyte death as well as inflammatory response and proliferation of connective tissue cells. Unlike other tissues, loss of cardiomyocytes does not lead to restorative myocyte proliferation/differentiation, but rather, repair by scar formation and compromised cardiac function. Recently, the potential of stem cells to regenerate the injured myocardium has received considerable attention. This cardiogenic potential of stem cells has been demonstrated by studies in which adult bone marrow (BM) or peripheral blood (PB) derived stem cells were transplanted into lethally irradiated mice and shown to give rise to cardiomyocytes in response to myocardial injury.1-5 The import of such studies is highlighted by a recent clinical study where patients with acute myocardial infarction were shown to benefit from direct intracoronary infusion of BM or circulating blood-derived stem cells6. While these reports have broad implications for the treatment of cardiovascular disease, the use of mixed populations of stem cells in these studies precludes identification of the exact population(s) that possesses this cardiogenic potential. These crude populations of BM and PB cells contain both hematopoietic and non-hematopoietic (i.e., stromal) stem cells. The overall goal of this proposal is to investigate whether the hematopoietic stem cell possesses this cardiogenic potential. To test the hypothesis that the cardiogenic potential observed in mixed populations of stem cells resides in the hematopoietic stem cell (HSC), we have developed protocols that permit the evaluation of the transdifferentiation potential of a single HSC in vivo7. Data presented in this proposal demonstrate that HSC-derived cells engraft into the myocardium of recipient mice under normal ambient conditions. Further, we detect HSC-derived cardiomyocytes in the myocardium of mice subjected to necrotic (isoproterenol) injury.
The specific aims of this project are focused on the contribution of these HSC-derived cells to the heart during normal ambient conditions and in response to myocardial injury: 1. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418:41-9. 2. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001;7:430-6. 3. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest. 2001;107:1395-402. 4. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci U S A. 2001;98:10344-9. 5. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701-5. 6. Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, Grunwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002;106:3009-17. 7. Masuya M, Drake CJ, Fleming PA, Reilly CM, Zeng H, Hill WD, Martin-Studdard A, Hess DC, Ogawa M. Hematopoietic origin of glomerular mesangial cells. Blood. 2003;101:2215-2218.
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