HEMATOPOIETIC STEM CELLS IN CARDIOVASCULAR REGENERATIVE MEDICINE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。心血管疾病是南卡罗来纳州住院和死亡的主要原因。心肌缺血损伤导致心肌细胞死亡、炎症反应和结缔组织细胞增殖。与其他组织不同，心肌细胞的损失不会导致恢复性心肌细胞增殖/分化，而是通过疤痕形成和心功能受损进行修复。近年来，干细胞再生损伤心肌的潜力受到了广泛的关注。干细胞的这种致心潜能已被研究证实，这些研究将成人骨髓（BM）或外周血（PB）来源的干细胞移植到受到致命辐射的小鼠体内，并显示心肌损伤后产生心肌细胞。最近的一项临床研究强调了这类研究的重要性，该研究显示急性心肌梗死患者从直接冠状动脉内输注BM或循环血液来源的干细胞中获益。虽然这些报道对心血管疾病的治疗具有广泛的意义，但在这些研究中使用混合干细胞群妨碍了对具有这种致心潜能的确切群体的识别。这些粗群的BM和PB细胞包含造血和非造血（即基质）干细胞。本提案的总体目标是研究造血干细胞是否具有这种心源性潜能。为了验证在混合干细胞群体中观察到的致心潜能存在于造血干细胞（HSC）中的假设，我们开发了允许在体内评估单个造血干细胞转分化潜能的方案7。本研究的数据表明，造血干细胞来源的细胞在正常环境条件下可以移植到受体小鼠的心肌中。此外，我们在坏死（异丙肾上腺素）损伤的小鼠心肌中检测hsc来源的心肌细胞。这个项目的具体目的是集中在这些hsc来源的细胞在正常环境条件下对心脏的贡献和对心肌损伤的反应。Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, ortizs - gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM。成体骨髓间充质干细胞的多能性。大自然。2002;418:41-9。2. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S.人骨髓源性成血管细胞对缺血心肌新生血管的影响中华医学杂志。2001;7:43 -6。3. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, majky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA。成体干细胞再生缺血心肌和血管内皮的研究。[J] .中国临床医学杂志，2001;17(1):1 -4。4. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P.动员骨髓细胞修复梗死心脏功能和存活率。科学通报，2001;28(3):344- 349。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.骨髓细胞再生梗死心肌。大自然。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, zeeiher AM。祖细胞移植与急性心肌梗死的再生增强（TOPCARE-AMI）。循环。2002;106:3009-17。7. Masuya M, Drake CJ, Fleming PA, Reilly CM, Zeng H, Hill WD, martinu - studard A, Hess DC, Ogawa M.肾小球系膜细胞造血来源。血。2003;101:2215 - 2218。

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.