HEMATOPOIETIC STEM CELLS IN CARDIOVASCULAR REGENERATIVE MEDICINE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。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以及结缔组织细胞的炎症反应和增殖。与其他组织不同，心肌细胞的丧失不会导致恢复性的心肌细胞增殖/分化，而是通过瘢痕形成和心脏功能受损来修复。最近，干细胞再生受损心肌的潜力受到相当大的关注。干细胞的这种心脏生成潜力已被研究证实，在这些研究中，成人骨髓(BM)或外周血(PB)来源的干细胞被移植到致死照射的小鼠体内，并被证明能在心肌损伤后产生心肌细胞。1-5最近的一项临床研究突出了这种研究的重要性，在该研究中，急性心肌梗死患者被证明受益于冠脉内直接输注骨髓或循环血源性干细胞6。虽然这些报告对心血管疾病的治疗有广泛的影响，但在这些研究中使用混合干细胞群体排除了识别具有这种致心潜力的确切群体(S)的可能性。这些原始的骨髓和外周血细胞群中既有造血系干细胞，也有非造血系(即基质)干细胞。这项建议的总体目标是研究造血干细胞是否具有这种生心潜力。为了验证在混合干细胞群体中观察到的生心潜力存在于造血干细胞(HSC)中的假设，我们开发了允许在活体7中评估单个HSC转分化潜力的方案。这项建议中提出的数据表明，在正常环境条件下，HSC来源的细胞可以移植到受体小鼠的心肌中。此外，我们在受到坏死性(异丙肾上腺素)损伤的小鼠的心肌中检测到HSC来源的心肌细胞。本项目的具体目标集中在这些干细胞来源的细胞在正常环境条件下和对心肌损伤的反应中对心脏的贡献：1.姜瑜，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，Largespda，Veraillie CM。成人骨髓间充质干细胞的多能性。大自然。2002年；418：41-9。2.Kocher AA，Schuster MD，Szbolcs MJ，Takuma S，Burkhoff D，Wang J，Homma S，Edwards NM，Itescu S。人骨髓来源血管母细胞对缺血心肌的新生血管可防止心肌细胞凋亡，减少重塑，改善心功能。奈特·梅德。2001年；7：430-6。3.Ka，Majka SM，Wang H，Pocius J，Hartley CJ，Majesky MW，Entman ML，Michael LH，Hirschi KK，Goodell MA。成体干细胞对缺血心肌和血管内皮细胞的再生。j Clin投资公司。2001；107：1395-402。4.Oric D，Kajstura J，Chimenti S，Limana F，Jakoniuk I，Quaini F，Nadal-Ginard B，Bodine DM，Leri A，Anversa P。动员的骨髓细胞修复梗塞的心脏，改善功能和存活。S学报，2001；98：10344-9。5.Oric 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年；410：701-5。阿斯穆斯B，沙钦格V，特普C，布里顿M，莱曼R，多伯特N，格伦瓦尔德F，艾歇尔A，乌尔比奇C，马丁H，霍尔策D，迪梅勒S，泽赫AM祖细胞移植和再生促进治疗急性心肌梗死发行量。2002年；106：3009-17。7.Masuya M，Drake CJ，Fleming PA，Reilly CM，Zeng H，Hill WD，Martin-Studdard A，Hess DC，Ogawa M.肾小球系膜细胞的造血起源。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.