HEMATOPOIETIC STEM CELLS IN CARDIOVASCULAR REGENERATIVE MEDICINE

造血干细胞在心血管再生医学中的应用

• 批准号: 7381237
• 负责人: Richard P Visconti
• 金额: $ 13.29万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381237
• 关键词: blood; bone marrow; injury; medicine; myocardium; stem cells

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。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肌细胞增殖/分化，而是通过瘢痕形成和受损的心脏功能进行修复。近年来，干细胞再生受损心肌的潜力受到了相当大的关注。干细胞的这种心源性潜力已经通过研究得到证实，在这些研究中，将成人骨髓（BM）或外周血（PB）来源的干细胞移植到致死性照射的小鼠中，并显示出响应于心肌损伤而产生心肌细胞。最近的一项临床研究突出了此类研究的重要性，该研究显示急性心肌梗死患者直接冠状动脉内输注获益骨髓或循环血液来源的干细胞6.虽然这些报告对心血管疾病的治疗具有广泛的影响，但在这些研究中使用混合干细胞群排除了具有这种心源性潜力的确切群体的鉴定。这些BM和PB细胞的粗群体含有造血细胞和非造血细胞（即，基质）干细胞。本研究的总体目标是研究造血干细胞是否具有这种心源性潜能。为了检验在混合干细胞群体中观察到的心源性潜能存在于造血干细胞（HSC）中的假设，我们已经开发了允许评价单个HSC在体内的转分化潜能的方案7。本提案中提供的数据表明，HSC衍生的细胞在正常环境条件下植入受体小鼠的心肌。此外，我们检测HSC衍生的心肌细胞在心肌坏死（异丙肾上腺素）损伤的小鼠。该项目的具体目标是关注这些HSC衍生细胞在正常环境条件下对心脏的贡献以及对心肌损伤的反应： 1. Jiang Y，Jahagirdar BN，Reinhardt RL，Schwartz RE，Keene CD，Ortiz-Gonzalez XR，Reyes M，Lenvik T，隆德T，Blackstad M，Du J，Aldrich S，Lisberg A，Low WC，Largaespada DA，Verfaillie CM.成人骨髓间充质干细胞的多能性。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的新生血管作用可防止心肌细胞凋亡，减少重构，改善心功能。Nat Med.2001;7：430-6. 3.杰克逊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的再生作用。《临床投资杂志》2001;107：1395-402. 4. Orlic D，Kajstura J，Chimenti S，利马纳F，Jakoniuk I，Quaini F，Nadal-Ginard B，Bodine DM，Leri A，Anversa P.动员的骨髓细胞修复梗死的心脏，改善功能和生存。美国国家科学院2001;98：10344-9. 5. Orlic D，Kajstura J，Chimenti S，Jakoniuk I，安德森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。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，Zeiher AM.急性心肌梗死中祖细胞移植和再生增强（TOPCARE-AMI）。流通2002;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.