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。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。心血管疾病是南卡罗来纳州住院和死亡的主要原因。心脏缺血性损伤会导致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心肌细胞增殖/分化，而是通过形成疤痕和心脏功能受损的修复。最近，干细胞再生受伤的心肌的潜力受到了相当大的关注。通过研究证明了干细胞的这种心脏病潜力，在这种研究中，成年骨髓（BM）或周围血（PB）衍生的干细胞被移植到致命的辐照小鼠中，并证明会导致心肌细胞响应心肌损伤。从最近的研究中，该研究的重要性是在临床上的兴趣，该研究的重要性是在临床上的限制，该研究涉及临时症状的依据。输注BM或循环血液衍生的干细胞6。尽管这些报告对治疗心血管疾病具有广泛的影响，但在这些研究中，干细胞混合种群的使用排除了具有这种心脏病潜力的确切种群的鉴定。这些BM和PB细胞的原油种群含有造血和非脊髓性（即基质）干细胞。该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力。为了检验在干细胞混合群体中观察到的心脏病潜力的假设存在于造血干细胞（HSC）中，我们开发了允许评估vivo7中单个HSC的转分化潜力的方案。该提案中提供的数据表明，在正常环境条件下，HSC衍生的细胞植入了受体小鼠的心肌。此外，我们检测到遭受坏死（异丙肾上腺素）损伤的小鼠心肌中HSC衍生的心肌细胞。该项目的具体目的集中在正常环境条件下这些HSC衍生细胞对心脏的贡献，并应对心肌损伤：1。JiangY，Jiang Y，Jahagirdar BN，Reinhardt RL，Schwartz RE，Schwartz RE，Keene CD，Ortiz-Gonzalez，Ortiz-Gonzalez Xr，Reyes M，Reyes M，Reyes M，Lownvik listh j j j j stad lund lund t，lund lund t，lund lund t，lund th duich lund t，lund t，duich s duich s duich s duich lund t，lund t duich lund s. WC，Largaespada DA，Verfaillie CM。衍生自成年骨髓的间充质干细胞的多能性。自然。 2002; 418：41-9。 2。KocherAA，Schuster MD，Szabolcs MJ，Takuma S，Burkhoff D，Wang J，Homma S，Homma S，Edwards NM，Itescu S.人类骨骼骨骼衍生的血管生成性血管生成性心肌细胞的新血管形成，可预防心脏骨髓骨膜细胞肌apopoptosis，并改善了重新固定的功能。 Nat Med。 2001; 7：430-6。 3。JacksonKA，Majka SM，Wang H，Pocius J，Hartley CJ，Majesky MW，Entman ML，Michael LH​​，Hirschi KK，Goodell MA。成年干细胞的缺血性心肌和血管内皮的再生。 J Clin Invest。 2001; 107：1395-402。 4。OrlicD，Kajstura J，Chimenti S，Limana F，Jakoniuk I，Quaini F，Nadal-Ginard B，Bodine DM，Leri A，AnversaP。动员骨髓细胞修复插孔的心脏，改善功能和存活。 Proc Natl Acad Sci U S A.2001; 98：10344-9。 5。OrlicD，Kajstura J，Chimenti S，Jakoniuk I，Anderson SM，Li B，Pickel J，McKay R，Nadal-Ginard B，Bodine DM，Leri A，Anversa P. Bone P. Bone P.骨髓细胞再生心肌。自然。 2001; 410：701-5。 6。AssmusB，Schachinger V，Teupe C，Britten M，Lehmann R，Dobert N，Grunwald F，Aicher A，Urbich C，Martin H，Hoelzer D，Hoelzer D，Dimmeler S，Zeiher AM。祖细胞的移植和急性心肌梗塞（Topcare-AMI）的再生​​增强。循环。 2002; 106：3009-17。 7. Masuya M，Drake CJ，Fleming PA，Reilly CM，Zeng H，Hill WD，Martin-Studdard A，Hess DC，Ogawa M.肾小球膜细胞的造血起源。血。 2003; 101：2215-2218。