Studies on New Strategy for Myocardial Infarction and Heart Failure by Bone-Marrow Derived Stem Cell Transplantation

骨髓干细胞移植治疗心肌梗塞和心力衰竭新策略的研究

• 批准号: 14370216
• 负责人: KITABATAKE Akira
• 金额: $ 8.9万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370216/
• 关键词: Bone marrow derived stem cell; Cell transplantation; Heart failure; Neovascalarization; GVHD; Immunological Anergy; T cell; Osteopontin

Myocardial regeneration with hone marrow derived stem-cell transplantation is a possible treatment option to reverse the deleterious hemodynamic and neurohumoral effects that occur after myocardial infarction and can lead to heart failure. Various preclinical animal studies show the potential to regenerate myocardium and improve perfusion to the infarct area to improve cardiac function but also suggest that stem cells may have pro-arrhythmic effects. Thus, first to know whether stem cells potentially self-renew and differentiate into cardiomyocytes or endothelial cells, we examined the effects of bone marrow-mononuclear CD34 positive cell transplantation on remodeling process by using cardiomayopathic hamsters as a model for heart failure. Four weeks after cell transplantation, echocardiography revealed a significant, but not greater extent of improvement of % fractional shortening. Rather, long-term pharmacological intervention such as combined therapy with ACE inhibitor and ARB have elicited much more improved than cell transplantation. Second to establish the efficient system of cell implantation, large number of progenitor cells would be needed. However, GVHD may be problematic. Thus, we clarified the role of osteopontin in cardiac remodeling and developed CTLA4Ig or ICOSIg to prevent GVHD by cell transplantation. Thud, to know the mechanisms of cell transplantation, we examined expression changes in DNA by micro-tip analysis. Fourth, to know the clinical outcome, we investigated efficacy and safety of autologous implantation of hone marrow-mononuclear cells in patients with ischaemic limbs because of peripheral arterial disease. In the current study, bone marrow derived stem-cell transplantationis a promising strategy for heart failure, establishing the efficient delivery and evaluation systems would he needed.

骨髓干细胞移植的心肌再生是一种可能的治疗选择，可以逆转心肌梗死后发生的有害血流动力学和神经体液影响，并可能导致心力衰竭。各种临床前动物研究表明，干细胞有可能再生心肌并改善梗死区的血流灌注，以改善心功能，但也表明干细胞可能具有抗心律失常的作用。因此，为了了解干细胞是否有可能自我更新并分化为心肌细胞或内皮细胞，我们以心肌病仓鼠为心力衰竭模型，观察了骨髓-单个核CD34阳性细胞移植对重塑过程的影响。细胞移植后4周，超声心动图显示短轴缩短率有显著改善，但改善程度不大。相反，长期的药物干预，如血管紧张素转换酶抑制剂和ARB的联合治疗，比细胞移植产生了更多的改善。其次，要建立高效的细胞植入系统，需要大量的祖细胞。然而，GVHD可能是有问题的。因此，我们阐明了骨桥蛋白在心脏重构中的作用，并开发了CTLA4Ig或ICOSIg来通过细胞移植预防GVHD。为了了解细胞移植的机制，我们用微尖分析检测了DNA的表达变化。第四，为了了解临床结果，我们研究了自体骨髓单个核细胞移植治疗因外周动脉疾病导致的肢体缺血的疗效和安全性。在目前的研究中，骨髓来源的干细胞移植是治疗心力衰竭的一种很有前途的策略，需要建立有效的输送和评估系统。

项目成果

Chiba S, Okamoto H, Kitabatake A, Uede T.: "Development of Atherosclerosis in E-μ Osteopontin Transgenic Mice."Heart Vessels. 6(3). 111-117 (2002)

Chiba S、Okamoto H、Kitabatake A、Uede T.：“E-μ 骨桥蛋白转基因小鼠的动脉粥样硬化的发展”，111-117 (2002)。

Onozuka H, Okamoto H, Kitabatake A.: "In vivo echocardiographic detection of cardiovascular lesions in apolipoprotein E-knockout mice using a novel high-frequency high-speed echocardiography technique."Circulation Journal. 66. 272-276 (2002)

Onozuka H、Okamoto H、Kitabatake A.：“使用新型高频高速超声心动图技术对载脂蛋白 E 敲除小鼠的心血管病变进行体内超声心动图检测。”循环杂志。

Matsui Y, Nan Jia, Okamot H, Kitabatake, Uede T.: "Osteopontin Defficiency Attenuates Atherosclerosis in Female Apolipoprotein E-Deficient Mice."Arterioscler Thromb Vasc Biol. 23. 1029-1034 (2003)

Matsui Y、Nan Jia、Okamot H、Kitabatake、Uede T.：“骨桥蛋白缺乏可减轻雌性载脂蛋白 E 缺陷小鼠的动脉粥样硬化。”动脉硬化血栓血管生物学。

Yutaka Matsui, Hiroshi Okamoto, Hideki Kumamoto, Satoru Chiha, Toshihiro Shimizu, Toshimitsu Uede, Akira Kitabatake: "Blockade of T cell costimulatory signals using adenovirus vectors could prevent both the onset and the progression of experimental autoim

Yutaka Matsui、Hiroshi Okamoto、Hideki Kumamoto、Satoru Chiha、Toshihiro Shimizu、Toshimitsu Uede、Akira Kitabatake：“使用腺病毒载体阻断 T 细胞共刺激信号可以防止实验性自身免疫性疾病的发生和进展。

Matsui Y, Okamoto H, Kitabatake A, Uede T.: "Adenovirus-mediated gene transfer of ICOSIg fusion protein ameliorates ongoing experimental autoimmune myocarditis"Human Gene Therapy. (In Press).

Matsui Y、Okamoto H、Kitabatake A、Uede T.：“腺病毒介导的 ICOSIg 融合蛋白基因转移可改善正在进行的实验性自身免疫性心肌炎”人类基因疗法。