Elucidation of the determinants of atherosclerosis progression in transplanted hearts using bone marrow transplantation

利用骨髓移植阐明移植心脏动脉粥样硬化进展的决定因素

• 批准号: 12670641
• 负责人: FUJII Satoshi
• 金额: $ 2.56万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670641/
• 关键词: atherosclerosis; monocyte; macrophage; mouse; bone marrow transplantation; bone marrow chimera; heart transplantation; gene; 骨髄キメラ

Atherosclerosis involves complex inflammatory processes between vascular cells and hematocytes in a hyperlipidemic background. Although macrophage specific expression of apolipoprotein (apo) E by bone marrow transplantation (BMT) decreases susceptibility to development of atherosclerosis in apoE deficient (-/-) mice, this method was insufficient for regression of advanced lesions. We hypothesized that atherosclerosis resistant trait potentially present in bone marrow-derived cells can induce regression of advanced lesions. To determine whether cellular manipulation using BMT can favorably affect serum lipoprotein metabolism and induce regression of advanced atheroma, C57BL6/J apoE-/- mice with severe hypercholesterolemia and pre-existing atherosclerotic lesions were irradiated and reconstituted with syngeneic bone marrow cells plus those from wild type (apoE+/+) mice (atherosclerosis susceptible B10.S/SgSlc mice and atherosclerosis resistant SJL/J mice). Stable mixed allogeneic chimera … More mice were established without any detrimental complications. As compared with non-treated apoE-/- mice, partial reconstitution of apoE-/- mice with wild-type marrow cells resulted in a significant reduction of atherogenic non-HDL cholesterol (B10.S 89%, SJL 72% reduction, respectively) and significant regression of the developed lesions 10 weeks after reconstitution, although amounts of serum apoE expressed in these chimeras were less than 1% of those produced in apoE+/+ mice. Furthermore, compared to mixed chimeras reconstituted with atherosclerosis susceptible B10.S bone marrow cells, mixed chimeras reconstituted with atherosclerosis resistant SJL cells resulted in almost complete regression of preexisting atheroma (93% regression, p<0.05 by ANOVA). These results show that resistance to atherosclerosis of SJL mice resides in bone marrow-derived cells independent of serum lipoprotein metabolism and clearance. Mixed allogeneic chimerism is a novel and safe cell-mediated gene therapy for advanced atherosclerosis. Less

动脉粥样硬化涉及高血压背景下血管细胞和血细胞之间复杂的炎症过程。尽管骨髓移植（BMT）可使apoE缺陷（-/-）小鼠中巨噬细胞特异性表达载脂蛋白（apo）E降低动脉粥样硬化发生的易感性，但该方法不足以使晚期病变消退。我们假设骨髓来源的细胞中潜在存在的抗动脉粥样硬化特性可以诱导晚期病变的消退。为了确定使用BMT的细胞操作是否可以有利地影响血清脂蛋白代谢并诱导晚期动脉粥样硬化的消退，对具有严重高胆固醇血症和预先存在的动脉粥样硬化病变的C57 BL 6/J apoE-/-小鼠进行照射，并用同基因骨髓细胞加上来自野生型（apoE+/+）小鼠（动脉粥样硬化易感的B10.S/SgSlc小鼠和动脉粥样硬化抗性的SJL/J小鼠）的骨髓细胞重建。稳定的混合异基因嵌合体 ...更多信息 建立小鼠而没有任何有害的并发症。与未治疗的apoE-/-小鼠相比，用野生型骨髓细胞部分重建apoE-/-小鼠导致致动脉粥样硬化的非HDL胆固醇显著降低（分别为B10.S减少89%，SJL减少72%）和重建后10周发生的病变显著消退，尽管在这些嵌合体中表达的血清apoE的量小于apoE+/+小鼠中产生的血清apoE的量的1%。此外，与用动脉粥样硬化易感性B10.S骨髓细胞重建的混合嵌合体相比，用动脉粥样硬化抗性SJL细胞重建的混合嵌合体导致预先存在的动脉粥样化几乎完全消退（93%消退，通过ANOVA，p<0.05）。这些结果表明SJL小鼠对动脉粥样硬化的抵抗力存在于骨髓来源的细胞中，不依赖于血清脂蛋白代谢和清除。混合异基因嵌合体是治疗晚期动脉粥样硬化的一种新的、安全的细胞介导的基因治疗方法。少

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