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

动脉粥样硬化涉及高脂血症背景下血管细胞和血细胞之间复杂的炎症过程。虽然骨髓移植（BMT）巨噬细胞特异性表达载脂蛋白（apo） E可以降低apoE缺陷（-/-）小鼠动脉粥样硬化的易感性，但这种方法不足以使晚期病变消退。我们假设骨髓源性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BMT是否能积极影响血清脂蛋白代谢并诱导晚期动脉粥样硬化的消退，我们对患有严重高胆固醇血症和先前存在动脉粥样硬化病变的C57BL6/J apoE-/-小鼠进行照射，并用同基因骨髓细胞和野生型（apoE+/+）小鼠（动脉粥样硬化易感B10）的骨髓细胞进行重组。S/SgSlc小鼠和抗动脉粥样硬化的SJL/J小鼠)。稳定的混合异体嵌合体……建立了更多的小鼠，没有任何有害的并发症。与未处理的apoE-/-小鼠相比，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高密度脂蛋白胆固醇（B10）显著降低。S减少89%，SJL减少72%)，重建10周后病变显著消退，尽管这些嵌合体中血清apoE的表达量不到apoE+/+小鼠的1%。此外，与动脉粥样硬化易感B10重组的混合嵌合体相比。S骨髓细胞，与抗动脉粥样硬化的SJL细胞重建的混合嵌合体几乎完全恢复了原有的动脉粥样硬化（回归93%，方差分析p<0.05）。这些结果表明，SJL小鼠对动脉粥样硬化的抵抗存在于骨髓源性细胞中，不依赖于血清脂蛋白代谢和清除。混合异体嵌合是一种新的、安全的细胞介导的晚期动脉粥样硬化基因治疗方法。少

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