Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines
Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines
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DOI：
10.1172/jci27019
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发表时间：
2006-07-01
影响因子：
15.9
通讯作者：
Li, Ren-Ke
中科院分区：
文献类型：
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作者：
Fazel, Shafie;Cimini, Massimo;Li, Ren-Ke
心肌梗死（MI）后骨髓干/祖细胞治疗的临床试验已显示出有希望的结果，但受益的机制尚不清楚。我们研究了内源性心肌修复的性质，这是依赖于c-kit受体的功能，这是表达在骨髓干细胞/祖细胞和最近发现的心脏干细胞。心肌梗死可增加心脏c-kit（+）细胞的数量。在骨髓嵌合小鼠中使用遗传标记，将这些细胞追溯到骨髓来源。募集的c-kW细胞通过增加VEGF和逆转血管生成素-1与血管生成素-2的心脏比率在梗死边缘区建立了促血管生成环境。这些振荡增强内皮细胞有丝分裂，并与广泛的肌成纤维细胞丰富的修复组织的建立。c-kit受体的突变干扰了细胞向心脏的移动，阻止了血管生成，减少了富含肌纤维母细胞的修复组织的形成，并导致了突发性心力衰竭和死亡。用野生型细胞替换突变骨髓挽救了心肌病表型。我们的结论是，与它们在肿瘤发生中的作用一致，骨髓c-kit+细胞作为梗死心肌血管生成开关的关键调节因子，从而驱动有效的心脏修复。
Clinical trials of bone marrow stem/progenitor cell therapy after myocardial infarction (MI) have shown promising results, but the mechanism of benefit is unclear. We examined the nature of endogenous myocardial repair that is dependent on the function of the c-kit receptor, which is expressed on bone marrow stem/progenitor cells and on recently identified cardiac stem cells. MI increased the number of c-kit(+) cells in the heart. These cells were traced back to a bone marrow origin, using genetic tagging in bone marrow chimeric mice. The recruited c-kW cells established a proangiogenic milieu in the infarct border zone by increasing VEGF and by reversing the cardiac ratio of angiopoietin-1 to angiopoietin-2. These oscillations potentiated endothelial mitogenesis and were associated with the establishment of an extensive myofibroblast-rich repair tissue. Mutations in the c-kit receptor interfered with the mobilization of the cells to the heart, prevented angiogenesis, diminished myofibroblast-rich repair tissue formation, and led to precipitous cardiac failure and death. Replacement of the mutant bone marrow with wild-type cells rescued the cardiomyopathic phenotype. We conclude that, consistent with their documented role in tumorigenesis, bone marrow c-kit+ cells act as key regulators of the angiogenic switch in infarcted myocardium, thereby driving efficient cardiac repair.