Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria.
J Thorac Cardiovasc Surg. 2011 Sep;142(3):687-96, 696.e1-2. doi: 10.1016/j.jtcvs.2011.01.014. Epub 2011 Mar 8.
Although adequate numbers of hematopoietic progenitor cells reside in the human bone marrow, the extent of endogenous neovascularization after myocardial infarction remains insufficient. The aim of this study was to identify the role of the CXC chemokine receptor 4/stromal cell-derived factor 1 axis in the mobilization and homing of hematopoietic progenitor cells in the ischemic heart.
Human bone marrow-derived hematopoietic progenitor cells or saline were injected systemically into athymic nude rats 48 hours after myocardial infarction. Myocardial and bone marrow expression of stromal cell-derived factor 1 and chemotaxis of hematopoietic progenitor cells were measured in vitro in the presence or absence of stromal cell-derived factor 1. The role of the CXC chemokine receptor 4/stromal cell-derived factor 1 axis was investigated by means of antibody blockade or systemic administration of granulocyte colony-stimulating factor. Morphologic analysis included measurement of the infarct area, capillary density, and apoptosis, whereas left ventricular function was measured by means of echocardiographic analysis.
Expression of postinfarct stromal cell-derived factor 1 was increased by 67% in the bone marrow and decreased by 43% in myocardium. Disruption of bone marrow stromal cell-derived factor 1/CXC chemokine receptor 4 interactions by antibody blockade resulted in a redirection of human hematopoietic progenitor cells from the bone marrow to the ischemic heart and augmented neovascularization and cardiomyocyte survival. Similarly, systemic administration of granulocyte colony-stimulating factor to block CXC chemokine receptor 4/stromal cell-derived factor 1 interaction resulted in increased mobilization and homing of hematopoietic progenitor cells to the ischemic heart, which translated to augmented myocardial neovascularization, prevention of apoptosis, and improved cardiac function.
Bone marrow stromal cell-derived factor 1 upregulation after myocardial ischemia prevents mobilization of endogenous hematopoietic progenitor cells. We provide evidence that disruption of stromal cell-derived factor 1/CXC chemokine receptor 4 interactions allows redirection of hematopoietic progenitor cells to ischemic myocardium and enhances recovery of left ventricular function.
尽管人类骨髓中存在足够数量的造血祖细胞，但心肌梗死后内源性新生血管的程度仍然不足。本研究旨在确定 CXC 趋化因子受体 4/基质细胞衍生因子 1 轴在动员和归巢造血祖细胞到缺血心肌中的作用。
心肌梗死后 48 小时，将人骨髓来源的造血祖细胞或生理盐水系统注入免疫缺陷裸鼠体内。在存在或不存在基质细胞衍生因子 1 的情况下，测量体外骨髓和心肌中基质细胞衍生因子 1 的表达和造血祖细胞的趋化性。通过抗体阻断或全身给予粒细胞集落刺激因子研究 CXC 趋化因子受体 4/基质细胞衍生因子 1 轴的作用。形态分析包括测量梗死面积、毛细血管密度和细胞凋亡，而左心室功能通过超声心动图分析进行测量。
骨髓基质细胞衍生因子 1 的表达在梗死后增加了 67%，而心肌中减少了 43%。通过抗体阻断破坏骨髓基质细胞衍生因子 1/CXC 趋化因子受体 4 相互作用，导致人类造血祖细胞从骨髓转移到缺血心脏，并增强了新生血管形成和心肌细胞存活。同样，全身给予粒细胞集落刺激因子阻断 CXC 趋化因子受体 4/基质细胞衍生因子 1 相互作用，导致造血祖细胞更多地动员和归巢到缺血心脏，从而导致心肌新生血管增加，凋亡减少，心功能改善。
心肌梗死后骨髓基质细胞衍生因子 1 的上调可防止内源性造血祖细胞的动员。我们提供的证据表明，破坏基质细胞衍生因子 1/CXC 趋化因子受体 4 相互作用允许造血祖细胞向缺血心肌重新定向，并增强左心室功能的恢复。
