Innere Medizin III, Eberhard Karls Universität, Tübingen, Otfried-Müller-Strasse 10, Tübingen, Germany.
Circulation. 2012 Feb 7;125(5):685-96. doi: 10.1161/CIRCULATIONAHA.111.070508. Epub 2012 Jan 5.
CXCR4-positive bone marrow cells (BMCs) are critically involved in cardiac repair mechanisms contributing to preserved cardiac function. Stromal cell-derived factor-1 (SDF-1) is the most prominent BMC homing factor known to augment BMC engraftment, which is a limiting step of stem cell-based therapy. After myocardial infarction, SDF-1 expression is rapidly upregulated and promotes myocardial repair.
We have established a bifunctional protein consisting of an SDF-1 domain and a glycoprotein VI (GPVI) domain with high binding affinity to the SDF-1 receptor CXCR4 and extracellular matrix proteins that become exposed after tissue injury. SDF1-GPVI triggers chemotaxis of CXCR4-positive cells, preserves cell survival, enhances endothelial differentiation of BMCs in vitro, and reveals proangiogenic effects in ovo. In a mouse model of myocardial infarction, administration of the bifunctional protein leads to enhanced recruitment of BMCs, increases capillary density, reduces infarct size, and preserves cardiac function.
These results indicate that administration of SDF1-GPVI may be a promising strategy to treat myocardial infarction to promote myocardial repair and to preserve cardiac function.
CXCR4 阳性骨髓细胞（BMCs）在心脏修复机制中起着至关重要的作用，有助于保持心脏功能。基质细胞衍生因子-1（SDF-1）是已知增强 BMC 植入的最重要的 BMC 归巢因子，而 BMC 植入是基于干细胞治疗的一个限制步骤。心肌梗死后，SDF-1 的表达迅速上调，并促进心肌修复。
我们构建了一种由 SDF-1 结构域和糖蛋白 VI（GPVI）结构域组成的双功能蛋白，该蛋白与 SDF-1 受体 CXCR4 和细胞外基质蛋白具有高亲和力，这些基质蛋白在组织损伤后会暴露出来。SDF1-GPVI 触发 CXCR4 阳性细胞的趋化作用，保存细胞存活，增强 BMC 在体外的内皮分化，并在鸡胚中显示出促血管生成作用。在心肌梗死的小鼠模型中，该双功能蛋白的给药可增强 BMC 的募集，增加毛细血管密度，减少梗死面积，保护心脏功能。
这些结果表明，SDF1-GPVI 的给药可能是一种有前途的治疗心肌梗死的策略，可促进心肌修复和保护心脏功能。
