Theiss Hans D, Vallaster Markus, Rischpler Christoph, Krieg Lisa, Zaruba Marc-Michael, Brunner Stefan, Vanchev Yordan, Fischer Rebekka, Gröbner Michael, Huber Bruno, Wollenweber Timm, Assmann Gerald, Mueller-Hoecker Josef, Hacker Markus, Franz Wolfgang-M
Medical Department I, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Stem Cell Res. 2011 Nov;7(3):244-55. doi: 10.1016/j.scr.2011.05.003. Epub 2011 May 16.
G-CSF based stem cell mobilization and stabilization of cardiac SDF-1 by DPP-IV-inhibition (dual stem cell therapy) improve heart function and survival after myocardial infarction. However, it is barely understood whether this new approach acts specifically through the SDF-1/CXCR4 axis, stimulation of resident cardiac stem cells and improved myocardial perfusion. Therefore, we aimed to clarify the role of the SDF1/CXCR4 axis with respect to the benefits of a dual stem cell based therapy.
METHODOLOGY/PRINCIPAL FINDINGS: After surgically induced ligation of the LAD, SDF-1/CXCR4 interactions were specifically blocked by the CXCR4 receptor antagonist AMD3100 in G-CSF and Diprotin A treated C57BL/6 mice. G-CSF+DipA treated and non-treated animals served as controls. Because AMD3100 is known to mobilize bone marrow derived stem cells (BMCs) in high concentrations, the optimal dosage (1.25mg per kg body weight) sufficient to block CXCR4 without stimulating mobilization was established. AMD3100 treatment of G-CSF and Diprotin A stimulated mice significantly decreased myocardial homing of circulating stem cells (FACS analysis) and inverted the beneficial effects of (i) cardiac remodeling (histological analyses), (ii) heart function (Millar tip catheterization) and (iii) survival (Kaplan-Meier curves). G-CSF treatment in combination with DPP-IV inhibition enhanced neovascularization at the infarct border zone which was related to an improved myocardial blood flow as measured by SPECT. Moreover, dual stem cell treatment effectively stimulated the pool of resident cardiac stem cells (FACS) which was reversed by AMD3100 treatment.
CONCLUSIONS/SIGNIFICANCE: Our data give final proof that homing through the SDF-1/CXCR-4 axis is essential for the success of dual stem cell therapy.
基于粒细胞集落刺激因子（G-CSF）的干细胞动员以及通过二肽基肽酶-IV（DPP-IV）抑制作用稳定心脏基质细胞衍生因子-1（SDF-1）（双重干细胞疗法）可改善心肌梗死后的心功能并提高生存率。然而，对于这种新方法是否通过SDF-1/CXCR4轴特异性发挥作用、刺激心脏驻留干细胞以及改善心肌灌注，人们了解甚少。因此，我们旨在阐明SDF1/CXCR4轴在基于双重干细胞疗法的益处方面所起的作用。
方法/主要发现：在通过手术诱导结扎左前降支（LAD）后，在接受G-CSF和二肽基肽酶抑制剂A（Diprotin A）治疗的C57BL/6小鼠中，CXCR4受体拮抗剂AMD3100特异性阻断了SDF-1/CXCR4相互作用。接受G-CSF+DipA治疗和未治疗的动物作为对照。由于已知高浓度的AMD3100可动员骨髓源性干细胞（BMCs），因此确定了足以阻断CXCR4而不刺激细胞动员的最佳剂量（每千克体重1.25毫克）。对接受G-CSF和Diprotin A刺激的小鼠进行AMD3100治疗，显著降低了循环干细胞的心肌归巢（流式细胞术分析），并逆转了（i）心脏重塑（组织学分析）、（ii）心功能（Millar尖端导管插入术）和（iii）生存率（Kaplan-Meier曲线）的有益效果。G-CSF治疗与DPP-IV抑制相结合可增强梗死边缘区的新生血管形成，这与通过单光子发射计算机断层扫描（SPECT）测量的改善心肌血流有关。此外，双重干细胞治疗有效刺激了心脏驻留干细胞池（流式细胞术），而AMD3100治疗可逆转这一作用。
结论/意义：我们的数据最终证明，通过SDF-1/CXCR-4轴归巢对于双重干细胞疗法的成功至关重要。
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