Background and Purpose- Bone marrow mononuclear cells (BM-MNCs) are a rich source of hematopoietic stem cells and have been widely used in experimental therapies for patients with ischemic diseases. Activation of angiogenesis is believed to be one of major BM-MNC mode of actions, but the essential mechanism by which BM-MNCs activate angiogenesis have hitherto been elusive. The objective of this study is to reveal the mechanism how BM-MNCs activate angiogenesis. Methods- We have evaluated the effect of direct cell-cell interaction between BM-MNC and endothelial cell on uptake of VEGF (vascular endothelial growth factor) into endothelial cells in vitro. Cerebral ischemia model was used to evaluate the effects of direct cell-cell interaction with transplanted BM-MNC on endothelial cell at ischemic tissue. Results- The uptake of VEGF into endothelial cells was increased by BM-MNC, while being inhibited by blockading the gap junction. Low-molecular-weight substance was transferred from BM-MNC into endothelial cells via gap junctions in vivo, followed by increased expression of hypoxia-inducible factor-1α and suppression of autophagy in endothelial cells. The concentration of glucose in BM-MNC cytoplasm was significantly higher than in endothelial cells, and transfer of glucose homologue from BM-MNC to endothelial cells was observed. Conclusions- Our findings demonstrated cell-cell interaction via gap junction is the prominent pathway for activation of angiogenesis at endothelial cells after ischemia and provided novel paradigm that energy source supply by stem cell to injured cell is one of the therapeutic mechanisms of cell-based therapy.

中文翻译：

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骨髓单核细胞通过间隙连接介导的细胞间相互作用激活血管生成。

背景和目的-骨髓单核细胞（BM-MNCs）是造血干细胞的丰富来源，已广泛用于缺血性疾病患者的实验治疗中。血管生成的激活被认为是主要的BM-MNC作用方式之一，但迄今为止，BM-MNC激活血管生成的基本机制尚不清楚。这项研究的目的是揭示BM-MNCs如何激活血管生成的机制。方法-我们评估了BM-MNC与内皮细胞之间直接细胞间相互作用对体外血管内皮细胞摄取VEGF（血管内皮生长因子）的影响。使用脑缺血模型评估与移植的BM-MNC直接细胞-细胞相互作用对缺血组织内皮细胞的影响。结果-BM-MNC可增加VEGF向内皮细胞的摄取，但可通过阻断间隙连接来抑制。低分子量物质通过体内的缝隙连接从BM-MNC转移到内皮细胞中，然后增加缺氧诱导因子1α的表达并抑制内皮细胞自噬。BM-MNC细胞质中的葡萄糖浓度显着高于内皮细胞，并且观察到葡萄糖同源物从BM-MNC转移至内皮细胞。结论-我们的研究结果表明，通过间隙连接的细胞间相互作用是缺血后内皮细胞激活血管生成的主要途径，并提供了新的范式，即干细胞向受损细胞的能量供应是基于细胞的疗法的治疗机制之一。 。