Low-level shear stress induces human mesenchymal stem cell migration through the SDF-1/CXCR4 axis via MAPK signaling pathways.
Low-level shear stress induces human mesenchymal stem cell migration through the SDF-1/CXCR4 axis via MAPK signaling pathways.
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DOI：
10.1089/scd.2012.0717
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发表时间：
2013-04
影响因子：
4
通讯作者：
Lin Yuan;N. Sakamoto;Guanbin Song;Masaaki Sato
中科院分区：
文献类型：
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作者：
Lin Yuan;N. Sakamoto;Guanbin Song;Masaaki Sato
间充质干细胞（MSCs）能够回家并迁移到受损组织中，因此被认为是临床应用的最佳治疗策略。我们之前证明，较高的剪切应力（bbb2.0 Pa）阻碍了人MSC （hMSC）的迁移，而较低的剪切应力（0.2 Pa）通过丝裂原活化蛋白激酶（MAPK）途径诱导细胞迁移。本文进一步研究了剪切应力诱导hMSC迁移的机制。将MSC单层机械损伤，随后暴露在0.2 Pa的低剪切应力下。在流动和静态条件下进行图像分析以量化细胞迁移速度。在静态条件下，伤口上游和下游边缘的hMSCs以相似的速度迁移以覆盖受伤区域，而剪切应力诱导伤口下游边缘的细胞迁移速度明显快于上游边缘的细胞。我们还发现，剪切应力上调基质来源因子-1 （SDF-1）的分泌，从而刺激其受体CXCR4在hMSCs中的表达，直到细胞覆盖受伤区域。CXCR4拮抗剂抑制细胞迁移和c-Jun n -末端激酶（JNK）和p38 MAPK的激活，但不影响细胞外信号调节激酶1/2 （ERK1/2）磷酸化。当分别评估上游和下游hMSCs中的MAPK激活时，下游细胞的ERK1/2激活时间比上游细胞早。这些结果表明，SDF-1/CXCR4轴通过JNK和p38 MAPK途径介导剪切应力诱导的hMSC迁移，上游和下游细胞之间迁移速度的差异可能是由于ERK1/2激活所致。
Mesenchymal stem cells (MSCs) are able to home and migrate into damaged tissues and are thus, considered an optimal therapeutic strategy for clinical use. We previously demonstrated that higher shear stress (>2 Pa) hindered human MSC (hMSC) migration, whereas lower shear stress (0.2 Pa) induced cell migration through mitogen-activated protein kinase (MAPK) pathways. Here the mechanisms underlying shear stress-induced hMSC migration have been studied further. An MSC monolayer was mechanically wounded and subsequently exposed to low-level shear stress of 0.2 Pa. Image analysis was performed to quantify cell migration speeds under both flow and static conditions. hMSCs along both upstream- and downstream edges of the wound migrated at a similar speed to cover the wounded area under static conditions, whereas shear stress induced cells along the downstream edge of the wound to migrate significantly faster than those along the upstream edge. We also found that shear stress upregulated the secretion of stromal-derived factor-1 (SDF-1), which stimulated its receptor CXCR4 expression in hMSCs until the cells covered the wounded area. A CXCR4 antagonist repressed both cell migration and activation of c-Jun N-terminal kinase (JNK) and p38 MAPK but did not affect extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. When MAPK activation in upstream- and downstream hMSCs was evaluated separately, ERK1/2 was activated earlier in downstream than in upstream cells. These results indicate that the SDF-1/CXCR4 axis mediates shear stress-induced hMSC migration through JNK and p38 MAPK pathways and that the difference in migration speeds between upstream- and downstream cells may be due to ERK1/2 activation.