Centre for Innovation (Formerly Research & Development), Canadian Blood Services, 8249-112 Street, Edmonton, AB, Canada T6G 2R8.
Centre for Innovation (Formerly Research & Development), Canadian Blood Services, 8249-112 Street, Edmonton, AB, Canada T6G 2R8 ; Division of Hematology, Department of Medicine, University of Alberta, 8440-112 Street, Edmonton, AB, Canada T6G 2B7.
Stem Cells Int. 2014;2014:610495. doi: 10.1155/2014/610495. Epub 2014 Mar 16.
Mesenchymal stromal cells (MSC) have great potential for cellular therapies as they can be directed to differentiate into certain lineages or to exert paracrine effects at sites of injury. The interactions between stromal cell-derived factor (SDF)-1 and its receptors CXCR4 and CXCR7 play pivotal roles in the migration of MSC to injured tissues. We evaluated whether a histone deacetylase inhibitor valproic acid (VPA) modulates the migration of cord blood (CB-) derived MSC towards SDF-1 and their proliferation and differentiation. We found that in MSC, VPA increased (i) the gene and total protein expression of CXCR4 and CXCR7 and primed migration towards a low gradient of SDF-1, (ii) the gene expression of MMP-2 and secretion and activation of proMMP-2, (iii) the proliferation and gene expression of pluripotency markers SOX2 and Oct-4, and exposure to lower concentrations of VPA (≤5 mM) had no effect on their differentiation to osteocytes and chondrocytes. Thus, our study indicates that VPA enhances the migration of CB MSC towards SDF-1 by increasing the expression of CXCR4, CXCR7, and MMP-2. VPA at low concentrations may be used for ex vivo treatment of MSC to increase their recruitment to sites of injury without compromising their ability to proliferate or differentiate.
间充质基质细胞 (MSC) 在细胞治疗方面具有巨大的潜力，因为它们可以被定向分化为特定的谱系，或在损伤部位发挥旁分泌作用。基质细胞衍生因子 (SDF)-1 及其受体 CXCR4 和 CXCR7 之间的相互作用在 MSC 向损伤组织迁移中起着关键作用。我们评估了组蛋白去乙酰化酶抑制剂丙戊酸 (VPA) 是否调节脐带来源的 MSC (CB-) 向 SDF-1 的迁移及其增殖和分化。我们发现，在 MSC 中，VPA 增加了 (i) CXCR4 和 CXCR7 的基因和总蛋白表达，并促进了向 SDF-1 低梯度的迁移，(ii) MMP-2 的基因表达和 proMMP-2 的分泌和激活，(iii) 多能性标志物 SOX2 和 Oct-4 的增殖和基因表达，并且暴露于较低浓度的 VPA(≤5mM)对其向成骨细胞和软骨细胞的分化没有影响。因此，我们的研究表明，VPA 通过增加 CXCR4、CXCR7 和 MMP-2 的表达来增强 CB MSC 向 SDF-1 的迁移。低浓度的 VPA 可用于 MSC 的体外治疗，以增加它们向损伤部位的募集，而不影响其增殖或分化的能力。
