Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases
Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases
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DOI：
10.1634/stemcells.2005-0271
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发表时间：
2006-05-01
期刊：
影响因子：
5.2
通讯作者：
Janowska-Wieczorek, Anna
中科院分区：
文献类型：
--
作者：
Son, Bo-Ra;Marquez-Curtis, Leah A.;Janowska-Wieczorek, Anna
人类间充质干细胞（MSC）越来越多地被认为是基于细胞的治疗策略，用于各种器官/组织的再生。然而，它们归巢和招募到受伤地点所需的信号尚未完全了解。由于基质衍生因子（SDF）-1和肝细胞生长因子（HGF）在组织/器官损伤过程中上调，在这项研究中，我们研究了这些因子是否化学吸引来自骨髓（BM）和脐带血（CB）的体外扩增的MSC。具体而言，我们研究了CXCR 4和c-met的MSC的表达，SDF-1和HGF的同源受体，以及它们在MSC早期和晚期传代后的功能。我们还确定了MSC是否表达基质金属蛋白酶（MMPs），包括膜1型（MT 1）-MMP，基质降解酶，促进造血干细胞的运输。我们将扩增的BM-或CB-衍生的MSC维持多达15-18代，监测1）各种组织标志物（心肌和骨骼肌、神经、肝和内皮细胞），2）功能性CXCR 4和c-met，和3）MMP的表达。我们发现，对于多达15-18代，BM和CB来源的MSC 1）表达心脏、肌肉、神经和肝脏标记物以及血管内皮（VE）标记物VE-钙粘蛋白的mRNA; 2）表达CXCR 4和c-met受体，并被SDF-1和HGF梯度强烈吸引; 3）表达MMP-2和MT 1-MMP转录物和蛋白;和4）是穿过重建的基底膜Matrigel的化学侵入性的。这些体外结果表明，SDF-1-CXCR 4和HGF-c-met轴，沿着MMPs，可能参与扩增的MSC向受损组织的募集。
Human mesenchymal stem cells (MSCs) are increasingly being considered in cell-based therapeutic strategies for regeneration of various organs/tissues. However, the signals required for their homing and recruitment to injured sites are not yet fully understood. Because stromal-derived factor (SDF)-1 and hepatocyte growth factor (HGF) become upregulated during tissue/organ damage, in this study we examined whether these factors chemoattract ex vivo-expanded MSCs derived from bone marrow (BM) and umbilical cord blood (CB). Specifically, we investigated the expression by MSCs of CXCR4 and c-met, the cognate receptors of SDF-1 and HGF, and their functionality after early and late passages of MSCs. We also determined whether MSCs express matrix metalloproteinases (MMPs), including membrane type 1 (MT1)-MMP, matrix-degrading enzymes that facilitate the trafficking of hematopoietic stem cells. We maintained expanded BM- or CB-derived MSCs for up to 15-18 passages with monitoring of the expression of 1) various tissue markers (cardiac and skeletal muscle, neural, liver, and endothelial cells), 2) functional CXCR4 and c-met, and 3) MMPs. We found that for up to 15-18 passages, both BM- and CB-derived MSCs 1) express mRNA for cardiac, muscle, neural, and liver markers, as well as the vascular endothelial (VE) marker VE-cadherin; 2) express CXCR4 and c-met receptors and are strongly attracted by SDF-1 and HGF gradients; 3) express MMP-2 and MT1-MMP transcripts and proteins; and 4) are chemoinvasive across the reconstituted basement membrane Matrigel. These in vitro results suggest that the SDF-1-CXCR4 and HGF-c-met axes, along with MMPs, may be involved in recruitment of expanded MSCs to damaged tissues.