Ho Ivy A W, Chan Kelly Y W, Ng Wai-Hoe, Guo Chang M, Hui Kam M, Cheang Philip, Lam Paula Y P
Laboratory of Cancer Gene Therapy, Division of Cellular and Molecular Research, National Cancer Center, Singapore.
Stem Cells. 2009 Jun;27(6):1366-75. doi: 10.1002/stem.50.
Human mesenchymal stem cells (MSCs) have increasingly been used as cellular vectors for the delivery of therapeutic genes to tumors. However, the precise mechanism of mobilization remains poorly defined. In this study, MSCs that expressed similar cell surface markers and exhibited multilineage differentiation potentials were isolated from various donors. Interestingly, different MSC isolates displayed differential migration ability toward human glioma cells. We hypothesized that distinct molecular signals may be involved in the varied tumor tropisms exhibited by different MSC isolates. To test this hypothesis, gene expression profiles of tumor-trophic MSCs were compared with those of non-tumor-trophic MSCs. Among the various differentially regulated genes, matrix metalloproteinase one (MMP1) gene expression and its protein activities were enhanced by 27-fold and 21-fold, respectively, in highly migrating MSCs compared with poorly migrating MSCs. By contrast, there was no change in the transcriptional levels of other MMPs. Functional inactivation of MMP1 abrogated the migratory potential of MSCs toward glioma-conditioned medium. Conversely, the nonmigratory phenotype of poorly migrating MSC could be rescued in the presence of either recombinant MMP1 or conditioned medium from the highly migrating MSCs. Ectopic expression of MMP1 in these poorly migrating cells also rendered the cells responsive to the signaling cues from the glioma cells in vivo. However, blocking the interaction of MMP1 and its cognate receptor PAR1 effectively diminished the migratory ability of MSCs. Taken together, this study provides, for the first time, supporting evidence that MMP1 is critically involved in the migration capacity of MSCs, acting through the MMP1/PAR1 axis.
人间充质干细胞（MSCs）越来越多地被用作将治疗性基因递送至肿瘤的细胞载体。然而，其动员的确切机制仍不清楚。在本研究中，从不同供体分离出表达相似细胞表面标志物并具有多向分化潜能的MSCs。有趣的是，不同的MSCs分离株对人胶质瘤细胞表现出不同的迁移能力。我们推测，不同的分子信号可能参与了不同MSCs分离株所表现出的不同肿瘤嗜性。为了验证这一假设，将趋瘤性MSCs与非趋瘤性MSCs的基因表达谱进行了比较。在各种差异调节基因中，与低迁移性MSCs相比，高迁移性MSCs中基质金属蛋白酶1（MMP1）基因表达及其蛋白活性分别增强了27倍和21倍。相比之下，其他MMPs的转录水平没有变化。MMP1的功能失活消除了MSCs向胶质瘤条件培养基的迁移潜能。相反，在存在重组MMP1或高迁移性MSCs的条件培养基的情况下，低迁移性MSCs的非迁移表型可以得到挽救。在这些低迁移性细胞中异位表达MMP1也使细胞在体内对来自胶质瘤细胞的信号线索产生反应。然而，阻断MMP1与其同源受体PAR1的相互作用有效地降低了MSCs的迁移能力。综上所述，本研究首次提供了支持性证据，表明MMP1通过MMP1/PAR1轴关键地参与了MSCs的迁移能力。
