VEGF-C and TGF-β reciprocally regulate mesenchymal stem cell commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes.
VEGF-C and TGF-β reciprocally regulate mesenchymal stem cell commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes.
复制标题
VEGF-C和TGF-β相互调节间充质干细胞对分化为淋巴内皮或成骨细胞表型的承诺。
DOI：
10.3892/ijmm.2016.2502
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发表时间：
2016-04
影响因子：
5.4
通讯作者：
Ishisaki A
中科院分区：
文献类型：
--
作者：
Igarashi Y;Chosa N;Sawada S;Kondo H;Yaegashi T;Ishisaki A
间充质干细胞（MSC）的分化方向受多种生长因子和细胞因子的刺激调节。我们最近建立了MSC系，[转化生长因子-β（TGF-β）-响应性SG-2细胞，骨形态发生蛋白（BMP）-响应性SG-3细胞和TGF-β/BMP-非响应性SG-5细胞]，来源于绿色荧光蛋白转基因小鼠的骨髓。在这项研究中，为了比较这些MSC系中的基因表达谱，我们使用DNA微阵列分析来表征在TGF-β响应性SG-2细胞中观察到的特异性基因表达谱。在SG-2细胞中高度表达的基因中，我们关注血管内皮生长因子（VEGF）受体3（VEGFR 3），FMS样酪氨酸激酶4（Flt 4）的基因产物。我们发现VEGFR 3的特异性配体VEGF-C可显著诱导SG-2细胞的增殖活性、迁移能力（如Transwell迁移实验所示）以及细胞外信号调节激酶（ERK）1/2的磷酸化。此外，VEGF-C显著增加了淋巴管内皮细胞标志物--β-同源框1（Prox 1）和淋巴管内皮透明质酸受体1（Lyve 1）的表达，并降低了这些细胞中成骨分化标志物基因的表达。TGF-β可显著增加SG-2细胞早期成骨分化标志基因的表达，并显著降低淋巴管内皮细胞标志基因的表达。我们的研究结果强烈表明：i）VEGF-C促进MSC的增殖活性和迁移能力;和ii）VEGF-C和TGF-β 1分别调节MSC向淋巴管内皮细胞或成骨细胞表型分化的承诺。我们的研究结果为MSC再生能力的分子机制提供了新的见解。
The direction of mesenchymal stem cell (MSC) differentiation is regulated by stimulation with various growth factors and cytokines. We recently established MSC lines, [transforming growth factor-β (TGF-β)-responsive SG-2 cells, bone morphogenetic protein (BMP)-responsive SG-3 cells, and TGF-β/BMP-non-responsive SG-5 cells], derived from the bone marrow of green fluorescent protein-transgenic mice. In this study, to compare gene expression profiles in these MSC lines, we used DNA microarray analysis to characterize the specific gene expression profiles observed in the TGF-β-responsive SG-2 cells. Among the genes that were highly expressed in the SG-2 cells, we focused on vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), the gene product of FMS-like tyrosine kinase 4 (Flt4). We found that VEGF-C, a specific ligand of VEGFR3, significantly induced the cell proliferative activity, migratory ability (as shown by Transwell migration assay), as well as the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in the SG-2 cells. Additionally, VEGF-C significantly increased the expression of prospero homeobox 1 (Prox1) and lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1), which are lymphatic endothelial cell markers, and decreased the expression of osteogenic differentiation marker genes in these cells. By contrast, TGF-β significantly increased the expression of early-phase osteogenic differentiation marker genes in the SG-2 cells and markedly decreased the expression of lymphatic endothelial cell markers. The findings of our study strongly suggest the following: i) that VEGF-C promotes the proliferative activity and migratory ability of MSCs; and ii) VEGF-C and TGF-β reciprocally regulate MSC commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes, respectively. Our findings provide new insight into the molecular mechanisms underlying the regenerative ability of MSCs.