Interaction of Mesenchymal Stem Cells with Fibroblast-like Synoviocytes via Cadherin-11 Promotes Angiogenesis by Enhanced Secretion of Placental Growth Factor
Interaction of Mesenchymal Stem Cells with Fibroblast-like Synoviocytes via Cadherin-11 Promotes Angiogenesis by Enhanced Secretion of Placental Growth Factor
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DOI：
10.4049/jimmunol.1302177
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发表时间：
2014-04-01
影响因子：
4.4
通讯作者：
Cho, Chul-Soo
中科院分区：
文献类型：
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作者：
Park, Su-Jung;Kim, Ki-Jo;Cho, Chul-Soo
骨髓间充质干细胞（MSC）存在于类风湿关节炎（RA）患者的滑膜中，但其在RA中的作用尚不清楚。胎盘生长因子（PlGF）表达在RA滑液中增加，并且阻断PlGF减弱小鼠关节炎的进展。在这项研究中，我们观察到，PlGF诱导MSC的趋化性在一个剂量依赖性的方式，这是由抗血管内皮生长因子受体-1肽阻断。MSC暴露于PlGF引起Akt和p38 MAPK的磷酸化增加。PI 3 K抑制剂（LY 294002）和p38 MAPK抑制剂（SB 203580）可抑制PlGF介导的趋化作用，而ERK 1/2抑制剂（PD 98059）则不抑制PlGF的趋化作用。成纤维细胞样滑膜细胞（FLS）组成型产生PlGF，但MSC释放的PlGF量可以忽略不计。值得注意的是，当RA患者的FLS和MSC共培养时，FLS产生的PlGF显著增加;这种增加依赖于加入的MSC的数量。此外，共培养条件培养基促进MSC的趋化性和增加血管生成的基质胶栓试验，这些都被抑制预孵育的培养基与抗PlGF抗体。Transwell实验表明，MSC到FLS的接触是通过共培养增加PlGF产量所必需的。钙粘蛋白-11在FLS和MSC中均表达，并且在共培养条件下，FLS中钙粘蛋白-11的小干扰RNA敲低显著废除了增强的PlGF产生。这些数据表明，在RA关节中PlGF水平的增加可以诱导MSC向滑膜的迁移，并且迁移的MSC与FLS通过钙粘蛋白-11的相互作用可能通过增强PlGF的分泌而促进血管生成和慢性滑膜炎。
Bone marrow-derived mesenchymal stem cells (MSC) exist in the synovium of patients with rheumatoid arthritis (RA), yet the role of MSC in RA is elusive. Placental growth factor (PlGF) expression is increased in RA synovial fluids, and blocking of PlGF attenuates progression of arthritis in mice. In this study, we observed that PlGF induced chemotaxis of MSC in a dose-dependent manner, which was blocked by anti-vascular endothelial growth factor receptor-1 peptide. MSC exposed to PlGF elicited increased phosphorylation of Akt and p38 MAPK. PlGF-mediated chemotaxis was inhibited by PI3K inhibitor (LY294002) and p38 MAPK inhibitor (SB203580), but not by ERK1/2 inhibitor (PD98059). Fibroblast-like synoviocytes (FLS) constitutively produced PlGF, but MSC released negligible amounts of PlGF. Of note, when FLS of RA patients and MSC were cocultured, PlGF production by FLS was significantly increased; such an increase was dependent on the number of added MSC. Moreover, coculture conditioned medium promoted chemotaxis of MSC and increased angiogenesis in Matrigel plugs assay, and these were suppressed by preincubation of the medium with anti-PlGF Ab. Transwell experiments revealed that MSC to FLS contact was required for the increase in PlGF production by coculture. Cadherin-11 was expressed both in FLS and MSC, and small interfering RNA knockdown of cadherin-11 in FLS significantly abrogated the enhanced PlGF production under coculture conditions. These data indicate that increased levels of PlGF in RA joints could induce the migration of MSC to the synovium, and interaction of migrated MSC with FLS via cadherin-11 may contribute to angiogenesis and chronic synovitis by enhancing the secretion of PlGF.