Rapamycin as an inhibitor of osteogenic differentiation in bone marrow-derived mesenchymal stem cells
Rapamycin as an inhibitor of osteogenic differentiation in bone marrow-derived mesenchymal stem cells
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DOI：
10.1007/s00776-006-1079-9
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发表时间：
2007-01-01
影响因子：
1.7
通讯作者：
Takakura, Yoshinori
中科院分区：
文献类型：
--
作者：
Isomoto, Shinji;Hattori, Koji;Takakura, Yoshinori
背景。培养的骨髓间充质干细胞的自体移植物已用于临床实践。对于那些无法使用骨髓的患者，使用免疫抑制剂药物的同种异体细胞移植将是未来的一种选择。然而，人们对免疫抑制剂对间充质干细胞的影响知之甚少。本研究评估了免疫抑制剂对间充质干细胞成骨分化的影响，并分析了免疫抑制剂药物调节地塞米松成骨作用的方式。方法。在有或没有地塞米松作为成骨补充剂的情况下培养大鼠骨髓细胞。在每个实验组中，添加三种免疫抑制剂（雷帕霉素、环孢素 A 或 FK506）中的一种。作为对照，在没有免疫抑制剂的情况下培养细胞。在组织学上，通过茜素红 S 染色和相差显微镜评估矿化。生化评估碱性磷酸酶活性、钙含量和骨钙素含量。结果。在组织学分析中，除了用FK506治疗的组外，在未用地塞米松治疗的组中，在茜素红S染色或相差显微镜下未观察到矿化结节。在用地塞米松治疗的组中观察到矿化结节，但在用雷帕霉素治疗的组中除外。生化分析发现，与对照组相比，雷帕霉素降低了间充质干细胞的碱性磷酸酶活性和钙含量； FK506增加碱性磷酸酶活性、钙含量和骨钙素含量；环孢菌素A的影响可以忽略不计。地塞米松增加碱性磷酸酶活性、钙含量和骨钙素含量，但这些作用被雷帕霉素减弱。结论。雷帕霉素对间充质干细胞没有成骨作用，但抑制地塞米松诱导的成骨分化作用。相比之下，FK506 对间充质干细胞具有成骨作用。因此，在间充质干细胞的同种异体移植中，FK506可能比雷帕霉素更有用。
Background. An autograft of cultured bone marrow-derived mesenchymal stem cells has already been used in clinical practice. In those patients whose bone marrow cannot be used, a cell allograft with the use of immunosuppressant drugs will be an option in the future. However, little is known about the effects of immunosuppressant drugs on mesenchymal stem cells. This study assessed the effects of immunosuppressant drugs on osteogenic differentiation of mesenchymal stem cells and analyzed the manner in which immunosuppressant drugs modulate the osteogenic effect of dexamethasone.Methods. Rat bone marrow cells were cultured with or without dexamethasone as an osteogenic supplement. In each experimental group, one of three immunosuppressants (rapamycin, cyclosporine A, or FK506) was added. As a control, cells were cultured without immunosuppressants. Histologically, mineralization was assessed by alizarin red S staining and phase-contrast microscopy. Biochemically, alkaline phosphatase activity, calcium content, and osteocalcin content were assessed.Results. On histological analysis, no mineralized nodules were seen on alizarin red S staining or phase-contrast microscopy in the groups not treated with dexamethasone, except in the group that was treated with FK506. Mineralized nodules were seen in the groups treated with dexamethasone, except in the group that was treated with rapamycin. On biochemical analysis, it was found that, compared to the control group, rapamycin reduced alkaline phosphatase activity and the calcium content of mesenchymal stem cells; FK506 increased alkaline phosphatase activity, calcium content, and osteocalcin content; and cyclosporine A had negligible effects. Dexamethasone increased alkaline phosphatase activity, calcium content, and osteocalcin content, but these effects were decreased by rapamycin.Conclusions. Rapamycin did not have an osteogenic effect on mesenchymal stem cells, but inhibited the effect of osteogenic differentiation induced by dexamethasone. In contrast, FK506 had an osteogenic effect on mesenchymal stem cells. Therefore, FK506 might be more useful than rapamycin in allogeneic transplantation of mesenchymal stem cells.