Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells
Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells
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DOI：
10.1016/j.bone.2004.01.016
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发表时间：
2004-05-01
期刊：
影响因子：
4.1
通讯作者：
van Blitterswijk, C
中科院分区：
文献类型：
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作者：
de Boer, J;Siddappa, R;van Blitterswijk, C
人骨髓间充质干细胞(HMSCs)是自体骨组织工程多潜能细胞的潜在来源。我们先前发现，锂或WNT3a过度激活WRIT信号转导通路，在刺激hMSC增殖的同时保持多能性。从我们用于骨组织工程的多孔磷酸钙支架中释放WNT3a或锂，可以为植入的hMSCs提供有丝分裂刺激。为了确定合适的释放谱，我们首先评估了WRIT过度激活对hMSCs成骨分化的影响。在这里，我们报告锂和WNT3a都强烈抑制地塞米松诱导的成骨标志物碱性磷酸酶(ALP)的表达。此外，锂部分抑制hMSCs的矿化，而WNT3a则完全阻断其矿化。成骨分化过程中的时间进程分析表明，在矿化开始之前暴露4d的WNT3a足以完全阻断矿化。WNT3a和锂暴露的hMSCs的基因表达谱显示，许多在增殖的hMSCs中正常表达的成骨和软骨标记物在WRIT刺激下下调。我们得出结论：Wnt信号抑制地塞米松诱导的hMSCs成骨。在未来的研究中，我们将尝试将锂或WNT3a从磷酸钙支架中的释放限制到成骨的增殖期。(C)2004 Elsevier Inc.保留所有权利。
Human mesenchymal stem cells (hMSCs) from the bone marrow represent a potential source of pluripotent cells for autologous bone tissue engineering. We previously discovered that over activation of the Writ signal transduction pathway by either lithium or Wnt3A stimulates hMSC proliferation while retaining pluripotency. Release of Wnt3A or lithium from porous calcium phosphate scaffolds, which we use for bone tissue engineering, could provide a mitogenic stimulus to implanted hMSCs. To define the proper release profile, we first assessed the effect of Writ over activation on osteogenic differentiation of hMSCs. Here, we report that both lithium and Wnt3A strongly inhibit dexamethasone-induced expression of the osteogenic marker alkaline phosphatase (ALP). Moreover, lithium partly inhibited mineralization of hMSCs whereas Wnt3A completely blocked it. Time course analysis during osteogenic differentiation revealed that 4 days of Wnt3A exposure before the onset of mineralization is sufficient to block mineralization completely. Gene expression profiling in Wnt3A and lithium-exposed hMSCs showed that many osteogenic and chondrogenic markers, normally expressed in proliferating hMSCs, are downregulated upon Writ stimulation. We conclude that Wnt signaling inhibits dexamethasone-induced osteogenesis in hMSCs. In future studies, we will try to limit release of lithium or Wnt3A from calcium phosphate scaffolds to the proliferative phase of osteogenesis. (C) 2004 Elsevier Inc. All rights reserved.