Activation of Hedgehog Signaling Inhibits Osteoblast Differentiation of Human Mesenchymal Stem Cells
Activation of Hedgehog Signaling Inhibits Osteoblast Differentiation of Human Mesenchymal Stem Cells
复制标题
DOI：
10.1634/stemcells.2008-0888
复制
发表时间：
2009-01-01
期刊：
影响因子：
5.2
通讯作者：
Peraldi, Pascal
中科院分区：
文献类型：
--
作者：
Plaisant, Magali;Fontaine, Coralie;Peraldi, Pascal
骨内的间充质干细胞负责生成成骨细胞、软骨细胞和脂肪细胞。在啮齿类动物中，印度刺猬已被证明在成骨细胞分化中发挥作用。然而，刺猬蛋白（Hh）在人类成骨细胞分化中的直接作用的证据缺失。使用不同的人类间充质干细胞模型，我们发现 Hh 信号在成骨细胞分化过程中减弱。这与 Smoothened 表达（触发 Hh 信号传导的关键伙伴）的减少以及展示初级纤毛（Hh 信号传导必需的细胞器）的细胞数量的减少有关。值得注意的是，用 sonic hedgehog 或两种能够激活 Hh 信号传导的分子处理人间充质干细胞会抑制成骨细胞分化。这种抑制通过矿化和成骨细胞基因表达的减少来体现。特别是，Hh 信号传导的激活会诱导 Runx2 表达的减少，Runx2 是控制成骨细胞分化早期的关键转录因子。一致地，在分化的第一天Hh信号的激活足以抑制成骨细胞分化，而分化的成骨细胞不受Hh信号的影响。总之，我们在此表明，使用各种 Hh 信号传导诱导剂和两种不同来源的间充质干细胞，Hh 信号传导抑制人成骨细胞分化，这与啮齿动物细胞中的描述形成鲜明对比。在筛选促成骨分子时应考虑到这种物种差异。干细胞2009； 27：703-713
Mesenchymal stem cells within the bone are responsible for the generation of osteoblasts, chondrocytes, and adipocytes. In rodents, Indian hedgehog has been shown to play a role in osteoblast differentiation. However, evidence for a direct function of hedgehog (Hh) in human osteoblastic differentiation is missing. Using different models of human mesenchymal stem cells we show that Hh signaling decreases during osteoblast differentiation. This is associated with a decrease in Smoothened expression, a key partner that triggers Hh signaling, and in the number of cells displaying a primary cilium, an organelle necessary for Hh signaling. Remarkably, treatment of human mesenchymal stem cells with sonic hedgehog or two molecules able to activate Hh signaling inhibits osteoblast differentiation. This inhibition is visualized through a decrease in mineralization and in the expression of osteoblastic genes. In particular, activation of Hh signaling induces a decrease in Runx2 expression, a key transcriptional factor controlling the early stage of osteoblast differentiation. Consistently, the activation of Hh signaling during the first days of differentiation is sufficient to inhibit osteoblast differentiation, whereas differentiated osteoblasts are not affected by Hh signaling. In summary, we show here, using various inducers of Hh signaling and mesenchymal stem cells of two different origins, that Hh signaling inhibits human osteoblast differentiation, in sharp contrast to what has been described in rodent cells. This species difference should be taken into account for screening for pro-osteogenic molecules. STEM CELLS 2009; 27: 703-713