Additive Effects of Sonic Hedgehog and Nell-1 Signaling in Osteogenic Versus Adipogenic Differentiation of Human Adipose-Derived Stromal Cells
Additive Effects of Sonic Hedgehog and Nell-1 Signaling in Osteogenic Versus Adipogenic Differentiation of Human Adipose-Derived Stromal Cells
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DOI：
10.1089/scd.2011.0461
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发表时间：
2012-08-01
影响因子：
4
通讯作者：
Soo, Chia
中科院分区：
文献类型：
--
作者：
James, Aaron W.;Pang, Shen;Soo, Chia
成骨（骨形成）和成脂（脂肪形成）间充质干细胞（MSC）分化之间存在理论上的反比关系。这种反向关系在理论上部分地支持骨质疏松症的临床实体，其中骨髓MSC具有随着年龄增加而增加的脂肪分化的偏好。最近已经研究了两种促成骨细胞因子，它们各自也具有抗脂肪形成特性：Sonic Hedgehog（SHH）和NELL-1蛋白。在本研究中，我们分析了具有生物活性的N-末端SHH（SHH-N）和NELL-1蛋白对人原代脂肪源性基质细胞（hASCs）成骨和成脂分化的潜在累加效应。我们观察到，重组SHH-N和NELL-1蛋白显着增强成骨分化和减少脂肪分化的所有标志物检查（碱性磷酸酶，茜素红和油红O染色，和成骨基因表达）。此外，SHH-N和NELL-1定向信号对hASCs的促成骨和抗成脂分化产生累加效应。NELL-1处理增加Hedgehog信号通路表达; Smoothened拮抗剂环巴胺的共同应用逆转了NELL-1的促成骨作用。总之，Hedgehog和Nell-1信号传导对ASC的促成骨和抗成脂分化发挥累加效应。这些研究表明，组合细胞因子SHH-N + NELL-1可能代表一个可行的未来技术诱导骨髓间充质干细胞的成骨分化。
A theoretical inverse relationship exists between osteogenic (bone forming) and adipogenic (fat forming) mesenchymal stem cell (MSC) differentiation. This inverse relationship in theory partially underlies the clinical entity of osteoporosis, in which marrow MSCs have a preference for adipose differentiation that increases with age. Two pro-osteogenic cytokines have been recently studied that each also possesses antiadipogenic properties: Sonic Hedgehog (SHH) and NELL-1 proteins. In the present study, we assayed the potential additive effects of the biologically active N-terminus of SHH (SHH-N) and NELL-1 protein on osteogenic and adipogenic differentiation of human primary adipose-derived stromal cell (hASCs). We observed that both recombinant SHH-N and NELL-1 protein significantly enhanced osteogenic differentiation and reduced adipose differentiation across all markers examined (alkaline phosphatase, Alizarin red and Oil red O staining, and osteogenic gene expression). Moreover, SHH-N and NELL-1 directed signaling produced additive effects on the pro-osteogenic and antiadipogenic differentiation of hASCs. NELL-1 treatment increased Hedgehog signaling pathway expression; coapplication of the Smoothened antagonist Cyclopamine reversed the pro-osteogenic effect of NELL-1. In summary, Hedgehog and Nell-1 signaling exert additive effects on the pro-osteogenic and antiadipogenic differentiation of ASCs. These studies suggest that the combination cytokines SHH-N + NELL-1 may represent a viable future technique for inducing the osteogenic differentiation of MSCs.