Nerve growth factor from Chinese cobra venom stimulates chondrogenic differentiation of mesenchymal stem cells.
Nerve growth factor from Chinese cobra venom stimulates chondrogenic differentiation of mesenchymal stem cells.
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DOI：
10.1038/cddis.2017.208
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发表时间：
2017-05-18
影响因子：
9
通讯作者：
Zhao J
中科院分区：
文献类型：
--
作者：
Lu Z;Lei D;Jiang T;Yang L;Zheng L;Zhao J
生长因子如转化生长因子β 1（transforming growth factor beta1，TGF-β1）在调节间充质干细胞（mesenchymal stem cells，MSCs）向软骨细胞分化中具有重要作用，促进软骨修复。然而，传统的生长因子因其价格昂贵、功能异质性和不可预测的作用（如囊肿形成）而限制了其临床应用。它可能是有利的软骨再生，以确定一个低成本的替代品具有更大的软骨特异性和容易获得。神经生长因子（nerve growth factor，NGF）作为一种神经肽，参与软骨的代谢，并被认为是介导骨髓间充质干细胞向软骨细胞分化的重要因素。我们从中华眼镜蛇蛇毒中分离出神经生长因子，并研究了神经生长因子在体外和体内对骨髓间充质干细胞（BMSCs）的成软骨潜能。结果显示，NGF显著上调软骨特异性标志物的表达。当应用于软骨修复4、8和12周时，NGF处理的BMSCs比未处理的BMSCs具有更大的治疗效果。尽管在其软骨形成潜力方面不如TGF-β1，但NGF显示出比TGF-β1显著更低的I型胶原蛋白（其是纤维软骨标志物）和RUNX 2（其对于终末软骨细胞分化至关重要）的表达，表明其软骨特异性。有趣的是，NGF很少诱导BMSCs分化成神经元表型，这可能是由于其他软骨形成补充剂的存在。此外，其潜在机制表明，NGF介导的软骨形成可能与通过NGF的特异性受体TrkA激活PI 3 K/AKT和MAPK/ERK信号通路有关。此外，由于眼镜蛇毒的丰富和廉价，以及分离和纯化方法的简化，NGF很容易获得。本研究首次证实了NGF的成软骨潜能，为临床软骨再生提供了参考。
Growth factors such as transforming growth factor beta1 (TGF-β1), have critical roles in the regulation of the chondrogenic differentiation of mesenchymal stem cells (MSCs), which promote cartilage repair. However, the clinical applications of the traditional growth factors are limited by their high cost, functional heterogeneity and unpredictable effects, such as cyst formation. It may be advantageous for cartilage regeneration to identify a low-cost substitute with greater chondral specificity and easy accessibility. As a neuropeptide, nerve growth factor (NGF) was involved in cartilage metabolism and NGF is hypothesized to mediate the chondrogenic differentiation of MSCs. We isolated NGF from Chinese cobra venom using a three-step procedure that we had improved upon from previous studies, and investigated the chondrogenic potential of NGF on bone marrow MSCs (BMSCs) both in vitro and in vivo. The results showed that NGF greatly upregulated the expression of cartilage-specific markers. When applied to cartilage repair for 4, 8 and 12 weeks, NGF-treated BMSCs have greater therapeutic effect than untreated BMSCs. Although inferior to TGF-β1 regarding its chondrogenic potential, NGF showed considerably lower expression of collagen type I, which is a fibrocartilage marker, and RUNX2, which is critical for terminal chondrocyte differentiation than TGF-β1, indicating its chondral specificity. Interestingly, NGF rarely induced BMSCs to differentiate into a neuronal phenotype, which may be due to the presence of other chondrogenic supplements. Furthermore, the underlying mechanism revealed that NGF-mediated chondrogenesis may be associated with the activation of PI3K/AKT and MAPK/ERK signaling pathways via the specific receptor of NGF, TrkA. In addition, NGF is easily accessed because of the abundance and low price of cobra venom, as well as the simplified methods for separation and purification. This study was the first to demonstrate the chondrogenic potential of NGF, which may provide a reference for cartilage regeneration in the clinic.
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