School of Regenerative Medicine, Manipal University, Allalasandra, GKVK post, Yelahanka, Bangalore, 560065, India.
Mol Neurobiol. 2018 May;55(5):4267-4279. doi: 10.1007/s12035-017-0633-0. Epub 2017 Jun 16.
Differentiation of pluripotent stem cells (PSCs) to neural lineages has gathered huge attention in both basic research and regenerative medicine. The major hurdle lies in the efficiency of differentiation and identification of small molecules that facilitate neurogenesis would partly circumvent this limitation. The small molecule Cyclosporine A (CsA), a commonly used immunosuppressive drug, has been shown to enhance in vivo neurogenesis. To extend the information to in vitro neurogenesis, we examined the effect of CsA on neural differentiation of PSCs. We found CsA to increase the expression of neural progenitor genes during early neural differentiation. Gene silencing approach revealed CsA-mediated neural induction to be dependent on blocking the Ca-activated phosphatase calcineurin (Cn) signaling. Similar observation with FK506, an independent inhibitor of Cn, further strengthened the necessity of blocking Cn for enhanced neurogenesis. Surprisingly, mechanistic insight revealed Cn-inhibition dependent upregulation of IL-6 protein to be necessary for CsA-mediated neurogenesis. Together, these findings provide a comprehensive understanding of the role of CsA in neurogenesis, thus suggesting a method for obtaining large numbers of neural progenitors from PSCs for possible transplantation.
多能干细胞（PSCs）向神经谱系的分化在基础研究和再生医学中引起了广泛关注。主要的障碍在于分化的效率，而促进神经发生的小分子的鉴定将部分克服这一限制。环孢素 A（CsA）是一种常用的免疫抑制剂，已被证明可以增强体内神经发生。为了将信息扩展到体外神经发生，我们研究了 CsA 对 PSCs 神经分化的影响。我们发现 CsA 在早期神经分化过程中增加了神经祖细胞基因的表达。基因沉默方法表明，CsA 介导的神经诱导依赖于阻断钙激活的磷酸酶钙调神经磷酸酶（Cn）信号。FK506 的类似观察结果，Cn 的独立抑制剂，进一步加强了阻断 Cn 以增强神经发生的必要性。令人惊讶的是，机制研究表明 Cn 抑制依赖性上调的 IL-6 蛋白对于 CsA 介导的神经发生是必要的。总之，这些发现为 CsA 在神经发生中的作用提供了全面的理解，从而为从 PSCs 获得大量神经祖细胞以进行可能的移植提供了一种方法。
