Stem cells research center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215001, China.
Neurology department, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215001, China.
Neurosci Lett. 2019 Aug 24;708:134345. doi: 10.1016/j.neulet.2019.134345. Epub 2019 Jun 20.
Although brain-derived neurotrophic factor (BDNF) induces the differentiation of induced pluripotent stem cells (iPSCs) into neural stem cells (NSCs), its exact mechanism remains unelucidated. Wnt/β-catenin and ERK5 are two important signalling pathways of the Wnt and MAPK signalling cascades and are speculated to be closely related to the differentiation of cells. In this study, we reported the role of the Wnt/β-catenin and ERK5 signalling pathways on the BDNF-induced differentiation of iPSCs into NSCs. We examined the expression of β-catenin and p-ERK5 using small interfering RNA (siRNA)-induced silencing of β-catenin and ERK genes. We found that BDNF significantly improved the efficiency of iPSC differentiation and that the expression of β-catenin and p-ERK5 in the BDNF culture medium was significantly upregulated. Furthermore, we found that the expression of the β-catenin component was downregulated by siRNA-β-catenin, and the expression of the p-ERK5 component was downregulated by siRNA-ERK5. Flow cytometry showed that the differentiation rate of iPSCs was also significantly decreased by RNA interference. The results suggested that the Wnt/β-catenin and ERK5 signalling pathways are activated in the process of BDNF-induced iPSC differentiation. Interestingly, our study showed that siRNA-ERK5 not only inhibits the activity of the ERK5 signalling pathway but also partially controls the activity of the Wnt/β-catenin signalling pathway. The results suggested that the Wnt/β-catenin and ERK5 signalling pathways are not independently involved in the process of BDNF-induced iPSC differentiation. Our study showed that BDNF promotes the differentiation of iPSCs into NSCs by activating the Wnt/β-catenin and ERK5 signalling pathways, and an interconnected relationship may exist between the Wnt/β-catenin and ERK5 signalling pathways.
虽然脑源性神经营养因子（BDNF）可诱导诱导多能干细胞（iPSCs）分化为神经干细胞（NSCs），但其确切机制仍不清楚。Wnt/β-catenin 和 ERK5 是 Wnt 和 MAPK 信号级联的两个重要信号通路，据推测与细胞分化密切相关。在这项研究中，我们报道了 Wnt/β-catenin 和 ERK5 信号通路在 BDNF 诱导 iPSC 分化为 NSCs 中的作用。我们使用小干扰 RNA（siRNA）诱导β-catenin 和 ERK 基因沉默来检测β-catenin 和 p-ERK5 的表达。我们发现 BDNF 可显著提高 iPSC 分化效率，BDNF 培养基中β-catenin 和 p-ERK5 的表达明显上调。此外，我们发现 siRNA-β-catenin 下调β-catenin 组成部分的表达，siRNA-ERK5 下调 p-ERK5 组成部分的表达。流式细胞术显示 RNA 干扰也显著降低了 iPSC 的分化率。结果表明，BDNF 诱导 iPSC 分化过程中激活了 Wnt/β-catenin 和 ERK5 信号通路。有趣的是，我们的研究表明，siRNA-ERK5 不仅抑制 ERK5 信号通路的活性，还部分控制 Wnt/β-catenin 信号通路的活性。这表明 Wnt/β-catenin 和 ERK5 信号通路并非独立参与 BDNF 诱导的 iPSC 分化过程。我们的研究表明，BDNF 通过激活 Wnt/β-catenin 和 ERK5 信号通路促进 iPSCs 分化为 NSCs，Wnt/β-catenin 和 ERK5 信号通路之间可能存在相互关联的关系。
