Shu Tao, Liu Chang, Pang Mao, Wang Juan, Liu Bin, Zhou Wei, Wang Xuan, Wu Tao, Wang Qiyou, Rong Limin
Department of Spine Surgery, The 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Department of Gynaecology, Common Splendor International Health Management, Guangzhou, Guangdong 510000, China.
Brain Res. 2018 Jan 1;1678:407-418. doi: 10.1016/j.brainres.2017.11.006. Epub 2017 Nov 11.
Induced pluripotent stem cells (iPSCs) possess the potential to differentiate into neural lineage cells. Matrix metalloproteinase 2 (MMP2), an endopeptidase in the extracellular matrix, has been shown to protect neural cells from injury. However, the mechanisms and effects of MMP2 on neural differentiation of iPSCs remain poorly understood. Here, we demonstrated a role for MMP2 in the differentiation of iPSCs to neurons via the AKT pathway. Treatment of iPSCs with MMP2 promoted their proliferation and differentiation into neural stem cells (NSCs), and then into neurons. The transcript and protein expression of Nestin and microtubule-associated protein 2 (MAP2) increased. Moreover, MMP2 markedly induced the expression of phospho-AKT (pAKT) during these differentiation stages. Consistently, silencing MMP2 using siRNA attenuated the expression of Nestin, MAP2 and pAKT, compared with the control group. In addition, the increasing levels of Nestin, MAP2 and pAKT in the MMP2 group were declined by pretreatment with the phosphoinositide 3-kinase (PI3K)/AKT inhibitor, LY294002. Furthermore, the study detected that TrkA and TrkB were perhaps the potential receptors for these effects of MMP2 on neural differentiation through PI3K/AKT signaling pathway. Taken together, these results suggest that MMP2 induces the differentiation of iPSCs into neurons by regulating the AKT signaling pathway.
诱导多能干细胞（iPSC）具有分化为神经谱系细胞的潜力。基质金属蛋白酶2（MMP2）是细胞外基质中的一种内肽酶，已被证明可保护神经细胞免受损伤。然而，MMP2对iPSC神经分化的机制和影响仍知之甚少。在此，我们证明了MMP2在iPSC通过AKT途径向神经元分化过程中的作用。用MMP2处理iPSC可促进其增殖并分化为神经干细胞（NSC），然后再分化为神经元。巢蛋白（Nestin）和微管相关蛋白2（MAP2）的转录本和蛋白表达增加。此外，MMP2在这些分化阶段显著诱导磷酸化AKT（pAKT）的表达。与对照组相比，使用小干扰RNA（siRNA）沉默MMP2可减弱Nestin、MAP2和pAKT的表达。此外，用磷酸肌醇3激酶（PI3K）/AKT抑制剂LY294002预处理可降低MMP2组中Nestin、MAP2和pAKT的升高水平。此外，该研究检测到酪氨酸激酶受体A（TrkA）和酪氨酸激酶受体B（TrkB）可能是MMP2通过PI3K/AKT信号通路对神经分化产生这些影响的潜在受体。综上所述，这些结果表明MMP2通过调节AKT信号通路诱导iPSC分化为神经元。
