Wyatt Lindsey A, Filbin Marie T, Keirstead Hans S
Department of Anatomy and Neurobiology, Sue and Bill Gross Stem Cell Research Center, Reeve-Irvine Research Center, School of Medicine, University of California at Irvine, Irvine, California, 92697-4292.
J Comp Neurol. 2014 Aug 15;522(12):2741-55. doi: 10.1002/cne.23580. Epub 2014 Apr 12.
We investigated the role of PTEN (phosphatase and tensin homolog deleted on chromosome 10) during neurite outgrowth of human embryonic stem cell (hESC)-derived neuronal progenitors. PTEN inhibits phosphoinositide 3-kinase (PI3K)/Akt signaling, a common and central outgrowth and survival pathway downstream of neuronal growth factors. It is known that PTEN inhibition, by either polymorphic mutation or gene deletion, can lead to the development of tumorigenesis (Stambolic et al., ; Tamura et al., ). However, temporary inhibition of PTEN, through pharmacological manipulation, could regulate signaling events such as the PI3K/Akt signaling pathway, leading to enhanced recovery of central nervous system (CNS) injury and disease. We demonstrate that pharmacological inhibition of PTEN in hESC-derived neuronal progenitors significantly increased neurite outgrowth in vitro in a dose- and time-dependent manner. Our results indicate that inhibition of PTEN augments neurite outgrowth beyond that of traditional methods such as elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, and depends on upregulation of the PI3K/Akt signaling pathway and its downstream effectors, such as mammalian target of rapamycin (mTOR). PTEN inhibition also rescued neurite outgrowth over an inhibitory substrate in vitro. These findings indicate a remarkable impact on hESC-derived neuronal progenitor plasticity through PTEN inhibition. Overall, these findings identify a novel therapeutic strategy for neurite outgrowth in CNS injury and disease.
我们研究了10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）在人胚胎干细胞（hESC）来源的神经祖细胞神经突生长过程中的作用。PTEN抑制磷酸肌醇3激酶（PI3K）/Akt信号通路，这是神经生长因子下游一条常见且核心的生长和存活通路。已知通过多态性突变或基因缺失抑制PTEN会导致肿瘤发生（斯坦博利克等人；田村等人）。然而，通过药物操作暂时抑制PTEN可以调节诸如PI3K/Akt信号通路等信号事件，从而增强中枢神经系统（CNS）损伤和疾病的恢复。我们证明，在hESC来源的神经祖细胞中对PTEN进行药物抑制能以剂量和时间依赖性方式显著增加体外神经突的生长。我们的结果表明，抑制PTEN能使神经突生长超过传统方法（如提高细胞内环磷酸腺苷（cAMP）水平），且依赖于PI3K/Akt信号通路及其下游效应分子（如雷帕霉素靶蛋白（mTOR））的上调。PTEN抑制还能在体外挽救抑制性底物上的神经突生长。这些发现表明通过抑制PTEN对hESC来源的神经祖细胞可塑性有显著影响。总体而言，这些发现确定了一种用于中枢神经系统损伤和疾病中神经突生长的新型治疗策略。
