Metformin Acts on Two Different Molecular Pathways to Enhance Adult Neural Precursor Proliferation/Self-Renewal and Differentiation.
Metformin Acts on Two Different Molecular Pathways to Enhance Adult Neural Precursor Proliferation/Self-Renewal and Differentiation.
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DOI：
10.1016/j.stemcr.2015.10.014
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发表时间：
2015-12-08
影响因子：
5.9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Fatt M;Hsu K;He L;Wondisford F;Miller FD;Kaplan DR;Wang J
招募内源性成体神经干细胞用于脑修复是一种很有前途的再生治疗策略。这一策略涉及刺激成人神经干细胞发展的多个阶段，包括增殖、自我更新和分化。目前，缺乏一种单一的治疗方法，可以作用于成人神经干细胞发育的这些多个阶段，以促进神经再生。在这里，我们展示了FDA批准的糖尿病药物二甲双胍，促进成年神经前体细胞(NPC)的增殖、自我更新和分化。具体地说，我们发现二甲双胍依赖于P53家族成员和转录因子TAp73促进成人鼻咽癌的增殖和自我更新，同时它通过激活AMPK-aPKC-CBP途径促进这些细胞的神经元分化。因此，二甲双胍代表了一种最佳的候选神经再生剂，不仅能够扩大成年鼻咽癌群体，而且通过激活两条不同的分子通路，随后推动他们向神经元分化。二甲双胍促进神经前体增殖/自我更新和分化需要TAp73促进神经前体增殖/自我更新二甲双胍激活aPKC-CBP途径诱导神经前体分化AMPK通过激活aPKC-CBP途径刺激神经元分化Wang及其同事使用成人神经前体细胞培养和BrdU进行体内标记，证明二甲双胍作用于成人神经前体发育的多个阶段，包括增殖、自我更新和分化。具体来说，二甲双胍需要TAp73基因的表达来促进神经前体的增殖/自我更新，而二甲双胍则激活aPKC-CBP途径来诱导神经前体分化。
The recruitment of endogenous adult neural stem cells for brain repair is a promising regenerative therapeutic strategy. This strategy involves stimulation of multiple stages of adult neural stem cell development, including proliferation, self-renewal, and differentiation. Currently, there is a lack of a single therapeutic approach that can act on these multiple stages of adult neural stem cell development to enhance neural regeneration. Here we show that metformin, an FDA-approved diabetes drug, promotes proliferation, self-renewal, and differentiation of adult neural precursors (NPCs). Specifically, we show that metformin enhances adult NPC proliferation and self-renewal dependent upon the p53 family member and transcription factor TAp73, while it promotes neuronal differentiation of these cells by activating the AMPK-aPKC-CBP pathway. Thus, metformin represents an optimal candidate neuro-regenerative agent that is capable of not only expanding the adult NPC population but also subsequently driving them toward neuronal differentiation by activating two distinct molecular pathways. Metformin enhances neural precursor proliferation/self-renewal and differentiation Metformin requires TAp73 to promote neural precursor proliferation/self-renewal Metformin activates the aPKC-CBP pathway to induce neural precursor differentiation AMPK stimulates neuronal differentiation by activating the aPKC-CBP pathway Wang and colleagues used both adult neural precursor cell culture and BrdU in vivo labeling to show that metformin acts on multiple stages of adult neural precursor development including proliferation, self-renewal, and differentiation. Specifically, metformin requires TAp73 gene expression to promote neural precursor proliferation/self-renewal, while metformin activates the aPKC-CBP pathway to induce neural precursor differentiation.