FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice
FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice
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DOI：
10.1073/pnas.1607079113
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发表时间：
2016-07-26
影响因子：
11.1
通讯作者：
Wernig, Marius
中科院分区：
文献类型：
--
作者：
Ahlenius, Henrik;Chanda, Soham;Wernig, Marius
我们和其他人已经证明，胚胎和新生儿成纤维细胞可以直接转化为具有成熟功能特性的诱导神经元（iN）细胞。然而，成年和老年小鼠成纤维细胞的重编程尚未得到详细探讨。从衰老生物体中生成功能齐全的iN细胞的能力对于老年疾病的体外建模尤为重要。在这里，我们证明了从接近寿命结束的小鼠身上提取的成纤维细胞产生功能性的iN细胞。老龄小鼠的iN细胞具有明显正常的主动和被动神经元膜特性，并形成丰富的突触连接。来自胚胎和新生小鼠的成纤维细胞的重编程效率逐渐下降，但来自所有年龄的出生小鼠的成纤维细胞的重编程效率保持相似。引人注目的是，与衰老有关的转录因子叉头盒O3 （FoxO3）的过度表达阻断了胚胎成纤维细胞的in细胞转化，而敲除或敲低FoxO3可提高成体来源的成纤维细胞的重编程效率，但对胚胎成纤维细胞没有影响，同时也增强了由此产生的in细胞的功能成熟。因此，FoxO3在细胞的神经元重编程易感性中起着核心作用，并且FoxO3的重要性似乎在发育过程中发生了变化。
We and others have shown that embryonic and neonatal fibroblasts can be directly converted into induced neuronal (iN) cells with mature functional properties. Reprogramming of fibroblasts from adult and aged mice, however, has not yet been explored in detail. The ability to generate fully functional iN cells from aged organisms will be particularly important for in vitro modeling of diseases of old age. Here, we demonstrate production of functional iN cells from fibroblasts that were derived from mice close to the end of their lifespan. iN cells from aged mice had apparently normal active and passive neuronal membrane properties and formed abundant synaptic connections. The reprogramming efficiency gradually decreased with fibroblasts derived from embryonic and neonatal mice, but remained similar for fibroblasts from postnatal mice of all ages. Strikingly, overexpression of a transcription factor, forkhead box O3 (FoxO3), which is implicated in aging, blocked iN cell conversion of embryonic fibroblasts, whereas knockout or knockdown of FoxO3 increased the reprogramming efficiency of adult-derived but not of embryonic fibroblasts and also enhanced functional maturation of resulting iN cells. Hence, FoxO3 has a central role in the neuronal reprogramming susceptibility of cells, and the importance of FoxO3 appears to change during development.