Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming
Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming
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DOI：
10.1016/j.stem.2015.12.003
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发表时间：
2016-03-03
期刊：
影响因子：
23.9
通讯作者：
Goetz, Magdalena
中科院分区：
文献类型：
--
作者：
Gascon, Sergio;Murenu, Elisa;Goetz, Magdalena
尽管对直接神经元重编程的广泛兴趣，但支撑命运转换的机制在很大程度上仍然未知。我们的研究揭示了一个关键的时间点，在此之后细胞要么成功转化为神经元，要么屈服于细胞死亡。与Bcl-2的共转导通过更快的神经元分化极大地改善了这个关键点的谈判。令人惊讶的是，突变体与Bax的亲和力降低或没有证明，Bcl-2发挥这种作用，通过一个独立的凋亡机制。与半胱天冬酶非依赖性作用一致，铁凋亡抑制剂通过抑制命运转换期间发生的脂质过氧化，有效地增加神经元重编程。全基因组表达分析证实，促进神经元重编程的治疗引起抗氧化应激反应。重要的是，Bcl-2和抗氧化治疗的共表达导致了前所未有的改善，在创伤性脑损伤后的神经胶质细胞到神经元的转换在体内，强调这些途径的相关性，在细胞重编程，无论细胞类型在体外和体内。
Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, co-expression of Bcl-2 and anti-oxidative treatments leads to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type in vitro and in vivo.