星形胶质细胞和纤维母细胞向功能性去甲肾上腺素能神经元的转化。

Conversion of Astrocytes and Fibroblasts into Functional Noradrenergic Neurons.

机构信息

Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.

出版信息

Cell Rep. 2019 Jul 16;28(3):682-697.e7. doi: 10.1016/j.celrep.2019.06.042.

DOI:10.1016/j.celrep.2019.06.042

PMID:31315047

Abstract

Dysfunction of noradrenergic (NA) neurons is associated with a number of neuronal disorders. Diverse neuronal subtypes can be generated by direct reprogramming. However, it is still unknown how to convert non-neuronal cells into NA neurons. Here, we show that seven transcription factors (TFs) (Ascl1, Phox2b, AP-2α, Gata3, Hand2, Nurr1, and Phox2a) are able to convert astrocytes and fibroblasts into induced NA (iNA) neurons. These iNA neurons express the genes required for the biosynthesis, release, and re-uptake of noradrenaline. Moreover, iNA neurons fire action potentials, receive synaptic inputs, and control the beating rate of co-cultured ventricular myocytes. Furthermore, iNA neurons survive and integrate into neural circuits after transplantation. Last, human fibroblasts can be converted into functional iNA neurons as well. Together, iNA neurons are generated by direct reprogramming, and they could be potentially useful for disease modeling and cell-based therapies.

摘要

去甲肾上腺素能 (NA) 神经元功能障碍与多种神经元疾病有关。不同的神经元亚型可以通过直接重编程产生。然而，目前尚不清楚如何将非神经元细胞转化为 NA 神经元。在这里，我们发现 7 种转录因子（TFs）（Ascl1、Phox2b、AP-2α、Gata3、Hand2、Nurr1 和 Phox2a）能够将星形胶质细胞和成纤维细胞转化为诱导性 NA（iNA）神经元。这些 iNA 神经元表达合成、释放和再摄取去甲肾上腺素所需的基因。此外，iNA 神经元能产生动作电位、接收突触输入，并控制共培养的心室肌细胞的跳动频率。此外，iNA 神经元在移植后存活并整合到神经回路中。最后，人成纤维细胞也可以被转化为功能性 iNA 神经元。总之，iNA 神经元是通过直接重编程产生的，它们可能对疾病建模和基于细胞的治疗有用。