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

Conversion of Astrocytes and Fibroblasts into Functional Noradrenergic Neurons.

Author information

1
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.
2
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.
3
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
4
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. Electronic address: lpcheng@gxmu.edu.cn.

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.

KEYWORDS:

astrocytes-to-neuron conversion; cell transplantation; direct neural reprogramming; fibroblast-to-neuron conversion; iNA neurons; induced noradrenergic neurons; mouse ventricular myocytes; noradrenaline release; optogenetic stimulation; single-cell RNA sequencing; transcription factors

PMID:
31315047
DOI:
10.1016/j.celrep.2019.06.042
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