Conversion of Astrocytes and Fibroblasts into Functional Noradrenergic Neurons

Abstract

Summary: 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. : Li et al. identified seven transcription factors that convert mouse astrocytes, fibroblasts, and human fibroblasts into induced noradrenergic (iNA) neurons. The iNA neurons are functional and integrate into neural circuits after transplantation. Single-cell RNA sequencing results showed that the transcriptome of iNA neurons converted from astrocytes and fibroblast are similar. Keywords: induced noradrenergic neurons, iNA neurons, direct neural reprogramming, astrocytes-to-neuron conversion, fibroblast-to-neuron conversion, transcription factors, noradrenaline release, mouse ventricular myocytes, optogenetic stimulation, cell transplantation, single-cell RNA sequencing