Retinoic Acid Receptor γ (Rarg) and Nuclear Receptor Subfamily 5, Group A, Member 2 (Nr5a2) Promote Conversion of Fibroblasts to Functional Neurons

Abstract

Somatic cells can be reprogrammed to neurons and various other cell types with retrovirus or lentivirus. The limitation of this technology is that these genome-integration viruses may increase the risk of gene mutation and cause insertional mutagenesis. We recently found that non-integration adenovirus carrying neuronal transcription factors can induce fibroblasts to neurons. However, the conversion efficiency by the adenovirus is lower than that of the retrovirus or lentivirus. Therefore, it is crucial to identify other factors or chemical compounds to obtain neurons with high efficiency. In this study we show that the combination of Rarg (retinoic acid receptor γ) and Nr5a2 (nuclear receptor subfamily 5, group A, member 2; also known as Lrh-1 (liver receptor homologue 1)) rapidly promote the iN cell maturation within 1 week and greatly facilitate the conversion with neuronal purities of ∼50% and yields of >130%. They also improve neuronal pattern formation, electrophysiological characteristics, and functional integration in vivo. Moreover, the chemical compound agonists to Rarg and Nr5a2 function effectively as well. This approach may be used for the generation and application of iN cells in regenerative medicine. Somatic cells can be reprogrammed to neurons and various other cell types with retrovirus or lentivirus. The limitation of this technology is that these genome-integration viruses may increase the risk of gene mutation and cause insertional mutagenesis. We recently found that non-integration adenovirus carrying neuronal transcription factors can induce fibroblasts to neurons. However, the conversion efficiency by the adenovirus is lower than that of the retrovirus or lentivirus. Therefore, it is crucial to identify other factors or chemical compounds to obtain neurons with high efficiency. In this study we show that the combination of Rarg (retinoic acid receptor γ) and Nr5a2 (nuclear receptor subfamily 5, group A, member 2; also known as Lrh-1 (liver receptor homologue 1)) rapidly promote the iN cell maturation within 1 week and greatly facilitate the conversion with neuronal purities of ∼50% and yields of >130%. They also improve neuronal pattern formation, electrophysiological characteristics, and functional integration in vivo. Moreover, the chemical compound agonists to Rarg and Nr5a2 function effectively as well. This approach may be used for the generation and application of iN cells in regenerative medicine.