NeuroD1 and Ascl1 Convert Human Glial Cells into Neurons in Ex Vivo Culture of Human Brain Tissue

Abstract

Abstract Transcription factor-mediated cell conversion has been reported in the central nervous system (CNS) of both rodents and non-human primates (NHPs). In particular, glia-to-neuron (GtN) conversion has been achieved in the brains and spinal cords of animal models of neurological disorders for neural regeneration and repair. However, whether GtN conversion can ultimately be used for human brain repair in patients is still unknown. To investigate the applicability of GtN conversion technology in the human brain, we established a long-term ex vivo culture system using human brain tissue that was surgically removed from epileptic patients to directly test GtN conversion. We demonstrate that both neural transcription factors NeuroD1 and Ascl1 can convert human glial cells into neurons. Importantly, both immunostaining and electrophysiological recordings revealed that the glia-converted neurons showed immature properties during the initial 1–2 weeks of conversion, and then acquired more mature neuronal properties after 3–4 weeks of conversion. These ex vivo conversion studies in human brain tissue pave the way toward future clinical trials using a transcription factor-based glia-to-neuron conversion approach to treat neurological disorders.