NEUROD1 efficiently converts peripheral blood cells into neurons with partial reprogramming by pluripotency factors.

The direct reprogramming of cells has tremendous potential in in vitro neurological studies. Previous attempts to convert blood cells into induced neurons have presented several challenges, necessitating a less invasive, efficient, rapid, and convenient approach. The current study introduces an optimized method for converting somatic cells into neurons using a nonsurgical approach that employs peripheral blood cells as an alternative source to fibroblasts. We have demonstrated the efficacy of a unique combination of transcription factors, including NEUROD1, and four Yamanaka reprogramming factors (OCT3/4, SOX2, KLF4, and c-MYC), in generating glutamatergic neurons within 3 wk. This approach, which requires only five pivotal factors (NEUROD1, OCT3/4, SOX2, KLF4, and c-MYC), has the potential to create functional neurons and circumvents the need for induced pluripotent stem cell (iPSC) intermediates, as evidenced by single-cell RNA sequencing and whole-genome bisulfite sequencing, along with lineage-tracing experiments using Cre-LoxP system. While fibroblasts have been widely used for neuronal reprogramming, our findings suggest that peripheral blood cells offer a potential alternative, particularly in contexts where minimally invasive sampling and procedures convenient for patients are emphasized. This method provides a rapid strategy for modeling neuronal diseases and contributes to advancements in drug discovery and personalized medicine.