Enhanced Rejuvenation in Induced Pluripotent Stem Cell-Derived Neurons Compared with Directly Converted Neurons from an Aged Mouse

Most neurodegenerative diseases are late-onset and aging-related, and no effective treatments have been developed. The successful generation of induced pluripotent stem cells (iPSCs) and the direct conversion of neurons from patients' specific somatic cells have offered cell resources for disease modeling and potential cell transplantation therapy. However, to date, no systematic studies have investigated which approach is more suitable for future cell therapy. In this study, using the two approaches mentioned above in parallel we successfully obtained functional neurons from tail-tip fibroblasts (TTFs) of a 1-year-old mouse, which were characterized by specialized morphologies, neuronal marker expressions, and electrophysiological properties. Genome-wide expression analysis revealed that a set of genes related to the stress response and DNA damage were expressed at a much higher level in iNs than in diNs derived from 1-year-old TTFs. Subsequently, significant decreases in mitochondrial dysfunction and DNA damage were observed in diNs compared with iNs derived from aged TTFs. Moreover, the levels of epigenetic markers such as 5hmC, H3K4me3, H3K9me3, and H3K27me3 in iNs were more similar to those in the old TTFs compared with those in diNs, indicating that the iNs converted directly from TTFs may retain some residual epigenetic memories. By contrast, reprogramming to iPSCs not only rejuvenated the cell stages, but also erased such epigenetic memories obtained along the aging process. Taken together, the results of our study are instructive and meaningful for future clinical applications.