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Assessment of Epigenetic and Transcriptomic Signatures During Induced Neural Stem Cell Conversion of Human Blood Cells

Cellular reprogramming by direct cell fate conversion has been shown to be associated with epigenetic de-aging. However, the dynamics of this process still remain elusive. Here, we generated induced neural stem cells (iNSCs) from erythroid progenitors of donors ranging from neonatal to 101 years of age by overexpression of the transcription factors SOX2 and MYC. First, performing DNA methylation analyses, we corroborated our previous finding that iNSCs generated from aged donors show pronounced epigenetic de-aging (data deposited as GSE295849). Studying the dynamic of epigenetic de-aging during iNSC conversion across time, we found that this process is largely protracted. Second, RNA sequencing analysis revealed that transcriptomic differences between young and old donor-derived iNSCs dissipate with extended time in conversion, too (data available through dbGaP). Concordant with this observation, established iNSC lines lack age-associated cellular hallmarks, similar to induced pluripotent stem cells and their derivatives. Finally, time course analyses on epigenome and transcriptome level both revealed that acquisition of a bona fide NSC signature extends greatly beyond the time point when proliferative PAX6-positive iNSCs emerge.