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A stably self-renewing adult blood-derived induced neural stem cell exhibiting patternability and epigenetic rejuvenation

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Ziller,  Michael J.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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41467_2018_Article_6398.pdf
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Citation

Sheng, C., Jungverdorben, J., Wiethoff, H., Lin, Q., Flitsch, L. J., Eckert, D., et al. (2018). A stably self-renewing adult blood-derived induced neural stem cell exhibiting patternability and epigenetic rejuvenation. NATURE COMMUNICATIONS, 9(1): 4047. doi:10.1038/s41467-018-06398-5.


Cite as: http://hdl.handle.net/21.11116/0000-0003-6FB0-A
Abstract
Recent reports suggest that induced neurons (iNs), but not induced pluripotent stem cell (iPSC)-derived neurons, largely preserve age-associated traits. Here, we report on the extent of preserved epigenetic and transcriptional aging signatures in directly converted induced neural stem cells (iNSCs). Employing restricted and integration-free expression of SOX2 and c-MYC, we generated a fully functional, bona fide NSC population from adult blood cells that remains highly responsive to regional patterning cues. Upon conversion, low passage iNSCs display a profound loss of age-related DNA methylation signatures, which further erode across extended passaging, thereby approximating the DNA methylation age of isogenic iPSC-derived neural precursors. This epigenetic rejuvenation is accompanied by a lack of ageassociated transcriptional signatures and absence of cellular aging hallmarks. We find iNSCs to be competent for modeling pathological protein aggregation and for neurotransplantation, depicting blood-to-NSC conversion as a rapid alternative route for both disease modeling and neuroregeneration.