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

Chao Sheng, Johannes Jungverdorben, Hendrik Wiethoff, Qiong Lin, Lea J. Flitsch, Daniela Eckert, Matthias Hebisch, Julia Fischer, Jaideep Kesavan, Beatrice Weykopf, Linda Schneider, Dominik Holtkamp, Heinz Beck, Andreas Till, Ullrich Wüllner, Michael J. Ziller, Wolfgang Wagner, Michael Peitz () and Oliver Brüstle ()
Additional contact information
Chao Sheng: University of Bonn Medical Center
Johannes Jungverdorben: University of Bonn Medical Center
Hendrik Wiethoff: University of Bonn Medical Center
Qiong Lin: RWTH Aachen University Medical School
Lea J. Flitsch: University of Bonn Medical Center
Daniela Eckert: University of Bonn Medical Center
Matthias Hebisch: University of Bonn Medical Center
Julia Fischer: University of Bonn Medical Center
Jaideep Kesavan: University of Bonn Medical Center
Beatrice Weykopf: University of Bonn Medical Center
Linda Schneider: University of Bonn Medical Center
Dominik Holtkamp: University of Bonn Medical Center
Heinz Beck: University of Bonn Medical Center
Andreas Till: University of Bonn Medical Center
Ullrich Wüllner: German Center for Neurodegenerative Diseases (DZNE)
Michael J. Ziller: Max Planck Institute of Psychiatry
Wolfgang Wagner: RWTH Aachen University Medical School
Michael Peitz: University of Bonn Medical Center
Oliver Brüstle: University of Bonn Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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 age-associated 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.

Date: 2018
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DOI: 10.1038/s41467-018-06398-5

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