Genome Editing in Neuroepithelial Stem Cells to Generate Human Neurons with High Adenosine-Releasing Capacity.

Daniel Poppe, Jonas Doerr, Marion Schneider, Ruven Wilkens, Julius A Steinbeck, Julia Ladewig, Allison Tam, David E Paschon, Philip D Gregory, Andreas Reik, Christa Müller, Philipp Koch, Oliver Brüstle

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2 Citations (Scopus)

Abstract

As a powerful regulator of cellular homeostasis and metabolism, adenosine is involved in diverse neurological processes including pain, cognition, and memory. Altered adenosine homeostasis has also been associated with several diseases such as depression, schizophrenia, or epilepsy. Based on its protective properties, adenosine has been considered as a potential therapeutic agent for various brain disorders. Since systemic application of adenosine is hampered by serious side effects such as vasodilatation and cardiac suppression, recent studies aim at improving local delivery by depots, pumps, or cell-based applications. Here, we report on the characterization of adenosine-releasing human embryonic stem cell-derived neuroepithelial stem cells (long-term self-renewing neuroepithelial stem [lt-NES] cells) generated by zinc finger nuclease (ZFN)-mediated knockout of the adenosine kinase (ADK) gene. ADK-deficient lt-NES cells and their differentiated neuronal and astroglial progeny exhibit substantially elevated release of adenosine compared to control cells. Importantly, extensive adenosine release could be triggered by excitation of differentiated neuronal cultures, suggesting a potential activity-dependent regulation of adenosine supply. Thus, ZFN-modified neural stem cells might serve as a useful vehicle for the activity-dependent local therapeutic delivery of adenosine into the central nervous system.
Original languageEnglish
Article number 29589874
Pages (from-to)477-486
Number of pages10
JournalStem Cells Translational Medicine
Volume7
Issue number6
Early online date28 Mar 2018
DOIs
Publication statusPublished - Jun 2018
Externally publishedYes

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Poppe, D., Doerr, J., Schneider, M., Wilkens, R., Steinbeck, J. A., Ladewig, J., ... Brüstle, O. (2018). Genome Editing in Neuroepithelial Stem Cells to Generate Human Neurons with High Adenosine-Releasing Capacity. Stem Cells Translational Medicine, 7(6), 477-486. [ 29589874]. https://doi.org/10.1002/sctm.16-0272