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Stem Cells Transl Med. 2018 Jun;7(6):477-486. doi: 10.1002/sctm.16-0272. Epub 2018 Mar 28.

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

Author information

1
Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, Bonn, Germany.
2
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
3
Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Mannheim, Germany.
4
Hector Institute for Translational Brain Research (HITBR gGmbH), Mannheim, Germany.
5
German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Sangamo Therapeutics, Richmond, California, USA.

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. Stem Cells Translational Medicine 2018;7:477-486.

KEYWORDS:

Adenosine kinase; Adenosine secretion; Gene-editing; Human neurons; Neuroepithelial stem cells

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