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

Autor: Philipp Koch, Christa E. Müller, Julius A. Steinbeck, Ruven Wilkens, Philip D. Gregory, Daniel Poppe, Marion Schneider, Julia Ladewig, Andreas Reik, David Paschon, Allison Tam, Jonas Doerr, Oliver Brüstle
Rok vydání: 2018
Předmět:
Gene‐editing
0301 basic medicine
Adenosine
Neurodegeneration/Neurological Disorders
Human Embryonic Stem Cells
Cellular homeostasis
Adenosine kinase
Polymorphism
Single Nucleotide
Mass Spectrometry
Cell Line
Mice
03 medical and health sciences
0302 clinical medicine
Translational Research Articles and Reviews
Human neurons
Neural Stem Cells
medicine
Animals
Humans
Enabling Technologies for Cell-Based Clinical Translation
Adenosine Kinase
Chromatography
High Pressure Liquid
Gene Editing
Mice
Knockout
Neurons
Enabling Technologies for Cell‐Based Clinical Translation
Adenosine secretion
biology
Cell Biology
General Medicine
Gene Delivery Systems/Gene Therapy/Gene Editing Technology
Embryonic stem cell
Zinc Finger Nucleases
Neural stem cell
Neural/Progenitor Stem Cells
ADK
Cell biology
Mice
Inbred C57BL
Neuroepithelial cell
030104 developmental biology
Karyotyping
biology.protein
Neuroepithelial stem cells
Stem cell
030217 neurology & neurosurgery
Developmental Biology
medicine.drug
Zdroj: Stem Cells Translational Medicine
ISSN: 2157-6580
2157-6564
DOI: 10.1002/sctm.16-0272
Popis: 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.
Databáze: OpenAIRE
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