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Engineered Neuroepithelial Stem Cells: A Safe Means to treat Central Nervous System Disorders?

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Review of “Genome Editing in Neuroepithelial Stem Cells to Generate Human Neurons with High Adenosine‐Releasing Capacity” from STEM CELLS Translational Medicine by Stuart P. Atkinson

The ability of the purine nucleoside adenosine to temper excessive neuronal activity makes it ideal for the treatment of various disorders of the central nervous system (CNS); however, side effects related to systemic adenosine delivery (including vasodilatation and cardiac suppression), rapid adenosine degradation, and low levels of adenosine transport across blood-brain barrier, combine to limit this promising strategy.

Now, researchers from the laboratory of Oliver Brüstle (University of Bonn) and Philipp Koch (University of Heidelberg, Mannheim, Germany) have devised a new and effective means to deliver adenosine for the treatment of CNS disorders. Writing in STEM CELLS Translational Medicine [1], Poppe et al. describe an engineered long‐term self‐renewing neuroepithelial stem cell line (lt‐NES) [2, 3] that gives rise to adenosine-secreting transplantable neurons [2, 4].

The authors employed zinc finger nucleases (ZFNs) to disrupt the adenosine kinase (ADK) gene in human lt‐NES cells previously established from human embryonic stem cells [2], an approach that inhibits the metabolism of adenosine and increases intracellular adenosine levels [5]. Encouragingly, engineered lt‐NES cells and their differentiated progeny (neurons and astrocytes) all exhibited a pronounced increase in adenosine release. However, further analysis of derived neurons established that neuronal excitation in vitro triggered extensive adenosine release - an ability that may permit activity‐dependent adenosine release from grafted engineered cells to counteract hyperexcitation locally.

As the authors reported no signs of tumorigenesis or neural overgrowth, they now hope to move their engineered lt‐NES cells into extensive preclinical studies to determine their suitability for cell‐based therapies for diseases such as depression, schizophrenia, or epilepsy.

To hear more about this exciting new strategy, stay tuned to the Stem Cells Portal.

References

  1. Poppe D, Doerr J, Schneider M, et al., Genome Editing in Neuroepithelial Stem Cells to Generate Human Neurons with High Adenosine‐Releasing Capacity. STEM CELLS Translational Medicine 2018;7:477-486.
  2. Koch P, Opitz T, Steinbeck JA, et al., A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration. Proceedings of the National Academy of Sciences 2009;106:3225-3230.
  3. Falk A, Koch P, Kesavan J, et al., Capture of Neuroepithelial-Like Stem Cells from Pluripotent Stem Cells Provides a Versatile System for In Vitro Production of Human Neurons. PLOS ONE 2012;7:e29597.
  4. Steinbeck JA, Koch P, Derouiche A, et al., Human embryonic stem cell-derived neurons establish region-specific, long-range projections in the adult brain. Cellular and Molecular Life Sciences 2012;69:461-470.
  5. Boison D, Adenosine-Based Cell Therapy Approaches for Pharmacoresistant Epilepsies. Neurodegenerative Diseases 2007;4:28-33.