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Astrocyte to NSC Conversion for Neurological Regeneration

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Review of “Conversion of Non-proliferating Astrocytes into Neurogenic Neural Stem Cells: Control by FGF2 and Interferon-γ“ from Stem Cells by Stuart P. Atkinson

The conversion of astrocytes into less abundant neural stem cells (NSCs) represents a potentially exciting strategy to generate the many neurons required for the treatment of neurological disorders and brain injuries. But how can we induce astrocyte to NSC conversion without the ectopic expression of neurogenic transcription factors?

The answer to this question comes from the lab of Marcel Leist (University of Konstanz, Germany) and their studies employing a defined and controllable in vitro system of post-mitotic murine astrocytes generated from embryonic stem cells (mAGES) [1]. Their new paper, published in Stem Cells, now suggests that basic fibroblast growth factor (bFGF/FGF2) supplementation and the inhibition of the inflammatory factor interferon gamma (IFNγ) mediates astrocyte cell cycle re-entry and conversion into neurogenic NSCs (NSC2) [2]. Does this new strategy represent a new  and exciting strategy for neurological regeneration?

The authors discovered that FGF2 treatment forced a high percentage of astrocytic cell-cycle re-entry via FGF receptor-induced phosphorylation of ERK and mediated the generation of self-renewing Nestin-expressing NSCs. Converted NSCs exhibited multipotential differentiation capacity, generating both astrocytes and neurons, and transcriptional patterns and functionality indicative of an NSC identity. However, contrary to other studies of astrocyte de-differentiation [3, 4], epidermal growth factor (EGF)-mediated signaling had no role in astrocyte to NSC conversion.

As neurodegenerative diseases and brain injuries often propitiate inflammatory conditions, the study also assessed if inflammatory factors had the power to inhibit the conversion process. Interestingly, IFNγ reduced astrocyte proliferation and inhibited conversion via the activation of the JAK/STAT pathway suggesting that IFNγ inhibition may act synergistically with FGF2 to promote the in vivo conversion of astrocytes to NSCs in the diseased/injured brain.

Great news! A (seemingly!) simple way to promote astrocyte to NSC conversion, and thereby, produce the neurons required to repair/regenerate the damaged brain. Hopefully, this knowledge, coupled to utility of the mAGES system, will spark the search for small molecule drug combinations which can safely and efficiently modulate the involved pathways and promote astrocyte to NSC conversion. 

Keep tuned to the Stem Cells Portal to find out more about this exciting neurological regeneration strategy.

Discussion Points

  • What functionality and lifespan do converted NSCs have?
  • Can we move this strategy in vivo and will it lead to recovery of lost function?
  • What combinations of small molecules and delivery systems can we use to modulate the FGF2 and IFNγ pathways?
  • Are there any side effects to modulation of the FGF2 and IFNγ pathways in vivo?
  • What other tissues, and resident abundant cells, can be converted into stem cells using this methodology?

References

  1. Kleiderman S, Sa JV, Teixeira AP, et al. Functional and phenotypic differences of pure populations of stem cell-derived astrocytes and neuronal precursor cells. Glia 2016;64:695-715.
  2. Kleiderman S, Gutbier S, Ugur Tufekci K, et al. Conversion of Nonproliferating Astrocytes into Neurogenic Neural Stem Cells: Control by FGF2 and Interferon-γ. STEM CELLS 2016;34:2861-2874.
  3. Nakatsuji Y and Miller RH. Density dependent modulation of cell cycle protein expression in astrocytes. J Neurosci Res 2001;66:487-496.
  4. Mayer SI, Rossler OG, Endo T, et al. Epidermal-growth-factor-induced proliferation of astrocytes requires Egr transcription factors. J Cell Sci 2009;122:3340-3350.