Conversion of nonproliferating astrocytes into neurogenic neural stem cells : Control by FGF2 and Interferon-γ

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2016
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Ugur Tufekci, Kemal
Ortega, Felipe
Sá, João V
Teixeira, Ana P
Brito, Catarina
Glaab, Enrico
Berninger, Benedikt
Alves, Paula M
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Conversion of astrocytes to neurons, via de-differentiation to neural stem cells (NSC), may be a new approach to treat neurodegenerative diseases and brain injuries. The signaling factors affecting such a cell conversion are poorly understood, and they are hard to identify in complex disease models or conventional cell cultures. To address this question, we developed a serum-free, strictly controlled culture system of pure and homogeneous "astrocytes generated from murine embryonic stem cells (ESC)." These stem cell derived astrocytes (mAGES), as well as standard primary astrocytes resumed proliferation upon addition of FGF. The signaling of FGF receptor tyrosine kinase converted GFAP-positive mAGES to nestin-positive NSC. ERK phosphorylation was necessary, but not sufficient, for cell cycle re-entry, as EGF triggered no de-differentiation. The NSC obtained by de-differentiation of mAGES were similar to those obtained directly by differentiation of ESC, as evidenced by standard phenotyping, and also by transcriptome mapping, metabolic profiling, and by differentiation to neurons or astrocytes. The de-differentiation was negatively affected by inflammatory mediators, and in particular, interferon-γ strongly impaired the formation of NSC from mAGES by a pathway involving phosphorylation of STAT1, but not the generation of nitric oxide. Thus, two antagonistic signaling pathways were identified here that affect fate conversion of astrocytes independent of genetic manipulation. The complex interplay of the respective signaling molecules that promote/inhibit astrocyte de-differentiation may explain why astrocytes do not readily form neural stem cells in most diseases. Increased knowledge of such factors may provide therapeutic opportunities to favor such conversions. Stem Cells 2016;34:2861-2874.

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ISO 690KIRNER, Susanne, Simon GUTBIER, Kemal UGUR TUFEKCI, Felipe ORTEGA, João V SÁ, Ana P TEIXEIRA, Catarina BRITO, Enrico GLAAB, Benedikt BERNINGER, Paula M ALVES, Marcel LEIST, 2016. Conversion of nonproliferating astrocytes into neurogenic neural stem cells : Control by FGF2 and Interferon-γ. In: Stem cells. 2016, 34(12), pp. 2861-2874. ISSN 0737-1454. eISSN 1549-4918. Available under: doi: 10.1002/stem.2483
BibTex
@article{Kirner2016-12Conve-36723,
  year={2016},
  doi={10.1002/stem.2483},
  title={Conversion of nonproliferating astrocytes into neurogenic neural stem cells : Control by FGF2 and Interferon-γ},
  number={12},
  volume={34},
  issn={0737-1454},
  journal={Stem cells},
  pages={2861--2874},
  author={Kirner, Susanne and Gutbier, Simon and Ugur Tufekci, Kemal and Ortega, Felipe and Sá, João V and Teixeira, Ana P and Brito, Catarina and Glaab, Enrico and Berninger, Benedikt and Alves, Paula M and Leist, Marcel}
}
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