Conversion of Nonproliferating Astrocytes into Neurogenic Neural Stem Cells

Control by FGF2 and Interferon-γ

Susanne Kleiderman, Simon Gutbier, Kemal Ugur Tufekci, Felipe Ortega, João V. Sá, Ana Margarida Teixeira, Ana Catarina Montes, Enrico Glaab, Benedikt Berninger, Paula M. Alves, Marcel Leist

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2861-2874
Number of pages14
JournalStem Cells
Volume34
Issue number12
DOIs
Publication statusPublished - 1 Dec 2016

Fingerprint

Neural Stem Cells
Fibroblast Growth Factor 2
Astrocytes
Interferons
Embryonic Stem Cells
Stem Cells
Phosphorylation
Neurons
Fibroblast Growth Factor Receptors
Nestin
Transcriptome
Epidermal Growth Factor
Neurodegenerative Diseases
Protein-Tyrosine Kinases
Brain Injuries
Cell Cycle
Nitric Oxide
Cell Culture Techniques
Serum

Keywords

  • Astrocytes
  • De-differentiation
  • FGF2
  • Interferon
  • Neural stem cells
  • Neurogenesis

Cite this

Kleiderman, S., Gutbier, S., Ugur Tufekci, K., Ortega, F., Sá, J. V., Teixeira, A. M., ... Leist, M. (2016). Conversion of Nonproliferating Astrocytes into Neurogenic Neural Stem Cells: Control by FGF2 and Interferon-γ. Stem Cells, 34(12), 2861-2874. https://doi.org/10.1002/stem.2483
Kleiderman, Susanne ; Gutbier, Simon ; Ugur Tufekci, Kemal ; Ortega, Felipe ; Sá, João V. ; Teixeira, Ana Margarida ; Montes, Ana Catarina ; Glaab, Enrico ; Berninger, Benedikt ; Alves, Paula M. ; Leist, Marcel. / Conversion of Nonproliferating Astrocytes into Neurogenic Neural Stem Cells : Control by FGF2 and Interferon-γ. In: Stem Cells. 2016 ; Vol. 34, No. 12. pp. 2861-2874.
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Kleiderman, S, Gutbier, S, Ugur Tufekci, K, Ortega, F, Sá, JV, Teixeira, AM, Montes, AC, Glaab, E, Berninger, B, Alves, PM & Leist, M 2016, 'Conversion of Nonproliferating Astrocytes into Neurogenic Neural Stem Cells: Control by FGF2 and Interferon-γ', Stem Cells, vol. 34, no. 12, pp. 2861-2874. https://doi.org/10.1002/stem.2483

Conversion of Nonproliferating Astrocytes into Neurogenic Neural Stem Cells : Control by FGF2 and Interferon-γ. / Kleiderman, Susanne; Gutbier, Simon; Ugur Tufekci, Kemal; Ortega, Felipe; Sá, João V.; Teixeira, Ana Margarida; Montes, Ana Catarina; Glaab, Enrico; Berninger, Benedikt; Alves, Paula M.; Leist, Marcel.

In: Stem Cells, Vol. 34, No. 12, 01.12.2016, p. 2861-2874.

Research output: Contribution to journalArticle

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AU - Kleiderman, Susanne

AU - Gutbier, Simon

AU - Ugur Tufekci, Kemal

AU - Ortega, Felipe

AU - Sá, João V.

AU - Teixeira, Ana Margarida

AU - Montes, Ana Catarina

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AU - Berninger, Benedikt

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AU - Leist, Marcel

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