Article (Scientific journals)
Conversion of non-proliferating astrocytes into neurogenic neural stem cells: control by FGF2 and IFN-gamma
Kleiderman, Susanne; Gutbier, Simon; Tufekci, Kemal U. et al.
2016In Stem Cells, 34 (12), p. 2861–2874
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Keywords :
astrocytes; neural stem cells; de-differentiation; neurogenesis; FGF2; interferon
Abstract :
[en] 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 form 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 gamma (IFNγ) 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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group)
ULHPC - University of Luxembourg: High Performance Computing
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Kleiderman, Susanne
Gutbier, Simon
Tufekci, Kemal U.
Ortega, Felipe
Sá, João V.
Teixeira, Ana P.
Brito, Catarina
Glaab, Enrico  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Berninger, Benedikt
Alves, Paula M.
Leist, Marcel
External co-authors :
Language :
Title :
Conversion of non-proliferating astrocytes into neurogenic neural stem cells: control by FGF2 and IFN-gamma
Publication date :
Journal title :
Stem Cells
Publisher :
Wiley, Malden, United States - Massachusetts
Volume :
Issue :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
FnR Project :
FNR5782168 - Exploring Parkinson'S Disease Inhibitor Efficacy On A Non-dopaminergic Target, 2013 (01/12/2013-31/05/2016) - Enrico Glaab
Funders :
FNR - Fonds National de la Recherche [LU]
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