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See detailConversion of non-proliferating astrocytes into neurogenic neural stem cells: control by FGF2 and IFN-gamma
Kleiderman, Susanne; Gutbier, Simon; Tufekci, Kemal U. et al

in Stem Cells (2016), 34(12), 28612874

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 ... [more ▼]

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. [less ▲]

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See detailProx1 is required for oligodendrocyte cell identity in adult neural stem cells of the subventricular zone
Bunk, Eva; Ertaylan, Goekhan; Ortega, Felipe et al

in Stem Cells (2016)

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See detailA population shift view of cellular reprogramming
del Sol Mesa, Antonio UL

in Stem Cells (2014)

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See detailA general strategy for cellular reprogramming: the importance of transcription factor cross-repression
Crespo, Isaac UL; del Sol Mesa, Antonio UL

in Stem Cells (2013)

Transcription factor cross-repression is an important concept in cellular differentiation. A bistable toggle switch constitutes a molecular mechanism that determines cellular commitment and provides ... [more ▼]

Transcription factor cross-repression is an important concept in cellular differentiation. A bistable toggle switch constitutes a molecular mechanism that determines cellular commitment and provides stability to transcriptional programs of binary cell fate choices. Experiments support that perturbations of these toggle switches can interconvert these binary cell fate choices, suggesting potential reprogramming strategies. However, more complex types of cellular transitions could involve perturbations of combinations of different types of multistable motifs. Here we introduce a method that generalizes the concept of transcription factor cross-repression to systematically predict sets of genes, whose perturbations induce cellular transitions between any given pair of cell types. Furthermore, to our knowledge, this is the first method that systematically makes these predictions without prior knowledge of potential candidate genes and pathways involved, providing guidance on systems where little is known. Given the increasing interest of cellular reprogramming in medicine and basic research, our method represents a useful computational methodology to assist researchers in the field in designing experimental strategies. [less ▲]

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See detailNeural stem cells maintain their stemness through protein kinase C zeta-mediated inhibition of TRIM32.
Hillje, Anna-Lena; Worlitzer, Maik M. A.; Palm, Thomas et al

in Stem Cells (2011), 29(9), 1437-47

Several studies over the last couple of years have delivered insights into the mechanisms that drive neuronal differentiation. However, the mechanisms that ensure the maintenance of stemness ... [more ▼]

Several studies over the last couple of years have delivered insights into the mechanisms that drive neuronal differentiation. However, the mechanisms that ensure the maintenance of stemness characteristics in neural stem cells over several rounds of cell divisions are still largely unknown. Here, we provide evidence that the neuronal fate determinant TRIM32 binds to the protein kinase C zeta. Through this interaction, TRIM32 is retained in the cytoplasm. However, during differentiation, this interaction is abrogated and TRIM32 translocates to the nucleus to initiate neuronal differentiation by targeting c-Myc for proteasomal degradation. [less ▲]

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