Conversion of non-proliferating astrocytes into neurogenic neural stem cells: control by FGF2 and IFN-gamma

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 ▲]

A population shift view of cellular reprogramming

in Stem Cells (2014)

Neural stem cells maintain their stemness through protein kinase C zeta-mediated inhibition of TRIM32.

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 ▲]