4.2 The stem cell potential of astrocytes
4.2.5 Reactivation studies in human astrocytes
Studies on the de-differentiation and neurogenic potential of human astrocytes are scarce.
This is mainly due to a lack of appropriate cell systems. There exist several protocols to generate human astrocytes from stem cells. The resulting populations, however, are het-erogeneous, containing other cell types, and many of the generated astrocytes are not really mature, expressing high levels of nestin or vimentin with a high percentage of pro-liferating cells. Thus, similar protocols as the one presented here need to be developed first, before de-differentiation can be properly investigated.
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The stem cell niches of the adult human brain are similarly organized compared with murine brains (Gallo and Gotz 2015). Neurogenesis in the hippocampus has been demon-strated in adult humans (Eriksson et al. 1998; Spalding et al. 2013). Within the subven-tricular zone, however, differences between mice and humans could be observed. In con-trast to mice, the neurogenesis of human neurons, destined for the olfactory bulb, de-creases drastically after birth and during early infancy (Bergmann et al. 2012; Sanai et al.
2011). Interestingly, it seems that neurons generated in the lateral ventricle wall are ded-icated to integrate in the striatum instead of the olfactory bulb (Ernst et al. 2014). Thus, neurogenesis does occur in the adult human brain, with only minor differences to the mouse system. Moreover, proliferating glia, namely NG2-glia, have been detected in the mouse as well as the human cortex (Geha et al. 2010; Reynolds and Hardy 1997). Very recently, human astrocytes have been successfully converted to neurons by a cocktail of small molecules in vitro, demonstrating a great cellular plasticity also of human cells (Zhang et al. 2015). Thus, the basic principles for a de-differentiation of human astro-cytes, and their conversion to neurons, are fulfilled, which involves proliferation, cellular plasticity, and adult neurogenesis. If the mechanisms of de-differentiation, however, are similar between the mouse and the human system, remains to be clarified.
4.2.6 Conclusion
The mAGES have been shown to be suitable to investigate cell cycle reactivation as well as de-differentiation and neurogenesis from astrocytes. Compared with primary cells, the homogeneity of mAGES facilitated studies of mechanisms.
FGF2, as single growth factor, has been identified to be sufficient for a conversion of astrocytes to neural stem cells and further to neurons. Although both ERK and AKT phorylation could be observed downstream of FGF2, only an inhibition of ERK phos-phorylation by U0126 reduced the cell cycle reactivation of mAGES (Fig. 22). Therefore, ERK may be a promising target to trigger cell cycle reactivation in astrocytes. A stimu-lation with EGF also resulted in the phosphorystimu-lation of ERK and AKT, but the induction or inhibition (gefinitib) of this pathway did not alter the de-differentiation of mAGES.
Thus, EGF is neither sufficient, nor necessary for the cell cycle reactivation. In contrast, the addition of IFNγ significantly decreased the de-differentiation of mAGES exposed to FGF2, which was restored in the presence of ruxolitinib, an inhibitor of STAT1 phos-phorylation.
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Thus, inhibiting or inducing signals can be identified and characterized in this system. In an inflammatory environment, which was simulated by the presence of inflammatory cy-tokines, mAGES failed to differentiate. This may explain, why astrocytes do not de-differentiate in vivo during inflammatory events, even if inducing signals might be pro-duced and released. The recovery of de-differentiation with ruxolitinib, however, demon-strates that a screening of small molecules and other compounds can be performed, with the aim of identifying substances that might enhance de-differentiation of astrocytes in a pathological environment.
As the cell system presented here can be easily manipulated at every stage, not only de-differentiation of astrocytes can be investigated, but also mechanism of neurogenesis from de-differentiated astrocytes may be targeted in future.
Fig. 22. Inducers and the de-differentiation of mAGES. SU5402 inhibits the FGF receptor TyrK and U0126 inhibits the phos-phorylation of ERK. Both inhibitors decrease the FGF2-induced de-differentiation of mAGES. Ly294002 inhibits Akt phosphorylation, but has no impact on the de-differentiation of mAGES. Epidermal growth factor (EGF) binds to its receptor (EGF-R), activates its TyrK, and induces a phosphorylation of ERK and Akt (not shown). Gefitinib inhibits the TyrK of the EGF-R. EGF and its inhibition by gefitinib have no impact on the de-differentiation of mAGES, neither alone nor in combination with FGF2. Interferon gamma (IFNγ) binds to its receptor (IFNG-R), and activates its receptor kinase (JAK). JAK phosphorylates STAT1, which inhibits the FGF2-induced de-differentiation of mAGES.
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