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    • However the relative contribution of factors provided by the

    2018-10-20

    However, the relative contribution of factors provided by the different niche 5-ht2 including the precursor cells themselves, endothelial cells, pericytes, neurons and astrocytes to this concert has not yet been systematically explored for the hippocampus. There are no widely usable in vitro systems that would allow further exploration of these questions, although the issue has been discussed for more than a decade (Wurmser et al., 2004). We and others have explored the effects of neuronal activity on precursor cell behavior in co-culture systems, identifying oscillatory excitation and BDNF release as putative mechanisms (Babu et al., 2009; Deisseroth et al., 2004). A few other studies have addressed the contribution of astrocytes (Barkho et al., 2006; Oh et al., 2010; Song et al., 2002). In one of these studies, it was found that astrocyte-dependent Wnt-signaling is a key factor for controlling neuronal differentiation from adult hippocampal precursor cells in vitro (Lie et al., 2005). For further exploration of the factors involved, a parallel examination of different cell types will be useful. Precursor cells from the SVZ have been co-cultured with neurons, endothelial and vascular smooth muscle (vSMC) lines in vitro demonstrating the strength of such an approach (Shen et al., 2004) but without leading to similar follow-up studies for the hippocampus. For the SVZ such studies have already led to a thorough understanding of the vascular niche and the identification of individual factors such as PEGF, SDF1/CXCR4 or VCAM1 (Andreu-Agulló et al., 2009; Kokovay et al., 2010, 2012).
    Results
    Discussion The essential role of astrocytes in the adult stem cell niche has been rarely investigated in the adult hippocampus. Only one study by Song et al. had shown that astrocytes from the adult hippocampus of rats increased the rate of proliferation and neuronal fate commitment (Song et al., 2002). A similar relationship was observed in SVZ precursor cells co-cultured with murine astrocytes of the early postnatal period (Lim and Alvarez-Buylla, 1999). Thus, we could reproducibly show that astrocytes secrete factors enhancing cell growth. This is also in line with the finding that astrocytic adenosine 5′-triphosphate release induces precursor cell proliferation in the adult hippocampus (Cao et al., 2013). On the other hand, we did not find here that astrocytes enhanced neuronal fate as proposed by Lie et al. (Lie et al., 2005). The key difference between their study and ours is, however, that they used neural precursor cells in direct contact with a feeder layer of astrocytes, which might point to the plausible idea that secreted and direct cell-to-cell mediators must go hand in hand. On one side this underscores the limitations of reductionistic assays, on the other side it confirms that single experiments will not deliver the full and complex picture. Second, we showed that endothelial cells can enhance neuronal differentiation. The influence of endothelial cells on supporting neuronal differentiation in murine precursor cells from adult SVZ had been observed previously (Shen et al., 2004). Although the study by Shen et al. was also performed in a transwell system with no direct cell contact of endothelial cells and precursor cells, an increased activation of Notch signaling target Hes1 was detected and seen as a mechanism for the continuous proliferation. Another study by Leventhal et al. showed that rat neural precursor cells from SVZ grown on top of endothelial cells had increased cell survival and generated more neurons, whereas co-cultures with fibroblasts and astrocytes did not (Leventhal et al., 1999). Taken together, our observed effects are in line with the reports by Shen et al. and Leventhal et al. but provide an additional perspective on the regulation in the hippocampal niche. One of the factors that have been identified as mediator between endothelial cells and neural stem cells of the SVZ is Pigment epithelium-derived factor (PEDF) (Ramírez-Castillejo et al., 2006). PEGF had a distinct effect on self-renewal (see, for example discussion in Ref. (Pumiglia and Temple, 2006)) and enhances Notch signaling (Andreu-Agulló et al., 2009). Our culture system will now allow similar investigations for adult hippocampal precursor cells.