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    • In this study we propose that astrocytic calcium

    2018-11-09

    In this study, we propose that astrocytic calcium waves are long-range signals capable of transmitting the occurrence of a purchase chir99021 injury to the SVZ, where they stimulate NSC proliferation and self-renewal and increase the migratory potential of NSPCs, as observed in various stroke models. Analysis of changes in gene expression in the SVZ after ischemia induced by a permanent occlusion of the middle cerebral artery showed a strong upregulation of components of the calcium-binding protein GO cluster, but not of signatures associated with immune cells or hypoxia. Given the typical properties of the SVZ reaction, in that it is fast and spatially limited to the injured hemisphere, we hypothesized that traveling astrocytic calcium waves arising from extensive tissue damage may transmit the information that a local injury has occurred over long distances to the SVZ. Interestingly, and similar to our findings, it was recently shown that calcium waves activate migratory behavior of microglia in the zebrafish brain in response to injury (Sieger et al., 2012). To study the effect of a physiological calcium signal carried only by astrocytes and transmitted to NSPCs in isolation, i.e., separated from simultaneously occurring processes such as neuronal transmission or spreading depression, we devised an in vitro co-culture system. NSCs can be very efficiently differentiated to astrocytes by addition of CNTF to the differentiation medium. A detailed characterization of calcium waves in these cells revealed a uniform propagating wave, recruiting all cells in a homogeneous fashion. Notably, the velocity of the astrocytic calcium waves of about 0.02 mm/s is three orders of magnitude slower compared with neuronal calcium waves, ranging between 30 and 50 mm/s (Stroh et al., 2013) and suggesting a differential mechanism of wave initiation and propagation. However, the velocity of these waves is in line with that of astrocytic calcium waves in the neocortex, at 0.014 ± 0.005 mm/s (Söhl et al., 2006). Also spreading depression, a form of neuronal slow propagation (3–6 mm/min, 0.05–0.1 mm/s) in rat cortex (Fujita et al., 2016) is accompanied by an astrocytic calcium wave (Peters et al., 2003). Central to our hypothesis, an elevation in intracellular calcium could be passed on from astrocytes to co-cultured neurospheres in vitro. We also observed the spreading of a calcium wave from the striatum to the adjacent SVZ in acute slices in vivo after electrical stimulation (Figure S4), showing kinetics similar to that of our in vitro data. In the astrocyte-neurosphere co-culture system we demonstrated an increase in sphere number, indicating increased self-renewal mediated by astrocytic calcium waves. Interestingly, we found a concomitant increase specifically in the population of the largest spheres. The largest spheres in a neurosphere culture typically arise from NSCs, in contrast to smaller spheres that originate in less primitive precursor cells or transient amplifying cells in vivo. Thus, the increase in the number of large spheres after a calcium signal may reflect a shift from asymmetric to symmetric division of stem cells, consistent with evidence from previous in vivo data (Zhang, 2004), rather than being the result of a simple change in proliferation that would affect all cells. Beyond this, calcium waves transmitted via gap junctions or by release of ATP and activation of purinergic receptors have been shown to influence neurogenesis in the adult brain SVZ (Lacar et al., 2011; Lin et al., 2007). The nature of the calcium signal to stem cells seems to be important for the type of response that is elicited. While NSC after astrocytic calcium wave did not change their differentiation potential, a previous study by one of the authors found that long-term optical stimulation of stem cells transduced with channelrhodopsin-2 led to an increase in neuronal differentiation and that this effect was likely due to calcium signaling (Stroh et al., 2011). In addition to initiating the injury response by an activation of quiescent NSCs, astrocytic calcium waves may have an important function in stimulating and guiding the migratory behavior of immature cells toward the injury. We showed that stimulating neurospheres with an astrocytic calcium wave was sufficient to increase cellular migratory potential. This was consistent with experiments showing that neurospheres cultivated from stroke mice display a higher migratory potential than that of neurospheres derived from non-stroke animals, indicating the induction of permanent changes (Zhang et al., 2007). The extent to which calcium signaling may contribute to directing neuroblast migration toward the injury site remains unclear, and a number of other signaling molecules have been suggested in this context. However, data on astrocytic calcium wave-induced responses in murine microglia (Schipke et al., 2002), as well as guidance of microglia in the zebrafish brain (Sieger et al., 2012), suggest that calcium waves are both necessary and sufficient for microglia migration to the site of injury.