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    • purchase CAL-101 Gregg and Weiss demonstrated that

    2018-10-22

    Gregg and Weiss (2003) demonstrated that intraventricular injection of EGF and TGF-α induces the generation of RGLCs in the SVZ in adult mice. Zhou et al. (2001) demonstrated that TGF-α induces, in vitro, the differentiation of mature astrocytes into radial cells. We analyzed the levels of TGF-α mRNA in the SVZ, and observed no differences among the groups over the time period investigated. It is possible that in our model, the increase in the number of RGLCs occurs by proliferation rather than differentiation of astrocytes (or ependymal cells) into RGLCs, since we observed an increase in both RGLCs and Ki67 in the lateral wall 7days after injury in the animals that received BMMC therapy. We attempted to quantify the number of proliferative RGLCs by analyzing the expression of nestin and Ki67 by confocal microscopy, in 800–900nm optical sections. In our previous study we demonstrated that RGLCs express nestin, a neural progenitor marker, although this stain is weaker than vimentin (Gubert et al., 2009). This characteristic could help us to distinguish the cell body of each radial process. Seven days post-surgery, we observed an increase in the number of nestin-positive processes in the BCCL+BMMC animals, as also observed with the vimentin staining (Supplemental Fig. 2). However, the SVZ is a dense cell layer, with many cells expressing nestin. Because the radial process is thin and tortuous, it was not possible to determine, in most cases, to which Ki67-positive cell body the process belongs. In a recent work from our group, it was shown that after a focal ischemia, most of the BMMCs migrate to internal organs, such as the liver and lungs. However, the small percentage of cells that reach the purchase CAL-101 parenchyma migrate preferentially to the lesion site (Vasconcelos-Dos-Santos et al., 2012). In our work, we observed a similar distribution of the transplanted cells into the liver and lungs, however since we did not perform a localized injury it was not possible to identify a brain region where the BMMCs would be preferentially confined. Even though we observed few BMMCs in the brain, there is some hypothesis that could explain how these cells are affecting the SVZ cells. First, it is possible that the number of BMMCs that infiltrate and survive into the brain would be enough to play this role through a paracrine signaling. A second possibility is through a “touch-and-go” mechanism, where the BMMCs would migrate to the injury site, release signals/molecules and then be cleared (for review see Uccelli et al., 2008). Moreover, we observed that the majority of RGLCs in the SVZ have a prominent contact/interaction with the blood vessels. Therefore, it would be possible to speculate that this interaction could transduce signals from the blood stream to the brain parenchyma through the RGLC processes. Our hypothesis is that BMMCs release cytokines and growth factors that could stimulate the proliferation and differentiation of SVZ cells. Bone-marrow cells express a wide range of factors, such as VEGF, BDNF, FGF-2, glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and hepatocyte growth factor (HGF), and they respond to an inflammation or injury by enhancing this expression (Chen et al., 2002; Kurozumi et al., 2005; Labouyrie et al., 1999; Ribeiro-Resende et al., 2009; Wang et al., 2006; Zaverucha-do-Valle et al., 2011). In addition, several other studies have demonstrated that bone-marrow cells can also modulate the expression of growth factor by neural cells, similarly to astrocytes (Gao et al., 2005; Gao et al., 2008). We analyzed the levels of several growth factors in the SVZ 3 and 7days post-surgery. BDNF expression increased in the treated animals 3days after the lesion and remained higher for at least 7days. Importantly, in the retina, Müller cells express BDNF, and this expression has been correlated with neuroprotection of retinal ganglion cells (Seki et al., 2005). Hence, in our model it is possible that RGLCs express BDNF, since we observed vimentin-positive radial processes labeled for BDNF. We also found that both the number of RGLCs and the levels of BDNF expression increased over the same period of time in the BCCL animals that received BMMC treatment. The increase in BDNF mRNA levels was observed also in the sham+BMMC animals, although the protein expression did not increase. Since, in this group, we only observed an increase in mRNA 7days after the insult, differently from the BCCL+BMMC animals that showed the increase after only 3days, it is possible that the increase in the protein expression could be observed only at later time points.