In support of this, treatments that block CXCL12 signaling were found to result in a marked impairment of migration and proliferation of the engrafted GSK2118436 clinical trial NSPCs [14]. Furthermore, locally

administered CXCL12 stimulates the recruitment of stem/progenitor cells, which promotes repair in stroke [15] and ischemic lesions [20], functional improvement of Alzheimer disease [19], skeletal regeneration [16], and wound healing [17]. The first clear demonstration that NSPCs could exhibit migratory activity toward the site of a brain tumor was provided by Aboody and colleagues [9]. NSPCs have the potential to specifically target the sites of brain tumors [9] and could thus be used as therapeutic vehicles [21]. If the targeted migration of NSPCs could be accelerated by promoting CXCL12 signaling, this would make NSPCs particularly useful in cell-based brain tumor therapy. However, the strategy of promoting migratory behavior in brain tumors by the manipulation of CXCL12 signaling has not been examined in vivo previously. To assess the effects of this strategy on brain tumors, this study used magnetic resonance imaging (MRI) to monitor the pathologic changes of brain tumors in vivo following combined treatment with NSPC implantation and CXCL12 facilitation. The effects

PCI-32765 ic50 of treatments on the natural development of glioma were investigated using a model of spontaneous brain tumor in which rats develop various gliomas several months after transplacental administration of N-ethyl-N-nitrosourea (ENU) as described previously [22], [23] and [24]. Furthermore, the immune rejection responses of the xenografts [25] were minimized by using the same species of NSPCs as that used in the ENU-induced rat brain tumor model. The tumorigenic potential of immortalized cells [26], [27] and [28] was avoided by applying NSPCs from primary cultures. The locations of cells were determined by injecting green

fluorescent protein (GFP)–expressing NSPCs (GFP-NSPCs) filipin from GFP-expressing transgenic rats intraventricularly into the brain of tumor-bearing rats. Simultaneously, these rats received an intracerebral injection of CXCL12 near to the tumor sites to promote NSPC migration. MRI was applied because it allows repeated imaging with a high spatial resolution; MRI can provide accurate tumor volume measurements and morphologic information over longitudinal time points and can thus be used to evaluate the effects of cell therapies [29]. T2-weighted MRI images (T2WIs) were acquired to measure tumor volumes and monitor the tumor morphology [30] for 42 days after surgery. T2WIs further confirmed the histologic features of the gliomas following the treatments. The findings of this study suggest that CXCL12 is an effective chemoattractant that facilitates the tumor-targeted migration of exogenous NSPCs and that CXCL12 and NSPC can act synergistically to promote tumor progression with severe hemorrhage.