stroke lesion via SDF-1/CXCR4 chemokine signaling. Additional studies will be required to substantiate this hypothesis. The previously observed effects of DPSCs on host axonal remodeling [7] led us to postulate that the cells might have a similar effect on the rescue of progressive corpus callosum atrophy following ischemic stroke. Indeed, we showed that there was a trend toward better preservation of interhemispheric axon projections in the postischemic brains of DPSC-treated animals in comparison with vehicle controls, although this did not reach statistical significance. The concept that stem/progenitor cells express an array of factors that may interact with host tissue is important and may underlie the non-neural replacement mechanisms of action of cell-based therapy that results in restoration of neurological function in a range of injury or disease scenarios [48]. Human dental pulp cells are known to secrete a range of factors, including NGF, BDNF, GDNF, and SDF-1 [4, 7]. Some of these factors have been shown to be beneficial specifically in ischemic stroke: BDNF provides trophic support and prevents parenchymal cells in the penumbra from further degradation [49], whereas GDNF secretion by reactive astrocytes along the IBZ has been associated with the rescue of dying cells in the ischemic border [50]. At 4 weeks poststroke, few DPSC-derived cells remain in the rodent brain; however, a large proportion of these cells had differentiated into GFAPexpressing cells, indicative of astrocytes. It is possible that these DPSC-derived GFAPpositive cells may also play active roles in improving neurological function after stroke, as suggested by other investigators [51]. Within the glial scar of the IBZ, expression of nestin by DPSC-derived cells suggests that these cells may undergo a recapitulation of neurodevelopmental molecular pathways. The observed engraftment of DPSC-derived cells into the wall of cerebral microvessels was a rare occurrence in this study. This observation is consistent with previous studies that showed that transplanted DPSCs [12, 52] and bone marrow-derived mesenchymal stem cells [12, 52] following myocardial infarction infrequently differentiated into endothelial, cardiac or smooth muscle cells. This suggests that transplanted stem/progenitor cells may not be involved structurally in the formation of new blood vessels following cerebral ischemia but instead may play a role in secreting factors, such as VEGF, to enhance endogenous angiogenesis and neurogenesis [53]. Recently, human VEGF was shown to be an important molecule contributing to cell-enhanced functional recovery following ischemic stroke [54]. Transplanted DPSCs may also play an immunomodulatory role through varied secreted factors to improve function after stroke. We and others have previously reported the immunomodulation properties of DPSCs to dampen immune responses, similarly to the properties described for other mesenchymal stem cell-like populations [55–57].
Conclusion This study provides preclinical evidence of the therapeutic efficacy of human adult DPSCs to enhance the recovery of poststroke sensorimotor deficits. DPSCs isolated from third molars are a clinically accessible source of stem cells. In this study, we transplanted DPSCs