The transplantation of neural precursor cells (NPCs) is known to be a promising approach to ameliorating behavioral deficits after stroke in a rodent model of middle cerebral artery occlusion (MCAo). Previous studies have shown that transplanted NPCs migrate toward the infarct region, survive and differentiate into mature neurons to some extent. However, the spatiotemporal dynamics of NPC migration following transplantation into stroke animals have yet to be elucidated. In this study, we investigated the fates of human embryonic stem cell (hESC)-derived NPCs (ENStem-A) for 8 weeks following transplantation into the side contralateral to the infarct region using 7.0T animal magnetic resonance imaging (MRI). T2- and T2*-weighted MRI analyses indicated that the migrating cells were clearly detectable at the infarct boundary zone by 1 week, and the intensity of the MRI signals robustly increased within 4 weeks after transplantation. Afterwards, the signals were slightly increased or unchanged. At 8 weeks, we performed Prussian blue staining and immunohistochemical staining using human-specific markers, and found that high percentages of transplanted cells migrated to the infarct boundary. Most of these cells were CXCR4-positive. We also observed that the migrating cells expressed markers for various stages of neural differentiation, including Nestin, Tuj1, NeuN, TH, DARPP-32 and SV38, indicating that the transplanted cells may partially contribute to the reconstruction of the damaged neural tissues after stroke. Interestingly, we found that the extent of gliosis (glial fibrillary acidic protein-positive cells) and apoptosis (TUNEL-positive cells) were significantly decreased in the cell-transplanted group, suggesting that hESC-NPCs have a positive role in reducing glia scar formation and cell death after stroke. No tumors formed in our study. We also performed various behavioral tests, including rotarod, stepping and modified neurological severity score tests, and found that the transplanted animals exhibited significant improvements in sensorimotor functions during the 8 weeks after transplantation. Taken together, these results strongly suggest that hESC-NPCs have the capacity to migrate to the infarct region, form neural tissues efficiently and contribute to behavioral recovery in a rodent model of ischemic stroke.
Animals ; Apoptosis ; Cell Differentiation ; *Cell Movement ; Embryonic Stem Cells/cytology/metabolism/*transplantation ; Glial Fibrillary Acidic Protein/genetics/metabolism ; Humans ; Infarction, Middle Cerebral Artery/metabolism/pathology/physiopathology/*surgery ; Male ; Neural Stem Cells/cytology/metabolism/*transplantation ; *Psychomotor Performance ; Rats ; Rats, Sprague-Dawley ; Receptors, CXCR4/genetics/metabolism

Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients can provide immense opportunities to model human diseases, which may lead to develop novel therapeutics. Huntington's disease (HD) is a devastating neurodegenerative genetic disease, with no available therapeutic options at the moment. We recently reported the characteristics of a HD patient-derived iPSC carrying 72 CAG repeats (HD72-iPSC). In this study, we investigated the in vivo roles of HD72-iPSC in the YAC128 transgenic mice, a commonly used HD mouse model carrying 128 CAG repeats. To do this, we transplanted HD72-iPSC-derived neural precursors into the striatum of YAC128 mice bilaterally and observed a significant behavioral improvement in the grafted mice. Interestingly, the transplanted HD72-iPSC-derived neural precursors formed GABAeric neurons efficiently, but no EM48-positive protein aggregates were detected at 12 weeks after transplantation. Taken together, these results indicate no HD pathology was developed from the grafted cells, or no transmission of HD pathology from the host to the graft occurred at 12 weeks post-transplantation.
Animals ; GABAergic Neurons ; Humans ; Huntington Disease* ; Induced Pluripotent Stem Cells ; Mice ; Mice, Transgenic ; Neurons ; Pathology ; Pluripotent Stem Cells* ; Transplants