Abstract
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.
Highlights
Stroke is one of the leading causes of death and disability worldwide
The first clinical trial using neural precursor cells (NPCs) in stroke patients was performed by ReNeuron using clonal, conditionally immortalized neural stem cells isolated from human fetal cortex, and the preliminary report suggests that the NPC transplantation is safe.[3]
Characterization of human embryonic stem cell (hESC)-NPCs (ENStem-A) To characterize hESC-NPCs (ENStem-A), we plated them on a coverslip precoated with laminin
Summary
Stroke is one of the leading causes of death and disability worldwide Thrombolytic treatments, such as tissue plasminogen activator, are effective for the treatment of stroke, o10% of stroke patients benefit from this type of treatment because of its narrow therapeutic time window (within 4.5 h after onset).[1] Despite extensive research using animal models, no neuroprotective agent has been demonstrated to be effective in the recovery of primary or secondary damage following stroke in clinical trials.[2]. The first clinical trial using NPCs in stroke patients was performed by ReNeuron using clonal, conditionally immortalized neural stem cells isolated from human fetal cortex, and the preliminary report suggests that the NPC transplantation is safe.[3] Most previous experimental studies have indicated that NPCs transplanted into the ipsilesional cerebral hemisphere before or after stroke underwent robust targeted transparenchymal migration toward the lesion boundary.[4,5,6,7] This intriguing phenomenon may be orchestrated by multiple factors or the host environment, which is not fully understood. Several studies have shown that embryonic stem cells or NPCs that were transplanted into the side contralateral to the cerebral infarction migrate toward the lesion and survive.[8,9,10] This result indicates that a strong, long-range chemotactic gradient sufficient to induce travel from the implantation site to the lesion site may be present
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