Browsing by Author "Corbett, Dale"
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Item Enriched environment enhances transplanted subventricular zone stem cell migration and functional recovery after stroke(2007) Rissanen, Anna; Hewlett, K.; Windle, V.; Chernenko, Garry A.; Ploughman, M.; Jolkkonen, Jukka; Weiss, S.; Corbett, DaleStroke patients suffer from severe impairments and significant effort is under way to develop therapies to improve functional recovery. Stem cells provide a promising form of therapy to replace neuronal circuits lost to injury. Indeed, previous studies have shown that a variety of stem cell types can provide some functional recovery in animal models of stroke. However, it is unlikely that replacement therapy alone will be sufficient to maximize recovery. The aim of the present study was to determine if rodent stem cell transplants combined with rehabilitation resulted in enhanced functional recovery after focal ischemia in rats. Middle cerebral artery occlusion was induced by injection of the vasoconstrictive peptide endothelin-1 adjacent to the middle cerebral artery. Seven days after stroke the rats received adult neural stem cell transplants isolated from mouse subventricular zone or vehicle injection and then subsequently were housed in enriched or standard conditions. The rats in the enriched housing also had access to running wheels once a week. Enriched housing and voluntary running exercise enhanced migration of transplanted stem cells toward the region of injury after stroke and there was a trend toward increased survival of stem cells. Enrichment also increased the number of endogenous progenitor cells in the subventricular zone of transplanted animals. Finally, functional recovery measured in the cylinder test was facilitated only when the stem cell transplants were combined with enrichment and running exercise 7 days after the transplant. These results suggest that the ability of transplanted stem cells in promoting recovery can be augmented by environmental factors such as rehabilitation.Item Long-term assessment of enriched housing and subventricular zone derived cell transplantation after focal ischemia in rats(2008) Rissanen, Anna; MacLellan, Crystal L.; Chernenko, Garry A.; Corbett, DaleThe potential for using stem cells to treat stroke has garnered much interest, but stem cell therapies must be rigorously tested in animal models before transplantation studies progress to clinical trials. An enriched environment enhances transplanted subventricular zone (SVZ) cell migration and functional benefit following stroke in rats. However, the ability of SVZ cells to survive, migrate, differentiate and promote functional recovery at protracted survival times (e.g., 3 months) has not been investigated. The vasoconstrictive peptide endothelin-1 was injected adjacent to the middle cerebral artery to produce focal ischemia. Seven days later, cells derived from the SVZ of adult mice (800,000 cells/rat or vehicle injection) were transplanted into the sensory-motor cortex and striatum, and rats were then housed in enriched or standard conditions. Rats in enriched housing had access to running wheels once per week. Recovery was assessed in the forelimb-use asymmetry task (cylinder) at 1, 2, or 3 months after transplantation immediately prior to euthanasia. Transplanted cell survival and migration were quantified using stereology. Cell phenotype was determined with immunohistochemistry and confocal microscopy. Enriched housing did not enhance survival or migration of transplanted SVZ cells at protracted survival times, and the majority (~ 99%) of cells died within 2 months of transplantation. Cell survival was significantly, and negatively, correlated with microglial activation. Many surviving cells expressed an astrocytic phenotype. Functional recovery was not improved at any time. Therapies involving transplantation of SVZ cells following stroke must be further optimized in order to enhance long-term cell survival and thereby maximize functional benefit.Item Transplantation of human embryonic stem cell-derived neural precursor cells and enriched environment after cortical stroke in rats: cell survival and functional recovery(2009) Rissanen, Anna; Lappalainen, Riikka S.; Narkilahti, Susanna; Suuronen, Riitta; Corbett, Dale; Sivenius, Juhani; Hovatta, Outi; Jolkkonen, JukkaCortical stem cell transplantation may help replace lost brain cells after stroke and improve the functional outcome. In this study, we transplanted human embryonic stem cell (hESC)-derived neural precursor cells (hNPCs) or vehicle into the cortex of rats after permanent distal middle cerebral artery occlusion (dMCAO) or sham-operation, and followed functional recovery in the cylinder and staircase tests. The hNPCs were examined prior to transplantation, and they expressed neuroectodermal markers but not markers for undifferentiated hESCs or non-neural cells. The rats were housed in either enriched environment or standard cages to examine the effects of additive rehabilitative therapy. In the behavioral tests dMCAO groups showed significant impairments compared with sham group before transplantation. Vehicle groups remained significantly impaired in the cylinder test 1 and 2 months after vehicle injection, whereas hNPC transplanted groups did not differ from the sham group. Rehabilitation or hNPC transplantation had no effect on reaching ability measured in the staircase test, and no differences were found in the cortical infarct volumes. After 2 months we measured cell survival and differentiation in vivo using stereology and confocal microscopy. Housing had no effect on cell survival or differentiation. The majority of the transplanted hNPCs were positive for the neural precursor marker nestin. A portion of transplanted cells expressed neuronal markers 2 months after transplantation, whereas only a few cells co-localized with astroglial or oligodendrocyte markers. In conclusion, hESC-derived neural precursor transplants provided some improvement in sensorimotor function after dMCAO, but did not restore more complicated sensorimotor functions.