Browsing by Author "Jolkkonen, Jukka"
Now showing 1 - 5 of 5
Results Per Page
Sort Options
Item Cell-based therapies and functional outcome in experimental stroke(2009) Rissanen, Anna; Schallert, Timothy; Jolkkonen, JukkaOne of the most promising frontiers in neuroscience is the potential for stem cells to treat brain damage. Cell-based strategies are of particular interest in neurological conditions because mature brains have limited capacity for self-repair. It is often argued that stem cells might be used to replace lost neurons and restore function (Lindvall et al., 2004). Prior to clinical trials, safety and efficacy must be demonstrated in animal models. Indeed, a recent review strongly suggests that preclinical and clinical trial procedures and outcome measures, including behavioral assessments, must be closely aligned and sophisticated (Ginsberg, 2008). Unfortunately, a lack of translational success has been observed in stroke neuroprotection trials conducted thus far, and this experience should serve to caution that histological benefits in animals are not a sufficient reason to move to the clinic carelessly.Item Challenges and possibilities of intravascular cell therapy in stroke(2009) Rissanen, Anna; Jolkkonen, JukkaStroke is the third leading cause of death in Western countries and more importantly a leading cause of adult disability. The recovery process of stroke patients might be enhanced by intensive rehabilitation, which acts through brain plasticity mechanisms. Restorative approaches such as cell-based therapies are clinically appealing as it might be possible to help patients even when treatment is initiated days or weeks after the ischemic insult. An extensive number of experimental transplantation studies have been conducted with cells of different origins (e.g., embryonic stem, fetal neural stem, human umbilical cord blood) with promising results. Noninvasive intravascular administration of cells, which provides a broad distribution of cells to the close proximity of ischemic tissue, has perhaps the most immediate access to clinical applications. However, surprisingly little is known about whole body biodistribution of intravascularly administered cells and mechanisms leading to improved functional recovery. This review examines the recent literature concerning intravascular cell-based therapies in experimental stroke.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 Prolonged bihemispheric alterations in unfolded protein response related gene expression after experimental stroke(2006) Rissanen, Anna; Sivenius, Juhani; Jolkkonen, JukkaAfter ischemia, endoplasmic reticulum (ER) stress pathways are activated that include unfolded protein response (UPR) and protein synthesis inhibition (PSI). Both of these mechanisms aim to restore ER functioning mainly by inhibition of translation and increased processing of excess proteins in ER. We were interested in the role of these pathways during spontaneous recovery after transient middle cerebral artery occlusion (MCAO) in rats. The spontaneous recovery of rats was assessed with a limb-placing test. The expression of ER-stress-related genes (IRE1, ATF6, GRP78, eif2α, ATF4, PERK) was studied by using in situ hybridization in different brain areas on post-operative days 2, 7, 14 and 28. Elevated signals were detected in striatum contralateral to the lesion on days 2 (PERK and IRE1) and 14 post-ischemia (IRE1). Gene expression was elevated on day 7 in the striatum ipsilateral to the lesion (ATF6 and GRP78) and on day 14 (GRP78) post-ischemia. Furthermore, elevated levels of GRP78 were detected on day 14 after ischemia in the ipsilateral sensorimotor cortex. These results suggest that altered gene expression related to unfolded protein response may be more long lasting than expected following focal cerebral ischemia. In addition, these results show that the response to ER stress differs ipsi- and contralaterally after MCAO in rats. Since these differences are detected in both hemispheres only in areas adjacent to the lesion, UPR may contribute to spontaneous recovery after MCAO in rats.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.