Bone Marrow Stromal Cells With Exercise and Thyroid Hormone Effect on Post-Stroke Injuries in Middle-aged Mice (original) (raw)
Related papers
2019
Introduction: Based on our previous findings, the treatment of stem cells alone or in combination with thyroid hormone (T3) and mild exercise could effectively reduce the risk of stroke damage in young mice. However, it is unclear whether this treatment is effective in aged or middle-aged mice. Therefore, this study designed to assess whether combination of Bone Marrow Stromal Cells (BMSCs) with T3 and mild treadmill exercise can decrease stroke complications in middle-aged mice. Methods: Under laser Doppler flowmetry monitoring, transient focal cerebral ischemia was produced by right Middle Cerebral Artery Occlusion (MCAO) for 45 min followed by 7 days of reperfusion in middle-aged mice. BMSCs (1×105) were injected into the right cerebral ventricle 24 h after MCAO, followed by daily injection of triiodothyronine (T3) (20 μg/100 g/d SC) and 6 days of running on a treadmill. Infarct size, neurological function, apoptotic cells and expression levels of Glial Fibrillary Acidic Protein (GFAP) were evaluated 1 week after stroke. Results: Post-ischemic treatment with BMSCs or with T3 and or mild treadmill exercise alone or in combination did not significantly change neurological function, infarct size, and apoptotic cells 7 days after ischemia in middle-aged mice (P>0.05). However, the expression of GFAP significantly reduced after treatment with BMSCs and or T3 (P<0.01). Conclusion: Our findings indicate that post-stroke treatment BMSCs with exercise and thyroid hormone cannot reverse neuronal damage 7 days after ischemia in middle-aged mice. These findings further support that age is an important variable in stroke treatment
Metabolic Brain Disease, 2017
This study examined whether post-stroke bone marrow stromal cells (BMSCs) therapy combined with exercise (EX) and/or thyroid hormone (TH) could reduce brain damage in an experimental ischemic stroke in mice. Focal cerebral ischemia was induced under Laser Doppler Flowmetry (LDF) guide by 45 min of middle cerebral artery occlusion (MCAO), followed by 7 days of reperfusion in albino mice. BMSCs were injected into the right cerebral ventricle 24 h after MCAO, followed by daily injection of T3 (20 μg/100 g weight S.C) and 6 days of running on a treadmill. Infarct size, neurobehavioral test, TUNEL and BrdU positive cells were evaluated at 7 days after MCAO. Treatment with BMSCs and mild EX alone significantly reduced the infarct volume by 23% and 44%, respectively (both, p < 0.001). The BMSCs + TH, BMSCs + EX, and BMSCs + EX + TH combination therapies significantly reduced the infarct volume by 26%, 51%, and 70%, respectively (all, p < 0.001). A significant improvement in the neurobehavioral functioning was observed in the EX, BMSCs + EX, and BMSCs + EX+ TH groups (p < 0.001). The number of TUNEL-positive cells (a marker of apoptosis) was significantly reduced in the EX, BMSCs, BMSCs + EX, BMSCs + TH, and BMSCs + EX + TH groups (all, p < 0.001). Moreover, the combination therapy considerably increased BrdU-labeled cells in the subventricular zone (SVZ) (p < 0.01). Our findings indicated that the combined treatment of BMSCs with mild EX and TH more efficiently reduces the cerebral infarct size after stroke. More likely, these effects mediate via enchaining generation of new neuronal cells and the attenuation of apoptosis in ischemia stroke in young mice.
Stem cell therapies in preclinical models of stroke associated with aging
Frontiers in Cellular Neuroscience, 2014
Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments related to unfavorable environments that are in part related to aging processes. Since stroke afflicts mostly the elderly, it is highly desirable and clinically important to test the efficacy of cell therapies in aged brain microenvironments. Although widely believed to be refractory to regeneration, recent studies using both neural precursor cells and bone marrow-derived mesenchymal stem cells for stroke therapy suggest that the aged rat brain is not refractory to cell-based therapy, and that it also supports plasticity and remodeling. Yet, important differences exist in the aged compared with young brain, i.e., the accelerated progression of ischemic injury to brain infarction, the reduced rate of endogenous neurogenesis and the delayed initiation of neurological recovery. Pitfalls in the development of cell-based therapies may also be related to age-associated comorbidities, e.g., diabetes or hyperlipidemia, which may result in maladaptive or compromised brain remodeling, respectively. These age-related aspects should be carefully considered in the clinical translation of restorative therapies.
One-Year Follow-Up After Bone Marrow Stromal Cell Treatment in Middle-Aged Female Rats With Stroke
2010
We sought to evaluate the long-term effects of bone marrow stromal cell (BMSC) treatment on retired breeder rats with stroke. Female retired breeder rats were subjected to 2-hour middle cerebral artery occlusion (MCAO) followed by an injection of 2 x 10(6) male BMSCs (n=8) or phosphate-buffered saline (n=11) into the ipsilateral internal carotid artery at 1 day after stroke. The rats were humanely killed 1 year later. Functional tests, in situ hybridization, and histochemical and immunohistochemical staining were performed. Significant recovery of neurological deficits was found in BMSC-treated rats beginning 2 weeks after cell injection compared with control animals. The beneficial effects of cell transplantation persisted for at least 1 year (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). In situ hybridization for the Y chromosome showed that donor cells survived in the brains of recipient rats, among which 22.3+/-1.95% of cells expressed the astrocyte marker glial fibrillary acidic protein, 16.8+/-2.13% expressed the neuronal marker microtubule-associated protein 2, and 5.5+/-0.42% and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1% of cells colocalized with the microglial marker IB4 and the endothelial cell marker von Willebrand factor, respectively. Only very few BMSCs, however, were found in peripheral organs such as the heart, lung, liver, spleen, and kidney in recipient rats. BMSCs significantly reduced axonal loss (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01), the thickness of the lesion scar wall (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01), and the number of Nogo-A-positive cells (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) along the scar border; meanwhile, synaptophysin expression (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) was significantly increased in BMSC-treated ischemic brains compared with control untreated brains. The beneficial effects of BMSCs on ischemic brain tissue persisted for at least 1 year. Most surviving BMSCs were present in the ischemic brain, but very few were found in other organs. The long-term improvement in functional outcome may be related to the structural and molecular changes induced by BMSCs.
International Journal of Molecular Sciences, 2013
The induction of angiogenesis will stimulate endogenous recovery mechanisms, which are involved in the long-term repair and restoration process of the brain after an ischemic event. Here, we tested whether exercise influences the pro-angiogenic factors and outcomes after cerebral infarction in rats. Wistar rats were exposed to two hours of middle-cerebral artery occlusion and reperfusion. Different durations of treadmill training were performed on the rats. The expression of matrix metalloproteinase 2 (MMP2) and vascular endothelial growth factor (VEGF)-related genes and proteins were higher over time post-ischemia, and exercise enhanced their expression. Sixteen days post-ischemia, the regional cerebral blood flow in the ischemic striatum was significantly increased in the running group over the sedentary. Although no difference was seen in infarct size between the running and sedentary groups, running evidently improved the neurobehavioral score. The effects of running on MMP2 expression, regional cerebral blood flow and outcome were abolished when animals were treated with bevacizumab (BEV), a VEGF-targeting antibody. Exercise therapy improves long-term stroke outcome by MMP2-VEGF-dependent mechanisms related to improved cerebral blood flow.
Gerontology, 2008
Background: Age-related brain injuries, including stroke, are a major cause of physical and mental disabilities. Objective: Therefore, studying the basic mechanism underlying functional recovery after brain stroke in aged subjects is of considerable clinical interest. Methods: This review summarizes the effects of age on recovery after stroke in an animal model, with emphasis on the underlying cellular mechanisms. Results: Data from our laboratory and elsewhere indicate that, behaviorally, aged rats were more severely impaired by stroke than young rats, and they also showed diminished functional recovery. Infarct volume did not differ significantly between young and aged animals, but critical differences were apparent in the cytological response to stroke, most notably an age-related acceleration in the development of the glial scar. Early infarct in older rats is associated with premature accumulation of BrdU-positive microglia and astrocytes, persistence of activated oligodendrocy...
Neuroscience Letters, 2003
Traumatic brain injury (TBI) causes cognitive impairments, motor deficits, and neuropsychiatric/behavioral deficits problems. Transplantation of bone marrow stromal cells (BMSCs) facilitates functional recovery from brain insults. Treadmill exercise increases neurogenesis and inhibits apoptosis. In this study, we investigated the effects of BMSC transplantation in combination with treadmill exercise on memory function, by evaluating its effect on neurogenesis and apoptosis in the hippocampus following TBI. Methods: TBI was induced using an electromagnetic-controlled cortical impact device. BMSCs were transplanted into both sides of traumatic scar region 1 week after TBI induction. One week after transplantation of BMSCs, the rats in the exercise groups were trained to run on a treadmill for 30 minutes once daily for 28 days. Step-down avoidance task and radial 8-arm maze test were conducted. Levels of 5-bromo-2ʹ-deoxyuridine and caspase-3 were evaluated using immunohistochemistry. Western blot was used to evaluate the expression of brain-derived neurotrophic factor (BDNF), tyrosine kinase B (TrkB), totalextracellular signal-regulated kinase 1 and 2 (t-ERK1/2), phosphorylated-ERK1/2 (p-ERK1/2), Bcl-2, and Bax. Results: TBI deteriorated memory function, suppressed neurogenesis, and accelerated apoptosis in the hippocampus. Treadmill exercise and BMSC transplantation independently improved memory function by increasing neurogenesis with suppression of apoptosis through the BDNF-ERK pathway in the TBI-induced rats. Combination of BMSC transplantation with treadmill exercise showed additional enhancement of neurogenesis and suppression of apoptosis in the hippocampus. Conclusions: The present study shows that treadmill exercise may aid the therapeutic effect of BMSC transplantation on TBI in rats.
Effect of a multinutrient intervention after ischemic stroke in female C57Bl/6 mice
Journal of Neurochemistry, 2017
Stroke can affect females very differently from males, and therefore preclinical research on underlying mechanisms and the effects of interventions should not be restricted to male subjects, and treatment strategies for stroke should be tailored to benefit both sexes. Previously, we demonstrated that a multinutrient intervention (Fortasyn) improved impairments after ischemic stroke induction in male C57Bl/6 mice, but the therapeutic potential of this dietary treatment remained to be investigated in females. We now induced a transient middle cerebral artery occlusion (tMCAo) in C57Bl/6 female mice and immediately after surgery switched to either Fortasyn or an isocaloric Control diet. The stroke females performed several behavioral and motor tasks before and after tMCAo and were scanned in an 11.7 Tesla MRI scanner to assess brain perfusion, integrity and functional connectivity. To assess brain plasticity, inflammation and vascular integrity, immunohistochemistry was performed after sacrifice of the mice. We found that the multinutrient intervention had diverse effects on the stroke-induced impairments in females. Similar to previous Accepted Article This article is protected by copyright. All rights reserved. observations in male stroke mice, brain integrity, sensorimotor integration and neurogenesis benefitted from Fortasyn, but impairments in activity and motor skills were not improved in female stroke mice. Overall, Fortasyn effects in the stroked females seem more modest in comparison to previously investigated stroked male mice. We suggest that with further optimization of treatment protocols more information on the efficacy of specific interventions in stroked females can be gathered. This in turn will help with the development of (gender-specific) treatment regimens for cerebrovascular diseases such as stroke.
Acta Neuropathologica, 2007
Old age is associated with a deWcient recovery from stroke, but the cellular mechanisms underlying such phenomena are poorly understood. To address this issue, focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3-and 20-month-old male Sprague-Dawley rats. Aged rats showed a delayed and suboptimal functional recovery in the post-stroke period. Using BrdU-labeling, quantitative immunohistochemistry and 3-D reconstruction of confocal images, we found that aged rats are predisposed to rapidly develop an infarct within the Wrst few days after ischemia. The emergence of the necrotic zone is associated with a high rate of cellular degeneration, premature accumulation of proliferating BrdU-positive cells that appear to emanate from capillaries in the infarcted area, and a large number of apoptotic cells. With double labeling techniques, we were able to identify, for the Wrst time, over 60% of BrdU-positive cells either as reactive microglia (45%), oligodendrocyte progenitors (17%), astrocytes (23%), CD8+ lymphocytes (4%), or apoptotic cells (<1%). Paradoxically, despite a robust reactive phenotype of microglia and astrocytes in aged rats, at 1-week post-stroke, the number of proliferating microglia and astrocytes was lower in aged rats than in young rats. Our data indicate that aging is associated with rapid infarct development and a poor prognosis for full recovery from stroke that is correlated with premature cellular proliferation and increased cellular degeneration and apoptosis in the infarcted area.
Accelerated infarct development, cytogenesis and apoptosis following cerebral ischemia in aged rats
Exp Gerontol, 2007
Old age is associated with a deWcient recovery from stroke, but the cellular mechanisms underlying such phenomena are poorly understood. To address this issue, focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3-and 20-month-old male Sprague-Dawley rats. Aged rats showed a delayed and suboptimal functional recovery in the post-stroke period. Using BrdU-labeling, quantitative immunohistochemistry and 3-D reconstruction of confocal images, we found that aged rats are predisposed to rapidly develop an infarct within the Wrst few days after ischemia. The emergence of the necrotic zone is associated with a high rate of cellular degeneration, premature accumulation of proliferating BrdU-positive cells that appear to emanate from capillaries in the infarcted area, and a large number of apoptotic cells. With double labeling techniques, we were able to identify, for the Wrst time, over 60% of BrdU-positive cells either as reactive microglia (45%), oligodendrocyte progenitors (17%), astrocytes (23%), CD8+ lymphocytes (4%), or apoptotic cells (<1%). Paradoxically, despite a robust reactive phenotype of microglia and astrocytes in aged rats, at 1-week post-stroke, the number of proliferating microglia and astrocytes was lower in aged rats than in young rats. Our data indicate that aging is associated with rapid infarct development and a poor prognosis for full recovery from stroke that is correlated with premature cellular proliferation and increased cellular degeneration and apoptosis in the infarcted area.