Stem cell therapies in preclinical models of stroke associated with aging (original) (raw)
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Journal of Cerebral Blood Flow & Metabolism, 2014
Neural stem cells (NSCs) show therapeutic potential for ischemia in young-adult animals. However, the effect of aging on NSC therapy is largely unknown. In this work, NSCs were transplanted into aged (24-month-old) and young-adult (3-month-old) rats at 1 day after stroke. Infarct volume and neurobehavioral outcomes were examined. The number of differentiated NSCs was compared in aged and young-adult ischemic rats and angiogenesis and neurogenesis were also determined. We found that aged rats developed larger infarcts than young-adult rats after ischemia ( P<0.05). The neurobehavioral outcome was also worse for aged rats comparing with young-adult rats. Brain infarction and neurologic deficits were attenuated after NSC transplantation in both aged and young-adult rats. The number of survived NSCs in aged rats was similar to that of the young-adult rats ( P>0.05) and most of them were differentiated into glial fibrillary acidic protein+ (GFAP+) cells. More importantly, angiogene...
PubMed, 2013
Cerebral plasticity and neurological recovery can be stimulated in the ischemic brain by exogenous pharmacological and cell-based treatments. Neurons, neuroblasts and endothelial cells synergistically interact with each other as a regenerative triad, creating an environment in which neurological recovery takes place. Developmental genetic programs are reactivated. Brain neurons and capillary cells are enabled to sprout, and glial cells support plasticity processes. Until now, the large majority of studies were performed in young, otherwise healthy animals, which lack the risk factors and co-morbidities associated with human stroke. Recent behavioral, histochemical and molecular biological studies have shown that restorative brain responses may differ between young and old animals, and that they are also modulated by vascular risk factors, such as hyperlipidemia and diabetes, which are highly prevalent in ischemic stroke. We claim that age aspects, vascular risk factors and co-morbidities should more intensively be examined in future experimental studies. Confounding effects of age, risk factors and co-morbidities should carefully be considered in clinical proof-of-concept trials.
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...
Journal of Cerebral Blood Flow & Metabolism
Cell transplantation therapy offers great potential to improve impairments after stroke. However, the importance of donor age on therapeutic efficacy is unclear. We investigated the regenerative capacity of transplanted cells focusing on donor age (young vs. old) for ischaemic stroke. The quantities of human mesenchymal stem cell (hMSC) secreted brain-derived neurotrophic factor in vitro and of monocyte chemotactic protein-1 at day 7 in vivo were both significantly higher for young hMSC compared with old hMSC. Male Sprague-Dawley rats subjected to transient middle cerebral artery occlusion that received young hMSC (trans-arterially at 24 h after stroke) showed better behavioural recovery with prevention of brain atrophy compared with rats that received old hMSC. Histological analysis of the peri-infarct cortex showed that rats treated with young hMSC had significantly fewer microglia and more vessels covered with pericytes. Interestingly, migration of neural stem/progenitor cells ex...
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.
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.
Frontiers in Neurology
Stroke is a major health problem worldwide. It has been estimated that 90% of the population attributable risk of stroke is due to risk factors such as aging, hypertension, hyperglycemia, diabetes mellitus and obesity, among others. However, most animal models of stroke use predominantly healthy and young animals. These models ignore the main comorbidities associated with cerebrovascular disease, which could be one explanation for the unsuccessful bench-to-bedside translation of protective and regenerative strategies by not taking the patient's situation into account. This lack of success makes it important to incorporate comorbidities into animal models of stroke in order to study the effects of the various therapeutic strategies tested. Regarding cell therapy, the administration of stem cells in the acute and chronic phases has been shown to be safe and effective in experimental animal models of stroke. This review aims to show the results of studies with promising new therapeutic strategies such as mesenchymal stem cells, which are being tested in preclinical models of stroke associated with comorbidities and in elderly animals.
Journal of Neuroinflammation, 2015
Background: Aging is not just a risk factor of stroke, but it has also been associated with poor recovery. It is known that stroke-induced neurogenesis is reduced but maintained in the aged brain. However, there is no consensus on how neurogenesis is affected after stroke in aged animals. Our objective is to determine the role of aging on the process of neurogenesis after stroke. Methods: We have studied neurogenesis by analyzing proliferation, migration, and formation of new neurons, as well as inflammatory parameters, in a model of cerebral ischemia induced by permanent occlusion of the middle cerebral artery in young-(2 to 3 months) and middle-aged mice (13 to 14 months). Results: Aging increased both microglial proliferation, as shown by a higher number of BrdU + cells and BrdU/ Iba1 + cells in the ischemic boundary and neutrophil infiltration. Interestingly, aging increased the number of M1 monocytes and N1 neutrophils, consistent with pro-inflammatory phenotypes when compared with the alternative M2 and N2 phenotypes. Aging also inhibited (subventricular zone) SVZ cell proliferation by decreasing both the number of astrocyte-like type-B (prominin-1 + /epidermal growth factor receptor (EGFR) + /nestin + /glial fibrillary acidic protein (GFAP) + cells) and type-C cells (prominin-1 + /EGFR + /nestin − /Mash1 + cells), and not affecting apoptosis, 1 day after stroke. Aging also inhibited migration of neuroblasts (DCX + cells), as indicated by an accumulation of neuroblasts at migratory zones 14 days after injury; consistently, aged mice presented a smaller number of differentiated interneurons (NeuN + /BrdU + and GAD67 + cells) in the peri-infarct cortical area 14 days after stroke. Conclusions: Our data confirm that stroke-induced neurogenesis is maintained but reduced in aged animals. Importantly, we now demonstrate that aging not only inhibits proliferation of specific SVZ cell subtypes but also blocks migration of neuroblasts to the damaged area and decreases the number of new interneurons in the cortical peri-infarct area. Thus, our results highlight the importance of using aged animals for translation to clinical studies.
Adult Neural Stem Cells: Response to Stroke Injury and Potential for Therapeutic Applications
Current Stem Cell Research & Therapy, 2011
The plasticity of neural stem/progenitor cells allows a variety of different responses to many environmental cues. In the past decade, significant research has gone into understanding the regulation of neural stem/progenitor cell properties, because of their promise for cell replacement therapies in adult neurological diseases. Both endogenous and grafted neural stem/progenitor cells are known to have the ability to migrate long distances to lesioned sites after brain injury and differentiate into new neurons. Several chemokines and growth factors, including stromal cell-derived factor-1 and vascular endothelial growth factor, have been shown to stimulate the proliferation, differentiation, and migration of neural stem/progenitor cells, and investigators have now begun to identify the critical downstream effectors and signaling mechanisms that regulate these processes. Both our own lab and others have shown that the extracellular matrix and matrix remodeling factors play a critical role in directing cell differentiation and migration of adult neural stem/progenitor cells within injured sites. Identification of these and other molecular pathways involved in stem cell homing into ischemic areas is vital for the development of new treatments. To ensure the best functional recovery, regenerative therapy may require the application of a combination approach that includes cell replacement, trophic support, and neural protection. Here we review the current state of our knowledge about endogenous adult and exogenous neural stem/progenitor cells as potential therapeutic agents for central nervous system injuries.