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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have generated stable, immortalized cell lines of human NSCs from primary human fetal telencephalon cultures via a retroviral vector encoding v-myc. HB1.F3, one of the human NSC lines, expresses a normal human karyotype of 46, XX, and nestin, a cell type-specific marker for NSCs. F3 has the ability to proliferate continuously and differentiate into cells of neuronal and glial lineage. The HB1.F3 human NSC line was used for cell therapy in a mouse model of intracerebral hemorrhage (ICH) stroke. Experimental ICH was induced in adult mice by intrastriatal administration of bacterial collagenase; 1 week after surgery, the rats were randomly divided into two groups so as to receive intracerebrally either human NSCs labeled with beta-galactosidase (n = 31) or phosphate-buffered saline (PBS) (n = 30). Transplanted NSCs were detected by 5-bromo-4-chloro-3-indolyl-beta-d-galactoside histochemistry or double labeling with beta-galactosidase (beta-gal) and mitogen-activated protein (MAP)2, neurofilaments (both for neurons), or glial fibrillary acidic protein (GFAP) (for astrocytes). Behavior of the animals was evaluated for period up to 8 weeks using modified Rotarod tests and a limb placing test. Transplanted human NSCs were identified in the perihematomal areas and differentiated into neurons (beta-gal/MAP2(+) and beta-gal/NF(+)) or astrocytes (beta-gal/GFAP(+)). The NSC-transplanted group showed markedly improved functional performance on the Rotarod test and limb placing after 2-8 weeks compared with the control PBS group (p < .001). These results indicate that the stable immortalized human NSCs are a valuable source of cells for cell replacement and gene transfer for the treatment of ICH and other human neurological disorders. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Brain transplantation of immortalized human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model. 1721

The standard method of detecting neurogenesis uses bromodeoxyuridine (BrdU) to label DNA synthesis followed by double labeling with neuronal markers. However, DNA synthesis may occur in events unrelated to neurogenesis including aneuploidy and abortive cell cycle reentry. Hence, it is important to confirm neurogenesis with methods other than BrdU incorporation. To this end, we have generated transgenic nestin-CreER mice that express tamoxifen-inducible Cre recombinase under the control of a nestin enhancer. When crossed with a ubiquitous Enhanced Green Fluorescent Protein (EGFP)-Cre-reporter line, the bitransgenic animals can reveal the nestin-positive progenitors and their progeny with EGFP after tamoxifen induction. This system has many applications including visualization of embryonic neural progenitors, detection of postnatally transformed radial glial cells, and labeling adult neural progenitors in the subventricular zone (SVZ). To examine the contribution of SVZ progenitors to cell replacement after stroke, tamoxifen-induced mice were challenged with focal ischemia or combined ischemia-hypoxia followed by BrdU injection. This analysis revealed only very few EGFP-positive cells outside the SVZ after focal ischemia but robust DNA synthesis by hippocampal neurons without immediate cell death following ischemia-hypoxia. These results suggest that the nestin-CreER system is a useful tool for detecting embryonic and adult neurogensis. They also confirm the existence of nonproliferative DNA synthesis by old neurons after experimental brain injury.
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PMID:Nestin-CreER mice reveal DNA synthesis by nonapoptotic neurons following cerebral ischemia hypoxia. 1725 45

Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular mechanisms underlying such phenomena are not known. Using BrdU-labeling, quantitative immunohistochemistry and 3D-reconstruction of confocal images in a rat model of mild cerebral ischemia, we found that aged rats are highly susceptible to develop an early infarct that is associated with premature cellular proliferation originating from the vascular tree. In aged rats we also found a rapid delimitation of the infarct area by capillary-derived neuroepithelial cells and an early incorporation of these cells into the glial scar. Since most proliferating cells at the infarct site are microglia or nestin-positive cells derived from the vascular wall, we conclude that the vasculature plays a hitherto unrecognized role as a source of proliferating neuroepithelial cells after stroke. Age-associated alterations in the timing and origin of the cytogenic response to cerebral ischemia may underlie the poor functional recovery from stroke. Clarifying the molecular basis of these phenomena could yield novel approaches to enhancing neurorestoration in the elderly. Studies of stroke in experimental animals have demonstrated the neuroprotective efficacy of a variety of interventions, but most of the strategies that have been clinically tested failed to show benefit in aged humans. One possible explanation for this discrepancy between laboratory and clinical investigations is the role that age plays in the recovery of the brain from insult. Although it is well known that aging is a risk factor for stroke (Barnett HJ, 2002), the majority of experimental studies of stroke have been performed on young animals, and therefore may not fully replicate the effects of ischemia on neural tissue in aged subjects (Wang LC et al., 1995; Davies M et al., 1995; Sutherland GR et al., 1996; Popa-Wagner A et al., 1998, 1999a). Hence, the aged post-acute animal model is clinically most relevant to stroke rehabilitation and cellular studies (Lindner MD et al., 2003; Brown AW et al., 2003; Badan I et al., 2003).
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PMID:Premature cellular proliferation following cortical infarct in aged rats. 1730 79

Nurr1 has been implicated as a transcription factor mediating the endogenous neuroprotective mechanism against stroke. We examined the in vivo and in vitro properties of a new human embryonic carcinoma Ntera-2 cell line carrying the human Nurr1 gene (NT2N.Nurr1). Adult Sprague-Dawley rats underwent experimental stroke initially and 14 days later were assigned randomly to receive stereotaxic transplantation of NT2N.Nurr1 cells or infusion of vehicle into their ischemic striatum. Transplantation of NT2N.Nurr1 cells promoted significant attenuation of behavioral impairments over a 56-day period after stroke, characterized by decreased hyperactivity, biased swing activity, and neurologic deficits, as well as significant reduction in ischemic striatal cell loss compared to vehicle-infused stroke animals. Transplanted NT2N.Nurr1 cells survived and expressed neuronal phenotypic markers in the ischemic striatum. In vitro results showed that cultured NT2.Nurr1 cells were already negative for nestin even before retinoic acid treatment, despite strong nestin immunoreactivity in NT2 cells. This indicates Nurr1 triggered a rapid commitment of NT2 cells into a neuronal lineage. Indeed, NT2.Nurr1 cells, at 4 weeks into RA treatment, displayed more abundant tyrosine hydroxylase positive cells than NT2 cells. Parallel ELISA studies showed further that cultured NT2N.Nurr1, but not NT2N cells, secreted glial cell derived neurotrophic factor. The present study shows efficacy of NT2N.Nurr1 cell grafts in ischemic stroke, with in vitro evidence suggesting the cells' excellent neuronal differentiation capability and ability to secrete GDNF as likely mechanisms mediating the observed therapeutic benefits.
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PMID:Transplantation of post-mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke: in vitro evidence of expedited neuronal differentiation and GDNF secretion. 1733 85

In the adult human brain, the presence of neural stem cells has been documented in the subgranular layer of the dentate gyrus of the hippocampus and in the subventricular zone of the lateral ventricles. Neurogenesis has also been reported in rodent models of ischemic stroke, traumatic brain injury, epileptic seizures, and intracerebral or subarachnoid hemorrhage. However, only sparse information is available about the occurrence of neurogenesis in the human brain under similar pathological conditions. In the present report, we describe neural progenitor cell proliferation in the brain of patients suffering from subarachnoid hemorrhage (SAH) resulting from ruptured aneurysm. Ten cerebral samples from both SAH and control patients obtained, respectively, during aneurysm clipping and deep brain tumor removal were analyzed by reverse transcription followed by polymerase chain reaction (RT-PCR) and/or immunohistochemistry (IHC). In tissue specimens from SAH patients, RT-PCR and IHC revealed the expression of a variety of markers consistent with CNS progenitor cells, including nestin, vimentin, SOX-2, and Musashi1 and -2. In the same specimens, double immunohistochemistry followed by confocal analysis revealed that Musashi2 consistently colocalized with the proliferation marker Ki67. By contrast, no such gene or protein expression profiles were detected in any of the control specimens. Thus, activation of neural progenitor cell proliferation may occur in adult human brain following subarachnoid hemorrhage, possibly contributing to the promotion of spontaneous recovery, in this pathological condition.
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PMID:Activation of endogenous neural stem cells in the adult human brain following subarachnoid hemorrhage. 1745 4

Ischemic stroke stimulates neurogenesis in the adult rodent brain. The molecules that mediate stroke-induced neurogenesis have not been fully investigated. Using a microarray containing 113 known genes associated with angiogenesis, we analyzed transcriptional profiles in subventricular zone (SVZ) tissue and in cultured neural progenitor cells isolated from the SVZ of adult mice subjected to middle cerebral artery occlusion (MCAo). Among the genes most robustly up-regulated by MCAo were chemokine ligand 2 (CCL2) and chemokine ligand 10 (CXCL10). Consistent with the mRNA data, immunofluorescent staining revealed that MCAo substantially increased the number of CCL2-positive cells in the ipsilateral SVZ and that CCL2-positive cells were positive for both glial fibrillary acidic protein (GFAP) and nestin. In vitro studies showed that incubation of neural progenitor cells with recombinant human CCL2 substantially increased the number of Tuj1-positive cells dose dependently compared with the number in the control group, indicating that CCL2 promotes neuronal differentiation. Blockage of CCL2 with a neutralized antibody against CCL2 abolished the effects of CCL2 on neural progenitor cell migration and differentiation. Treatment of neural progenitor cells with CCL2 did not alter the number of BrdU cells and the number of apoptotic cells compared with those in the control group, suggesting that CCL2 does not affect neural progenitor cell proliferation and cell survival. These data demonstrate that in addition to its role in cell motility, CCL2 plays an important role in neuronal differentiation.
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PMID:Chemokine ligand 2 (CCL2) induces migration and differentiation of subventricular zone cells after stroke. 1751 Sep 81

In this research, we investigated striatal neurogenesis in 3-, 6-, 12-, and 18-month-old rats after cerebral ischemic injury. All rats were subjected to a 20-min middle cerebral artery occlusion (MCAO), given 5'-bromodeoxyuridine (BrdU, 30 mg/kg, i.p.) once daily during days 4-7 and sacrificed 2 weeks after MCAO. Neurogenesis was assessed with double immunohistochemical/immunofluorescence labeling of BrdU and doublecortin (DCX), microtubule-associated protein 2 (MAP-2), or 67-kDa glutamic acid decarboxylase (GAD(67)). In 6-, 12-, and 18-month-old rats, the numbers of nestin(+), BrdU(+)-DCX(+) (a marker of newborn neuronal progenitors/immature neuron), BrdU(+)-MAP-2(+) (a marker of newborn mature neuron), and BrdU(+)-GAD(67)(+) (a marker of newborn GABAergic neuron) cells decreased dramatically in the ipsilateral striatum to MCAO compared with that in 3-month-old rats. The results indicated that stroke-induced striatal neurogenesis still existed in aging rats. However, the capacity of neurogenesis in older rats was considerably lower than that in young adults. Meanwhile, the apoptosis of neural precursors and immature neurons, indicated by double labeling of active caspase-3 and nestin/DCX/Tuj-1(beta-tubulin III)/CRMP-4 (collapsin response-mediated protein-4), increased noticeably in the ipsilateral striatum of older rats. Taken together, the results suggested that aging-related attenuation of ischemia-induced striatal neurogenesis might be related to decrease of neural precursors and increase of apoptosis of newborn neurons.
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PMID:Age-related decrease of striatal neurogenesis is associated with apoptosis of neural precursors and newborn neurons in rat brain after ischemia. 1766

Stroke is a neurodegenerative disorder and the leading cause of disability in adult humans. Treatments to support efficient recovery in stroke patients are lacking. Several studies have demonstrated the ability of grafted neural stem cells (NSCs) to partly improve impaired neurological functions in stroke-subjected animals. Recently, we reported that NSCs from human fetal striatum and cortex exhibit region-specific differentiation in vitro, but survive, migrate and form neurons to a similar extent after intrastriatal transplantation in newborn rats. Here, we have transplanted the same cells into the stroke-damaged striatum of adult rats. The two types of NSCs exhibited a similar robust survival (30%) at 1 month after transplantation, and migrated throughout the damaged striatum. Striatal NSCs migrated farther and occupied a larger volume of striatum. In the transplantation core, cells were undifferentiated and expressed nestin and, to a lesser extent, also GFAP, betaIII-tubulin, DCX and calretinin, markers of immature neural lineage. Immunocytochemistry using markers of proliferation (p-H3 and Ki67) revealed a very low content of proliferating cells (<1%) in the grafts. Human cells outside the transplantation core differentiated, exhibited mature neuronal morphology and expressed mature neuronal markers such as HuD, calbindin and parvalbumin. Interestingly, striatal NSCs generated a greater number of parvalbumin+ and calbindin+ neurons. Virtually none of the grafted cells differentiated into astrocytes or oligodendrocytes. Based on these data, human fetal striatum- and cortex-derived NSCs could be considered potentially safe and viable for transplantation, with strong neurogenic potential, for further exploration in animal models of stroke.
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PMID:Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke-damaged rat striatum. 1768 40

Human bone marrow contains two major cell types, hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). MSCs possess self-renewal capacity and pluripotency defined by their ability to differentiate into osteoblasts, chondrocytes, adipocytes and muscle cells. MSCs are also known to differentiate into neurons and glial cells in vitro, and in vivo following transplantation into the brain of animal models of neurological disorders including ischemia and intracerebral hemorrhage (ICH) stroke. In order to obtain sufficient number and homogeneous population of human MSCs, we have clonally isolated permanent and stable human MSC lines by transfecting primary cell cultures of fetal human bone marrow MSCs with a retroviral vector encoding v-myc gene. One of the cell lines, HM3.B10 (B10), was found to differentiate into neural cell types including neural stem cells, neurons, astrocytes and oligodendrocytes in vitro as shown by expression of genetic markers for neural stem cells (nestin and Musashi1), neurons (neurofilament protein, synapsin and MAP2), astrocytes (glial fibrillary acidic protein, GFAP) and oligodendrocytes (myelin basic protein, MBP) as determined by RT-PCR assay. In addition, B10 cells were found to differentiate into neural cell types as shown by immunocytochical demonstration of nestin (for neural stem cells), neurofilament protein and beta-tubulin III (neurons) GFAP (astrocytes), and galactocerebroside (oligodendrocytes). Following brain transplantation in mouse ICH stroke model, B10 human MSCs integrate into host brain, survive, differentiate into neurons and astrocytes and induce behavioral improvement in the ICH animals. B10 human MSC cell line is not only a useful tool for the studies of organogenesis and specifically for the neurogenesis, but also provides a valuable source of cells for cell therapy studies in animal models of stroke and other neurological disorders.
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PMID:Multilineage potential of stable human mesenchymal stem cell line derived from fetal marrow. 1806 66

Kallikrein, a serine proteinase, has been identified as an angiogenic growth factor recently. We investigated whether delayed treatment with exogenous kallikrein enhances neurogenesis and angiogenesis after focal cortical infarction in stroke-prone renovascular hypertensive rats. Human tissue kallikrein (1.6 x 10(-2) PNAU/kg) or vehicle was given through a tail vein daily for 6 consecutive days starting 24 h after distal middle cerebral artery occlusion (MCAO). Cell proliferation was examined by using 5'-bromo-2'-deoxyuridine (BrdU, 50 mg/kg). Rats were sacrificed at 3, 7, 14 or 28 d after MCAO, respectively. Treatment with kallikrein significantly increased the number of BrdU(+) cells in the subventricular zone (SVZ) and the peri-infarction region initiating 3 d after MCAO compared with the vehicle group (all p<0.05). Kallikrein significantly increased the number of BrdU(+)/DCX(+) cells and BrdU(+)/nestin(+) cells in the SVZ as well as vascular density in the peri-infarction region compared with the vehicle group (all p<0.05), which increased at 3 d, peaked at 7-14 d after MCAO, and then gradually decreased. Kallikrein markedly increased the number of BrdU(+)/NeuN(+) cells in the peri-infarction region compared with the vehicle group at 14 d and 28 d after MCAO (all p<0.05). The kallikrein group showed better functional improvement after stroke (all p<0.05). Our study demonstrates that delayed administration of kallikrein at 24 h after cortical infarction promotes the SVZ neuroblasts proliferation, migration, and selective differentiation. Moreover, kallikrein enhanced endogenous neurogenesis is associated with angiogenesis, both attributing to functional improvement after stroke. Therefore, kallikrein may have a potential therapeutic perspective on ischemic stroke.
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PMID:Exogenous kallikrein enhances neurogenesis and angiogenesis in the subventricular zone and the peri-infarction region and improves neurological function after focal cortical infarction in hypertensive rats. 1835 82


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