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More than 300 missense mutations in PSEN1 gene have been correlated to the early-onset Alzheimer's disease (EOAD), but given the high diversity of PS1 (the PSEN1 gene product) substrates and the involvement of PS1 in multiple biological functions, different mutants may represent different EOAD etiologies, and how each mutant contributes to the EOAD remains to be further investigated. Here we report the identification of a novel PSEN1 p.Tyr159Ser in a family with multiple EOAD cases. The mutant PS1 protein (PS1Y159S) was analyzed for its activity in producing amyloid-ß (Aß) and for the efficiency in maturation in vitro. We also screened other mutations and SNPs that may modify the effect of PSEN1 p.Tyr159Ser on AD pathogenesis. The blood samples of the family were collected for whole-exome gene sequencing and analysis. The identified mutant PS1 and several other PS1 mutants were co-expressed with the APP Swedish mutant to compare the effects on APP processing and PS1 maturation.1. The proband and her siblings over 50 years old showed typical AD or MCI symptoms. Exon sequencing identified the p.Tyr159Ser mutation in the PSEN1 gene. As not until the age of 78 did the proband's mother who carried this mutation displayed the symptoms of uncharacterized neuropsychiatry instead of AD, but all the mutation bearing lower generation developed AD or MCI after the age of 50, we also analyzed mutations/SNPs that are different between the mother and the lower generation. By in vitro assays, we found that the Y159S substitution strongly increased Aß42/Aß40 ratio and significantly affected PS1 maturation. The newly discovered PSEN1 p.Tyr159Ser is an AD-causing mutation, yet, the carriers are not obligated AD patients. Mutations/SNPs in other gene may modify the effects of this mutation, and the identification of these mutations/SNPs may facilitate the discovery of AD-preventing mechanisms and methods.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Femenino , Humanos , Persona de Mediana Edad , Mutación , Presenilina-1/genéticaRESUMEN
Cell transplantation therapy provides a regenerative strategy for neural repair. We tested the hypothesis that selective excitation of transplanted induced pluripotent stem cell-derived neural progenitor cells (iPS-NPCs) could recapitulate an activity-enriched microenvironment that confers regenerative benefits for the treatment of stroke. Mouse iPS-NPCs were transduced with a novel optochemogenetics fusion protein, luminopsin 3 (LMO3), which consisted of a bioluminescent luciferase, Gaussia luciferase, and an opsin, Volvox Channelrhodopsin 1. These LMO3-iPS-NPCs can be activated by either photostimulation using light or by the luciferase substrate coelenterazine (CTZ). In vitro stimulations of LMO3-iPS-NPCs increased expression of synapsin-1, postsynaptic density 95, brain derived neurotrophic factor (BDNF), and stromal cell-derived factor 1 and promoted neurite outgrowth. After transplantation into the ischemic cortex of mice, LMO3-iPS-NPCs differentiated into mature neurons. Synapse formation between implanted and host neurons was identified using immunogold electron microscopy and patch-clamp recordings. Stimulation of transplanted cells with daily intranasal administration of CTZ enhanced axonal myelination, synaptic transmission, improved thalamocortical connectivity, and functional recovery. Patch-clamp and multielectrode array recordings in brain slices showed that CTZ or light stimulation facilitated synaptic transmission and induced neuroplasticity mimicking the LTP of EPSPs. Stroke mice received the combined LMO3-iPS-NPC/CTZ treatment, but not cell or CTZ alone, showed enhanced neural network connections in the peri-infarct region, promoted optimal functional recoveries after stroke in male and female, young and aged mice. Thus, excitation of transplanted cells via the noninvasive optochemogenetics treatment provides a novel integrative cell therapy with comprehensive regenerative benefits after stroke.SIGNIFICANCE STATEMENT Neural network reconnection is critical for repairing damaged brain. Strategies that promote this repair are expected to improve functional outcomes. This study pioneers the generation and application of an optochemogenetics approach in stem cell transplantation therapy after stroke for optimal neural repair and functional recovery. Using induced pluripotent stem cell-derived neural progenitor cells (iPS-NPCs) expressing the novel optochemogenetic probe luminopsin (LMO3), and intranasally delivered luciferase substrate coelenterazine, we show enhanced regenerative properties of LMO3-iPS-NPCs in vitro and after transplantation into the ischemic brain of different genders and ages. The noninvasive repeated coelenterazine stimulation of transplanted cells is feasible for clinical applications. The synergetic effects of the combinatorial cell therapy may have significant impacts on regenerative approach for treatments of CNS injuries.
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Células-Madre Neurales/trasplante , Optogenética/métodos , Recuperación de la Función , Trasplante de Células Madre/métodos , Accidente Cerebrovascular , Animales , Diferenciación Celular/fisiología , Femenino , Células Madre Pluripotentes Inducidas/trasplante , Masculino , Ratones , Remielinización/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
GPCR 37 (GPR37) is a GPCR expressed in the CNS; its physiological and pathophysiological functions are largely unknown. We tested the role of GPR37 in the ischemic brain of GPR37 knockout (KO) mice, exploring the idea that GPR37 might be protective against ischemic damage. In an ischemic stroke model, GPR37 KO mice exhibited increased infarction and cell death compared with wild-type (WT) mice, measured by 2,3,5-triphenyl-2H-tetrazolium chloride and TUNEL staining 24 h after stroke. Moreover, more severe functional deficits were detected in GPR37 KO mice in the adhesive-removal and corner tests. In the peri-infarct region of GPR37 KO mice, there was significantly more apoptotic and autophagic cell death accompanied by caspase-3 activation and attenuated mechanistic target of rapamycin signaling. GPR37 deletion attenuated astrocyte activation and astrogliosis compared with WT stroke controls 24-72 h after stroke. Immunohistochemical staining showed more ionized calcium-binding adapter molecule 1-positive cells in the ischemic cortex of GPR37 KO mice, and RT-PCR identified an enrichment of M1-type microglia or macrophage markers in the GPR37 KO ischemic cortex. Western blotting demonstrated higher levels of inflammatory factors IL-1ß, IL-6, monocyte chemoattractant protein, and macrophage inflammatory protein-1α in GPR37-KO mice after ischemia. Thus, GPR37 plays a multifaceted role after stroke, suggesting a novel target for stroke therapy.-McCrary, M. R., Jiang, M. Q., Giddens, M. M., Zhang, J. Y., Owino, S., Wei, Z. Z., Zhong, W., Gu, X., Xin, H., Hall, R. A., Wei, L., Yu, S. P. Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice.
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Isquemia Encefálica/fisiopatología , Muerte Celular/fisiología , Receptores Acoplados a Proteínas G/fisiología , Accidente Cerebrovascular/fisiopatología , Animales , Apoptosis , Autofagia , Encéfalo/metabolismo , Encéfalo/patología , Isquemia Encefálica/patología , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Inflamación/patología , Inflamación/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genética , Corteza Sensoriomotora/fisiopatología , Transducción de Señal , Accidente Cerebrovascular/patología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Stroke is a leading threat to human life and health in the US and around the globe, while very few effective treatments are available for stroke patients. Preclinical and clinical studies have shown that therapeutic hypothermia (TH) is a potential treatment for stroke. Using novel neurotensin receptor 1 (NTR1) agonists, we have demonstrated pharmacologically induced hypothermia and protective effects against brain damages after ischemic stroke, hemorrhage stroke, and traumatic brain injury (TBI) in rodent models. To further characterize the mechanism of TH-induced brain protection, we examined the effect of TH (at ±33°C for 6h) induced by the NTR1 agonist HPI-201 or physical (ice/cold air) cooling on inflammatory responses after ischemic stroke in mice and oxygen glucose deprivation (OGD) in cortical neuronal cultures. Seven days after focal cortical ischemia, microglia activation in the penumbra reached a peak level, which was significantly attenuated by TH treatments commenced 30min after stroke. The TH treatment decreased the expression of M1 type reactive factors including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-12, IL-23, and inducible nitric oxide synthase (iNOS) measured by RT-PCR and Western blot analyses. Meanwhile, TH treatments increased the expression of M2 type reactive factors including IL-10, Fizz1, Ym1, and arginase-1. In the ischemic brain and in cortical neuronal/BV2 microglia cultures subjected to OGD, TH attenuated the expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), two key chemokines in the regulation of microglia activation and infiltration. Consistently, physical cooling during OGD significantly decreased microglia migration 16h after OGD. Finally, TH improved functional recovery at 1, 3, and 7days after stroke. This study reveals the first evidence for hypothermia mediated regulation on inflammatory factor expression, microglia polarization, migration and indicates that the anti-inflammatory effect is an important mechanism underlying the brain protective effects of a TH therapy.
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Movimiento Celular/fisiología , Polaridad Celular/fisiología , Citocinas/metabolismo , Hipotermia Inducida/métodos , Infarto de la Arteria Cerebral Media/terapia , Microglía/fisiología , Recuperación de la Función/fisiología , Animales , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Células Cultivadas , Corteza Cerebral/citología , Modelos Animales de Enfermedad , Embrión de Mamíferos , Glucosa/deficiencia , Hipoxia , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Neuronas/metabolismo , Neuronas/patología , Oligopéptidos/uso terapéutico , Oxígeno , Fosfopiruvato Hidratasa/metabolismoRESUMEN
GluN3A or NR3A is a developmentally regulated N-methyl-d-aspartate receptor (NMDAR) subunit, showing a unique inhibitory role that decreases NMDAR current and the receptor-mediated Ca(2+) influx. In the neonatal brain, GluN3A is shown to associate with synaptic maturation and spine formation and plays a neuroprotective role. Its functional role in the adult brain, however, is largely unknown. We tested the hypothesis that, disrespecting the relatively lower expression level of GluN3A in the adult brain, this inhibitory NMDAR subunit shows a protective action against ischemia-induced brain injury. In littermate wild-type (WT) and GluN3A knockout (KO) mice, focal cerebral ischemia was induced by permanent occlusion of right distal branches of the middle cerebral artery (MCA) plus 10-min ligation of both common carotid arteries (CCAs). Twenty-four hours after focal cerebral ischemia, the infarction volume assessed using 2,3,5-triphenyltetrazolium chloride (TTC) staining was significantly larger in GluN3A KO mice compared with WT mice. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining demonstrated enhanced cell death in GluN3A KO mice. Moreover, the deletion of GluN3A hindered sensorimotor functional recovery after stroke. It is suggested that, although the expression level is relatively lower in the adult brain, GluN3A is still a noteworthy regulator in ischemia-induced excitotoxicity and brain injury.
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Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevención & control , Subunidades de Proteína/deficiencia , Receptores de N-Metil-D-Aspartato/deficiencia , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/prevención & control , Factores de Edad , Animales , Células Cultivadas , Masculino , Ratones , Ratones Noqueados , Neuronas/metabolismoRESUMEN
BACKGROUND/AIM: Evidence suggests that gut microbiota can affect various neurological diseases, including stroke. Stroke patients have an increase in harmful gut bacteria and a decrease in beneficial bacteria. This increases intestinal permeability, increases the risk of infection, and even affects many inflammatory factors. While probiotics may affect stroke prognosis by improving the gut environment. This study aimed to investigate the effect of probiotic Bifico on the neural function in mice after focal cerebral ischemia and explore its mechanisms of action. MATERIALS AND METHODS: A focal cerebral ischemia model was established in mice. Four weeks before modeling, animals were divided into three groups: Stroke plus Vehicle group, Stroke plus Pre-Bifico group and Bifico group. The infarct volume and neurobehaviors were evaluated. Whole-gene expression profiling was performed at different days after treatment (D1, D7, D14, D28) by RNA-seq. Differentially expressed genes (DEGs) were the processed for Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG). Some inflammation and immune related genes were screened and their expression was analyzed. RESULTS: Compared to the Stroke plus Vehicle group and Bifico group, the infarct volume and neurological score were significantly reduced in the Pre-Bifico group. There were 2 DEGs at D1, 193 DEGs at D7, 70 DEGs at D28 between Stroke plus Pre-Bifico group and Stroke plus Vehicle group. For GO analysis, there were 139 significant terms at D7 and 195 at D28. For KEGG, there were 2 significant pathways at D7 and 9 at D28. Among 87 genes related to inflammation and immunity, 6 DEGs were identified. The expression of CCL9 was significantly elevated at most time points after stroke compared to the Stroke plus Vehicle group, while that of CCL6, CXCL10, CD48, CD72 and CLEC7A was highly expressed only in the recovery stage of stroke. CONCLUSION: Oral pre-treatment with Bifico for 28 days can reduce cerebral infarction and promote recovery of neurological function in stroke mice, which may be ascribed to the regulation of immunity and inflammation in the brain.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Ratones , Animales , Perfilación de la Expresión Génica , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/genética , Inflamación/genética , Isquemia Encefálica/complicaciones , Isquemia Encefálica/genética , Infarto , TranscriptomaRESUMEN
Transcranial photobiomodulation refers to irradiation of the brain through the skull using low-intensity red or near-infrared light, which is the most commonly studied method of light energy biotherapy for central nervous system disorders. The absorption of photons by specific chromophores within the cell elevates ATP synthesis, reduces oxidative stress damage, alleviates inflammation or mediates the activation of transcription factors and signaling mediators through secondary mediators, which in turn trigger downstream signaling pathways to cause a series of photobiological effects including upregulation of neurotrophic factors. Multiple mechanisms are simultaneously involved in the pathological process of central nervous system disorders. The pleiotropic treatment of transcranial photobiomodulation towards multiple targets plays a beneficial role in improving hemodynamics, neural repair and improving behaviors in central nervous system disorders such as ischemic stroke, traumatic brain injury, neurodegenerative diseases, epilepsy and depression. This review mainly introduces the mechanism and recent preclinical and clinical advances of transcranial photobiomodulation for central nervous system disorders, which will provide a reference for clinicians to understand and engage in related studies, and calls for more and larger studies to validate and develop a wider application of transcranial photobiomodulation in central nervous system.
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Lesiones Traumáticas del Encéfalo , Accidente Cerebrovascular Isquémico , Terapia por Luz de Baja Intensidad , Humanos , Terapia por Luz de Baja Intensidad/métodos , Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Cráneo , Accidente Cerebrovascular Isquémico/metabolismoRESUMEN
Background and purpose: The best method for selecting patients with acute vertebrobasilar artery occlusion (VBAO) who would benefit from endovascular treatment (EVT) is still the key question. This study aimed to assess the efficacy of magnetic resonance imaging (MRI) for selecting patients with acute VBAO for EVT. Materials and methods: A total of 14 patients with suspected acute VBAO on MR angiography (MRA) in the EVT database (from April 2016 to August 2019) were enrolled. Acute Stroke Prognosis Early Computed Tomography Score (ASPECTS) and pons-midbrain index were assessed on diffusion-weighted imaging (DWI). EVT included a stent retriever and a rescue treatment (angioplasty and/or stenting). The proportion of successful reperfusion and favorable functional outcomes (modified Rankin Scale ≤ 3) at 90 days was documented. Results: A total of 11 patients were included in the final analysis. The median DWI-ASPECTS and pons-midbrain index were 7 and 2, respectively. Underlying stenosis was detected in 10 of 11 (90.9%) patients. Balloon angioplasty and/or stenting were used as rescue therapy for five patients and two patients, respectively. A total of nine patients (81.8%) achieved successful reperfusion (mTICI, 2b, or 3). The 90-day mRS score of 0-3 was achieved in six (54.5%) patients. The mortality rate within 90 days was 18.2% (two of 11 patients). Conclusion: DWI plus MRA could help select the patients with acute VBAO for EVT by assessing ASPECTS and the pons-midbrain index. Patients could achieve good reperfusion and favorable functional outcomes.
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BACKGROUND: Patient and socioeconomic factors both contribute to disparities in post-mastectomy reconstruction (PMR) rates. We sought to explore PMR patterns across the US and to determine if PMR rates were associated with Medicaid expansion. METHODS: The NCDB was used to identify women who underwent PMR between 2004-2016. The data was stratified by race, state Medicaid expansion status, and region. A multivariate model was fit to determine the association between Medicaid expansion and receipt of PMR. RESULTS: In comparison to Caucasian women receiving PMR in Medicaid expansion states, African American (AA) women in Medicaid expansion states were less likely to receive PMR (OR .96 [.92-1.00] P < .001). Patients in the Northeast (NE) had better PMR rates vs any other region in the US, for both Caucasian and AA women (Caucasian NE ref, Caucasian-South .80 [.77-.83] vs AA NE 1.11 [1.04-1.19], AA-South (.60 [.58-.63], P < .001). Interestingly, AA patients residing in the NE had the highest receipt of PMR 1.11 (1.04-1.19), even higher than their Caucasian counterparts residing in the same region (ref). Rural AA women had the lowest rates of PMR vs rural Caucasian women (.40 [.28-.58] vs .79 [.73-.85], P < .001]. DISCUSSION: Racial disparities in PMR rates persisted despite Medicaid expansion. When stratified by region, however, AA patients in the NE had higher rates of PMR than AA women in other regions. The largest disparities were seen in AA women in the rural US. Breast cancer disparities continue to be a complex problem that was not entirely mitigated by improved insurance coverage.
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Neoplasias de la Mama , Medicaid , Neoplasias de la Mama/cirugía , Femenino , Disparidades en Atención de Salud , Humanos , Cobertura del Seguro , Mastectomía , Patient Protection and Affordable Care Act , Estados UnidosRESUMEN
Stroke causes significant mortality and morbidity. Currently, there are no treatments which can regenerate brain tissue lost to infarction. Neural progenitor cells (NPCs) are at the forefront of preclinical studies for regenerative stroke therapies. NPCs can differentiate into and replace neurons and promote endogenous recovery mechanisms such as angiogenesis via trophic factor production and release. The stroke core is hypothetically the ideal location for replacement of neural tissue since it is in situ and develops into a potential space where injections may be targeted with minimal compression of healthy peri-infarct tissue. However, the compromised perfusion and tissue degradation following ischemia create an inhospitable environment resistant to cellular therapy. Overcoming these limitations is critical to advancing cellular therapy. In this work, the therapeutic potential of mouse-induced pluripotent stem cell derived NPCs is tested encapsulated in a basic fibroblast growth factor (bFGF) binding chondroitin sulfate-A (CS-A) hydrogel transplanted into the infarct core in a mouse sensorimotor cortex mini-stroke model. It is shown that CS-A encapsulation significantly improves vascular remodeling, cortical blood flow, and sensorimotor behavioral outcomes after stroke. It is found these improvements are negated by blocking bFGF, suggesting that the sustained trophic signaling endowed by the CS-A hydrogel combined with NPC transplantation can promote tissue repair.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Encéfalo , Isquemia Encefálica/terapia , Glicosaminoglicanos , Ratones , Regeneración , Accidente Cerebrovascular/terapiaRESUMEN
The original version of this article was updated to correct the misspelling of Li-Ping Liu's name.
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Ischemic stroke remains a serious threat to human life. Generation of neuronal and vascular cells is an endogenous regenerative mechanism in the adult brain, which may contribute to tissue repair after stroke. However, the regenerative activity is typically insufficient for significant therapeutic effects after brain injuries. Pyruvate kinase isoform M2 (PKM2) is a key regulator for energy metabolism. PKM2 also has nonmetabolic roles involving regulations of gene expression, cell proliferation, and migration in cancer cells as well as noncancerous cells. In a focal ischemic stroke mouse model, recombinant PKM2 (rPKM2) administration (160 ng/kg, intranasal delivery) at 1 h after stroke showed the significant effect of a reduced infarct volume of more the 60%. Delayed treatment of rPKM2, however, lost the acute neuroprotective effect. We then tested a novel hypothesis that delayed treatment of PKM2 might show proregenerative effects for long-term functional recovery and this chronic action could be mediated by its downstream STAT3 signaling. rPKM2 (160 ng/kg) was delivered to the brain using noninvasive intranasal administration 24 h after the stroke and repeated every other day. Western blot analysis revealed that, 7 days after the stroke, the levels of PKM2 and phosphorylated STAT3 and the expression of angiogenic factors VEGF, Ang-1, and Tie-2 in the peri-infarct region were significantly increased in the rPKM2 treatment group compared with those of the stroke vehicle group. To label proliferating cells, 5-bromo-2'-deoxyuridine (BrdU, 50 mg/kg, i.p.) was injected every day starting 3 days after stroke. At 14 days after stroke, immunohistochemistry showed that rPKM2 increased cell homing of doublecortin (DCX)-positive neuroblasts to the ischemic cortex. In neural progenitor cell (NPC) cultures, rPKM2 (0.4-4 nM) increased the expression of integrin ß1 and the activation/phosphorylation of focal adhesion kinase (FAK). A mediator role of FAK in PKM2-promoted cell migration was verified in FAK-knockout fibroblast cultures. In the peri-infarct region of the brain, increased numbers of Glut-1/BrdU and NeuN/BrdU double-positive cells indicated enhanced angiogenesis and neurogenesis, respectively, compared to stroke vehicle mice. Using Laser Doppler imaging, we observed better recovery of the local blood flow in the peri-infarct region of rPKM2-treated mice 14 days after stroke. Meanwhile, rPKM2 improved the sensorimotor functional recovery measured by the adhesive removal test. Inhibiting the STAT3 phosphorylation/activation by the STAT3 inhibitor, BP-1-102 (3 mg/kg/day, o.g.), abolished all beneficial effects of rPKM2 in the stroke mice. Taken together, this investigation provides the first evidence demonstrating that early treatment of rPKM2 shows an acute neuroprotective effect against ischemic brain damage, whereas delayed rPKM2 treatment promotes regenerative activities in the poststroke brain leading to better functional recovery. The underlying mechanism involves activation of the STAT3 and FAK signals in the poststroke brain.
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Proteína-Tirosina Quinasas de Adhesión Focal/genética , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Piruvato Quinasa , Recuperación de la Función/efectos de los fármacos , Factor de Transcripción STAT3/genética , Animales , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Circulación Cerebrovascular/efectos de los fármacos , Modelos Animales de Enfermedad , Proteína Doblecortina , Fibroblastos/efectos de los fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Infarto de la Arteria Cerebral Media/fisiopatología , Ratones , Ratones Endogámicos C57BL , Fosfopiruvato Hidratasa/metabolismo , Piruvato Quinasa/farmacología , Piruvato Quinasa/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Células Madre/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Ischemic stroke is a leading cause of human death and disability while clinical treatments are limited. The adult brain possesses endogenous regenerative activities that may benefit tissue repair after stroke. Trophic factors such as stromal cell-derived factor 1 alpha (SDF-1α) are upregulated in the ischemic brain, which promote endogenous regeneration. The regenerative response, however, is normally insufficient. Transplantation of exogenous cells has been explored as regenerative therapies. One promising cell type for transplantation is induced pluripotent stem (iPS) cells which are cells genetically reprogrammed from adult somatic cells. We hypothesized that transplanting neural progenitor cells derived from iPS cells (iPS-NPCs) could provide cell replacement and trophic support. The trophic factor SDF-1α was overexpressed in iPS-NPCs by lentiviral transduction to test if SDF-1α could increase regeneration in the ischemic brain. These SDF-1α-iPS-NPCs were differentiated in vitro to express mature neuronal and synaptic markers. Differentiated cells expressed functional Na+ and K+ channels, and fired action potentials. In the oxygen glucose deprivation (OGD) test, SDF-1α-iPS-NPCs survived significantly better compared to control iPS-NPCs. In mice subjected to focal cerebral ischemia in the sensorimotor cortex, iPS-NPCs and SDF-1α-iPS-NPCs were intracranially transplanted into the ischemic cortex 7 days after stroke. Neuronal differentiation of transplanted cells was identified using NeuN 14 days after transplantation. Mice that received SDF-1α-iPS-NPCs had greater numbers of NeuN/BrdU and Glut-1/BrdU co-labeled cells in the peri-infarct area and improved locomotion compared to the control iPS-NPC transplantation. Thus, SDF-1α upregulation in transplanted cells may be a therapeutic strategy to enhance endogenous neurovascular repair after ischemic stroke in adult mice.
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One of the exciting advances in modern medicine and life science is cell-based neurovascular regeneration of damaged brain tissues and repair of neuronal structures. The progress in stem cell biology and creation of adult induced pluripotent stem (iPS) cells has significantly improved basic and pre-clinical research in disease mechanisms and generated enthusiasm for potential applications in the treatment of central nervous system (CNS) diseases including stroke. Endogenous neural stem cells and cultured stem cells are capable of self-renewal and give rise to virtually all types of cells essential for the makeup of neuronal structures. Meanwhile, stem cells and neural progenitor cells are well-known for their potential for trophic support after transplantation into the ischemic brain. Thus, stem cell-based therapies provide an attractive future for protecting and repairing damaged brain tissues after injury and in various disease states. Moreover, basic research on naïve and differentiated stem cells including iPS cells has markedly improved our understanding of cellular and molecular mechanisms of neurological disorders, and provides a platform for the discovery of novel drug targets. The latest advances indicate that combinatorial approaches using cell based therapy with additional treatments such as protective reagents, preconditioning strategies and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the characteristics of cell therapy in different ischemic models and the application of stem cells and progenitor cells as regenerative medicine for the treatment of stroke.
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Trasplante de Células Madre , Accidente Cerebrovascular/terapia , Animales , Isquemia Encefálica/fisiopatología , Isquemia Encefálica/terapia , Humanos , Accidente Cerebrovascular/fisiopatologíaRESUMEN
OBJECTIVE: Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues. DATA SOURCES: This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: "stem cells," "hypoxic preconditioning," "ischemic preconditioning," and "cell transplantation." STUDY SELECTION: Original articles and critical reviews on the topics were selected. RESULTS: Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified. CONCLUSIONS: In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications.