RESUMEN
Traumatic brain injury (TBI) is a devastating neurological disorder, although the underlying pathophysiology is poorly understood. TBI causes blood-brain barrier (BBB) disruption, immune cell trafficking, neuroinflammation and neurodegeneration. CCL20 is an important chemokine mediating neuroinflammation. Human mesenchymal stem cell (hMSC) therapy is a promising regenerative approach but the inflammatory microenvironment in the brain tends to decrease the efficacy of the hMSC transplantation. Reducing the inflammation prior to hMSC therapy improves the outcome. We developed a combined nano-cell therapy by using dendrimers complexed with plasmids (dendriplexes) targeting CCL20 and its sole receptor CCR6 to reduce inflammation followed by hMSC transplantation. Treatment of TBI mice with shRNA conjugated dendriplexes followed by hMSC administration downregulated the inflammatory markers and significantly increased brain-derived neurotrophic factor (BDNF) expression in the cerebral cortex indicating future possible neurogenesis and improved behavioral deficits. Taken together, this nano-cell therapy ameliorates neuroinflammation and promotes brain tissue repair after TBI.
Asunto(s)
Lesiones Traumáticas del Encéfalo/terapia , Factor Neurotrófico Derivado del Encéfalo/genética , Quimiocina CCL20/genética , Inflamación/terapia , Receptores CCR6/genética , Animales , Barrera Hematoencefálica/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/patología , Quimiocina CCL20/antagonistas & inhibidores , Dendrímeros/química , Dendrímeros/farmacología , Humanos , Inflamación/genética , Inflamación/patología , Trasplante de Células Madre Mesenquimatosas , Ratones , Plásmidos/química , Plásmidos/genética , Plásmidos/farmacología , ARN Interferente Pequeño/farmacología , Receptores CCR6/antagonistas & inhibidoresRESUMEN
Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord leading to muscle atrophy, paralysis, and death. Mitochondrial dysfunction is a major contributor to motor neuron degeneration associated with ALS progression. Mitochondrial abnormalities have been determined in spinal cords of animal disease models and ALS patients. However, molecular mechanisms leading to mitochondrial dysfunction in sporadic ALS (sALS) patients remain unclear. Also, segmental or regional variation in mitochondrial activity in the spinal cord has not been extensively examined in ALS. In our study, the activity of mitochondrial electron transport chain complex IV was examined in post-mortem gray and white matter of the cervical and lumbar spinal cords from male and female sALS patients and controls. Mitochondrial distribution and density in spinal cord motor neurons, lateral funiculus, and capillaries in gray and white matter were analyzed by immunohistochemistry. Results showed that complex IV activity was significantly decreased only in gray matter in both cervical and lumbar spinal cords from ALS patients. In ALS cervical and lumbar spinal cords, significantly increased mitochondrial density and altered distribution were observed in motor neurons, lateral funiculus, and cervical white matter capillaries. Discrete decreased complex IV activity in addition to changes in mitochondria distribution and density determined in the spinal cord in sALS patients are novel findings. These explicit mitochondrial defects in the spinal cord may contribute to ALS pathogenesis and should be considered in development of therapeutic approaches for this disease.
Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Médula Espinal/metabolismo , Médula Espinal/patología , Adulto , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Sustancia Gris/patología , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitocondrias/patología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Sustancia Blanca/patologíaRESUMEN
Human umbilical cord blood (HUCB) cells have shown efficacy in rodent models of focal ischemia and in vitro systems that recapitulate stroke conditions. One potential mechanism of protection is through secretion of soluble factors that protect neurons and oligodendrocytes (OLs) from oxidative stress. To overcome practical issues with cellular therapies, identification of soluble factors released by HUCB and other stem cells may pave the way for treatment modalities that are safer for a larger percentage of stroke patients. Among these soluble factors is leukemia inhibitory factor (LIF), a cytokine that exerts pleiotropic effects on cell survival. Here, data show that LIF effectively reduced infarct volume, reduced white matter injury and improved functional outcomes when administered to rats following permanent middle cerebral artery occlusion. To further explore downstream signaling, primary oligodendrocyte cultures were exposed to oxygen-glucose deprivation to mimic stroke conditions. LIF significantly reduced lactate dehydrogenase release from OLs, reduced superoxide dismutase activity and induced peroxiredoxin 4 (Prdx4) transcript. Additionally, the protective and antioxidant capacity of LIF was negated by both Akt inhibition and co-incubation with Prdx4-neutralising antibodies, establishing a role for the Akt signaling pathway and Prdx4-mediated antioxidation in LIF protection.
Asunto(s)
Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Factor Inhibidor de Leucemia/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Oligodendroglía/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Factor Inhibidor de Leucemia/farmacología , Fármacos Neuroprotectores/farmacología , Proteína Oncogénica v-akt/metabolismo , Peroxirredoxinas/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Accidente Cerebrovascular/tratamiento farmacológico , Sustancia Blanca/efectos de los fármacosRESUMEN
Human umbilical cord blood (HUCB) cells protect the brain against ischemic injury, yet the mechanism of protection remains unclear. Using both in vitro and in vivo paradigms, this study examined the role of Akt signaling and peroxiredoxin 4 expression in human umbilical cord blood cell-mediated protection of oligodendrocytes from ischemic conditions. As previously reported, the addition of HUCB cells to oligodendrocyte cultures prior to oxygen glucose deprivation significantly enhanced oligodendrocyte survival. The presence of human umbilical cord blood cells also increased Akt phosphorylation and elevated peroxiredoxin 4 expression in oligodendrocytes. Blocking either Akt or peroxiredoxin 4 activity with Akt Inhibitor IV or a peroxiredoxin 4-neutralizing antibody, respectively, negated the protective effects of human umbilical cord blood cells. In vivo, systemic administration of human umbilical cord blood cells 48 h after middle cerebral artery occlusion increased Akt phosphorylation and peroxiredoxin 4 protein expression while reducing proteolytic cleavage of caspase 3 in oligodendrocytes residing in the ipsilateral external capsule. Moreover, human umbilical cord blood cells protected striatal white matter bundles from degeneration following middle cerebral artery occlusion. These results suggest that the soluble factors released from human umbilical cord blood cells converge on Akt to elevate peroxiredoxin 4 levels, and these effects contribute to oligodendrocyte survival.
Asunto(s)
Isquemia Encefálica/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Cordón Umbilical/citología , Animales , Isquemia Encefálica/patología , Isquemia Encefálica/terapia , Caspasa 3/biosíntesis , Supervivencia Celular , Humanos , Oligodendroglía/patología , Peroxirredoxinas/biosíntesis , Fosforilación , Ratas , Ratas Sprague-DawleyRESUMEN
Delayed neuronal death associated with stroke has been increasingly linked to the immune response to the injury. Splenectomy prior to middle cerebral artery occlusion (MCAO) is neuroprotective and significantly reduces neuroinflammation. The present study investigated whether splenic signaling occurs through interferon gamma (IFNγ). IFNγ was elevated early in spleens but later in the brains of rats following MCAO. Splenectomy decreased the amount of IFNγ in the infarct post-MCAO. Systemic administration of recombinant IFNγ abolished the protective effects of splenectomy with a concurrent increase in INFγ expression in the brain. These results suggest a role for spleen-derived IFNγ in stroke pathology.
Asunto(s)
Interferón gamma/fisiología , Degeneración Nerviosa/fisiopatología , Bazo/fisiopatología , Accidente Cerebrovascular/fisiopatología , Animales , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Hipoxia de la Célula , Células Cultivadas , Femenino , Fluoresceínas , Colorantes Fluorescentes , Inmunohistoquímica , Infarto de la Arteria Cerebral Media/patología , Interferón gamma/farmacología , Flujometría por Láser-Doppler , Ligadura , Masculino , Arteria Cerebral Media/fisiología , Neuroglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oligodendroglía/metabolismo , Compuestos Orgánicos , Embarazo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacología , Transducción de Señal/fisiología , Bazo/metabolismo , EsplenectomíaRESUMEN
Altered lipoprotein metabolism is considered a pathogenic component of amyotrophic lateral sclerosis (ALS). Apolipoprotein A1 (ApoA1), a major high-density lipoprotein (HDL) protein, is associated with prevention of vascular damage. However, ApoA1's effects on damaged endothelium in ALS are unknown. This study aimed to determine therapeutic potential of ApoA1 for endothelial cell (EC) repair under a pathologic condition reminiscent of ALS. We performed in vitro studies using mouse brain ECs (mBECs) exposed to plasma from symptomatic G93A SOD1 mice. Dosage effects of ApoA1, including inhibition of the phosphoinoside 3-kinase (PI3K)/Akt signaling pathway and integration of ApoA1 into mBECs were examined. Also, human bone marrow-derived endothelial progenitor cells (hBM-EPCs) and mBECs were co-cultured without cell contact to establish therapeutic mechanism of hBM-EPC transplantation. Results showed that ApoA1 significantly reduced mBEC death via the PI3K/Akt downstream signaling pathway. Also, ApoA1 was incorporated into mBECs as confirmed by blocked ApoA1 cellular integration. Co-culture system provided evidence that ApoA1 was secreted by hBM-EPCs and incorporated into injured mBECs. Thus, our study findings provide important evidence for ApoA1 as a potential novel therapeutic for endothelium protection in ALS. This in vitro study lays the groundwork for further in vivo research to fully determine therapeutic effects of ApoA1 in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral , Animales , Apolipoproteína A-I/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Endotelio/metabolismo , Humanos , Ratones , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
The human population is in the midst of battling a rapidly-spreading virus- Severe Acute Respiratory Syndrome Coronavirus 2, responsible for Coronavirus disease 2019 or COVID-19. Despite the resurgences in positive cases after reopening businesses in May, the country is seeing a shift in mindset surrounding the pandemic as people have been eagerly trickling out from federally-mandated quarantine into restaurants, bars, and gyms across America. History can teach us about the past, and today's pandemic is no exception. Without a vaccine available, three lessons from the 1918 Spanish flu pandemic may arm us in our fight against COVID-19. First, those who survived the first wave developed immunity to the second wave, highlighting the potential of passive immunity-based treatments like convalescent plasma and cell-based therapy. Second, the long-term consequences of COVID-19 are unknown. Slow-progressive cases of the Spanish flu have been linked to bacterial pneumonia and neurological disorders later in life, emphasizing the need to reduce COVID-19 transmission. Third, the Spanish flu killed approximately 17 to 50 million people, and the lack of human response, overcrowding, and poor hygiene were key in promoting the spread and high mortality. Human behavior is the most important strategy for preventing the virus spread and we must adhere to proper precautions. This review will cover our current understanding of the pathology and treatment for COVID-19 and highlight similarities between past pandemics. By revisiting history, we hope to emphasize the importance of human behavior and innovative therapies as we wait for the development of a vaccine. Graphical Abstract.
Asunto(s)
COVID-19/terapia , Tratamiento Basado en Trasplante de Células y Tejidos , COVID-19/patología , COVID-19/prevención & control , COVID-19/virología , Historia del Siglo XX , Humanos , Inmunización Pasiva , Influenza Pandémica, 1918-1919/historia , Pandemias/historia , Medicina Regenerativa/historia , SARS-CoV-2/patogenicidad , Sueroterapia para COVID-19RESUMEN
Neovascularization is an integral process of inflammatory reactions and subsequent repair cascades in tissue injury. Monocytes/macrophages play a key role in the inflammatory process including angiogenesis as well as the defence mechanisms by exerting microbicidal and immunomodulatory activity. Current studies have demonstrated that recruited monocytes/macrophages aid in regulating angiogenesis in ischemic tissue, tumours and chronic inflammation. In terms of neovascularization followed by tissue regeneration, monocytes/macrophages should be highly attractive for cell-based therapy compared to any other stem cells due to their considerable advantages: non-oncogenic, non-teratogenic, multiple secretary functions including pro-angiogenic and growth factors, straightforward cell harvesting procedure and non-existent ethical controversy. In addition to adult origins such as bone marrow or peripheral blood, umbilical cord blood (UCB) can be a potential source for autologous or allogeneic monocytes/macrophages. Especially, UCB monocytes should be considered as the first candidate owing to their feasibility, low immune rejection and multiple characteristic advantages such as their anti-inflammatory properties by virtue of their unique immune and inflammatory immaturity, and their pro-angiogenic ability. In this review, we present general characteristics and potential of monocytes/macrophages for cell-based therapy, especially focusing on neovascularization and UCB-derived monocytes.
Asunto(s)
Isquemia/metabolismo , Monocitos/metabolismo , Monocitos/trasplante , Sistema Nervioso/metabolismo , Animales , Sistema Cardiovascular/fisiopatología , Sangre Fetal/citología , Humanos , Mediadores de Inflamación/metabolismo , Modelos Biológicos , Monocitos/citología , Neovascularización Fisiológica , Sistema Nervioso/irrigación sanguíneaRESUMEN
Secondary neurodegeneration resulting from stroke is mediated by delayed proinflammatory signaling and immune cell activation. Although it remains unknown which cell surface markers signify a proinflammatory phenotype, increased isolectin binding occurs on CD11b-expressing immune cells within injured brain tissue. Several reports have confirmed the efficacy of human umbilical cord blood (HUCB) cell therapy in reducing ischemic injury in rat after middle cerebral artery occlusion (MCAO), and these effects were attributed in part to dampened neuroinflammation. The present study examined the time course of lectin binding to cells of microglia/macrophage lineage within 96 hr after MCAO and whether delayed HUCB cell treatment alters the migration and/or morphological characteristics of these cells throughout the period of infarct expansion. Isolectin binding was up-regulated in response to injury, was maximal at 96 hr, and colocalized with cells that expressed the putative proinflammatory markers MMP-9 and nitric oxide. Isolectin-tagged fluorescence was also significantly increased at 72 hr and localized to greater numbers of amoeboid, CD11b-expressing cells relative to 51 hr. Treatment with 1 x 10(6) HUCB cells significantly reduced total lectin binding at 72 hr, as well as the total area occupied by lectin-tagged fluorescence at both 51 and 72 hr, relative to vehicle-treated controls. This effect was accompanied by a shift in the morphology of CD11b-positive cells from amoeboid to ramified shape. These data indicate that HUCB cell therapy suppressed the recruitment of proinflammatory, isolectin-binding cells during the period of infarct expansion, thus offering a potential mechanism for the protective effects of HUCB cell therapy.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Infarto de la Arteria Cerebral Media/inmunología , Infarto de la Arteria Cerebral Media/terapia , Macrófagos/fisiología , Microglía/fisiología , Animales , Antígeno CD11b/metabolismo , Movimiento Celular , Humanos , Técnicas In Vitro , Infarto de la Arteria Cerebral Media/patología , Lectinas/metabolismo , Macrófagos/patología , Metaloproteinasa 9 de la Matriz/metabolismo , Microglía/patología , Neuroinmunomodulación , Óxido Nítrico/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Traumatic brain injury (TBI) causes death and disability in the United States and around the world. The traumatic insult causes the mechanical injury of the brain and primary cellular death. While a comprehensive pathological mechanism of TBI is still lacking, the focus of the TBI research is concentrated on understanding the pathophysiology and developing suitable therapeutic approaches. Given the complexities in pathophysiology involving interconnected immunologic, inflammatory, and neurological cascades occurring after TBI, the therapies directed to a single mechanism fail in the clinical trials. This has led to the development of the paradigm of a combination therapeutic approach against TBI. While there are no drugs available for the treatment of TBI, stem cell therapy has shown promising results in preclinical studies. But, the success of the therapy depends on the survival of the stem cells, which are limited by several factors including route of administration, health of the administered cells, and inflammatory microenvironment of the injured brain. Reducing the inflammation prior to cell administration may provide a better outcome of cell therapy following TBI. This review is focused on different therapeutic approaches of TBI and the present status of the clinical trials.
Asunto(s)
Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Animales , Terapia Combinada/métodos , Terapia Combinada/tendencias , Humanos , Trasplante de Células Madre Mesenquimatosas/tendenciasRESUMEN
Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration in the brain and spinal cord. Progressive paralysis of the diaphragm and other respiratory muscles leading to respiratory dysfunction and failure is the most common cause of death in ALS patients. Respiratory impairment has also been shown in animal models of ALS. Vascular pathology is another recently recognized hallmark of ALS pathogenesis. Central nervous system (CNS) capillary damage is a shared disease element in ALS rodent models and ALS patients. Microvascular impairment outside of the CNS, such as in the lungs, may occur in ALS, triggering lung damage and affecting breathing function. Stem cell therapy is a promising treatment for ALS. However, this therapeutic strategy has primarily targeted rescue of degenerated motor neurons. We showed functional benefits from intravenous delivery of human bone marrow (hBM) stem cells on restoration of capillary integrity in the CNS of an superoxide dismutase 1 (SOD1) mouse model of ALS. Due to the widespread distribution of transplanted cells via this route, administered cells may enter the lungs and effectively restore microvasculature in this respiratory organ. Here, we provided preliminary evidence of the potential role of microvasculature dysfunction in prompting lung damage and treatment approaches for repair of respiratory function in ALS. Our initial studies showed proof-of-principle that microvascular damage in ALS mice results in lung petechiae at the late stage of disease and that systemic transplantation of mainly hBM-derived endothelial progenitor cells shows potential to promote lung restoration via re-established vascular integrity. Our new understanding of previously underexplored lung competence in this disease may facilitate therapy targeting restoration of respiratory function in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/terapia , Microvasos/patología , Neuronas Motoras/metabolismo , Trasplante de Células Madre , Animales , Humanos , Pulmón/patología , Médula Espinal/patologíaRESUMEN
Repairing the damaged blood-CNS-barrier in amyotrophic lateral sclerosis (ALS) is necessary to prevent entry of detrimental blood-borne factors contributing to motor neuron dysfunction. Recently, we showed benefits of human bone marrow endothelial progenitor cell (hBM-EPC) transplantation into symptomatic ALS mice on barrier restoration by replacing damaged endothelial cells (ECs). Additionally, transplanted cells may endogenously repair ECs by secreting angiogenic factors as our subsequent in vitro study demonstrated. Based on these study results, hBM-EPCs may secrete extracellular vesicles, which may contain and transfer diverse vesicular biomolecules towards maintenance of EC functionality. The study aimed to characterize extracellular vesicles (EVs) derived from hBM-EPCs as potential cell-free therapeutics for endothelium repair in ALS. EVs were isolated from hBM-EPC media at different culture times and vesicle properties were evaluated. The protective effects of EVs on mouse brain endothelial cells (mBECs) exposed to ALS mouse plasma were investigated. Uptake and blockage of EVs from GFP-transfected hBM-EPCs in ECs were determined in vitro. Results showed that EVs isolated from hBM-EPCs as nanosized vesicles significantly reduced mBEC damage from the pathological environment and these EVs were taken up by cells. Blockage of ß1 integrin on EVs prevented internalization of vesicles in mBECs. Together, these results provide evidence for potential of hBM-EPC-derived EVs as novel cell-free therapeutics for repair of endothelium in ALS. Although determining translational potential of hBM-EPC-derived EVs will require evaluation in vivo, this in vitro study represents a step towards an extracellular vesicle-based approach for repair of the damaged microvascular endothelium in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/terapia , Células Progenitoras Endoteliales/ultraestructura , Vesículas Extracelulares/trasplante , Esclerosis Amiotrófica Lateral/sangre , Animales , Barrera Hematoencefálica , Células de la Médula Ósea , Células Cultivadas , Medios de Cultivo Condicionados/química , Modelos Animales de Enfermedad , Endotelio Vascular/patología , Vesículas Extracelulares/ultraestructura , Genes Reporteros , Humanos , Masculino , Ratones , Superóxido Dismutasa-1/genéticaRESUMEN
Although many potential therapeutics have improved motor and cognitive function in animal models of experimental stroke, very few have been found to have similar beneficial effects in clinical trials. In this review, we examine the advantages and disadvantages of the currently available rodent models in the development of cellular therapies for stroke and how they have been applied. The lack of translation between the animal work and clinical benefits is not because the animal models are not useful. If the recommendations of the Stroke Academic Industry Roundtable are followed, then the studies will produce more clinically relevant information about potential new cell therapies. However, it will also be necessary to design clinical trials in a manner consistent with the preclinical study results.
Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Modelos Animales de Enfermedad , Accidente Cerebrovascular/terapia , Animales , Embolización Terapéutica , Humanos , Evaluación de Resultado en la Atención de Salud , Ratas , Factores de TiempoRESUMEN
The umbilical cord of a healthy neonate contains within it a multipotential treatment for a myriad of diseases and injuries. What was once tossed into the biohazard waste without a second thought is now known to be a goldmine of antigenically immature cells that rival the use of bone marrow for reconstitution of blood lineages. Umbilical cord blood (UCB) is emerging as an effective and feasible clinical treatment as its availability increases and benefits are realized. Basic science research has demonstrated a broad therapeutic capacity ranging from cell replacement to cell protection and anti-inflammation in a number of animal disease and injury models. UCB is easily obtained with no harm to infant or mother and can be stored at cryogenic temperatures with relatively little loss of cells upon thaw. The heterogeneous mononuclear fraction has been identified and characterized and transplanted both locally and systemically to treat animal models of stroke, myocardial infarction, Amytrophic Lateral Sclerosis, San Filippo, spinal cord injury, traumatic brain injury, and age-related neurodegeneration, among others. In the pages to follow, we share protocols for the identification and research use of the mononuclear cell fraction of UCB.
Asunto(s)
Técnicas de Cultivo de Célula , Tratamiento Basado en Trasplante de Células y Tejidos , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Sangre Fetal/citología , Trasplante de Células Madre Hematopoyéticas/métodos , Animales , Biomarcadores/metabolismo , Encéfalo/citología , Técnicas de Cultivo de Célula/instrumentación , Técnicas de Cultivo de Célula/métodos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Recién Nacido , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/trasplanteRESUMEN
Traumatic brain injury is a leading cause of death and disability around the world. So far, drugs are not available to repair brain damage. Human mesenchymal stem cell (hMSC) transplantation therapy is a promising approach, although the inflammatory microenvironment of the injured brain affects the efficacy of transplanted hMSCs. We hypothesize that reducing the inflammation in the cerebral microenvironment by reducing pro-inflammatory chemokines prior to hMSC administration will improve the efficacy of hMSC therapy. In a rat model of lateral fluid percussion injury, combined pioglitazone (PG) and hMSC (combination) treatment showed less anxiety-like behavior and improved sensorimotor responses to a noxious cold stimulus. Significant reduction in brain lesion volume, neurodegeneration, microgliosis and astrogliosis were observed after combination treatment. TBI induced expression of inflammatory chemokine CCL20 and IL1-ß were significantly decreased in the combination treatment group. Combination treatment significantly increased brain-derived neurotrophic factor (BDNF) level and subventricular zone (SVZ) neurogenesis. Taken together, reducing proinflammatory cytokine expression in the cerebral tissues after TBI by PG administration and prior to hMSC therapy improves the outcome of the therapy in which BDNF could have a role.
Asunto(s)
Antiinflamatorios/administración & dosificación , Lesiones Traumáticas del Encéfalo/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Pioglitazona/administración & dosificación , Administración Intranasal , Animales , Antiinflamatorios/farmacología , Lesiones Traumáticas del Encéfalo/etiología , Lesiones Traumáticas del Encéfalo/inmunología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Quimiocina CCL20/metabolismo , Terapia Combinada , Modelos Animales de Enfermedad , Femenino , Humanos , Interleucina-1beta/metabolismo , Ventrículos Laterales/metabolismo , Masculino , Pioglitazona/farmacología , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
INTRODUCTION: The United States has been actively involved in major armed conflicts over the last 15 years. As a result, a significant proportion of active duty service personnel and returning veterans have endured combat, putting them at risk for developing post-traumatic stress disorder (PTSD), a disabling disorder that may occur after exposure to a traumatic event. Current therapies often require long-term, time-intensive and costly commitment from the patient and have variable degrees of success. There remains an ongoing need for better therapies, including complementary medicine approaches that can effectively reduce PTSD symptoms. While anecdotal evidence suggests that routine practice of Brazilian Jiu Jitsu (BJJ) can reduce symptoms of PTSD, there have been no formal studies to address this. MATERIALS AND METHODS: This study was approved by the University of South Florida Institutional Review Board (#PRO00019430). Male US active duty service members and veterans from the Tampa area participated in a 5-month (40 sessions) BJJ training program. Before beginning and again midway through and upon completion of training the participants completed several validated self-report measures that addressed symptoms of PTSD and other co-morbid conditions. Effect size and 95% confidence intervals were determined using a within-person single-group pretest-posttest design. RESULTS: Study participants demonstrated clinically meaningful improvements in their PTSD symptoms as well as decreased symptoms of major depressive disorder, generalized anxiety and decreased alcohol use; effect sizes varied from 0.80 to 1.85. CONCLUSIONS: The results from this first-of-kind pilot study suggest that including BJJ as a complementary treatment to standard therapy for PTSD may be of value. It will be necessary to validate these promising results with a larger subject cohort and a more rigorous experimental design before routinely recommending this complementary therapy.
Asunto(s)
Artes Marciales/psicología , Personal Militar/psicología , Trastornos por Estrés Postraumático/terapia , Veteranos/psicología , Adulto , Femenino , Florida , Humanos , Masculino , Artes Marciales/educación , Artes Marciales/estadística & datos numéricos , Personal Militar/estadística & datos numéricos , Proyectos Piloto , Psicometría/instrumentación , Psicometría/métodos , Trastornos por Estrés Postraumático/psicología , Encuestas y Cuestionarios , Estados Unidos , Veteranos/estadística & datos numéricosRESUMEN
BACKGROUND: Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation. RESULTS: We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis. CONCLUSION: The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.
Asunto(s)
Envejecimiento/patología , Sangre Fetal/fisiología , Hipocampo/citología , Neuronas/citología , Regeneración/fisiología , Células Madre/citología , Animales , Ciclo Celular/fisiología , Proliferación Celular , Senescencia Celular/fisiología , Humanos , Inyecciones Intravenosas , Leucocitos Mononucleares/citología , Masculino , Microglía/citología , Fenotipo , Ratas , Ratas Endogámicas F344 , Ratas Sprague-DawleyRESUMEN
Stem cell transplantation to replace damaged tissue or correct metabolic disease holds the promise of helping a myriad of human afflictions. Although a great deal of attention has focused on pluripotent stem cells derived from embryos, adult stem cells have been described in a variety of tissues, and they likely will prove to be as beneficial as embryonic stem cells in cell replacement therapy and control of inbred errors of metabolism. We describe methods by which stem cells can be introduced into the nervous system, although the techniques are applicable to any portion of the body to be targeted or any cell that may be used for cell therapy. The first and most straight-forward method is introduction of stem cells directly into the brain parenchyma. The second, which in our hands has proven to be superior in some instances, is introduction of the stem cells into the circulatory system.
Asunto(s)
Trasplante de Células Madre/métodos , Células Madre/metabolismo , Animales , Ratones , Cuidados Posoperatorios , RatasRESUMEN
The 796RMB cell line is a multipotent stem cell line isolated from human fetal midbrain tissues, a region from which dopamine neurons of the substantia nigra develop. It would be useful to increase the dopaminergic characteristics of this cell line to enhance its usefulness as a cell therapy for Parkinson's disease utilizing transplantation protocols. Sertoli cells and its conditioned media isolated from the testis have been previously shown to enhance tyrosine hydroxylase expression in ventral mesencephalon neurons both in vitro and in vivo. Therefore, the present preliminary study investigated the ability of Sertoli cell pre-conditioned medium to enhance differentiation of the 796MB cell line toward the domaminergic phenotype. Results showed that secretory products derived from Sertoli cell conditioned medium increased cell proliferation and enhanced dopaminergic neuronal differentiation of the 796RMB cell line. These findings may lead to alternative therapeutic cell transplantation protocols for the treatment of Parkinson's disease.
Asunto(s)
Medios de Cultivo Condicionados/farmacología , Mesencéfalo/citología , Neuronas/fisiología , Células de Sertoli/química , Células Madre/efectos de los fármacos , Animales , Animales Recién Nacidos , Recuento de Células/métodos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Dopamina/metabolismo , Feto , Humanos , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Ratas , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Numerous data support passage of maternal cells into the fetus during pregnancy in both human and animal models. However, functional benefits of maternal microchimerism in utero are unknown. The current study attempted to take advantage of this route for prenatal delivery of alpha-N-acetylglucosaminidase (Naglu) enzyme into the enzyme-deficient mouse model of Sanfilippo syndrome type B (MPS III B). Enzymatically sufficient mononuclear cells from human umbilical cord blood (MNC hUCB) were intravenously administered into heterozygote females modeling MPS III B on the 5th day of pregnancy during blastocyst implantation. The major findings were 1) administered MNC hUCB cells transmigrated and diffused into the embryos (E12.5); 2) some transmigrated cells expressed CD34 and CD117 antigens; 3) transmigrated cells were found in both the maternal and embryonic parts of placentas; 4) transmigrated cells corrected Naglu enzyme activity in all embryos; 5) administered MNC hUCB cells were extensively distributed in the organs and the blood of heterozygote mothers at one week after transplantation. Results indicate that prenatal delivery of Naglu enzyme by MNC hUCB cell administration into mothers of enzyme-deficient embryos is possible and may present a significant opportunity for new biotechnologies to treat many inherited disorders.