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The primary objective of this study was to investigate the potential facilitating effects of daily rehabilitation for chronic cerebral ischemia following the intravenous infusion of mesenchymal stem cells (MSC) in rats. The middle cerebral artery (MCA) was occluded by intraluminal occlusion using a microfilament (MCAO). Eight weeks after MCAO induction, the rats were used as a chronic cerebral ischemia model. Four experimental groups were studied: Vehicle group (medium only, no cells); Rehab group (vehicle + rehabilitation), MSC group (MSC only); and Combined group (MSC + rehabilitation). Rat MSCs were intravenously infused eight weeks after MCAO induction, and the rats received daily rehabilitation through treadmill exercise for 20 min. Behavioral testing, lesion volume assessment using magnetic resonance imaging (MRI), and histological analysis were performed during the observation period until 16 weeks after MCAO induction. All treated animals showed functional improvement compared with the Vehicle group; however, the therapeutic efficacy was greatest in the Combined group. The combination therapy is associated with enhanced neural plasticity shown with histological analysis and MRI diffusion tensor imaging. These findings provide behavioral evidence for enhanced recovery by combined therapy with rehabilitation and intravenous infusion of MSCs, and may form the basis for the development of clinical protocols in the future.
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Isquemia Encefálica , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Ratos , Animais , Ratos Sprague-Dawley , Imagem de Tensor de Difusão , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infusões Intravenosas , Isquemia Encefálica/tratamento farmacológico , Transplante de Células-Tronco Mesenquimais/métodos , Modelos Animais de DoençasRESUMO
Malignant glioma is a highly invasive tumor, and elucidating the glioma invasion mechanism is essential for developing novel therapies. We aimed to highlight actin alpha 2, smooth muscle (ACTA2) as potential biomarkers of brain invasion and distant recurrence in malignant gliomas. Using the human malignant glioma cell line, U251MG, we generated ACTA2 knockdown (KD) cells treated with small interfering RNA, and the cell motility and proliferation of the ACTA2 KD group were analyzed. Furthermore, tumor samples from 12 glioma patients who underwent reoperation at the time of tumor recurrence were utilized to measure ACTA2 expression in the tumors before and after recurrence. Thereafter, we examined how ACTA2 expression correlates with the time to tumor recurrence and the mode of recurrence. The results showed that the ACTA2 KD group demonstrated a decline in the mean motion distance and proliferative capacity compared to the control group. In the clinical glioma samples, ACTA2 expression was remarkably increased in recurrent samples compared to the primary samples from the same patients, and the higher the change in ACTCA2 expression from the start to relapse, the shorter the progression-free survival. In conclusion, ACTA2 may be involved in distant recurrence in clinical gliomas.
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Since the 1990s, our group has been conducting basic research on regenerative medicine using various cell types to treat several central nervous system diseases, including spinal cord injury (SCI). We have reported many positive effects of the intravenous administration of mesenchymal stem cells (MSCs) derived from the bone marrow. In the current study, MSCs were administered intravenously to a rat model of severe SCI (crush injury) during the acute to subacute stages-considerable motor function recovery was observed. Furthermore, MSC transplantation in a chronic-phase SCI model improved motor function. In this review, we discuss recent updates in basic research on the intravenous infusion of MSCs and prospects for SCI research.
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Spinal cord injury (SCI) can cause paralysis with a high disease burden with limited treatment options. A single intravenous infusion of mesenchymal stem cells (MSCs) improves motor function in rat SCI models, possibly through the induction of axonal sprouting and remyelination. Repeated infusions (thrice at weekly intervals) of MSCs were administered to rats with chronic SCI to determine if multiple-dosing regimens enhance motor improvement. Chronic SCI rats were randomized and infused with vehicle (vehicle), single MSC injection at week 6 (MSC-1) or repeatedly injections of MSCs at 6, 7, and 8 weeks (MSC-3) after SCI induction. In addition, a single high dose of MSCs (HD-MSC) equivalent to thrice the single dose was infused at week 6. Locomotor function, light and electron microscopy, immunohistochemistry and ex vivo diffusion tensor imaging were performed. Repeated infusion of MSCs (MSC-3) provided the greatest functional recovery compared to single and single high-dose infusions. The density of remyelinated axons in the injured spinal cord was the greatest in the MSC-3 group, followed by the MSC-1, HD-MSC and vehicle groups. Increased sprouting of the corticospinal tract and serotonergic axon density was the greatest in the MSC-3 group, followed by MSC-1, HD-MSC, and vehicle groups. Repeated infusion of MSCs over three weeks resulted in greater functional improvement than single administration of MSCs, even when the number of infused cells was tripled. MSC-treated rats showed axonal sprouting and remyelination in the chronic phase of SCI.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Traumatismos da Medula Espinal , Ratos , Animais , Infusões Intravenosas , Imagem de Tensor de Difusão , Traumatismos da Medula Espinal/terapia , Medula Espinal/fisiologia , Tratos Piramidais , Recuperação de Função Fisiológica/fisiologia , Transplante de Células-Tronco Mesenquimais/métodosRESUMO
BACKGROUND: Perinatal brain injury is multifactorial and primarily associated with brain prematurity, inflammation, and hypoxia-ischemia. Although recent advances in perinatal medicineãhave improved the survival rates of preterm infants, neurodevelopmental disorders remain a significant complication. We tested whether the intravenous infusion of mesenchymal stem cells (MSCs) had therapeutic efficacy against perinatal brain injury in rats. METHODS: Pregnant rats at embryonic day (E) 18 received lipopolysaccharide and the pups were born at E21. On postnatal day (PND) 7, the left common carotid artery of each pup was ligated, and they were exposed to 8% oxygen for 2 h. They were randomized on PND10, and MSCs or vehicle were intravenously infused. We performed behavioral assessments, measured brain volume using MRI, and performed histological analyses on PND49. RESULTS: Infused MSCs showed functional improvements in our model. In vivo MRI revealed that MSC infusion increased non-ischemic brain volume compared to the vehicle group. Histological analyses showed that cortical thickness, the number of NeuN+ and GAD67+ cells, and synaptophysin density in the non-ischemic hemisphere in the MSC group were greater than the vehicle group, but less than the control group. CONCLUSIONS: Infused MSCs improve sensorimotor and cognitive functions in perinatal brain injury and enhance neuronal growth. IMPACT: Intravenous infusion of MSCs improved neurological function in rats with perinatal brain injury, including motor, sensorimotor, cognitive, spatial, and learning memory. Infused MSCs increased residual (non-ischemic) tissue volume, number of neuronal cells, GABAergic cells, and cortical synapses in the contralesional (right) hemisphere. Intravenous administration of MSC might be suitable for the treatment of perinatal brain injury.
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Lesões Encefálicas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Ratos , Animais , Humanos , Recém-Nascido , Infusões Intravenosas , Ratos Sprague-Dawley , Recém-Nascido Prematuro , Lesões Encefálicas/terapia , Células-Tronco Mesenquimais/fisiologia , Modelos Animais de DoençasRESUMO
Intravenous infusion of stem cells is a minimally invasive cellular delivery method, though a few have been reported in a critical limb-threatening ischemia (CLTI) animal model or patients. In the present study, we hypothesized that intravenous infusion of bone-marrow derived mesenchymal stem cells (MSCs) improves tissue perfusion in a rat hindlimb ischemia model. Hindlimb ischemia was generated in Sprague-Dawley rats by femoral artery removal, then seven days after ischemic induction intravenous infusion of 1 × 106 MSCs (cell group) or vehicle (control group) was performed. As compared with the control, tissue perfusion was significantly increased in the cell group. Histological findings showed that capillary density was significantly increased in the cell group, with infused green fluorescent protein (GFP)-MSCs distributed in the ischemic limb. Furthermore, gene expression of vascular endothelial growth factor (VEGF) was significantly increased in ischemic hindlimb muscle tissues of rats treated with MSC infusion. In conclusion, intravenous infusion of bone-marrow derived MSCs improved tissue perfusion in ischemic hindlimbs through angiogenesis, suggesting that intravenous infusion of MSCs was a promising cell delivery method for treatment of CLTI.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Doenças Vasculares Periféricas , Animais , Medula Óssea/metabolismo , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/metabolismo , Membro Posterior/irrigação sanguínea , Infusões Intravenosas , Isquemia/patologia , Extremidade Inferior , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Neovascularização Fisiológica/fisiologia , Perfusão , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Although limited spontaneous recovery occurs after spinal cord injury (SCI), current knowledge reveals that multiple forms of axon growth in spared axons can lead to circuit reorganization and a detour or relay pathways. This hypothesis has been derived mainly from studies of the corticospinal tract (CST), which is the primary descending motor pathway in mammals. The major CST is the dorsal CST (dCST), being the major projection from cortex to spinal cord. Two other components often called "minor" pathways are the ventral and the dorsal lateral CSTs, which may play an important role in spontaneous recovery. Intravenous infusion of mesenchymal stem cells (MSCs) provides functional improvement after SCI with an enhancement of axonal sprouting of CSTs. Detailed morphological changes of CST pathways, however, have not been fully elucidated. The primary objective was to evaluate detailed changes in descending CST projections in SCI after MSC infusion. The MSCs were infused intravenously one day after SCI. A combination of adeno-associated viral vector (AAV), which is an anterograde and non-transsynaptic axonal tracer, was injected 14 days after SCI induction. The AAV with advanced tissue clearing techniques were used to visualize the distribution pattern and high-resolution features of the individual axons coursing from above to below the lesion. The results demonstrated increased observable axonal connections between the dCST and axons in the lateral funiculus, both rostral and caudal to the lesion core, and an increase in observable axons in the dCST below the lesion. This increased axonal network could contribute to functional recovery by providing greater input to the spinal cord below the lesion.
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Células-Tronco Mesenquimais , Traumatismos da Medula Espinal , Animais , Tratos Piramidais/fisiologia , Recuperação de Função Fisiológica/fisiologia , Axônios/patologia , Medula Espinal/metabolismo , Células-Tronco Mesenquimais/metabolismo , Regeneração Nervosa/fisiologia , MamíferosRESUMO
Background Selecting the appropriate direct oral anticoagulants (DOACs) for embolic ischemic stroke patients, especially on concurrent antiplatelet therapy, is important. However, a limited number of studies have reported on the pharmacological differences in platelet aggregation of each DOAC. We aimed to evaluate the antiplatelet effects of selected DOACs, by comparing dabigatran (a direct oral thrombin inhibitor) and factor Xa (FXa) inhibitors (apixaban and rivaroxaban) in patients who had suffered a cardioembolic stroke. Methods We retrospectively evaluated 12 patients diagnosed with a cardioembolic stroke who took any DOAC without an antiplatelet drug and underwent platelet aggregation tests within 60 days from the onset of symptoms. The platelet aggregation tests were analyzed by both light transmission aggregometry and VerifyNow®. Results Six patients (50%) took dabigatran, while the other six (50%) took an FXa inhibitor (n = 4 for apixaban and n = 2 for rivaroxaban). From the light transmission aggregometry analysis, it was found that the maximal extent of aggregation for adenosine diphosphate (ADP) was significantly higher with dabigatran than with FXa inhibitors, and the ED50 value of ADP on platelet aggregation was significantly lower with dabigatran than with FXa inhibitors. Moreover, the VerifyNow® analyses revealed that P2Y12 reaction units were significantly higher with dabigatran than with FXa inhibitors. Conclusions Dabigatran had little impact on platelet aggregation compared to FXa inhibitors in patients who had suffered a cardioembolic stroke with atrial fibrillation, and who took DOACs for secondary prevention within 60 days from the onset.
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Fibrilação Atrial , AVC Embólico , Difosfato de Adenosina/farmacologia , Administração Oral , Anticoagulantes/uso terapêutico , Antitrombinas/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Humanos , Projetos Piloto , Agregação Plaquetária , Piridonas/efeitos adversos , Estudos Retrospectivos , Rivaroxabana/efeitos adversosRESUMO
BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) categorized with and without Hunner lesions is a condition that displays chronic pelvic pain related to the bladder with no efficacious treatment options. There are strong associations suggested between Hunner-type IC and autoimmune diseases. Recently, we established an animal model of Hunner-type IC using a Toll-like receptor-7 (TLR7) agonist. Intravenous infusion of mesenchymal stem cells (MSCs) can be used to treat injury via multimodal and orchestrated therapeutic mechanisms including anti-inflammatory effects. Here, we investigated whether infused MSCs elicit therapeutic efficacy associated with the TLR7-related anti-inflammatory pathway in our Hunner-type IC model. METHODS: Voiding behaviors were monitored 24 h prior to the Loxoribine (LX), which is a TLR7 agonist instillation in order to establish a Hunner-type IC model (from - 24 to 0 h) in female Sprague-Dawley rats. LX was instilled transurethrally into the bladder. At 0 h, the initial freezing behavior test confirmed that no freezing behavior was observed in any of the animals. The LX-instilled animals were randomized. Randomized LX-instilled rats were intravenously infused with MSCs or with vehicle through the right external jugular vein. Sampling tissue for green fluorescent protein (GFP)-positive MSCs were carried out at 48 h. Second voiding behavior tests were monitored from 72 to 96 h. After the final evaluation of the freezing behavior test at 96 h after LX instillation (72 h after MSC or vehicle infusion), histological evaluation with H&E staining and quantitative real-time polymerase chain reaction (RT-PCR) to analyze the mRNA expression levels of inflammatory cytokines were performed. RESULTS: Freezing behavior was reduced in the MSC group, and voiding behavior in the MSC group did not deteriorate. Hematoxylin-eosin staining showed that mucosal edema, leukocyte infiltration, and hemorrhage were suppressed in the MSC group. The relative expression of interferon-ß mRNA in the bladder of the MSC group was inhibited. Numerous GFP-positive MSCs were distributed mainly in the submucosal and mucosal layers of the inflammatory bladder wall. CONCLUSION: Intravenous infusion of MSCs may have therapeutic efficacy in a LX-instilled Hunner-type IC rat model via a TLR7-related anti-inflammatory pathway.
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Cistite Intersticial/terapia , Interferon beta/metabolismo , Células-Tronco Mesenquimais , Receptor 7 Toll-Like/agonistas , Animais , Comportamento Animal , Cistite Intersticial/induzido quimicamente , Cistite Intersticial/metabolismo , Cistite Intersticial/patologia , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Infusões Intravenosas , Dor Pélvica/etiologia , Ratos , Ratos Sprague-Dawley , Bexiga Urinária/patologia , MicçãoRESUMO
BACKGROUND: Surgical reconstruction options of soft-tissue defects often include random pattern skin flaps. Flap survival depends on flap size and rotation arc and can be challenging regarding flap perfusion, leading to wound healing complications, insufficient wound coverage, and even flap loss. Therefore, novel approaches that promote skin flap survival are required. Bone marrow-derived mesenchymal stem cells intravenous infusion is therapeutically effective in various experimental disease models by means of multimodal and orchestrated mechanisms including anti-inflammatory and immunomodulatory effects, and by means of microvasculature reestablishment. METHODS: A modified McFarlane-type rodent skin flap model was used. After skin flap surgery, intravenous infusion of mesenchymal stem cells or vehicle was performed. In vivo optical near-infrared imaging using indocyanine green was performed, followed by histologic analysis, including hematoxylin and eosin and Masson trichrome staining, and gene expression analysis. RESULTS: The flap survival area was greater in the mesenchymal stem cell group. In vivo optical near-infrared perfusion imaging analysis suggested that skin blood perfusion was greater in the mesenchymal stem cell group. Ex vivo histologic analysis demonstrated that the skin structure was more clearly observed in the mesenchymal stem cell group. The dermal thickness was greater in the mesenchymal stem cell group, according to the Masson trichrome staining results. The authors observed a higher expression of fibroblast growth factor 2 mRNA in the tissues of the mesenchymal stem cell group using quantitative reverse-transcription polymerase chain reaction. CONCLUSION: These results suggest that intravenous infusion of bone marrow-derived mesenchymal stem cells promotes skin survival of random pattern flaps, which is associated with increased blood perfusion and higher expression of fibroblast growth factor 2.
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Sobrevivência de Enxerto/fisiologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Retalhos Cirúrgicos/transplante , Animais , Modelos Animais de Doenças , Humanos , Infusões Intravenosas , Masculino , RatosRESUMO
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disorder in which motor neurons within the brain and spinal cord degenerate. A single infusion of mesenchymal stem cells (MSCs) delays disease progression by protecting motor neurons and restoring the blood-spinal cord barrier in the SOD1G93A transgenic ALS rat model. However, the therapeutic effect of a single infusion of MSCs is transient and does not block disease progression. In this study, we demonstrated that repeated administration of MSCs (weekly, four times) increased the survival period, protected motor functions, and reduced deterioration of locomotor activity compared to a single infusion and vehicle infusion, after which rats displayed progressive deterioration of hind limb function. We also compared the days until gait ability was lost in rats and found that the repeated-infused group maintained gait ability compared to the single-infusion and vehicle-infusion groups. These results suggest that repeated administration of MSCs may prevent the deterioration of motor function and extend the lifespan in ALS.
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Esclerose Lateral Amiotrófica/fisiopatologia , Esclerose Lateral Amiotrófica/terapia , Longevidade , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Neurônios Motores/patologia , Superóxido Dismutase-1/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Barreira Hematoencefálica/patologia , Estimativa de Kaplan-Meier , Ratos TransgênicosRESUMO
BACKGROUND: Although spinal cord injury (SCI) is a major cause of disability, current therapeutic options remain limited. Recent progress in cellular therapy with mesenchymal stem cells (MSCs) has provided improved function in animal models of SCI. We investigated the safety and feasibility of intravenous infusion of MSCs for SCI patients and assessed functional status after MSC infusion. METHODS: In this phase 2 study of intravenous infusion of autologous MSCs cultured in auto-serum, a single infusion of MSCs under Good Manufacturing Practice (GMP) production was delivered in 13 SCI patients. In addition to assessing feasibility and safety, neurological function was assessed using the American Spinal Injury Association Impairment Scale (ASIA), International Standards for Neurological and Functional Classification of Spinal Cord (ISCSCI-92). Ability of daily living was assessed using Spinal Cord Independence Measure (SCIM-III). The study protocol was based on advice provided by the Pharmaceuticals and Medical Devices Agency in Japan. The trial was registered with the Japan Medical Association (JMA-IIA00154). RESULTS: No serious adverse events were associated with MSC injection. There was neurologic improvement based on ASIA grade in 12 of the 13 patients at six months post-MSC infusion. Five of six patients classified as ASIA A prior to MSC infusion improved to ASIA B (3/6) or ASIA C (2/6), two ASIA B patients improved to ASIA C (1/2) or ASIA D (1/2), five ASIA C patients improved and reached a functional status of ASIA D (5/5). Notably, improvement from ASIA C to ASIA D was observed one day following MSC infusion for all five patients. Assessment of both ISCSCI-92, SCIM-III also demonstrated functional improvements at six months after MSC infusion, compared to the scores prior to MSC infusion in all patients. CONCLUSION: While we emphasize that this study was unblinded, and does not exclude placebo effects or a contribution of endogenous recovery or observer bias, our observations provide evidence supporting the feasibility, safety and functional improvements of infused MSCs into patients with SCI.
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Transplante de Células-Tronco Mesenquimais/métodos , Traumatismos da Medula Espinal/terapia , Atividades Cotidianas , Adulto , Idoso , Vértebras Cervicais , Estudos de Coortes , Estudos de Viabilidade , Feminino , Humanos , Infusões Intravenosas , Japão , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/diagnóstico , Traumatismos da Medula Espinal/etiologia , Transplante Autólogo , Resultado do TratamentoRESUMO
OBJECTIVE: Reperfusion therapy is a standard therapeutic strategy for acute stroke. Non-favorable outcomes are thought to partially result from impaired microcirculatory flow in ischemic tissue. Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in stroke. One suggested therapeutic mechanism is the restoration of the microvasculature. The goal of this study was to determine whether infused MSCs enhance the therapeutic efficacy of reperfusion therapy following stroke in rats. METHODS: First, to establish a transient middle cerebral artery occlusion (MCAO) model displaying approximately identical neurologic function and lesion volume as seen in permanent MCAO (pMCAO) at day 7 after stroke induction, we transiently occluded the MCA for 90, 110, and 120 minutes. We found that the 110-minute occlusion met these criteria and was used as the transient MCAO (tMCAO) model. Next, 4 MCAO groups were used to compare the therapeutic efficacy of infused MSCs: (1) pMCAO+vehicle, (2) tMCAO+vehicle, (3) pMCAO+MSC, and (4) tMCAO+MSC. Our ischemic model was a unique ischemic model system in which both pMCAO and tMCAO provided similar outcomes during the study period in the groups without MSC infusion groups. Behavioral performance, ischemic volume, and regional cerebral blood flow (rCBF) using arterial spin labeling-magnetic resonance imaging and histologic evaluation of microvasculature was performed. RESULTS: The behavioral function, rCBF, and restoration of microvasculature were greater in group 4 than in group 3. Thus, infused MSCs facilitated the therapeutic efficacy of MCA reperfusion in this rat model system. CONCLUSIONS: Intravenous infusion of MSCs may enhance therapeutic efficacy of reperfusion therapy.
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Circulação Cerebrovascular , Infarto da Artéria Cerebral Média/patologia , Transplante de Células-Tronco Mesenquimais/métodos , Animais , Revascularização Cerebral/métodos , Infusões Intravenosas , Masculino , Microvasos/patologia , Ratos , Ratos Sprague-DawleyRESUMO
ALS is a devastating neurodegenerative disease with few curative strategies. Both sporadic and familial ALS display common clinical features that show progressive paralysis. The pathogenesis remains unclear, but disruption of the blood-spinal cord barrier (BSCB) may contribute to the degeneration of motor neurons. Thus, restoration of the disrupted BSCB and neuroprotection for degenerating motor neurons could be therapeutic targets. We tested the hypothesis that an intravenous infusion of MSCs would delay disease progression through the preservation of BSCB function and increased expression of a neurotrophic factor, neurturin, in SOD1G93A ALS rats. When the open-field locomotor function was under 16 on the Basso, Beattie, and Bresnahan (BBB) scoring scale, the rats were randomized into two groups; one received an intravenous infusion of MSCs, while the other received vehicle alone. Locomotor function was recorded using BBB scoring and rotarod testing. Histological analyses, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), were performed. The MSC group exhibited reduced deterioration of locomotor activity compared to the vehicle group, which displayed progressive deterioration of hind limb function. We observed the protection of motor neuron loss and preservation of microvasculature using Evans blue leakage and immunohistochemical analyses in the MSC group. Confocal microscopy revealed infused green fluorescent protein+ (GFP+) MSCs in the spinal cord, and the GFP gene was detected by nested PCR. Neurturin expression levels were significantly higher in the MSC group. Thus, restoration of the BSCB and the protection of motor neurons might be contributing mechanisms to delay disease progression in SOD1G93A ALS rats.
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Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/terapia , Células-Tronco Mesenquimais/citologia , Degeneração Neural/patologia , Superóxido Dismutase/genética , Animais , Modelos Animais de Doenças , Progressão da Doença , Feminino , Infusões Intravenosas/métodos , Locomoção/fisiologia , Neurônios Motores/citologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/terapia , Ratos Transgênicos , Medula Espinal/metabolismoRESUMO
OBJECTIVES: Ischaemic spinal cord injury (SCI) is one of the most serious complications of aortic surgery. Ischaemic SCIs occur due to various aetiologies, and prediction of the risk is difficult. Magnetic resonance imaging (MRI) is useful to detect the details of spinal cord infarction. There are few studies about MRI for evaluating ischaemic SCI after cardiovascular surgery and aortic events. We report 9 cases of postoperative ischaemic SCI and analyse their MRI features. METHODS: T2-weighted MRI scans of 9 patients who developed ischaemic SCI due to cardiovascular surgery and aortic events between 2012 and 2017 were evaluated. RESULTS: In all patients, high-intensity areas were observed on T2-weighted magnetic resonance images. The site of infarction was the thoracic spinal cord level (9 cases) and additionally at the lumbar spinal cord level (5 cases). The area of infarction area was categorized based on the arterial territory: anterior spinal artery territory (3 cases), posterior spinal artery territory (2 cases), spinal sulcal artery territory (1 case) and artery of Adamkiewicz territory (3 cases). CONCLUSIONS: MRI revealed the infarction sites in all cases and the differences in the infarction patterns in each case. MRI could thus be useful for investigating the aetiology of ischaemic SCI following aortic surgeries and events.
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Traumatismos da Medula Espinal , Isquemia do Cordão Espinal , Humanos , Infarto , Imageamento por Ressonância Magnética , Medula Espinal/diagnóstico por imagem , Isquemia do Cordão Espinal/diagnóstico por imagem , Isquemia do Cordão Espinal/etiologiaRESUMO
Ischemic spinal cord injury (iSCI) is a devastating complication of aortic surgery, with few strategies for prevention. Intravenous infusion of mesenchymal stem cells (MSCs) for iSCI has been shown to provide functional improvement through protection of gray matter. The purpose of this study was to investigate additional mechanisms which may exert therapeutic efficacy in iSCI. Severe iSCI was created to occlude the descending aorta, which was cross-clamped 5 mm distal to the left subclavian artery for 16 min. One day after iSCI induction, iSCI rats were randomized into two groups: one received intravenous infusion of MSCs (MSC-group), the other received vehicle (no cells; vehicle-group). Locomotor function and in vivo MRI were recorded. H&E, Nissl and toluidine blue stainings, immunohistochemical analysis, diffusion tensor imaging (DTI), and the assessment of blood-spinal cord barrier (BSCB) stability were performed. MSC treated animals exhibited gradual improvement in hind-limb locomotor function during the 4-week study period; however the vehicle-treated group displayed persistent motor deficits. In the MSC-treated group we observed the protection of white and gray matter volume reduction of axonal and neuronal loss or degeneration and preservation of microvasculature including BSCB function. Intravenous infusion of MSCs may provide therapeutic efficacy to improve functional outcomes in a rat model of severe iSCI via protection of white and gray matter.
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Substância Cinzenta/patologia , Células-Tronco Mesenquimais , Atividade Motora/fisiologia , Isquemia do Cordão Espinal/terapia , Substância Branca/patologia , Administração Intravenosa , Animais , Modelos Animais de Doenças , Substância Cinzenta/diagnóstico por imagem , Imageamento por Ressonância Magnética , Ratos , Isquemia do Cordão Espinal/diagnóstico por imagem , Isquemia do Cordão Espinal/patologia , Substância Branca/diagnóstico por imagemAssuntos
Dano Encefálico Crônico/terapia , Infarto Cerebral/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Traumatismos da Medula Espinal/terapia , Animais , Barreira Hematoencefálica , Terapia Baseada em Transplante de Células e Tecidos , Doença Crônica , Humanos , Plasticidade Neuronal , Neuroproteção , Remielinização , Acidente Vascular Cerebral/terapiaRESUMO
PURPOSE: The purpose of this study was to elucidate the efficacy and safety of carbonate apatite (CO3Ap) granules in 2-stage sinus floor augmentation through the radiographic and histomorphometric assessment of bone biopsy specimens. METHODS: Two-stage sinus floor augmentation was performed on 13 patients with a total of 17 implants. Radiographic assessment using panoramic radiographs was performed immediately after augmentation and was also performed 2 additional times, at 7±2 months and 18±2 months post-augmentation, respectively. Bone biopsy specimens taken from planned implant placement sites underwent micro-computed tomography, after which histological sections were prepared. RESULTS: Postoperative healing of the sinus floor augmentation was uneventful in all cases. The mean preoperative residual bone height was 3.5±1.3 mm, and this was increased to 13.3±1.7 mm by augmentation with the CO3Ap granules. The mean height of the augmented site had decreased to 10.7±1.9 mm by 7±2 months after augmentation; however, implants with lengths in the range of 6.5 to 11.5 mm could still be placed. The mean height of the augmented site had decreased to 9.6±1.4 mm by 18±2 months post-augmentation. No implant failure or complications were observed. Few inflammatory cells or foreign body giant cells were observed in the bone biopsy specimens. Although there were individual differences in the amount of new bone detected, new bone was observed to be in direct contact with the CO3Ap granules in all cases, without an intermediate layer of fibrous tissue. The amounts of bone and residual CO3Ap were 33.8%±15.1% and 15.3%±11.9%, respectively. CONCLUSIONS: In this first demonstration, low-crystalline CO3Ap granules showed excellent biocompatibility, and bone biopsy showed them to be replaced with bone in humans. CO3Ap granules are a useful and safe bone substitute for two-stage sinus floor augmentation.Trial Registration: ICTRP Identifier: JPRN-UMIN000019281.
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CD3 bispecific constructs show promising therapeutic potential as anti-tumor antibodies, but it has concurrently been difficult to manage cytokine release syndrome (CRS) in clinical use. Currently, the most effective measure for reducing CRS is considered a combination of intra-patient/animal dose escalation and corticosteroid premedication. To examine how effectively an intra-animal ascending dose regimen without premedication would mitigate CRS, we compared plasma cytokine levels in two groups of cynomolgus monkeys; one group was given a single dose, and the other a three-fold daily ascending dose of a CD3 bispecific construct that targets and cross-reacts with both glypican 3 and CD3 (ERY22). Ascending doses up to 1000⯵g/kg of ERY22 dramatically reduced the peak cytokine levels of IL-6, TNF-α, and IFN-γ, IL-2 as well the clinical severity of CRS compared with a single dose of 1000⯵g/kg. Peak cytokine levels following the single and ascending doses were 60,095â¯pg/mL and 1221â¯pg/mL for IL-6; 353â¯pg/mL and 14â¯pg/mL for TNF-α; 123â¯pg/mL and 16â¯pg/mL for IFN-γ; and 2219â¯pg/mL and 42â¯pg/mL for IL-2. The tolerance acquired with daily ascending doses up to 1000⯵g/kg remained in effect for the following weekly doses of 1000⯵g/kg.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Imunoterapia/métodos , Neoplasias/terapia , Linfócitos T/imunologia , Animais , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/imunologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/imunologia , Complexo CD3/imunologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/imunologia , Esquema de Medicação , Interferon gama/sangue , Interleucina-2/sangue , Interleucina-6/sangue , Macaca fascicularis , Masculino , Neoplasias/imunologia , Fator de Necrose Tumoral alfa/sangueRESUMO
Cerebral small vessel disease (CSVD) is not only a cause of vascular dementia (VD) but also a contributing factor to Alzheimer's disease (AD). The essential pathological feature of CSVD is the disruption of blood-brain barrier (BBB). Dysfunction of BBB due to degeneration of both endothelial cells and pericytes in capillaries leads to neuronal damage and progressive brain atrophy. Moreover, deterioration of amyloid-ß (Aß) clearance due to the failure of the transvascular BBB transport system results in accumulation of Aß in the brain. Intravenous infusion of mesenchymal stem cells (MSCs) elicits functional recovery in experimental models including stroke and spinal cord injury. One effect of MSCs is to restore disrupted BBB through remodeling of microvasculature. Using spontaneously hypertensive rats (stroke-prone) with impaired cognitive function as a CSVD model, we have shown that infused MSCs has a therapeutic effect for cognitive function. Restoration of BBB function via remodeling of microvasculature and inhibition of Aß accumulation could inhibit progressive brain atrophy and lead to restore cognitive dysfunction. Gene expression analysis indicated that infused MSCs activates both transforming growth factor-ß and angiopoietin 1 signaling pathways and promotes the remodeling of microvasculature. Thus, infused MSCs may represent a novel therapy for both VD and AD.