73 research outputs found
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Sex-Specific Effects of a Wartime-Like Radiation Exposure on Cognitive Function.
Evaluating the risk for central nervous system (CNS) effects after whole-body or partial-body irradiation presents challenges due in part to the varied exposure scenarios in the context of occupational, accidental or wartime releases. Risk estimations are further complicated by the fact that robust changes in brain function are unlikely to manifest until significantly late post exposure times. Collectively, the current data regarding CNS radiation risk are conflicting in humans and a survey of the animal model data shows that it is similarly inconsistent. Due to the sparseness of such data, the current study was conducted using male and female mice to evaluate the brain for the delayed effects of a 2 Gy whole-body exposure to c rays starting six months postirradiation. Behavioral testing indicated sex-specific differences in the induction of anxiety-like behaviors and in the ability to abolish fear memories. Molecular analyses showed alterations in post-synaptic protein levels that might affect synaptic plasticity and increased levels of global DNA methylation, suggesting a potential epigenetic mechanism that might contribute to radiation-induced cognitive dysfunction. These data add to the understanding of the CNS response to whole-body irradiation and may lead to improved risk assessment and provide guidance in the development of effective radiation countermeasures to protect military personnel and civilians alike
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Functional equivalence of stem cell and stem cell-derived extracellular vesicle transplantation to repair the irradiated brain.
Cranial radiotherapy, although beneficial for the treatment of brain tumors, inevitably leads to normal tissue damage that can induce unintended neurocognitive complications that are progressive and debilitating. Ionizing radiation exposure has also been shown to compromise the structural integrity of mature neurons throughout the brain, an effect believed to be at least in part responsible for the deterioration of cognitive health. Past work has shown that cranially transplanted human neural stem cells (hNSCs) or their extracellular vesicles (EVs) afforded long-term beneficial effects on many of these cognitive decrements. To provide additional insight into the potential neuroprotective mechanisms of cell-based regenerative strategies, we have analyzed hippocampal neurons for changes in structural integrity and synaptic remodeling after unilateral and bilateral transplantation of hNSCs or EVs derived from those same cells. Interestingly, hNSCs and EVs similarly afforded protection to host neurons, ameliorating the impact of irradiation on dendritic complexity and spine density for neurons present in both the ipsilateral and contralateral hippocampi 1 month following irradiation and transplantation. These morphometric improvements were accompanied by increased levels of glial cell-derived growth factor and significant attenuation of radiation-induced increases in postsynaptic density protein 95 and activated microglia were found ipsi- and contra-lateral to the transplantation sites of the irradiated hippocampus treated with hNSCs or hNSC-derived EVs. These findings document potent far-reaching neuroprotective effects mediated by grafted stem cells or EVs adjacent and distal to the site of transplantation and support their potential as therapeutic agents to counteract the adverse effects of cranial irradiation
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New Concerns for Neurocognitive Function during Deep Space Exposures to Chronic, Low Dose-Rate, Neutron Radiation.
As NASA prepares for a mission to Mars, concerns regarding the health risks associated with deep space radiation exposure have emerged. Until now, the impacts of such exposures have only been studied in animals after acute exposures, using dose rates ∼1.5×105 higher than those actually encountered in space. Using a new, low dose-rate neutron irradiation facility, we have uncovered that realistic, low dose-rate exposures produce serious neurocognitive complications associated with impaired neurotransmission. Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/d) exposures of mice to a mixed field of neutrons and photons result in diminished hippocampal neuronal excitability and disrupted hippocampal and cortical long-term potentiation. Furthermore, mice displayed severe impairments in learning and memory, and the emergence of distress behaviors. Behavioral analyses showed an alarming increase in risk associated with these realistic simulations, revealing for the first time, some unexpected potential problems associated with deep space travel on all levels of neurological function
Persistent oxidative stress in human neural stem cells exposed to low fluences of charged particles.
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miRNA-based therapeutic potential of stem cell-derived extracellular vesicles: a safe cell-free treatment to ameliorate radiation-induced brain injury.
PurposeThis review compiles what is known about extracellular vesicles (EVs), their bioactive cargo, and how they might be used to treat radiation-induced brain injury. Radiotherapy (RT) is effective in cancer treatment, but can cause substantial damage to normal central nervous system tissue. Stem cell therapy has been shown to be effective in treating cognitive dysfunction arising from RT, but there remain safety concerns when grafting foreign stem cells into the brain (i.e. immunogenicity, teratoma). These limitations prompted the search for cell-free alternatives, and pointed to EVs that have been shown to have similar ameliorating effects in other tissues and injury models.ConclusionsEVs are nano-scale and lipid-bound vesicles that readily pass the blood-brain barrier. Arguably the most important bioactive cargo within EVs are RNAs, in particular microRNAs (miRNA). A single miRNA can modulate entire gene networks and signalling within the recipient cell. Determining functionally relevant miRNA could lead to therapeutic treatments where synthetically-derived EVs are used as delivery vectors for miRNA. Stem cell-derived EVs can be effective in treating brain injury including radiation-induced cognitive deficits. Of particular interest are systemic modes of administration which obviate the need for invasive procedures
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Extracellular Vesicle-Derived miR-124 Resolves Radiation-Induced Brain Injury.
Radiation-induced cognitive dysfunction (RICD) is a progressive and debilitating health issue facing patients following cranial radiotherapy to control central nervous system cancers. There has been some success treating RICD in rodents using human neural stem cell (hNSC) transplantation, but the procedure is invasive, requires immunosuppression, and could cause other complications such as teratoma formation. Extracellular vesicles (EV) are nanoscale membrane-bound structures that contain biological contents including mRNA, miRNA, proteins, and lipids that can be readily isolated from conditioned culture media. It has been previously shown that hNSC-derived EV resolves RICD following cranial irradiation using an immunocompromised rodent model. Here, we use immunocompetent wild-type mice to show that hNSC-derived EV treatment administered either intravenously via retro-orbital vein injection or via intracranial transplantation can ameliorate cognitive deficits following 9 Gy head-only irradiation. Cognitive function assessed on the novel place recognition, novel object recognition, and temporal order tasks was not only improved at early (5 weeks) but also at delayed (6 months) postirradiation times with just a single EV treatment. Improved behavioral outcomes were also associated with reduced neuroinflammation as measured by a reduction in activated microglia. To identify the mechanism of action, analysis of EV cargo implicated miRNA (miR-124) as a potential candidate in the mitigation of RICD. Furthermore, viral vector-mediated overexpression of miR-124 in the irradiated brain ameliorated RICD and reduced microglial activation. Our findings demonstrate for the first time that systemic administration of hNSC-derived EV abrogates RICD and neuroinflammation in cranially irradiated wild-type rodents through a mechanism involving miR-124. SIGNIFICANCE: Radiation-induced neurocognitive decrements in immunocompetent mice can be resolved by systemic delivery of hNSC-derived EVs involving a mechanism dependent on expression of miR-124
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Extracellular Vesicle-Derived miR-124 Resolves Radiation-Induced Brain Injury.
Radiation-induced cognitive dysfunction (RICD) is a progressive and debilitating health issue facing patients following cranial radiotherapy to control central nervous system cancers. There has been some success treating RICD in rodents using human neural stem cell (hNSC) transplantation, but the procedure is invasive, requires immunosuppression, and could cause other complications such as teratoma formation. Extracellular vesicles (EV) are nanoscale membrane-bound structures that contain biological contents including mRNA, miRNA, proteins, and lipids that can be readily isolated from conditioned culture media. It has been previously shown that hNSC-derived EV resolves RICD following cranial irradiation using an immunocompromised rodent model. Here, we use immunocompetent wild-type mice to show that hNSC-derived EV treatment administered either intravenously via retro-orbital vein injection or via intracranial transplantation can ameliorate cognitive deficits following 9 Gy head-only irradiation. Cognitive function assessed on the novel place recognition, novel object recognition, and temporal order tasks was not only improved at early (5 weeks) but also at delayed (6 months) postirradiation times with just a single EV treatment. Improved behavioral outcomes were also associated with reduced neuroinflammation as measured by a reduction in activated microglia. To identify the mechanism of action, analysis of EV cargo implicated miRNA (miR-124) as a potential candidate in the mitigation of RICD. Furthermore, viral vector-mediated overexpression of miR-124 in the irradiated brain ameliorated RICD and reduced microglial activation. Our findings demonstrate for the first time that systemic administration of hNSC-derived EV abrogates RICD and neuroinflammation in cranially irradiated wild-type rodents through a mechanism involving miR-124. SIGNIFICANCE: Radiation-induced neurocognitive decrements in immunocompetent mice can be resolved by systemic delivery of hNSC-derived EVs involving a mechanism dependent on expression of miR-124
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