Explore the vast range of titles available.

Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial-cell-like phenotype after acute ischaemic cardiac injury. Fibroblast-derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal-to-endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair. This study shows that cardiac injury induces cardiac fibroblasts to undergo mesenchymal–endothelial transition and acquire an endothelial-cell like fate, a process mediated, in part, by a p53-dependent mechanism — use of a small molecule activator of p53 increases mesenchymal–endothelial transition, leading to reduced scarring and better preservation of heart function. Cardiac repair by mesenchymal-to-endothelial transition Cardiac fibroblasts are thought to be terminally differentiated cells. Arjun Deb and colleagues now show that cardiac injury prompts these fibroblasts to undergo mesenchymal–endothelial transition (MEndoT) and acquire endothelial-cell-like fate, a process mediated, in part, via a p53-dependent mechanism. They find that decreasing MEndoT by p53 deletion leads to reduced vascular density after ischaemic injury and worsened heart function. Conversely, use of a small-molecule activator of p53 increases MEndoT, leading to better preservation of heart function and reduced scarring.

The demands of deep space pose a health risk to the central nervous system that has long been a concern when sending humans to space. While little is known about how spaceflight affects transcription spatially in the brain, a greater understanding of this process has the potential to aid strategies that mitigate the effects of spaceflight on the brain. Therefore, we performed GeoMx Digital Spatial Profiling of mouse brains subjected to either spaceflight or grounded controls. Four brain regions were selected: Cortex, Frontal Cortex, Corunu Ammonis I, and Dentate Gyrus. Antioxidants have emerged as a potential means of attenuating the effects of spaceflight, so we treated a subset of the mice with a superoxide dismutase mimic, MnTnBuOE-2-PyP 5+ (BuOE). Our analysis revealed hundreds of differentially expressed genes due to spaceflight in each of the four brain regions. Both common and region-specific transcriptomic responses were observed. Metabolic pathways and pathways sensitive to oxidative stress were enriched in the four brain regions due to spaceflight. These findings enhance our understanding of brain regional variation in susceptibility to spaceflight conditions. BuOE reduced the transcriptomic effects of spaceflight at a large number of genes, suggesting that this compound may attenuate oxidative stress-induced brain damage caused by the spaceflight environment.

The health risks associated with spaceflight-induced ocular structural and functional damage has become a recent concern for NASA. The goal of the present study was to characterize the effects of spaceflight and reentry to 1 g on the structure and integrity of the retina and blood-retinal barrier (BRB) in the eye. To investigate possible mechanisms, changes in protein expression profiles were examined in mouse ocular tissue after spaceflight. Ten week old male C57BL/6 mice were launched to the International Space Station (ISS) on Space-X 12 at the Kennedy Space Center (KSC) on August, 2017. After a 35-day mission, mice were returned to Earth alive. Within 38 +/− 4 hours of splashdown, mice were euthanized and ocular tissues were collected for analysis. Ground control (GC) and vivarium control mice were maintained on Earth in flight hardware or normal vivarium cages respectively. Repeated intraocular pressure (IOP) measurements were performed before the flight launch and re-measured before the mice were euthanized after splashdown. IOP was significantly lower in post-flight measurements compared to that of pre-flight (14.4–19.3 mmHg vs 16.3–20.3 mmHg) (p < 0.05) for the left eye. Flight group had significant apoptosis in the retina and retinal vascular endothelial cells compared to control groups (p < 0.05). Immunohistochemical analysis of the retina revealed that an increased expression of aquaporin-4 (AQP-4) in the flight mice compared to controls gave strong indication of disturbance of BRB integrity. There were also a significant increase in the expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) and a decrease in the expression of the BRB-related tight junction protein, Zonula occludens-1 (ZO-1). Proteomic analysis showed that many key proteins and pathways responsible for cell death, cell cycle, immune response, mitochondrial function and metabolic stress were significantly altered in the flight mice compared to ground control animals. These data indicate a complex cellular response that may alter retina structure and BRB integrity following long-term spaceflight.

The development of eye pathology is a serious concern for astronauts who spend time in deep space. Microgravity is a major component of the spaceflight environment which could have adverse effects on ocular health. The use of centrifugation to exert forces that partially or fully mimic Earth-level gravity in space is a possible countermeasure to mitigate the effects of microgravity on the eye. Therefore, we subjected mice on the International Space Station (ISS) to microgravity (0 G) or artificial gravity by centrifugation at 0.33 G, 0.67 G, and 1 G, and then performed RNA sequencing (RNA-seq) on optic nerve and retinal tissue after returning them to Earth alive. We find that the microgravity environment induces transcriptomic changes in the optic nerve and retina consistent with an increased oxidative stress load, inflammation, apoptosis, and lipid metabolic stress. We also find that adding artificial gravity on board the ISS attenuates the transcriptomic response to microgravity in a dose-dependent manner. Such attenuation may effectively protect from and mitigate spaceflight-induced detrimental effects on ocular tissue.

Extended spaceflight has been shown to adversely affect astronaut visual acuity. The purpose of this study was to determine whether spaceflight alters gene expression profiles and induces oxidative damage in the retina. Ten week old adult C57BL/6 male mice were flown aboard the ISS for 35 days and returned to Earth alive. Ground control mice were maintained on Earth under identical environmental conditions. Within 38 (+/−4) hours after splashdown, mice ocular tissues were collected for analysis. RNA sequencing detected 600 differentially expressed genes (DEGs) in murine spaceflight retinas, which were enriched for genes related to visual perception, the phototransduction pathway, and numerous retina and photoreceptor phenotype categories. Twelve DEGs were associated with retinitis pigmentosa, characterized by dystrophy of the photoreceptor layer rods and cones. Differentially expressed transcription factors indicated changes in chromatin structure, offering clues to the observed phenotypic changes. Immunofluorescence assays showed degradation of cone photoreceptors and increased retinal oxidative stress. Total retinal, retinal pigment epithelium, and choroid layer thickness were significantly lower after spaceflight. These results indicate that retinal performance may decrease over extended periods of spaceflight and cause visual impairment.

Spaceflight poses many challenges for humans. Ground-based analogs typically focus on single parameters of spaceflight and their associated acute effects. This study assesses the long-term transcriptional effects following single and combination spaceflight analog conditions using the mouse model: simulated microgravity via hindlimb unloading (HLU) and/or low-dose γ-ray irradiation (LDR) for 21 days, followed by 4 months of readaptation. Changes in gene expression and epigenetic modifications in brain samples during readaptation were analyzed by whole transcriptome shotgun sequencing (RNA-seq) and reduced representation bisulfite sequencing (RRBS). The results showed minimal gene expression and cytosine methylation alterations at 4 months readaptation within single treatment conditions of HLU or LDR. In contrast, following combined HLU+LDR, gene expression and promoter methylation analyses showed multiple altered pathways involved in neurogenesis and neuroplasticity, the regulation of neuropeptides, and cellular signaling. In brief, neurological readaptation following combined chronic LDR and HLU is a dynamic process that involves pathways that regulate neuronal function and structure and may lead to late onset neurological sequelae.

It has been proposed that neuroinflammatory response plays an important role in the neurovascular remodeling in the brain after stress. The goal of the present study was to characterize changes in the gene expression profiles associated with neuroinflammation, neuronal function, metabolism and stress in mouse brain tissue. Ten-week old male C57BL/6 mice were launched to the International Space Station (ISS) on SpaceX-12 for a 35-day mission. Within 38 ± 4 h of splashdown, mice were returned to Earth alive. Brain tissues were collected for analysis. A novel digital color-coded barcode counting technology (NanoStringTM) was used to evaluate gene expression profiles in the spaceflight mouse brain. A set of 54 differently expressed genes (p < 0.05) significantly segregates the habitat ground control (GC) group from flight (FLT) group. Many pathways associated with cellular stress, inflammation, apoptosis, and metabolism were significantly altered by flight conditions. A decrease in the expression of genes important for oligodendrocyte differentiation and myelin sheath maintenance was observed. Moreover, mRNA expression of many genes related to anti-viral signaling, reactive oxygen species (ROS) generation, and bacterial immune response were significantly downregulated. Here we report that significantly altered immune reactions may be closely associated with spaceflight-induced stress responses and have an impact on the neuronal function.

There are serious concerns about possible late radiation damage to ocular tissue from prolonged space radiation exposure, and occupational and medical procedures. This study aimed to investigate the effects of whole-body high-energy proton exposure at a single dose on apoptosis, oxidative stress, and blood-retina barrier (BRB) integrity in the retina and optic nerve head (ONH) region and to compare these radiation-induced effects with those produced by fractionated dose. Six-month-old C57BL/6 male mice were either sham irradiated or received whole-body high energy proton irradiation at an acute single dose of 0.5 Gy or 12 equal dose fractions for a total dose of 0.5 Gy over twenty-five days. At four months following irradiation, mice were euthanized and ocular tissues were collected for histochemical analysis. Significant increases in the number of apoptotic cells were documented in the mouse retinas and ONHs that received proton radiation with a single or fractionated dose (p < 0.05). Immunochemical analysis revealed enhanced immunoreactivity for oxidative biomarker, 4-hydroxynonenal (4-HNE) in the retina and ONH following single or fractionated protons with more pronounced changes observed with a single dose of 0.5 Gy. BRB integrity was also evaluated with biomarkers of aquaporin-4 (AQP-4), a water channel protein, a tight junction (TJ) protein, Zonula occludens-1 (ZO-1), and an adhesion molecule, the platelet endothelial cell adhesion molecule-1 (PECAM-1). A significantly increased expression of AQP-4 was observed in the retina following a single dose exposure compared to controls. There was also a significant increase in the expression of PECAM-1 and a decrease in the expression of ZO-1 in the retina. These changes give a strong indication of disturbance to BRB integrity in the retina. Interestingly, there was very limited immunoreactivity of AQP-4 and ZO-1 seen in the ONH region, pointing to possible lack of BRB properties as previously reported. Our data demonstrated that exposure to proton radiation of 0.5 Gy induced oxidative stress-associated apoptosis in the retina and ONH, and changes in BRB integrity in the retina. Our study also revealed the differences in BRB biomarker distribution between these two regions. In response to radiation insults, the cellular response in the retina and ONH may be differentially regulated in acute or hyperfractionated dose schedules.

Astronauts exhibit an assortment of clinical abnormalities in their eyes during long-duration spaceflight. The purpose of this study was to determine whether spaceflight induces epigenomic and transcriptomic reprogramming in the retina or alters the epigenetic clock. The mice were flown for 37 days in animal enclosure modules on the International Space Station; ground-based control animals were maintained under similar housing conditions. Mouse retinas were isolated and both DNA methylome and transcriptome were determined by deep sequencing. We found that a large number of genes were differentially methylated with spaceflight, whereas there were fewer differentially expressed genes at the transcriptome level. Several biological pathways involved in retinal diseases such as macular degeneration were significantly altered. Our results indicated that spaceflight decelerated the retinal epigenetic clock. This study demonstrates that spaceflight impacts the retina at the epigenomic and transcriptomic levels, and such changes could be involved in the etiology of eye-related disorders among astronauts.

The goal of the present study was to characterize acute oxidative damage in ocular structure and retinal function after exposure to spaceflight, and to evaluate the efficacy of an antioxidant in reducing spaceflight-induced changes in the retina. Ten-week-old adult C57BL/6 male mice were flown aboard the ISS on Space-X 24 over 35 days, and returned to Earth alive. The mice received a weekly injection of a superoxide dismutase mimic, MnTnBuOE-2-PyP 5+ (BuOE), before launch and during their stay onboard the ISS. Ground control mice were maintained on Earth under identical environmental conditions. Before the launch, intraocular pressure (IOP) was measured using a handheld tonometer and retinal function was evaluated using electroretinogram (ERG). ERG signals were recorded when the mouse eye was under dark-adapted conditions in response to ultraviolet monochromatic light flashes. Within 20 h after splashdown, IOP and ERG assessments were repeated before euthanasia. There were significant increases in body weight for habitat control groups post-flight compared to pre-flight measurements. However, the body weights were similar among flight groups before launch and after splashdown. The IOP measurements were similar between pre- and post-flight groups with no significant differences between BuOE-treated and saline controls. Immunofluorescence evaluation showed increases in retinal oxidative stress and apoptotic cell death after spaceflight. BuOE treatment significantly decreased the level of the oxidative stress biomarker. ERG data showed that the average amplitudes of the a- and b-wave were significantly decreased (39% and 32% by spaceflight, respectively) compared to that of habitat ground controls. These data indicate that spaceflight conditions induce oxidative stress in the retina, which may lead to photoreceptor cell damage and retinal function impairment.