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A model of subcellular events in space flight. Location of subcellular components at any time depends on the integrity and integration of structural contribution of cytoskeletal compartments (microtubules, intermediate filaments, microfilaments). The position of the nucleus depends on the intermediate filaments network, which together with other scaffold proteins, modifies gene transcription. At 1g, compressive or stretching forces are mechanically balanced by cytoskeletal reorganization to provide the internal resistance to nucleus sedimentation. In space, the response caused by unloading is transmitted likewise to/from the nucleus through the cytoskeleton. If we represent the cell as a nucleated tensegrity structure, we expect exposure to microgravity to cause sudden nuclear repositioning. Later on, chronic exposure elicits adaptive changes, likely initiated by cytoskeleton-bound signaling. In summary, this study reports a general softening of a model of microvascular ECs in SF, with reduction of cell motility. The general reorganization of the cytoskeleton showed remarkable loss of actin stress fibers and compensative enlargement of microtubules and intermediate filaments. Cell signaling was altered, at least concerning Hh, with increased frequency of primary cilia. DNA damage repair mechanisms were activated (PML bodies) and even saturated (γH2AX). Territories of marker chromosomes were found altered compared to GCs
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Microgravity and space radiation (SR) are two highly influential factors affecting humans in space flight (SF). Many health problems reported by astronauts derive from endothelial dysfunction and impaired homeostasis. Here, we describe the adaptive response of human, capillary endothelial cells to SF. Reference samples on the ground and at 1g onboa...
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Plant and animal life forms have progressively developed mechanisms for perceiving and responding to gravity on Earth, where homeostatic mechanisms require feedback. Lack of gravity, as in the International Space Station (ISS), induces acute intra-generational changes in the quality of life. These include reduced bone calcium levels and muscle tone...
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... Another important aspect to consider when studying the biological effects of microgravity is its interplay with space radiation that poses a constant threat to the DNA integrity of astronauts 33,34 . Cells have developed sophisticated systems that can find and repair DNA lesions as a defense mechanism against the effects of DNA damage. ...
Progress in mechanobiology allowed us to better understand the important role of mechanical forces in the regulation of biological processes. Space research in the field of life sciences clearly showed that gravity plays a crucial role in biological processes. The space environment offers the unique opportunity to carry out experiments without gravity, helping us not only to understand the effects of gravitational alterations on biological systems but also the mechanisms underlying mechanoperception and cell/tissue response to mechanical and gravitational stresses. Despite the progress made so far, for future space exploration programs it is necessary to increase our knowledge on the mechanotransduction processes as well as on the molecular mechanisms underlying microgravity-induced cell and tissue alterations. This white paper reports the suggestions and recommendations of the SciSpacE Science Community for the elaboration of the section of the European Space Agency roadmap “Biology in Space and Analogue Environments” focusing on “How are cells and tissues influenced by gravity and what are the gravity perception mechanisms?” The knowledge gaps that prevent the Science Community from fully answering this question and the activities proposed to fill them are discussed.
... The NASA Open Science Data Repository (OSDR) (7,8) was filtered to identify human sequencing datasets from spaceflight experiments on the ISS. 9 candidate studies were identified, 5 of which fulfilled the requirements of having both untreated control and untreated flight samples. These studies include OSD-118 (20,21), OSD-174 (22,23), OSD-258 (24,25), OSD-323 (26,27), and OSD-431 (28,29). These studies contain data from a variety of cell types and mission lengths, allowing for a large variety in the obtained data and reducing the effect of tissue-specific expression and confounding factors in further analyses. ...
Space exploration has captured the imagination of humanity for generations. From the first steps on the moon to the recent Mars rover and Artemis lunar exploration missions, space travel has always been an ambitious goal for humanity. However, as we venture further into space and prepare for long-term missions to other planets, the physiological and health risks associated with prolonged space travel are becoming more prominent. Most current research on astronaut health focuses on identifying individual genes or pathways for specific symptoms astronauts face. The human system is complex and delicate, and the effects of microgravity, radiation, and isolation on astronaut health during long-duration spaceflight are still not fully understood. This study used a novel ranking and analysis methodology to combine space omics data from multiple datasets in the NASA OSDR repository. The data was used to generate a multi-omic, integrative bioinformatics analysis pipeline, which identified and characterized a genome-wide spaceflight gene expression correlation loss as a central biosignature for astronaut health on the International Space Station (ISS). Our findings indicate that genome-wide correlation loss corresponds to a breakdown in gene synchronization and cooperation, showcasing the systemic symptoms spaceflight induces and their genomic roots.
... The NASA Open Science Data Repository (OSDR) (7,8) OSD-323 (26,27), and OSD-431 (28,29). These studies contain data from a variety of cell types and mission lengths, allowing for a large variety in the obtained data and reducing the effect of tissue-specific expression and confounding factors in further analyses. ...
Space exploration has captured the imagination of humanity for generations. From the first steps on the moon to the recent Mars rover and Artemis lunar exploration missions, space travel has always been an ambitious goal for humanity. However, as we venture further into space and prepare for long-term missions to other planets, the physiological and health risks associated with prolonged space travel are becoming more prominent. Most current research on astronaut health focuses on identifying individual genes or pathways for specific symptoms astronauts face. The human system is complex and delicate, and the effects of microgravity, radiation, and isolation on astronaut health during long-duration spaceflight are still not fully understood. This study used a novel ranking and analysis methodology to combine space omics data from multiple datasets in the NASA OSDR repository. The data was used to generate a multi-omic, integrative bioinformatics analysis pipeline, which identified and characterized a genome-wide spaceflight gene expression correlation loss as a central biosignature for astronaut health on the International Space Station (ISS). Our findings indicate that genome-wide correlation loss corresponds to a breakdown in gene synchronization and cooperation, showcasing the systemic symptoms spaceflight induces and their genomic roots.
... Comparison of our data with previously published analyses supports the idea that microgravity might reduce YAP1 transcriptional activity. Barravecchia et al. 70 observed a reduced nuclear YAP1 immunostaining signal in flight cells compared to the bright signal obtained on Earth. Liu et al. 16 described a list of 45 genes upregulated in fibroblasts due to YAP1 activation or in response to increased matrix stiffness, of which 37 were downregulated by at least two-folds in our cells in microgravity, a situation corresponding to mechanical unloading. ...
In space, cells sustain strong modifications of their mechanical environment. Mechanosensitive molecules at the cell membrane regulate mechanotransduction pathways that induce adaptive responses through the regulation of gene expression, post-translational modifications, protein interactions or intracellular trafficking, among others. In the current study, human osteoblastic cells were cultured on the ISS in microgravity and at 1 g in a centrifuge, as onboard controls. RNAseq analyses showed that microgravity inhibits cell proliferation and DNA repair, stimulates inflammatory pathways and induces ferroptosis and senescence, two pathways related to ageing. Morphological hallmarks of senescence, such as reduced nuclear size and changes in chromatin architecture, proliferation marker distribution, tubulin acetylation and lysosomal transport were identified by immunofluorescence microscopy, reinforcing the hypothesis of induction of cell senescence in microgravity during space flight. These processes could be attributed, at least in part, to the regulation of YAP1 and its downstream effectors NUPR1 and CKAP2L.
... Lamin A is known to maintain the positional stability of DDR foci in the nucleus [78], to suppress LINE1 retrotransposons and to guarantee robust DSB repair in concert with the longevity factor SIRT6 [79]. Third, microgravity was demonstrated to activate metabolic pathways [80] and consequently ROS formation [52], which in turn is known to activate NF-кB [81]. Regardless of the mechanism, low-level replication stress in primary cells was shown to activate the PARP1-NF-кB axis and thereby a detoxification program, while above a certain stress threshold, associated with DSBs, DDR involving ATM are induced [50]. ...
The impact of space radiation and microgravity on DNA damage responses has been discussed controversially, largely due to the variety of model systems engaged. Here, we performed side-by-side analyses of human hematopoietic stem/progenitor cells (HSPC) and peripheral blood lymphocytes (PBL) cultivated in a 2D clinostat to simulate microgravity before, during and after photon and particle irradiation. We demonstrate that simulated microgravity (SMG) accelerates the early phase of non-homologous end joining (NHEJ)-mediated repair of simple, X-ray-induced DNA double-strand breaks (DSBs) in PBL, while repair kinetics in HSPC remained unaltered. Repair acceleration was lost with increasing LET of ion exposures, which increases the complexity of DSBs, precluding NHEJ and requiring end resection for successful repair. Such cell-type specific effect of SMG on DSB repair was dependent on the NF-кB pathway pre-activated in PBL but not HSPC. Already under unperturbed growth conditions HSPC and PBL suffered from SMG-induced replication stress associated with accumulation of single-stranded DNA and DSBs, respectively. We conclude that in PBL, SMG-induced DSBs promote repair of radiation-induced damage in an adaptive-like response. HSPC feature SMG-induced single-stranded DNA and FANCD2 foci, i.e., markers of persistent replication stress and senescence that may contribute to a premature decline of the immune system in space.
... For this reason, we tested the expression levels of LC3β in our model, also considering that in our previous studies, LC3β was found to be upregulated in 2D TCam-2 cells exposed to s-microgravity [28,29]. In addition, LC3β was also upregulated in other cell models exposed to simulated or real microgravity, indicating that it can represent a good marker to evaluate a possible induction of the autophagic process during altered gravity challenges [34,38]. In line with the results coming from ultrastructural analyses, LC3β protein expression also does not show significant difference between 3D TCam-2 cultured control and RPM-exposed cells ( Figure 9D). ...
One of the hallmarks of microgravity-induced effects in several cellular models is represented by the alteration of oxidative balance with the consequent accumulation of reactive oxygen species (ROS). It is well known that male germ cells are sensitive to oxidative stress and to changes in gravitational force, even though published data on germ cell models are scarce. We previously studied the effects of simulated microgravity (s-microgravity) on a 2D cultured TCam-2 seminoma-derived cell line, considered the only human cell line available to study in vitro mitotically active human male germ cells. In this study, we used a corresponding TCam-2 3D cell culture model that mimics cell–cell contacts in organ tissue to test the possible effects induced by s-microgravity exposure. TCam-2 cell spheroids were cultured for 24 h under unitary gravity (Ctr) or s-microgravity conditions, the latter obtained using a random positioning machine (RPM). A significant increase in intracellular ROS and mitochondria superoxide anion levels was observed after RPM exposure. In line with these results, a trend of protein and lipid oxidation increase and increased pCAMKII expression levels were observed after RPM exposure. The ultrastructural analysis via transmission electron microscopy revealed that RPM-exposed mitochondria appeared enlarged and, even if seldom, disrupted. Notably, even the expression of the main enzymes involved in the redox homeostasis appears modulated by RPM exposure in a compensatory way, with GPX1, NCF1, and CYBB being downregulated, whereas NOX4 and HMOX1 are upregulated. Interestingly, HMOX1 is involved in the heme catabolism of mitochondria cytochromes, and therefore the positive modulation of this marker can be associated with the observed mitochondria alteration. Altogether, these data demonstrate TCam-2 spheroid sensitivity to acute s-microgravity exposure and indicate the capability of these cells to trigger compensatory mechanisms that allow them to overcome the exposure to altered gravitational force.
... As mechanosensitive cells, ECs undergo morphological and functional changes when exposed to µg conditions. Barravecchia et al. [108] performed high-throughput RNA sequencing of human microvascular ECs to identify the genome-wide effects of µg during the ENDO campaign to the ISS in 2015. They found that 32 gene sets of the Hallmark collection were deregulated due to µg exposure (19 up-and 12 downregulated) activating pathways for metabolism and a pro-proliferative phenotype. ...
Microgravity (µg) has a massive impact on the health of space explorers. Microgravity changes the proliferation, differentiation, and growth of cells. As crewed spaceflights into deep space are being planned along with the commercialization of space travelling, researchers have focused on gene regulation in cells and organisms exposed to real (r-) and simulated (s-) µg. In particular, cancer and metastasis research benefits from the findings obtained under µg conditions. Gene regulation is a key factor in a cell or an organism’s ability to sustain life and respond to environmental changes. It is a universal process to control the amount, location, and timing in which genes are expressed. In this review, we provide an overview of µg-induced changes in the numerous mechanisms involved in gene regulation, including regulatory proteins, microRNAs, and the chemical modification of DNA. In particular, we discuss the current knowledge about the impact of microgravity on gene regulation in different types of bacteria, protists, fungi, animals, humans, and cells with a focus on the brain, eye, endothelium, immune system, cartilage, muscle, bone, and various cancers as well as recent findings in plants. Importantly, the obtained data clearly imply that µg experiments can support translational medicine on Earth.
... Accordingly, recent results from in vitro studies suggested that space radiation stimulates endothelial activation, through mechanisms such as hypoxia and inflammation, DNA repair and apoptosis, inhibition of autophagic flux and promotion of an aged-like phenotype. Conversely, microgravity activates pathways for metabolism and a pro-proliferative phenotype, thus revealing possible opposite effects (Barravecchia et al., 2022). Overall, microgravity and exposure to radiations seem to be apparently divergent mechanisms but actually they could converge in promoting neoplastic transformation, and their synergistic effects should further be investigated in this regard. ...
Spaceflight and its associated stressors, such as microgravity, radiation exposure, confinement, circadian derailment and disruptive workloads represent an unprecedented type of exposome that is entirely novel from an evolutionary stand point. Within this perspective, we aimed to review the effects of prolonged spaceflight on immune-neuroendocrine systems, brain and brain-gut axis, cardiovascular system and musculoskeletal apparatus, highlighting in particular the similarities with an accelerated aging process. In particular, spaceflight-induced muscle atrophy/sarcopenia and bone loss, vascular and metabolic changes, hyper and hypo reaction of innate and adaptive immune system appear to be modifications shared with the aging process. Most of these modifications are mediated by molecular events that include oxidative and mitochondrial stress, autophagy, DNA damage repair and telomere length alteration, among others, which directly or indirectly converge on the activation of an inflammatory response. According to the inflammaging theory of aging, such an inflammatory response could be a driver of an acceleration of the normal, physiological rate of aging and it is likely that all the systemic modifications in turn lead to an increase of inflammaging in a sort of vicious cycle. The most updated countermeasures to fight these modifications will be also discussed in the light of their possible application not only for astronauts' benefit, but also for older adults on the ground.
... Interestingly, space radiation and microgravity can have opposite effects on specific molecular pathways. Radiation, as shown with transcriptomic analysis, inhibited autophagy, thereby promoting an aged-like phenotype, while microgravity generated a proliferative phenotype [72]. Such nuances should be taken into account to create a tailored protection that safeguards the health of astronauts. ...
Embryogenesis and fetal development are highly delicate and error-prone processes in their core physiology, let alone if stress-associated factors and conditions are involved. Space radiation and altered gravity are factors that could radically affect fertility and pregnancy and compromise a physiological organogenesis. Unfortunately, there is a dearth of information examining the effects of cosmic exposures on reproductive and proliferating outcomes with regard to mammalian embryonic development. However, explicit attention has been given to investigations exploring discrete structures and neural networks such as the vestibular system, an entity that is viewed as the sixth sense and organically controls gravity beginning with the prenatal period. The role of the gut microbiome, a newly acknowledged field of research in the space community, is also being challenged to be added in forthcoming experimental protocols. This review discusses the data that have surfaced from simulations or actual space expeditions and addresses developmental adaptations at the histological level induced by an extraterrestrial milieu.
... Recently, we described the response of human microvascular endothelial cells (HMEC-1) to SF [1], focusing on this cell type because the endothelium exerts a fundamental role in maintaining the homeostasis. Many health issues reported by astronauts are linked to endothelial suffering, shared to a certain degree by the elderly, severely sedentary individuals, and healthy volunteers in bed-rest studies. ...
... Interestingly, immunofluorescence showed that the autophagic marker MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta) was almost undetectable in SF [1], suggesting inhibition of the autophagy flux. This hypothesis was supported by transcriptomic data showing activation, in SF, of the MTORC1 and PI3K-AKT-MTOR signaling pathways, key negative controllers of autophagy. ...
... Autophagy requires an efficient YAP1 nucleus-cytoplasm shuttling mechanism, which in turn requires cytoskeleton integrity. Space-flown samples show marked cytoskeletal disruption and loss of YAP1 signaling, in addition to activation of stressrelated pathways [1] (Figure 1). This means that stimuli that on Earth would increase autophagy, in space are insufficient to activate the autophagic flux. ...
Microgravity and space radiation (SR) are the two environmental factors that most affect human crews in space flight (SF). The endothelium is highly sensitive to gravitational unloading and several health problems reported by astronauts derive from endothelial dysfunction and impaired homeostasis. Recently, we found that space-flown, endothelial cells show cell softening, the presence of stress granules, reduced motility, profound cytoskeletal reorganization, an increased number of primary cilia, mitochondrial senescence, activation of DNA repair mechanisms, changes of chromosome territories, telomere shortening and increased apoptosis. The transcriptomic study showed activation of oxidative stress, inflammation and DNA damage repair pathways. In general, pathways for metabolism and a pro-proliferative phenotype are activated by microgravity and downregulated by SR. SR upregulates pathways for endothelial activation (hypoxia, cytokines, inflammation), DNA repair and apoptosis, promoting macroautophagy/autophagy flux and an ageing-like phenotype, which instead are downregulated by microgravity. Microgravity and SR exert opposite effects on the MTORC1 gene pathway: SR inhibits the pathway (with consequent enhancement of autophagy), while microgravity strongly stimulates MTORC1 (with consequent inhibition of autophagy). The sum of both contributions results in the net effect of autophagy inhibition in space-flown cells. Microgravity and SR should be considered separately to tailor effective countermeasures to protect astronauts’ health. Potentiation of autophagy is worthy of further investigation as a possible physiological countermeasure to SF-induced cell stress.
