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The topic “Translation from Microgravity Research to Earth Application” comprises publications focusing on space life sciences, gravitational biology and space medicine [...]

Neuronal activity is the key modulator of nearly every aspect of behavior, affecting cognition, learning, and memory as well as motion. Hence, disturbances of the transmission of synaptic signals are the main cause of many neurological disorders. Lesions to nervous tissues are associated with phenotypic changes mediated by astrocytes becoming reactive. Reactive astrocytes form the basis of astrogliosis and glial scar formation. Astrocyte reactivity is often targeted to inhibit axon dystrophy and thus promote neuronal regeneration. Here, we aim to understand the impact of gravitational loading induced by hypergravity to potentially modify key features of astrocyte reactivity. We exposed primary murine astrocytes as a model system closely resembling the in vivo reactivity phenotype on custom-built centrifuges for cultivation as well as for live-cell imaging under hypergravity conditions in a physiological range (2g and 10g). We revealed spreading rates, migration velocities, and stellation to be diminished under 2g hypergravity. In contrast, proliferation and apoptosis rates were not affected. In particular, hypergravity attenuated reactivity induction. We observed cytoskeletal remodeling of actin filaments and microtubules under hypergravity. Hence, the reorganization of these key elements of cell structure demonstrates that fundamental mechanisms on shape and mobility of astrocytes are affected due to altered gravity conditions. In future experiments, potential target molecules for pharmacological interventions that attenuate astrocytic reactivity will be investigated. The ultimate goal is to enhance neuronal regeneration for novel therapeutic approaches.

A return to the Moon, Mars expeditions, and a rise in space tourism will lead to an increasing number of human spaceflights. The 'Gravitational biology and space medicine' Collection focuses on the challenges to the health of humans in space during long-term space missions and the physiological changes during short-term altered gravity conditions, the possible influence of space radiation, available countermeasures and possible applications on Earth. In addition, studies reporting on in vivo changes in space-flown mice were published. Finally, this Collection also brings together articles reporting experiments using cells cultured under conditions of real microgravity on the International Space Station, or exposed in ground-based facilities, in order to study morphological and molecular alterations in different cell types.

Plants represent an essential part of future life support systems that will enable human space travel to distant planets and their colonization. Therefore, insights into changes and adaptations of plants in microgravity are of great importance. Despite considerable efforts, we still know very little about how plants respond to microgravity environments on the molecular level, partly due to a lack of sufficient hardware and flight opportunities. The plant Arabidopsis thaliana, the subject of this study, represents a well-studied model organism in gravitational biology, particularly for the analysis of transcriptional and metabolic changes. To overcome the limitations of previous plant hardware that often led to secondary effects and to allow for the extraction not only of RNA but also of phytohormones and proteins, we developed a new experimental platform, called ARABIDOMICS, for exposure and fixation under altered gravity conditions. Arabidopsis seedlings were exposed to hypergravity during launch and microgravity during the free-fall period of the MAPHEUS 5 sounding rocket. Seedlings were chemically fixed inflight at defined time points, and RNA and phytohormones were subsequently analyzed in the laboratory. RNA and phytohormones extracted from the fixed biological samples were of excellent quality. Changes in the phytohormone content of jasmonate, auxin, and several cytokinins were observed in response to hypergravity and microgravity.

Experimental cell research studying three-dimensional (3D) tissues in space and on Earth using new techniques to simulate microgravity is currently a hot topic in Gravitational Biology and Biomedicine. This review will focus on the current knowledge of the use of stem cells and specialized cells for tissue engineering under simulated microgravity conditions. We will report on recent advancements in the ability to construct 3D aggregates from various cell types using devices originally created to prepare for spaceflights such as the random positioning machine (RPM), the clinostat, or the NASA-developed rotating wall vessel (RWV) bioreactor, to engineer various tissues such as preliminary vessels, eye tissue, bone, cartilage, multicellular cancer spheroids, and others from different cells. In addition, stem cells had been investigated under microgravity for the purpose to engineer adipose tissue, cartilage, or bone. Recent publications have discussed different changes of stem cells when exposed to microgravity and the relevant pathways involved in these biological processes. Tissue engineering in microgravity is a new technique to produce organoids, spheroids, or tissues with and without scaffolds. These 3D aggregates can be used for drug testing studies or for coculture models. Multicellular tumor spheroids may be interesting for radiation experiments in the future and to reduce the need for in vivo experiments. Current achievements using cells from patients engineered on the RWV or on the RPM represent an important step in the advancement of techniques that may be applied in translational Regenerative Medicine.

Despite of long period of investigation (over 100 years), still a lot of questions remain unclear about molecular mechanisms of plant graviperception. This requires designing new experiments and new approaches to be applied in gravitational biology. Investigation of plant cell reactions under clinorotation (plant disorientation in respect to gravity vector) is of significant importance to such type of research. Clinorotation is known to cause changes of cell polarity and exert mechanical stress in plant cells. Microtubular cytoskeleton is highly dynamic structure and it responds to both of these stresses. Due to turgor pressure and cell elongation, endogenous mechanical forces influence microtubule orientation in order to coordinate cell growth. Rearrangements of microtubules are regulated by numerous associated proteins which functional activity is not fully clear. In this review, we discuss how MT associated proteins regulate cortical MT arrays under mechanical stress and consider how these proteins may act as plant cell gravisensors. Investigation of microtubule associated proteins under clinorotation might shed the light on molecular mechanism of plant cytoskeleton arrangement and its involvement in initial reactions of cell graviperception.

Purpose of Review The precise impact that gravity, or the lack of gravity, plays in the key phases of mammalian reproduction remains a mystery. Humans and all other known living species have adapted to the effects of gravity on Earth. Only recently has the study of gravitational biology become truly possible. As humans spend increasingly longer periods of time in space, the effect of minimal gravity (microgravity) on mammalian reproduction must be addressed.

Gravity is an important biomechanical signal effecting the morphology and function of organisms. Reduction of gravitational forces, as experienced during spaceflight, cause alterations in the biological systems. Magnetic levitation technique is one of the most recent ground-based technology to mimic weightlessness environment. In addition to providing a platform to investigate biological effects of the weightlessness, this platform presents a novel opportunity to biofabricate 3-dimensional (3D) structures in a scaffold-and nozzle-free fashion. In this study, various controllable self-assembled 3D living structures were fabricated via magnetic levitation technique. This strategy may offer an easy and cost-effective opportunity for a wide range of space biotechnology researches., TUBITAK (215S86)

Gravity constituted the only constant environmental parameter, during the evolutionary period of living matter on Earth. However, whether gravity has affected the evolution of species, and its impact is still ongoing. The topic has not been investigated in depth, as this would require frequent and long-term experimentations in space or an environment of altered gravity. In addition, each organism should be studied throughout numerous generations to determine the profound biological changes in evolution. Here, we review the significant abnormalities presented in the cardiovascular, immune, vestibular and musculoskeletal systems, due to altered gravity conditions. We also review the impact that gravity played in the anatomy of snakes and amphibians, during their evolution. Overall, it appears that gravity does not only curve the space–time continuum but the biological continuum, as well.

Since opportunities for spaceflight experiments are scarce, ground-based microgravity simulation devices (MSDs) offer accessible and economical alternatives for gravitational biology studies. Among the MSDs, the random positioning machine (RPM) provides simulated microgravity conditions on the ground by randomizing rotating biological samples in two axes to distribute the Earth’s gravity vector in all directions over time. Real-time microscopy and image acquisition during microgravity simulation are of particular interest to enable the study of how basic cell functions, such as division, migration, and proliferation, progress under altered gravity conditions. However, these capabilities have been difficult to implement due to the constantly moving frames of the RPM as well as mechanical noise. Therefore, we developed an image acquisition module that can be mounted on an RPM to capture live images over time while the specimen is in the simulated microgravity (SMG) environment. This module integrates a digital microscope with a magnification range of 20× to 700×, a high-speed data transmission adaptor for the wireless streaming of time-lapse images, and a backlight illuminator to view the sample under brightfield and darkfield modes. With this module, we successfully demonstrated the real-time imaging of human cells cultured on an RPM in brightfield, lasting up to 80 h, and also visualized them in green fluorescent channel. This module was successful in monitoring cell morphology and in quantifying the rate of cell division, cell migration, and wound healing in SMG. It can be easily modified to study the response of other biological specimens to SMG.

Research on Artificial Gravity (AG) created by linear acceleration or centrifugation has a long history and could significantly contribute to realize long-term human spaceflight in the future. Employing centrifuges plays a prominent role in human physiology and gravitational biology. This article gives a short review about the background of Artificial Gravity with respect to hypergravity (including partial gravity) and provides information about actual ESA ground-based facilities for research on a variety of biosystems such as cells, plants, animals or, particularly, humans.

Introduction: Microgravity (µg) is an extreme stressor for plants, animals, and humans and influences biological systems. Humans in space experience various health problems during and after a long-term stay in orbit. Various studies have demonstrated structural alterations and molecular biological changes within the cellular milieu of plants, bacteria, microorganisms, animals, and cells. These data were obtained by proteomics investigations applied in gravitational biology to elucidate changes in the proteome occurring when cells or organisms were exposed to real µg (r-µg) and simulated µg (s-µg). Areas covered: In this review, we summarize the current knowledge about the impact of µg on the proteome in plants, animals, and human cells. The literature suggests that µg impacts the proteome and thus various biological processes such as angiogenesis, apoptosis, cell adhesion, cytoskeleton, extracellular matrix proteins, migration, proliferation, stress response, and signal transduction. The changes in cellular function depend on the respective cell type. Expert commentary: This data is important for the topics of gravitational biology, tissue engineering, cancer research, and translational regenerative medicine. Moreover, it may provide new ideas for countermeasures to protect the health of future space travelers.

Cardiovascular system is adapted to gravity, and reactions to its vanishing in space are presumably dependent on body size. Dependency of hematological parameters and body fluids reaction to simulated microgravity have never been studied as an allometric function before. Thus we estimated RBC, blood and extracellular fluid volumes in hindlimb-unloaded (HLU) or control (ATT) mice, rats and rabbits.RBC decrease was found to be size-independent, and the allometric dependency for red blood loss in HLU and ATT animals shared a common power (−0.054±0.008) but differrent Y0 (8.66±0.40 and 10.73±0.49 correspondingly, pOur data underscore the importance of size-independent mechanisms of cardiovascular adaptation to weightlessness. Despite use of mice hampers application of a straightforward translational approach, this species is useful for gravitational biology as a tool to investigate size-independent mechanisms of mammalian adaptation to microgravity.

Space flight in an environment with reduced gravity has severe effects on the body. Astronauts suffer from a significant decrease in bone mineral density during space missions, but the molecular mechanisms responsible for such changes in bone density are unclear. To identify these mechanisms, unique experiments on medaka fish were performed twice at the International Space Station (ISS). One was a two-month long experiment for the analysis of bone growth, which revealed a decrease in the mineral density of pharyngeal bones. Another was a short-term experiment for live imaging of transgenic medaka lines and transcriptome analysis during 8 days, which revealed an increase in the expression levels of five genes. Overall, these studies on medaka fish provided an initial explanation of the process.

To study the impact of gravity on living systems on the cellular up to the organismic level, a variety of experimental platforms are available for gravitational biology and biomedical research providing either an almost stimulus-free microgravity environment (near weightlessness) of different duration and boundary conditions. The spectrum of real-microgravity research platforms is complemented by devices which are used to either increase the gravity level (centrifuges) or modify the impact of gravity on biological systems (clinostats and random-positioning machines)—the so-called ground-based facilities. Rotating biological samples horizontally or in a two- or three-dimensional mode is often used to randomize the effect of gravity in the attempt to eliminate the gravity effect on sensing mechanisms and gravity-related responses. Sophisticated centrifuges have been designed allowing studies from cells up to humans, either on ground under hypergravity conditions (> 1 g) or in space, where they offer the chance to stepwise increase the acceleration force from 0 g (microgravity) to 1 g or higher and vice versa. In such a way, centrifuges are used to determine threshold values of gravisensitivity and to unravel molecular and cellular mechanisms of gravity sensing and gravity-related responses. By using the whole spectrum of experimental platforms, gravitational biologists gain deep insight into gravity-related biological processes and continuously increase our knowledge of how gravity affects life on Earth.

Plant development strongly relies on environmental conditions. Growth of plants in Biological Life Support Systems (BLSS), which are a necessity to allow human survival during long-term space exploration missions, poses a particular problem for plant growth, as in addition to the traditional environmental factors, microgravity (or reduced gravity such as on Moon or Mars) and limited gas exchange hamper plant growth. Studying the effects of reduced gravity on plants requires real or simulated microgravity experiments under highly standardized conditions, in order to avoid the influence of other environmental factors. Analysis of a large number of biological replicates, which is necessary for the detection of subtle phenotypical differences, can so far only be achieved in Ground Based Facilities (GBF). Besides different experimental conditions, the usage of a variety of different plant growth chambers was a major factor that led to a lack of reproducibility and comparability in previous studies. We have developed a flexible and customizable plant growth chamber, called ARAbidopsis DISH (ARADISH), which allows plant growth from seed to seedling, being realized in a hydroponic system or on Agar. By developing a special holder, the ARADISH can be used for experiments with Arabidopsis thaliana or a plant with a similar habitus on common GBF hardware, including 2D clinostats and Random Positioning Machines (RPM). The ARADISH growth chamber has a controlled illumination system of red and blue light emitting diodes (LED), which allows the user to apply defined light conditions. As a proof of concept we tested a prototype in a proteomic experiment in which plants were exposed to simulated microgravity or a 90° stimulus. We optimized the design and performed viability tests after several days of growth in the hardware that underline the utility of ARADISH in microgravity research.

Gravity has constantly influenced both physical and biological phenomena throughout Earth's history. The gravitational field has played a major role in shaping evolution when life moved from water to land, even if, for a while, it has been generally deemed to influence natural selection only by limiting the range of acceptable body sizes, according to Galilei's principle. Indeed, to counteract gravity, living organisms would need to develop systems to provide cell membrane rigidity, fluid flow regulation, and appropriate structural support for locomotion. However, gravity may influence in a more deep and subtle fashion the way the cells behave and build themselves.

Dating back to the Apollo and Skylab missions, it has been reported that astronauts suffered from bacterial and viral infections during space flight or after returning to Earth. Blood analyses revealed strongly reduced capability of human lymphocytes to become active upon mitogenic stimulation. Since then, a large number of in vitro studies on human immune cells have been conducted in space, in parabolic flights, and in ground-based facilities. It became obvious that microgravity affects cell morphology and important cellular functions. Observed changes include cell proliferation, the cytoskeleton, signal transduction and gene expression. This review gives an overview of the current knowledge of T cell regulation under altered gravity conditions obtained by in vitro studies with special emphasis on the cell culture conditions used. We propose that future in vitro experiments should follow rigorous standardized cell culture conditions, which allows better comparison of the results obtained in different flight- and ground-based experiment platforms.

SJ-10 program provides a mission of space microgravity experiments including both fields of microgravity science and space life science aboard the 24th recoverable satellite of China. Scientific purpose of the program is to promote the scientific research in the space microgravity environment by operating the satellite at lower earth orbit for 2 weeks. There are totally 27 experiments, including 17 ones in the field of microgravity science (microgravity fluid physics 6, microgravity combustion 3, and space materials science 8) and 10 in the field of space life science (radiation biology 3, gravitational biology 3, and space biotechnology 4). These experiments were selected from more than 200 applications. The satellite will be launched in the end of 2015 or a bit later. It is expected that many fruitful scientific results on microgravity science and space life science will be contributed by this program.

The microgravity environment aboard orbiting spacecraft has provided a unique laboratory to explore topics in basic plant biology as well as applied research on the use of plants in bioregenerative life support systems. Our group has utilized the European Modular Cultivation System (EMCS) aboard the International Space Station (ISS) to study plant growth, development, tropisms, and gene expression in a series of spaceflight experiments. The most current project performed on the ISS was termed Seedling Growth-1 (SG-1) which builds on the previous TROPI (for tropi sms) experiments performed in 2006 and 2010. Major technical and operational changes in SG-1 (launched in March 2013) compared to the TROPI experiments include: (1) improvements in lighting conditions within the EMCS to optimize the environment for phototropism studies, (2) the use of infrared illumination to provide high-quality images of the seedlings, (3) modifications in procedures used in flight to improve the focus and overall quality of the images, and (4) changes in the atmospheric conditions in the EMCS incubator. In SG-1, a novel red-light-based phototropism in roots and hypocotyls of seedlings that was noted in TROPI was confirmed and now can be more precisely characterized based on the improvements in procedures. The lessons learned from sequential experiments in the TROPI hardware provide insights to other researchers developing space experiments in plant biology.

OBJECTIVE: When exposed to microgravity in vitro, cells change their gene expression patterns, protein contents and growth behavior. More than one hundred reports were published about the characterization of cells from malignant and healthy tissues, as well as of endothelial cells and stem cells exposed to microgravity conditions.RESEARCH DESIGN AND METHODS: We retrieved publications about microgravity related studies on each type of cell, extracted the proteins mentioned therein and analyzed them subsequently using Pathway Studio aiming to identify biological processes affected by microgravity culture conditions. Main outcome measures; Results: The Pathway Studio analysis of the proteins found in each group of manuscripts revealed 66 different biological processes, 19 of them were always detected when the four groups of proteins were analyzed.CONCLUSIONS: Since a response to the removal of gravity is common to all the different cell types, at least some of the 19 biological processes could play a role in cellular adaption to microgravity. The application of computer programs, helping to extract and analyze proteins and genes mentioned in publications will become essential for scientists interested to get an overview of the rapidly growing fields of science, such as gravitational biology, translational regenerative medicine and space medicine.

Experiments in space either on orbital missions on-board the ISS, or in suborbital missions using sounding rockets, like TEXUS as well as parabolic flight campaigns are still the gold standard to achieve real microgravity conditions in the field of gravitational biology and medicine. However, during launch, and in flight, hypergravity and vibrations occur which might interfere with the effects of microgravity. It is therefore important to know these effects and discriminate them from the microgravity effects. This can be achieved by ground-based facilities like centrifuges or vibration platforms. Recently, we have conducted several experiments with different thyroid cancer cell lines. This study, as part of the ESA-CORA-GBF 2010-203 project, focused on the influence of vibration and hypergravity on benign human thyroid follicular epithelial cells (Nthy-ori 3-1 cell line). Gene and in part protein expression regulation under both conditions were analyzed for VCAN, ITGA10, ITGB1, OPN, ADAM19, ANXA1, TNFA, ABL2, ACTB, PFN2, TLN1, EZR, RDX, MSN, CTGF, PRKCA, and PRKAA1 using quantitative real-time PCR and Western Blot. We found that hypergravity and vibration affected genes and proteins involved in the extracellular matrix, the cytoskeleton, apoptosis, cell growth and signaling. Vibration always led to a down-regulation, whereas hypergravity resulted in a more heterogeneous expression pattern. Overall we conclude that both conditions can influence gene regulation and production of various genes and proteins. As a consequence, it is important to perform control experiments on hypergravity and vibration facilities in parallel to flight experiments.

All organisms on earth have evolved at unit gravity and thus are probably adapted to function optimally at 1 g. However, with the advent of space exploration, it has been shown that organisms are capable of surviving at much less than 1 g, as well as at greater than 1 g. Organisms subjected to increased g levels exhibit alterations in physiological processes that compensate for novel environmental stresses, such as increased weight and density-driven sedimentation. Weight drives many chemical, biological, and ecological processes on earth. Altering weight changes these processes. The most important physiological changes caused by microgravity include bone demineralization, skeletal muscle atrophy, vestibular problems causing space motion sickness, cardiovascular deconditioning, etc. Manned missions into space and significant concerns in developmental and evolutionary biology in zero and low gravity conditions demand a concentrated research effort in space-medicine, physiology and on a larger scale — gravitational biophysics. Space exploration is a new frontier with long-term missions to the moon and Mars not far away. Research in these areas would also provide us with fascinating insights into how gravity has shaped our evolution on this planet and how it still governs some of the basic life processes. Understanding the physiological changes caused by long-duration microgravity remains a daunting challenge. The present concise review deals with the effects of altered gravity on the biological processes at the cellular, organic and systemic level which will be helpful for the researchers aspiring to venture in this area. The effects observed in plants and animals are presented under the classifications such as cells, plants, invertebrates, vertebrates and humans.

Before there was access to space, all experiments on plant tropisms were conducted upon the background of gravity. The gravity vector could be disrupted, such as with clinorotation and random positioning machines, and by manipulating incident angles of root growth with respect to gravity, such as with Darwin's plants on slanted plates, but gravity could not be removed from the experimental equation. Access to microgravity through spaceflight has opened new doors to plant research. Here we provide an overview of some of the methodologies of conducting plant research in the unique spaceflight environment.

Gravity plays an important role for the evolution, orientation and development of organisms. Most of us, however, tend to overlook its importance because--due to its constant presence from the beginning of evolution some 4 billion years ago--this environmental parameter is almost hardwired into our interpretation of reality. This negligence of gravity is the more surprising as we all have our strong fights with this factor, especially during the very early and again during the late phases of our lives. On the other hand, scientists have been fascinated to observe the effects of gravity especially on plants and microorganisms for more than a hundred years, since Darwin and Sachs demonstrated the role of the root cap for downward growing plants. Different experimental approaches are nowadays available in order to change the influence of gravity and to study the corresponding influences on the physiology of biological systems. With the advent of spaceflight, a long-term nearly nullification of gravity is possible. Utilisation of this so-called "microgravity" condition for research in life sciences thus became an important asset in the space programs of various space agencies around the world. The German Space Life Sciences Program is managed--like all other space programs and activities in Germany--by the German Aerospace Center (DLR) in its role as space agency for Germany. Within the current space program, approved by the German government in May 2001, the overall goal for its life sciences part was defined as to gain scientific knowledge and to disclose new application potential by research under space conditions, especially by utilising the microgravity environment of the International Space Station. Three main scientific fields have been identified in collaboration with the scientific community: integrative human physiology, biotechnological applications of the microgravity environment, and fundamental biology of gravity and radiation responses (i.e., gravitational and radiation biology). In the present contribution, specific goals as well as achievements and perspectives of research in gravitational biology are given. In addition, some information is provided on spaceflight opportunities available.

Scientists and technicians have been innovative in order to find experimental approaches to study the influence of gravity. Depending on the scientific question and the time course of events which are under investigation, different experimental platforms are available to provide conditions of altered gravitational stimulation on ground and to prepare space experiments i.e. under real microgravity conditions. The application profile ranges from studies with molecules or single cells up to humans.

Scope of gravitational biology is discussed with allometry and size of living organisms., 資料番号: AA0048095049