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Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (28 February 2025) | Viewed by 25447

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Prof. Dr. Daniela Grimm

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1. Department of Microgravity and Translational Regenerative Medicine, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
2. Department of Biomedicine, Aarhus University, Aarhus, Denmark
Interests: space medicine; translational regenerative medicine; tissue engineering; cancer research; biomarker
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Space travel has always been a dream of humankind. Deep space exploration will increase the time humans or rodents will spend in microgravity (µg). Moreover, they are exposed to cosmic radiation, hypodynamia, and isolation.

Life in space has enormous well-described effects on health. To counteract these health problems, studies focusing on cardiovascular changes, bone loss, muscle atrophy or the immune system, among others, have been performed in recent years.

This Special Issue (SI) focuses on the impact of real microgravity on humans, animals, microorganisms, and plants during spaceflights. It addresses the impact of cosmic radiation, available countermeasures, and possible applications on Earth.

In addition, studies investigating the effects of simulated microgravity on cells, animals and microorganisms will be published. Ground-based facilities created to provide microgravity on Earth can be used to study molecular biological changes in cells, plants and microorganisms.

Articles and reviews will be published reporting recent advances in gravitational biology, translational regenerative medicine, space medicine and cancer research. Omics investigations and bioinformatics studies will be collected in this Special Issue.

Prof. Dr. Daniela Grimm
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

cells
humans
animals
plants
microorganisms
microgravity
weightlessness
cancer research
tissue engineering
space-related health problems

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Published Papers (10 papers)

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Research

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23 pages, 2986 KiB

Open AccessArticle

Dynamic Mechanical Load as a Trigger for Growth and Proliferation in Porcine Epithelial Cells

by Stefan Kahlert, Constanze Nossol, Marcus Krüger, Sascha Kopp, Daniela Grimm, Simon L. Wuest and Hermann-Josef Rothkötter

Biomolecules 2025, 15(3), 455; https://doi.org/10.3390/biom15030455 - 20 Mar 2025

Viewed by 365

Abstract

The impact of gravity is a basic force determining our existence on Earth. Changes in orientation with respect to the gravity vector trigger alternating mechanical forces on organisms, organs, and cells. In the intestines of mammals, epithelial cells are continuously exposed to changed orientations to gravity. In this study, we employed dynamic cultivation systems to mimic the load changes and the resulting mechanical forces. The morphological and functional response of non-cancer-derived porcine epithelial cell lines IPEC-1 and IPEC-J2 was analyzed. We found that dynamic growth conditions affect morphology in the enterocyte model IPEC-1 but not in IPEC-J2. Changes in IPEC-1 were accompanied by modifications of the distribution and structure of the F-actin cytoskeleton rather than the amount. The structure of the apical brush border and the tight junction system seemed to be largely unaffected; however, a robust decrease in transepithelial resistance was found in IPEC-1 and partially in IPEC-J2. We further detected an increase in Ki67, pointing towards accelerated proliferation. In line with this finding, we detected a doubling of cellular mitochondrial respiration, which was not linked to a general increase in the respiratory chain capacity. Dynamic cultivation of confluent epithelial cell layers did not evoke signs of senescence. In summary, we identified the mechanical load cycle as a relevant parameter for the modulation of the morphological structure and physiological behaviour of intestinal epithelial cells. Full article

(This article belongs to the Special Issue Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants)

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17 pages, 6948 KiB

Open AccessArticle

The Formation of Stable Lung Tumor Spheroids during Random Positioning Involves Increased Estrogen Sensitivity

by Balkis Barkia, Viviann Sandt, Daniela Melnik, José Luis Cortés-Sánchez, Shannon Marchal, Bjorn Baselet, Sarah Baatout, Jayashree Sahana, Daniela Grimm, Markus Wehland, Herbert Schulz, Manfred Infanger, Armin Kraus and Marcus Krüger

Biomolecules 2024, 14(10), 1292; https://doi.org/10.3390/biom14101292 - 12 Oct 2024

Cited by 2 | Viewed by 1756

Abstract

The formation of tumor spheroids on the random positioning machine (RPM) is a complex and important process, as it enables the study of metastasis ex vivo. However, this process is not yet understood in detail. In this study, we compared the RPM-induced spheroid formation of two cell types of lung carcinoma (NCI-H1703 squamous cell carcinoma cells and Calu-3 adenocarcinoma cells). While NCI-H1703 cells were mainly present as spheroids after 3 days of random positioning, Calu-3 cells remained predominantly as a cell layer. We found that two-dimensional-growing Calu-3 cells have less mucin-1, further downregulate their expression on the RPM and therefore exhibit a higher adhesiveness. In addition, we observed that Calu-3 cells can form spheroids, but they are unstable due to an imbalanced ratio of adhesion proteins (β₁-integrin, E-cadherin) and anti-adhesion proteins (mucin-1) and are likely to disintegrate in the shear environment of the RPM. RPM-exposed Calu-3 cells showed a strongly upregulated expression of the estrogen receptor alpha gene ESR1. In the presence of 17β-estradiol or phenol red, more stable Calu-3 spheroids were formed, which was presumably related to an increased amount of E-cadherin in the cell aggregates. Thus, RPM-induced tumor spheroid formation depends not solely on cell-type-specific properties but also on the complex interplay between the mechanical influences of the RPM and, to some extent, the chemical composition of the medium used during the experiments. Full article

(This article belongs to the Special Issue Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants)

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17 pages, 18387 KiB

Open AccessArticle

Integration of Proteomic and Metabolomic Data Reveals the Lipid Metabolism Disorder in the Liver of Rats Exposed to Simulated Microgravity

by Mengyao Ru, Jun He, Yungang Bai, Kun Zhang, Qianqian Shi, Fang Gao, Yunying Wang, Baoli Li and Lan Shen

Biomolecules 2024, 14(6), 682; https://doi.org/10.3390/biom14060682 - 12 Jun 2024

Cited by 3 | Viewed by 1654

Abstract

Long-term exposure to microgravity is considered to cause liver lipid accumulation, thereby increasing the risk of non-alcoholic fatty liver disease (NAFLD) among astronauts. However, the reasons for this persistence of symptoms remain insufficiently investigated. In this study, we used tandem mass tag (TMT)-based quantitative proteomics techniques, as well as non-targeted metabolomics techniques based on liquid chromatography–tandem mass spectrometry (LC–MS/MS), to comprehensively analyse the relative expression levels of proteins and the abundance of metabolites associated with lipid accumulation in rat liver tissues under simulated microgravity conditions. The differential analysis revealed 63 proteins and 150 metabolites between the simulated microgravity group and the control group. By integrating differentially expressed proteins and metabolites and performing pathway enrichment analysis, we revealed the dysregulation of major metabolic pathways under simulated microgravity conditions, including the biosynthesis of unsaturated fatty acids, linoleic acid metabolism, steroid hormone biosynthesis and butanoate metabolism, indicating disrupted liver metabolism in rats due to weightlessness. Finally, we examined differentially expressed proteins associated with lipid metabolism in the liver of rats exposed to stimulated microgravity. These findings contribute to identifying the key molecules affected by microgravity and could guide the design of rational nutritional or pharmacological countermeasures for astronauts. Full article

(This article belongs to the Special Issue Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants)

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15 pages, 2370 KiB

Open AccessArticle

Changes in Gravitaxis and Gene-Expression in an Euglena gracilis Culture over Time

by Julia Krüger, Peter Richter, Julia Stoltze, Binod Prasad, Sebastian M. Strauch, Marcus Krüger, Adeel Nasir and Michael Lebert

Biomolecules 2024, 14(3), 327; https://doi.org/10.3390/biom14030327 - 9 Mar 2024

Viewed by 2237

Abstract

Age-dependent changes in the transcription levels of 5-day-old Euglena gracilis cells, which showed positive gravitaxis, 6-day-old cells without gravitactic orientation, and older cells (9- and 11-day-old, which displayed a precise negative gravitaxis) were determined through microarray analysis. Hierarchical clustering of four independent cell cultures revealed pronounced similarities in transcription levels at the same culture age, which proves the reproducibility of the cultivation method. Employing the non-oriented cells from the 6-day-old culture as a reference, about 2779 transcripts were found to be differentially expressed. While positively gravitactic cells (5-day-old culture) showed only minor differences in gene expression compared to the 6-day reference, pronounced changes of mRNAs (mainly an increase) were found in older cells compared to the reference culture. Among others, genes coding for adenylyl cyclases, photosynthesis, and metabolic enzymes were identified to be differentially expressed. The investigated cells were grown in batch cultures, so variations in transcription levels most likely account for factors such as nutrient depletion in the medium and self-shading. Based on these findings, a particular transcript (e.g., transcript 19556) was downregulated using the RNA interference technique. Gravitaxis and phototaxis were impaired in the transformants, indicating the role of this transcript in signal transduction. Results of the experiment are discussed regarding the increasing importance of E. gracilis in biotechnology as a source of valuable products and the possible application of E. gracilis in life-support systems. Full article

(This article belongs to the Special Issue Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants)

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14 pages, 6595 KiB

Open AccessArticle

Space Flight Enhances Stress Pathways in Human Neural Stem Cells

by Nicholas Carpo, Victoria Tran, Juan Carlos Biancotti, Carlos Cepeda and Araceli Espinosa-Jeffrey

Biomolecules 2024, 14(1), 65; https://doi.org/10.3390/biom14010065 - 3 Jan 2024

Cited by 10 | Viewed by 2522

Abstract

Mammalian cells have evolved to function under Earth’s gravity, but how they respond to microgravity remains largely unknown. Neural stem cells (NSCs) are essential for the maintenance of central nervous system (CNS) functions during development and the regeneration of all CNS cell populations. Here, we examined the behavior of space (SPC)-flown NSCs as they readapted to Earth’s gravity. We found that most of these cells survived the space flight and self-renewed. Yet, some showed enhanced stress responses as well as autophagy-like behavior. To ascertain if the secretome from SPC-flown NSCs contained molecules inducing these responses, we incubated naïve, non-starved NSCs in a medium containing SPC-NSC secretome. We found a four-fold increase in stress responses. Proteomic analysis of the secretome revealed that the protein of the highest content produced by SPC-NSCs was secreted protein acidic and rich in cysteine (SPARC), which induces endoplasmic reticulum (ER) stress, resulting in the cell’s demise. These results offer novel knowledge on the response of neural cells, particularly NSCs, subjected to space microgravity. Moreover, some secreted proteins have been identified as microgravity sensing, paving a new venue for future research aiming at targeting the SPARC metabolism. Although we did not establish a direct relationship between microgravity-induced stress and SPARC as a potential marker, these results represent the first step in the identification of gravity sensing molecules as targets to be modulated and to design effective countermeasures to mitigate intracranial hypertension in astronauts using structure-based protein design. Full article

(This article belongs to the Special Issue Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants)

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24 pages, 4662 KiB

Open AccessEditor’s ChoiceArticle

Structural and Molecular Changes of Human Chondrocytes Exposed to the Rotating Wall Vessel Bioreactor

by Paul Steinwerth, Jessica Bertrand, Viviann Sandt, Shannon Marchal, Jayashree Sahana, Miriam Bollmann, Herbert Schulz, Sascha Kopp, Daniela Grimm and Markus Wehland

Biomolecules 2024, 14(1), 25; https://doi.org/10.3390/biom14010025 - 24 Dec 2023

Cited by 3 | Viewed by 2553

Abstract

Over the last 30 years, the prevalence of osteoarthritis (OA), a disease characterized by a loss of articular cartilage, has more than doubled worldwide. Patients suffer from pain and progressive loss of joint function. Cartilage is an avascular tissue mostly consisting of extracellular matrix with embedded chondrocytes. As such, it does not regenerate naturally, which makes an early onset of OA prevention and treatment a necessity to sustain the patients’ quality of life. In recent years, tissue engineering strategies for the regeneration of cartilage lesions have gained more and more momentum. In this study, we aimed to investigate the scaffold-free 3D cartilage tissue formation under simulated microgravity in the NASA-developed rotating wall vessel (RWV) bioreactor. For this purpose, we cultured both primary human chondrocytes as well as cells from the immortalized line C28/I2 for up to 14 days on the RWV and analyzed tissue morphology, development of apoptosis, and expression of cartilage-specific proteins and genes by histological staining, TUNEL-assays, immunohistochemical detection of collagen species, and quantitative real-time PCR, respectively. We observed spheroid formation in both cell types starting on day 3. After 14 days, constructs from C28/I2 cells had diameters of up to 5 mm, while primary chondrocyte spheroids were slightly smaller with 3 mm. Further inspection of the 14-day-old C28/I2 spheroids revealed a characteristic cartilage morphology with collagen-type 1, -type 2, and -type 10 positivity. Interestingly, these tissues were less susceptible to RWV-induced differential gene expression than those formed from primary chondrocytes, which showed significant changes in the regulation of IL6, ACTB, TUBB, VIM, COL1A1, COL10A1, MMP1, MMP3, MMP13, ITGB1, LAMA1, RUNX3, SOX9, and CASP3 gene expression. These diverging findings might reflect the differences between primary and immortalized cells. Taken together, this study shows that simulated microgravity using the RWV bioreactor is suitable to engineer dense 3D cartilage-like tissue without addition of scaffolds or any other artificial materials. Both primary articular cells and the stable chondrocyte cell line C28/I2 formed 3D neocartilage when exposed for 14 days to an RWV. Full article

(This article belongs to the Special Issue Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants)

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17 pages, 5379 KiB

Open AccessArticle

Transcriptomic Effects on the Mouse Heart Following 30 Days on the International Space Station

by Alicia L. Veliz, Lana Mamoun, Lorelei Hughes, Richard Vega, Bailey Holmes, Andrea Monteon, Jillian Bray, Michael J. Pecaut and Mary Kearns-Jonker

Biomolecules 2023, 13(2), 371; https://doi.org/10.3390/biom13020371 - 15 Feb 2023

Cited by 8 | Viewed by 3761

Abstract

Efforts to understand the impact of spaceflight on the human body stem from growing interest in long-term space travel. Multiple organ systems are affected by microgravity and radiation, including the cardiovascular system. Previous transcriptomic studies have sought to reveal the changes in gene expression after spaceflight. However, little is known about the impact of long-term spaceflight on the mouse heart in vivo. This study focuses on the transcriptomic changes in the hearts of female C57BL/6J mice flown on the International Space Station (ISS) for 30 days. RNA was isolated from the hearts of three flight and three comparable ground control mice and RNA sequencing was performed. Our analyses showed that 1147 transcripts were significantly regulated after spaceflight. The MAPK, PI3K-Akt, and GPCR signaling pathways were predicted to be activated. Transcripts related to cytoskeleton breakdown and organization were upregulated, but no significant change in the expression of extracellular matrix (ECM) components or oxidative stress pathway-associated transcripts occurred. Our results indicate an absence of cellular senescence, and a significant upregulation of transcripts associated with the cell cycle. Transcripts related to cellular maintenance and survival were most affected by spaceflight, suggesting that cardiovascular transcriptome initiates an adaptive response to long-term spaceflight. Full article

(This article belongs to the Special Issue Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants)

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14 pages, 5510 KiB

Open AccessArticle

Oligodendrocyte Progenitors Display Enhanced Proliferation and Autophagy after Space Flight

by Victoria Tran, Nicholas Carpo, Carlos Cepeda and Araceli Espinosa-Jeffrey

Biomolecules 2023, 13(2), 201; https://doi.org/10.3390/biom13020201 - 19 Jan 2023

Cited by 7 | Viewed by 2674

Abstract

Intracranial hypertension (ICP) and visual impairment intracranial pressure (VIIP) are some of the consequences of long-term space missions. Here we examined the behavior of oligodendrocyte progenitors (OLPs) after space flight using time-lapse microscopy. We show that most OLPs divided more than ground control (GC) counterparts did. Nonetheless, a subpopulation of OLPs flown to space presented a significant increase in autophagic cell death. Examination of the proteomic profile of the secretome of space flown OLPs (SPC-OLPs) revealed that the stress protein heat shock protein-90 beta “HSP-90β” was the 5^th most enriched (6.8 times) and the secreted protein acidic and rich in cysteine “SPARC” was the 7^th most enriched (5.2 times), with respect to ground control cells. SPARC induces endoplasmic reticulum stress, which leads to autophagy. Given the roles and importance of these two proteins in mammalian cells’ metabolism, their upregulation may hold the key to modulating cell proliferation and autophagy, in order to mitigate ICP and VIIP during and after space missions. Full article

(This article belongs to the Special Issue Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants)

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22 pages, 6617 KiB

Open AccessArticle

Effects of High Glucose on Human Endothelial Cells Exposed to Simulated Microgravity

by Justina Jokšienė, Jayashree Sahana, Markus Wehland, Herbert Schulz, José Luis Cortés-Sánchez, Judit Prat-Duran, Daniela Grimm and Ulf Simonsen

Biomolecules 2023, 13(2), 189; https://doi.org/10.3390/biom13020189 - 17 Jan 2023

Cited by 4 | Viewed by 3314

Abstract

A diabetogenic state induced by spaceflight provokes stress and health problems in astronauts. Microgravity (µg) is one of the main stressors in space causing hyperglycaemia. However, the underlying molecular pathways and synergistic effects of µg and hyperglycaemia are not fully understood. In this study, we investigated the effects of high glucose on EA.hy926 endothelial cells in simulated µg (s-µg) using a 3D clinostat and static normogravity (1g) conditions. After 14 days of cell culture under s-µg and 1g conditions, we compared the expression of extracellular matrix (ECM), inflammation, glucose metabolism, and apoptosis-related genes and proteins through qPCR, immunofluorescence, and Western blot analyses, respectively. Apoptosis was evaluated via TUNEL staining. Gene interactions were examined via STRING analysis. Our results show that glucose concentrations had a weaker effect than altered gravity. µg downregulated the ECM gene and protein expression and had a stronger influence on glucose metabolism than hyperglycaemia. Moreover, hyperglycaemia caused more pronounced changes in 3D cultures than in 2D cultures, including bigger and a greater number of spheroids, upregulation of NOX4 and the apoptotic proteins NF-κB and CASP3, and downregulation of fibronectin and transglutaminase-2. Our findings bring new insights into the possible molecular pathways involved in the diabetogenic vascular effects in µg. Full article

(This article belongs to the Special Issue Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants)

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15 pages, 1628 KiB

Open AccessReview

Cellular and Molecular Effects of Microgravity on the Immune System: A Focus on Bioactive Lipids

by Marina Fava, Noemi De Dominicis, Giulia Forte, Monica Bari, Alessandro Leuti and Mauro Maccarrone

Biomolecules 2024, 14(4), 446; https://doi.org/10.3390/biom14040446 - 5 Apr 2024

Cited by 5 | Viewed by 3261

Abstract

Microgravity is one of the main stressors that astronauts are exposed to during space missions. This condition has been linked to many disorders, including those that feature dysfunctional immune homeostasis and inflammatory damage. Over the past 30 years, a significant body of work has been gathered connecting weightlessness—either authentic or simulated—to an inefficient reaction to pathogens, dysfunctional production of cytokines and impaired survival of immune cells. These processes are also orchestrated by a plethora of bioactive lipids, produced by virtually all cells involved in immune events, which control the induction, magnitude, outcome, compartmentalization and trafficking of immunocytes during the response to injury. Despite their crucial importance in inflammation and its modulation, however, data concerning the role of bioactive lipids in microgravity-induced immune dysfunctions are surprisingly scarce, both in quantity and in variety, and the vast majority of it focuses on two lipid classes, namely eicosanoids and endocannabinoids. The present review aims to outline the accumulated knowledge addressing the effects elicited by microgravity—both simulated and authentic—on the metabolism and signaling of these two prominent lipid groups in the context of immune and inflammatory homeostasis. Full article

(This article belongs to the Special Issue Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants)

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