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Microgravity and Cell Adherence

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 52357

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Dr. Johann Bauer

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Max Planck Institute, Martinsried, Germany
Interests: cell adhesion; organoid formation
Special Issues, Collections and Topics in MDPI journals

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Dear colleagues,

Cell adherence is changed when cells are exposed to microgravity. This is true for human and animal tissue cells, as well as for microorganisms exposed to simulated or real microgravity. In human or animal cells, changes of adherence became especially apparent when scaffold-free organoid formation was investigated, which included the cells’ detachment from the surface of the culture flasks, followed by three-dimensional aggregation. In this process, distinct proteins and genes coding for them have already been identified, which contribute either to a cell’s adherence to a substratum or to contact with neighboring cells. Furthermore, adhesion-dependent initiation of microbial biofilm formation can be triggered by microgravity-induced changes of gene expression patterns, protein accumulation, and carbohydrate metabolism.

In both cases, the kind and force of adherence are regulated by external and internal signals. External signals are exerted by features of the surface to which the cells adhere. Internal signals have been described repeatedly. However, their generation by the influence of microgravity requires further investigation.

Articles and reviews will be collected in which either the chemical/biochemical background of external signals is described, or cellular mechanisms are unveiled that up- or down-regulate the cells’ adhesion to their environment under microgravity.

Dr. Johann Bauer
Guest Editor

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Keywords

Cell monolayer
Organoid formation
Adhesion proteins
Tight junction

Published Papers (11 papers)

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Editorial

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4 pages, 173 KiB

Open AccessEditorial

Microgravity and Cell Adherence

by Johann Bauer

Int. J. Mol. Sci. 2020, 21(6), 2214; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062214 - 23 Mar 2020

Cited by 8 | Viewed by 2174

Abstract

Cell adhesion is an inevitable precondition for enabling cells to assemble into three-dimensional tissues [...] Full article

(This article belongs to the Special Issue Microgravity and Cell Adherence)

Research

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23 pages, 5395 KiB

Open AccessArticle

Insight in Adhesion Protein Sialylation and Microgravity Dependent Cell Adhesion—An Omics Network Approach

by Thomas J. Bauer, Erich Gombocz, Markus Wehland, Johann Bauer, Manfred Infanger and Daniela Grimm

Int. J. Mol. Sci. 2020, 21(5), 1749; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051749 - 04 Mar 2020

Cited by 8 | Viewed by 3233

Abstract

The adhesion behavior of human tissue cells changes in vitro, when gravity forces affecting these cells are modified. To understand the mechanisms underlying these changes, proteins involved in cell-cell or cell-extracellular matrix adhesion, their expression, accumulation, localization, and posttranslational modification (PTM) regarding changes during exposure to microgravity were investigated. As the sialylation of adhesion proteins is influencing cell adhesion on Earth in vitro and in vivo, we analyzed the sialylation of cell adhesion molecules detected by omics studies on cells, which change their adhesion behavior when exposed to microgravity. Using a knowledge graph created from experimental omics data and semantic searches across several reference databases, we studied the sialylation of adhesion proteins glycosylated at their extracellular domains with regards to its sensitivity to microgravity. This way, experimental omics data networked with the current knowledge about the binding of sialic acids to cell adhesion proteins, its regulation, and interactions in between those proteins provided insights into the mechanisms behind our experimental findings, suggesting that balancing the sialylation against the de-sialylation of the terminal ends of the adhesion proteins’ glycans influences their binding activity. This sheds light on the transition from two- to three-dimensional growth observed in microgravity, mirroring cell migration and cancer metastasis in vivo. Full article

(This article belongs to the Special Issue Microgravity and Cell Adherence)

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19 pages, 14703 KiB

Open AccessArticle

EMT Transcription Factors Are Involved in the Altered Cell Adhesion under Simulated Microgravity Effect or Overloading by Regulation of E-cadherin

by Shuliang Shi, Qiao Li, Qiuying Cao, Yan Diao, Yao Zhang, Lei Yue and Lijun Wei

Int. J. Mol. Sci. 2020, 21(4), 1349; https://doi.org/10.3390/ijms21041349 - 17 Feb 2020

Cited by 21 | Viewed by 2858

Abstract

In order to study the effect of stress changes on cell adhesion, HUVEC, and MCF-7 cells were treated with simulated microgravity effect (SMG) and overloading (OL). Methods: Rotating Wall Vessel (2D-RWVS) bioreactor was used to create different culture conditions. In addition, the alteration of cell adhesion states, adhesion proteins, and relating factors of adhesion molecules under these two conditions were detected using cell adhesion assay, immunofluorescence, western blot, and qRT-PCR technology. Results: The results showed that the adhesion of cells decreased under SMG, while increased under OL. The expressions of integrin β1, paxillin, and E-cadherin under SMG condition were down-regulated as compared to that of the control group showing a time-dependent pattern of the decreasing. However, under OL condition, the expressions of adhesion proteins were up-regulated as compared to that of the control group, with a time-dependent pattern of increasing. EMT transcription factors Snail, twist, and ZEB1 were up-regulated under SMG while down-regulated under OL. Conclusion: Collectively our results indicated that cells could respond to stress changes to regulate the expressions of adhesion proteins and adapt their adhesion state to the altered mechanical environment. The altered cell adhesion in response to the mechanical stress may involve the changed expression of EMT-inducing factors, Snail, Twist, and ZEB1under the SMG/OL conditions. Full article

(This article belongs to the Special Issue Microgravity and Cell Adherence)

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16 pages, 2982 KiB

Open AccessArticle

Changes in the Surface Expression of Intercellular Adhesion Molecule 3, the Induction of Apoptosis, and the Inhibition of Cell-Cycle Progression of Human Multidrug-Resistant Jurkat/A4 Cells Exposed to a Random Positioning Machine

by Alisa Sokolovskaya, Ekaterina Korneeva, Danila Zaichenko, Edward Virus, Dmitry Kolesov, Aleksey Moskovtsev and Aslan Kubatiev

Int. J. Mol. Sci. 2020, 21(3), 855; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030855 - 28 Jan 2020

Cited by 10 | Viewed by 3424

Abstract

Experiments from flight- and ground-based model systems suggest that unexpected alterations of the human lymphoblastoid cell line Jurkat, as well as effects on cell growth, metabolism, and apoptosis, can occur in altered gravity conditions. Using a desktop random positioning machine (RPM), we investigated the effects of simulated microgravity on Jurkat cells and their multidrug-resistant subline, Jurkat/A4 cells. The viability of Jurkat/A4 cells decreased after simulated microgravity in contrast with the Jurkat cells. At the same time, the viability between the experimental Jurkat cells and control Jurkat cells was not significantly different. Of note, Jurkat cells appeared as less susceptible to apoptosis than their multidrug-resistant clone Jurkat/A4 cells, whereas cell-cycle analysis showed that the percentage of Jurkat/A4 cells in the S-phase was increased after 72 and 96 h of RPM-simulated microgravity relative to their static counterparts. The differences in Jurkat cells at all phases between static and simulated microgravity were not significant. The surface expression of the intercellular adhesion molecule 3 (ICAM-3)—also known as cluster of differentiation (CD)50—protein was changed for Jurkat/A4 cells following exposure to the RPM. Changes in cell morphology were observed in the Jurkat/A4 cells after 96 h of RPM-simulated microgravity. Thus, we concluded that Jurkat/A4 cells are more sensitive to RPM-simulated microgravity as compared with the parental Jurkat cell line. We also suggest that intercellular adhesion molecule 3 may be an important adhesion molecule involved in the induction of leukocyte apoptosis. The Jurkat/A4 cells with an acquired multidrug resistance phenotype could be a useful model for studying the effects of simulated microgravity and testing anticancer drugs. Full article

(This article belongs to the Special Issue Microgravity and Cell Adherence)

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26 pages, 5260 KiB

Open AccessArticle

Effect of Unloading Condition on the Healing Process and Effectiveness of Platelet Rich Plasma as a Countermeasure: Study on In Vivo and In Vitro Wound Healing Models

by Francesca Cialdai, Alessandra Colciago, Desiré Pantalone, Angela Maria Rizzo, Stefania Zava, Lucia Morbidelli, Fabio Celotti, Daniele Bani and Monica Monici

Int. J. Mol. Sci. 2020, 21(2), 407; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020407 - 09 Jan 2020

Cited by 26 | Viewed by 3952

Abstract

Wound healing is a very complex process that allows organisms to survive injuries. It is strictly regulated by a number of biochemical and physical factors, mechanical forces included. Studying wound healing in space is interesting for two main reasons: (i) defining tools, procedures, and protocols to manage serious wounds and burns eventually occurring in future long-lasting space exploration missions, without the possibility of timely medical evacuation to Earth; (ii) understanding the role of gravity and mechanical factors in the healing process and scarring, thus contributing to unravelling the mechanisms underlying the switching between perfect regeneration and imperfect repair with scarring. In the study presented here, a new in vivo sutured wound healing model in the leech (Hirudo medicinalis) has been used to evaluate the effect of unloading conditions on the healing process and the effectiveness of platelet rich plasma (PRP) as a countermeasure. The results reveal that microgravity caused a healing delay and structural alterations in the repair tissue, which were prevented by PRP treatment. Moreover, investigating the effects of microgravity and PRP on an in vitro wound healing model, it was found that PRP is able to counteract the microgravity-induced impairment in fibroblast migration to the wound site. This could be one of the mechanisms underlying the effectiveness of PRP in preventing healing impairment in unloading conditions. Full article

(This article belongs to the Special Issue Microgravity and Cell Adherence)

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27 pages, 2586 KiB

Open AccessArticle

The Role of C-X-C Chemokine Receptor Type 4 (CXCR4) in Cell Adherence and Spheroid Formation of Human Ewing’s Sarcoma Cells under Simulated Microgravity

by Alexander Romswinkel, Manfred Infanger, Carlo Dietz, Florian Strube and Armin Kraus

Int. J. Mol. Sci. 2019, 20(23), 6073; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20236073 - 02 Dec 2019

Cited by 11 | Viewed by 3347

Abstract

We studied the behavior of Ewing’s Sarcoma cells of the line A673 under simulated microgravity (s-µg). These cells express two prominent markers—the oncogene EWS/FLI1 and the chemokine receptor CXCR4, which is used as a target of treatment in several types of cancer. The cells were exposed to s-µg in a random-positioning machine (RPM) for 24 h in the absence and presence of the CXCR4 inhibitor AMD3100. Then, their morphology and cytoskeleton were examined. The expression of selected mutually interacting genes was measured by qRT-PCR and protein accumulation was determined by western blotting. After 24 h incubation on the RPM, a splitting of the A673 cell population in adherent and spheroid cells was observed. Compared to 1 g control cells, EWS/FLI1 was significantly upregulated in the adherent cells and in the spheroids, while CXCR4 and CD44 expression were significantly enhanced in spheroids only. Transcription of CAV-1 was upregulated and DKK2 and VEGF-A were down-regulated in both, adherent in spheroid cells, respectively. Regarding, protein accumulation EWS/FLI1 was enhanced in adherent cells only, but CD44 decreased in spheroids and adherent cells. Inhibition of CXCR4 did not change spheroid count, or structure. Under s-µg, the tumor marker EWS/FLI1 is intensified, while targeting CXCR4, which influences adhesion proteins, did not affect spheroid formation. Full article

(This article belongs to the Special Issue Microgravity and Cell Adherence)

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27 pages, 5052 KiB

Open AccessArticle

Short-Term Microgravity Influences Cell Adhesion in Human Breast Cancer Cells

by Mohamed Zakaria Nassef, Sascha Kopp, Daniela Melnik, Thomas J. Corydon, Jayashree Sahana, Marcus Krüger, Markus Wehland, Thomas J. Bauer, Christian Liemersdorf, Ruth Hemmersbach, Manfred Infanger and Daniela Grimm

Int. J. Mol. Sci. 2019, 20(22), 5730; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225730 - 15 Nov 2019

Cited by 30 | Viewed by 5034

Abstract

With the commercialization of spaceflight and the exploration of space, it is important to understand the changes occurring in human cells exposed to real microgravity (r-µg) conditions. We examined the influence of r-µg, simulated microgravity (s-µg, incubator random positioning machine (iRPM)), hypergravity (hyper-g), and vibration (VIB) on triple-negative breast cancer (TNBC) cells (MDA-MB-231 cell line) with the aim to study early changes in the gene expression of factors associated with cell adhesion, apoptosis, nuclear factor “kappa-light-chain-enhancer” of activated B-cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. We had the opportunity to attend a parabolic flight (PF) mission and to study changes in RNA transcription in the MDA-MB cells exposed to PF maneuvers (29th Deutsches Zentrum für Luft- und Raumfahrt (DLR) PF campaign). PF maneuvers induced an early up-regulation of ICAM1, CD44 and ERK1 mRNAs after the first parabola (P1) and a delayed upregulation of NFKB1, NFKBIA, NFKBIB, and FAK1 after the last parabola (P31). ICAM-1, VCAM-1 and CD44 protein levels were elevated, whereas the NF-κB subunit p-65 and annexin-A2 protein levels were reduced after the 31st parabola (P31). The PRKCA, RAF1, BAX mRNA were not changed and cleaved caspase-3 was not detectable in MDA-MB-231 cells exposed to PF maneuvers. Hyper-g-exposure of the cells elevated the expression of CD44 and NFKBIA mRNAs, iRPM-exposure downregulated ANXA2 and BAX, whereas VIB did not affect the TNBC cells. The early changes in ICAM-1 and VCAM-1 and the rapid decrease in the NF-κB subunit p-65 might be considered as fast-reacting, gravity-regulated and cell-protective mechanisms of TNBC cells exposed to altered gravity conditions. This data suggest a key role for the detected gravity-signaling elements in three-dimensional growth and metastasis. Full article

(This article belongs to the Special Issue Microgravity and Cell Adherence)

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20 pages, 6319 KiB

Open AccessArticle

Apoptosis Induction and Alteration of Cell Adherence in Human Lung Cancer Cells under Simulated Microgravity

by Carlo Dietz, Manfred Infanger, Alexander Romswinkel, Florian Strube and Armin Kraus

Int. J. Mol. Sci. 2019, 20(14), 3601; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143601 - 23 Jul 2019

Cited by 32 | Viewed by 5156

Abstract

Background: Lung cancer cells are known to change proliferation and migration under simulated microgravity. In this study, we sought to evaluate cell adherence, apoptosis, cytoskeleton arrangement, and gene expression under simulated microgravity. Methods: Human lung cancer cells were exposed to simulated microgravity in a random-positioning machine (RPM). Cell morphology and adherence were observed under phase-contrast microscopy, cytoskeleton staining was performed, apoptosis rate was determined, and changes in gene and protein expression were detected by real-time PCR with western blot confirmation. Results: Three-dimensional (3D)-spheroid formation was observed under simulated microgravity. Cell viability was not impaired. Actin filaments showed a shift in alignment from longitudinal to spherical. Apoptosis rate was significantly increased in the spheroids compared to the control. TP53, CDKN2A, PTEN, and RB1 gene expression was significantly upregulated in the adherent cells under simulated microgravity with an increase in corresponding protein production for p14 and RB1. SOX2 expression was significantly upregulated in the adherent cells, but protein was not. Gene expressions of AKT3, PIK3CA, and NFE2L2 remained unaltered. Conclusion: Simulated microgravity induces alteration in cell adherence, increases apoptosis rate, and leads to upregulation of tumor suppressor genes in human lung cancer cells. Full article

(This article belongs to the Special Issue Microgravity and Cell Adherence)

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25 pages, 10939 KiB

Open AccessArticle

Real Microgravity Influences the Cytoskeleton and Focal Adhesions in Human Breast Cancer Cells

by Mohamed Zakaria Nassef, Sascha Kopp, Markus Wehland, Daniela Melnik, Jayashree Sahana, Marcus Krüger, Thomas J. Corydon, Hergen Oltmann, Burkhard Schmitz, Andreas Schütte, Thomas J. Bauer, Manfred Infanger and Daniela Grimm

Int. J. Mol. Sci. 2019, 20(13), 3156; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133156 - 28 Jun 2019

Cited by 69 | Viewed by 7069

Abstract

With the increasing number of spaceflights, it is crucial to understand the changes occurring in human cells exposed to real microgravity (r-µg) conditions. We tested the effect of r-µg on MCF-7 breast cancer cells with the objective to investigate cytoskeletal alterations and early changes in the gene expression of factors belonging to the cytoskeleton, extracellular matrix, focal adhesion, and cytokines. In the Technische Experimente unter Schwerelosigkeit (TEXUS) 54 rocket mission, we had the opportunity to conduct our experiment during 6 min of r-µg and focused on cytoskeletal alterations of MCF-7 breast cancer cells expressing the Lifeact-GFP marker protein for the visualization of F-actin as well as the mCherry-tubulin fusion protein using the Fluorescence Microscopy Analysis System (FLUMIAS) for fast live-cell imaging under r-µg. Moreover, in a second mission we investigated changes in RNA transcription and morphology in breast cancer cells exposed to parabolic flight (PF) maneuvers (31st Deutsches Zentrum für Luft- und Raumfahrt (DLR) PF campaign). The MCF-7 cells showed a rearrangement of the F-actin and tubulin with holes, accumulations in the tubulin network, and the appearance of filopodia- and lamellipodia-like structures in the F-actin cytoskeleton shortly after the beginning of the r-µg period. PF maneuvers induced an early up-regulation of KRT8, RDX, TIMP1, CXCL8 mRNAs, and a down-regulation of VCL after the first parabola. E-cadherin protein was significantly reduced and is involved in cell adhesion processes, and plays a significant role in tumorigenesis. Changes in the E-cadherin protein synthesis can lead to tumor progression. Pathway analyses indicate that VCL protein has an activating effect on CDH1. In conclusion, live-cell imaging visualized similar changes as those occurring in thyroid cancer cells in r-µg. This result indicates the presence of a common mechanism of gravity perception and sensation. Full article

(This article belongs to the Special Issue Microgravity and Cell Adherence)

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Review

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20 pages, 268 KiB

Open AccessReview

The Impact of Spaceflight and Simulated Microgravity on Cell Adhesion

by Xiao Lin, Kewen Zhang, Daixu Wei, Ye Tian, Yongguang Gao, Zhihao Chen and Airong Qian

Int. J. Mol. Sci. 2020, 21(9), 3031; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093031 - 25 Apr 2020

Cited by 31 | Viewed by 5957

Abstract

Microgravity induces a number of significant physiological changes in the cardiovascular, nervous, immune systems, as well as the bone tissue of astronauts. Changes in cell adhesion properties are one aspect affected during long-term spaceflights in mammalian cells. Cellular adhesion behaviors can be divided into cell–cell and cell–matrix adhesion. These behaviors trigger cell–cell recognition, conjugation, migration, cytoskeletal rearrangement, and signal transduction. Cellular adhesion molecule (CAM) is a general term for macromolecules that mediate the contact and binding between cells or between cells and the extracellular matrix (ECM). In this review, we summarize the four major classes of adhesion molecules that regulate cell adhesion, including integrins, immunoglobulin superfamily (Ig-SF), cadherins, and selectin. Moreover, we discuss the effects of spaceflight and simulated microgravity on the adhesion of endothelial cells, immune cells, tumor cells, stem cells, osteoblasts, muscle cells, and other types of cells. Further studies on the effects of microgravity on cell adhesion and the corresponding physiological behaviors may help increase the safety and improve the health of astronauts in space. Full article

(This article belongs to the Special Issue Microgravity and Cell Adherence)

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15 pages, 940 KiB

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Guanylyl Cyclase-cGMP Signaling Pathway in Melanocytes: Differential Effects of Altered Gravity in Non-Metastatic and Metastatic Cells

by Krassimira Ivanova and Ruth Hemmersbach

Int. J. Mol. Sci. 2020, 21(3), 1139; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031139 - 08 Feb 2020

Cited by 6 | Viewed by 9177

Abstract

Human epidermal melanocytes as melanin producing skin cells represent a crucial barrier against UV-radiation and oxidative stress. It was shown that the intracellular signaling molecule cyclic guanosine-3′,5′-monophosphate (cGMP), generated by the guanylyl cyclases (GCs), e.g., the nitric oxide (NO)-sensitive soluble GC (sGC) and the natriuretic peptide-activated particulate GC (GC-A/GC-B), plays a role in the melanocyte response to environmental stress. Importantly, cGMP is involved in NO-induced perturbation of melanocyte–extracellular matrix interactions and in addition, increased NO production during inflammation may lead to loss of melanocytes and support melanoma metastasis. Further, the NO-sensitive sGC is expressed predominantly in human melanocytes and non-metastatic melanoma cells, whereas absence of functional sGC but up-regulated expression of GC-A/GC-B and inducible NO synthase (iNOS) are detected in metastatic cells. Thus, suppression of sGC expression as well as up-regulated expression of GC-A/GC-B/iNOS appears to correlate with tumor aggressiveness. As the cGMP pathway plays important roles in melanocyte (patho)physiology, we present an overview on the differential effects of altered gravity (hypergravity/simulated microgravity) on the cGMP signaling pathway in melanocytes and melanoma cells with different metastatic potential. We believe that future experiments in real microgravity may benefit from considering cGMP signaling as a possible factor for melanocyte transformation and in medication. Full article

(This article belongs to the Special Issue Microgravity and Cell Adherence)

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