The effects of microgravity on differentiation and cell growth in stem cells and cancer stem cells

Grimm, Daniela; Wehland, Markus; Corydon, Thomas J.; Richter, Peter; Prasad, Binod; Bauer, Johann; Egli, Marcel; Kopp, Sascha; Lebert, Michael; Krüger, Marcus

doi:10.1002/sctm.20-0084

Cited by 61 publications

(94 citation statements)

References 119 publications

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“…Another approach for cartilage tissue engineering is the use of mesenchymal stem cells (MSC) derived either from bone marrow or from adipose tissue [ 77 ]. In general, simulated microgravity seemed to be beneficial in promoting the differentiation of MSC into a chondrogenic phenotype.…”

Section: Discussionmentioning

confidence: 99%

Tissue Engineering of Cartilage Using a Random Positioning Machine

Wehland

Steinwerth

Aleshcheva

et al. 2020

IJMS

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Articular cartilage is a skeletal tissue of avascular nature and limited self-repair capacity. Cartilage-degenerative diseases, such as osteoarthritis (OA), are difficult to treat and often necessitate joint replacement surgery. Cartilage is a tough but flexible material and relatively easy to damage. It is, therefore, of high interest to develop methods allowing chondrocytes to recolonize, to rebuild the cartilage and to restore joint functionality. Here we studied the in vitro production of cartilage-like tissue using human articular chondrocytes exposed to the Random Positioning Machine (RPM), a device to simulate certain aspects of microgravity on Earth. To screen early adoption reactions of chondrocytes exposed to the RPM, we performed quantitative real-time PCR analyses after 24 h on chondrocytes cultured in DMEM/F-12. A significant up-regulation in the gene expression of IL6, RUNX2, RUNX3, SPP1, SOX6, SOX9, and MMP13 was detected, while the levels of IL8, ACAN, PRG4, ITGB1, TGFB1, COL1A1, COL2A1, COL10A1, SOD3, SOX5, MMP1, and MMP2 mRNAs remained unchanged. The STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) analysis demonstrated among others the importance of these differentially regulated genes for cartilage formation. Chondrocytes grown in DMEM/F-12 medium produced three-dimensional (3D) spheroids after five days without the addition of scaffolds. On day 28, the produced tissue constructs reached up to 2 mm in diameter. Using specific chondrocyte growth medium, similar results were achieved within 14 days. Spheroids from both types of culture media showed the typical cartilage morphology with aggrecan positivity. Intermediate filaments form clusters under RPM conditions as detected by vimentin staining after 7 d and 14 d. Larger meshes appear in the network in 28-day samples. Furthermore, they were able to form a confluent chondrocyte monolayer after being transferred back into cell culture flasks in 1 g conditions showing their suitability for transplantation into joints. Our results demonstrate that the cultivation medium has a direct influence on the velocity of tissue formation and tissue composition. The spheroids show properties that make them interesting candidates for cellular cartilage regeneration approaches in trauma and OA therapy.

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Section: Discussionmentioning

confidence: 99%

Tissue Engineering of Cartilage Using a Random Positioning Machine

Wehland

Steinwerth

Aleshcheva

et al. 2020

IJMS

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“…The microgravity-induced decrease in cell proliferation was also seen in other cell phenotypes [22,32,48,49]. However, there are controversial evidences about the effects of microgravity on cell growth in stem cells and cardiomyocytes differentiating from pluripotent stem cells [50][51][52][53][54]. These introduce the hypothesis that the effects induced by microgravity are not only phenotype-dependent but also dependent on the functional and metabolic status of the cells tested.…”

Section: Discussionmentioning

confidence: 99%

A Protective Strategy to Counteract the Oxidative Stress Induced by Simulated Microgravity on H9C2 Cardiomyocytes

Guarnieri

Morabito

Bevere

et al. 2021

Oxidative Medicine and Cellular Longevity

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Microgravity affects human cardiovascular function inducing heart rhythm disturbances and even cardiac atrophy. The mechanisms triggered by microgravity and the search for protection strategies are difficult to be investigated in vivo. This study is aimed at investigating the effects induced by simulated microgravity on a cardiomyocyte-like phenotype. The Random Positioning Machine (RPM), set in a CO2 incubator, was used to simulate microgravity, and H9C2 cell line was used as the cardiomyocyte-like model. H9C2 cells were exposed to simulated microgravity up to 96 h, showing a slower cell proliferation rate and lower metabolic activity in comparison to cell grown at earth gravity. In exposed cells, these effects were accompanied by increased levels of intracellular reactive oxygen species (ROS), cytosolic Ca2+, and mitochondrial superoxide anion. Protein carbonyls, markers of protein oxidation, were significantly increased after the first 48 h of exposition in the RPM. In these conditions, the presence of an antioxidant, the N-acetylcysteine (NAC), counteracted the effects induced by the simulated microgravity. In conclusion, these data suggest that simulated microgravity triggers a concomitant increase of intracellular ROS and Ca2+ levels and affects cell metabolic activity which in turn could be responsible for the slower proliferative rate. Nevertheless, the very low number of detectable dead cells and, more interestingly, the protective effect of NA, demonstrate that simulated microgravity does not have “an irreversible toxic effect” but, affecting the oxidative balance, results in a transient slowdown of proliferation.

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“…There are other unique environmental stimuli such as microgravity and the electromagnetic effect. Up to the present, research about the effect of space flight on organ development is increasing with the use of pluripotent stem cells [ 93 ]. Regarding pluripotency, the effect of space microgravity on the self-renewal capacity of mouse iPSCs was studied via live-imaging of Oct4 -GFP reporter in spacecraft [ 94 ].…”

Section: Physical Stimulation For Directed Differentiationmentioning

confidence: 99%

Response of Pluripotent Stem Cells to Environmental Stress and Its Application for Directed Differentiation

Kaitsuka

Hakim

2021

Biology

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Pluripotent stem cells have unique characteristics compared to somatic cells. In this review, we summarize the response to environmental stresses (hypoxic, oxidative, thermal, and mechanical stresses) in embryonic stem cells (ESCs) and their applications in the differentiation methods directed to specific lineages. Those stresses lead to activation of each specific transcription factor followed by the induction of downstream genes, and one of them regulates lineage specification. In short, hypoxic stress promotes the differentiation of ESCs to mesodermal lineages via HIF-1α activation. Concerning mechanical stress, high stiffness tends to promote mesodermal differentiation, while low stiffness promotes ectodermal differentiation via the modulation of YAP1. Furthermore, each step in the same lineage differentiation favors each appropriate stiffness of culture plate; for example, definitive endoderm favors high stiffness, while pancreatic progenitor favors low stiffness during pancreatic differentiation of human ESCs. Overall, treatments utilizing those stresses have no genotoxic or carcinogenic effects except oxidative stress; therefore, the differentiated cells are safe and could be useful for cell replacement therapy. In particular, the effect of mechanical stress on differentiation is becoming attractive for the field of regenerative medicine. Therefore, the development of a stress-mediated differentiation protocol is an important matter for the future.

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The effects of microgravity on differentiation and cell growth in stem cells and cancer stem cells

Cited by 61 publications

References 119 publications

Tissue Engineering of Cartilage Using a Random Positioning Machine

Tissue Engineering of Cartilage Using a Random Positioning Machine

A Protective Strategy to Counteract the Oxidative Stress Induced by Simulated Microgravity on H9C2 Cardiomyocytes

Response of Pluripotent Stem Cells to Environmental Stress and Its Application for Directed Differentiation

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