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Microgravity and space radiation exert either opposite or synergic effects on single molecular pathways

ABSTRACT: Microgravity and space radiation (SR) are two highly influential factors affecting humans in space flight. 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 space. Reference samples on ground and at 1g onboard allowed discrimination between the contribution of microgravity and SR within the combined response to space. Cell softening and reduced motility occurred in space, with loss of actin stress fibers and a greater distribution of microtubules and intermediate filaments in compensation. The frequency of primary cilia also increased. DNA repair mechanisms were indeed activated. Transcriptomics highlighted the opposing effect of microgravity from SR on specific molecular pathways: radiation, unlike microgravity, stimulated pathways for endothelial activation (hypoxia, inflammation), DNA repair and apoptosis, promoting an ageing-like phenotype; microgravity, unlike SR, activated pathways for metabolism and pro-proliferation phenotype. Thus, microgravity and SR should be considered separately to tailor effective countermeasures to protect astronauts’ health.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157937 | GEO | 2021/12/22

REPOSITORIES: GEO

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Project description:Microgravity leads to a 10-15% loss of bone mass in astronauts during space flight. Osteoclast is the multinucleated bone resorbing cell. In this study, we used NASA developed ground based Rotary Wall Vessel Bioreactor (RWV), Rotary Cell Culture System (RCCS) to simulate microgravity (Î¼Xg) conditions and demonstrated a significant increase (2-fold) in osteoclastogenesis compared to ground based control (Xg) mouse bone marrow cultures. We further determined the gene expression profiling of RAW 264.7 osteoclast progenitor cells in microgravity by agilent microarray analysis. Gene expression pattern was functional group clustered by transcriptome analysis using gene ontology tree machine (GOTM) for cell proliferation/survival, differentiation and function. We confirm the microgravity modulated gene expression critical for osteoclast differentiation by real-time RT-PCR and Western blot analysis in murine bone marrow cultures. We identify transcription factors such as c-Jun, c-Fos, PU-1 critical for osteoclast differentiation is up-regulated in microgravity conditions. In addition, microgravity resulted in 2.3 and 2.0-fold increase in the level of cathepsin K and MMP-9 matrix metalloproteinase expression in preosteoclast cells involved in the bone resorption process respectively. We also demonstrate a significant increase in the expression levels of M-CSF receptor, c-Fms and PLCÎ³2 and S100A8 molecules that play an important role in Ca2+ signaling essential for osteoclast function. Further, microgravity stimulated preosteoclast cells showed elevated cytosolic Ca2+ levels compared to ground based control cells. Thus, microgravity regulated gene expression profiling in preosteoclast cells provide new insights in to molecular mechanisms and therapeutic targets of osteoclast differentiation/activation responsible for bone loss and fracture risk in astronauts during space flight mission. Microgravity associated with space flight is a challenge for normal bone homeostasis. Astronauts experience 10-15% bone loss during a space flight mission. We aimed to determine the effect of simulated microgravity on osteoclast preosteoclasts cells. RAW264.7 cells (1.5 x 106 /ml) were loaded in RCCS with DMEM containing 10% FBS for 24 h. The cells were stimulated with RANKL (80ng/ml) for 24 h to obtain preosteoclasts in parallel with ground based control cells. Total RNA was isolated using RNAzol reagent (Biotecx Labs, Houston, TX) from control (Xg) and microgravity (Î¼Xg) subjected cells and hybridized with Agilent whole mouse genome 4x44K array system. Slides were washed and scanned on an Agilent G2565 microarray scanner. Data obtained were analyzed with Agilent feature extraction and GeneSpring GX v7.3.1 software packages (Genus biosystem, Inc. Northbrook, IL, USA).

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Microgravity and space radiation exert either opposite or synergic effects on single molecular pathways

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