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Molecular etiology behind spaceflight-induced impediment of male mouse bone fracture repair

ABSTRACT: Spaceflight triggers molecular signal of apoptosis and inhibits cell migration to impede bone fracture repair in male mice Activated apoptosis and inhibited cell migration. Adverse impacts of spaceflight on musculoskeletal health increases the risk of bone fracture and impaired healing. Its yet elusive molecular comprehension warrants an immediate attention in the advent of increasingly frequent space travels. Here we examined the effect of spaceflight on bone healing using a 2mm femoral segmental bone defect (SBD) model. Forty, 9-week old, C57BL/6J male mice were randomized by cage into spaceflight or ground groups; 10 mice from spaceflight or ground groups, respectively underwent SBD surgery and rest served as unoperated sham controls. Surgery/sham procedures occurred 4 days prior to launch, thereafter the spaceflight mice were housed in the rodent habitat at International Space Station for around 4 weeks before their euthanasia. Feeding on same diet, the ground sham/surgery mice were in equivalent housing condition. The right leg femur from half of the spaceflight and ground groups were investigated by micro-computed tomography (µCT). In parallel, the callus regions from surgery groups and corresponding femoral segments in sham mice were probed by global transcriptomics and metabolomics assay. µCT confirmed escalated bone loss in sham spaceflight; and a concomitant trend towards habituation was highlighted by gene-metabolite networks linked to active cellular homeostasis and inhibited morbidity signal in sham spaceflight. The morbidity signal was switched in the spaceflight surgery mice and µCT analyses of spaceflight callus revealed an increased trabeculae spacing and decreased trabecular connectivity. Activated apoptotic signal in spaceflight callus was synchronized with inhibited cell migration signal that was critical for wounds to recruit growth factors, cytokines, and angiogenic agents. A major pro-apoptotic and anti-migration signal, namely RANK-NFκB axis emerged as the central node in spaceflight callus. Concluding, SBD in spaceflight triggered a unique biomolecular mechanism to meet failed regeneration, which merits a customized intervention strategy.

ORGANISM(S): Mus musculus

PROVIDER: GSE161618 | GEO | 2021/06/30

REPOSITORIES: GEO

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Project description:This study presents the first global transcriptional profiling and phenotypic characterization of the major human opportunistic fungal pathogen, Candida albicans, grown in spaceflight conditions. Microarray analysis revealed that C. albicans subjected to short-term spaceflight culture differentially regulated 454 genes compared to synchronous ground controls, which represented 8.4% of the analyzed ORFs. Spaceflight-cultured C. albicans induced genes involved in cell aggregation (similar to flocculation), which was validated by microscopic and flow cytometry analysis. We also observed enhanced random budding of spaceflight-cultured cells as opposed to more normal bipolar budding patterns for ground samples, in accordance with the gene expression data. Furthermore, genes involved in antifungal agent and stress resistance were differentially regulated in spaceflight, including induction of ABC transporters and members of the major facilitator family, downregulation of ergosterol-encoding genes, and upregulation of genes involved in oxidative stress resistance. Finally, downregulation of genes involved in the actin cytoskeleton was observed. Interestingly, the transcriptional regulator Cap1 and over 30% of the Cap1 regulon was differentially expressed in spaceflight-cultured C. albicans. A potential role for Cap1 in the spaceflight response of C. albicans is suggested, as this regulator is involved in random budding, cell aggregation, actin cytoskeleton, and oxidative stress resistance; all related to observed spaceflight-associated changes of C. albicans. While culture of C. albicans in microgravity potentiates a global change in gene expression that could induce a virulence-related phenotype, no increased virulence in a murine intraperitoneal (i.p.) infection model was observed. This study represents an important basis for the assessment of the risk that commensal flora could play during spaceflight missions. Furthermore, since the low fluid-shear environment of microgravity is relevant to physical forces encountered by pathogens during the infection process, insights gained from this study could identify novel infectious disease mechanisms, with downstream benefits for the general public. Cells were grown for 24 hours on the space shuttle or as ground-based controls, preserved in RNALater, and stored at -80C. Four samples of each flight- and ground-based controls were harvested for microarray analysis. GAP is Group Activation Pack and each GAP contains 8 FPAs. The numbers represent the # assigned to the particular GAP and the number assigned to the specific FPA (1-8) within the indicated GAP. The same hardware is used for the flight samples and the ground samples.

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Molecular etiology behind spaceflight-induced impediment of male mouse bone fracture repair

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