Abstract
Introduction: A multitude of structural, haemodynamic and electromechanical cardiovascular disorders have been observed in humans following space-travel. These abnormalities are thought to emerge from transient alterations in autonomic nervous system (ANS). However, since the ANS is cardiac neural crest (CNC)-derived, whether microgravity-induced cardiomyopathies reflect CNC dysfunction, is unknown. Hypothesis: Impairment of CNCs underlies microgravity-induced cardiomyopathies. Methods: Myocardial explants from adult cKit CreERT2/+ ;IRG mice (n=5/group), as well as cKit CreERT2/+ ;IRG- derived (iPSC Kit-Cre ; n=6/group) and Wnt1-Cre;tdTomato -derived (iPSC Wnt1-Cre ; n=18/group) induced pluripotent stem cells, were cultured under static (SC) or simulated microgravity conditions (rotary cell-culture system; RCCS). Results: CNC lineage-tracing in cardiac explants illustrated that, compared to SC, RCCS abolished the pool of cKit + CNCs in adult hearts, indicated by quantitation of cKit CreERT2 - mediated EGFP expression ( p <0.05). Cardiogenesis modeling experiments with iPSC Kit-Cre yielded fewer beating EBs ( p =0.0005), and ~10-fold reduction in EGFP + cardiomyocytes ( p =0.01), in RCCS vs . SC. Microarray analyses suggested that RCCS-mediated alterations in BMP and Wnt/β-catenin pathways, downregulated ANS and CNC-related gene programs, and enhanced vasculogenic differentiation without affecting the expression of cardiac mesoderm-related genes. Differences were verified by quantitative PCR. Modeling CNC development in iPSC Wnt1-Cre further confirmed an RCCS-mediated dramatic impairment in development and function of CNCs, indicated by quantitation of tdTomato expression in day-10 and day-21 beating embryoid bodies ( p <0.0001). Intriguingly, the effect of RCCS in CNCs could be only partially rescued upon transfer to SC. Conclusions: Together these data indicate that microgravity negatively regulates the development and function of CNCs, thus partly explaining the cellular and molecular mechanisms of microgravity-induced cardiomyopathies. Moreover, these findings are expected to have important implications in space exploration, since they suggest an essential role for gravity in vertebrate development.
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