Abstract
Microgravity has a profound effect on cardiovascular function, however, little is known about the impact of microgravity on progenitors that reside within the heart. We investigated the effect of simulated microgravity exposure on progenitors isolated from the neonatal and adult human heart by quantifying changes in functional parameters, gene expression and protein levels after 6-7 days of 2D clinorotation. Utilization of neonatal and adult cardiovascular progenitors in ground-based studies has provided novel insight into how microgravity may affect cells differently depending on age.Simulated microgravity exposure did not impact AKT or ERK phosphorylation levels and did not influence cell migration, but elevated transcripts for paracrine factors were identified in neonatal and adult cardiovascular progenitors. Age-dependent responses surfaced when comparing the impact of microgravity on differentiation. Endothelial cell tube formation was unchanged or increased in progenitors from adults whereas neonatal cardiovascular progenitors showed a decline in tube formation (p<0.05). Von Willebrand Factor, an endothelial differentiation marker, and MLC2v and Troponin T, markers for cardiomyogenic differentiation, were elevated in expression in adult progenitors after simulated microgravity. DNA repair genes and telomerase reverse transcriptase which are highly expressed in early stem cells were increased in expression in neonatal but not adult cardiac progenitors after growth under simulated microgravity conditions. Neonatal cardiac progenitors demonstrated higher levels of MESP1, OCT4, and brachyury, markers for early stem cells. MicroRNA profiling was used to further investigate the impact of simulated microgravity on cardiovascular progenitors. Fifteen microRNAs were significantly altered in expression, including microRNAs-99a and 100 (which play a critical role in cell dedifferentiation). These microRNAs were unchanged in adult cardiac progenitors.The effect of exposure to simulated microgravity in cardiovascular progenitors is age-dependent. Adult cardiac progenitors showed elevated expression of markers for endothelial and cardiomyogenic differentiation whereas neonatal progenitors acquired characteristics of dedifferentiating cells.
Highlights
Microgravity, as experienced by humans when in space, affects cardiovascular function resulting in post-flight orthostatic intolerance, cardiac atrophy, and heart rhythm disturbances [1]
hepatocyte growth factor (HGF), serum-derived factor-1α (SDF-1α), vascular endothelial growth factor (VEGFa), and insulin-like growth factor-1 (IGF-1) are growth factors that can be secreted by cardiac progenitors and can help enhance cardiac repair [21,22,23,24,25]
Isl-1+ neonatal and adult cardiovascular progenitors exhibited similar responses to simulated microgravity in terms of cell migration and extracellular signal-regulated kinase (ERK)/AKT activation, but opposing responses when comparing the effect of simulated microgravity on cell differentiation
Summary
Microgravity, as experienced by humans when in space, affects cardiovascular function resulting in post-flight orthostatic intolerance, cardiac atrophy, and heart rhythm disturbances [1]. Simulations of gravitational changes while here on earth have demonstrated that cell types, such as cardiomyocytes, are force-sensitive. This may be due to mechanosensors which operate within mechanotransduction pathways that alter cell function upon exposure to changes in the force of gravity [2]. Exposure of other stem cell types to simulated microgravity such as embryonic stem cells [7], umbilical cord blood stem cells [8], adipose-derived stem cells [9], liver stem cells [10], and cancer stem cells [11] have established a link between gravitational force and changes in cell identity, either towards stemness or differentiation
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