Biogenesis of Pro-senescent Microparticles by Endothelial Colony Forming Cells from Premature Neonates is driven by SIRT1-Dependent Epigenetic Regulation of MKK6

Abstract : Senescent cells may exert detrimental effect on microenvironment through the secretion of soluble factors and the release of extracellular vesicles, such as microparticles, key actors in ageing and cardiovascular diseases. We previously reported that sirtuin-1 (SIRT1) deficiency drives accelerated senescence and dysfunction of endothelial colony-forming cells (ECFC) in PT neonates. Because preterm birth (PT) increases the risk for cardiovascular diseases during neonatal period as well as at adulthood, we hypothesized that SIRT1 deficiency could control the biogenesis of microparticles as part of a senescence–associated secretory phenotype (SASP) of PT-ECFC and investigated the related molecular mechanisms. Compared to control ECFC, PT-ECFC displayed a SASP associated with increased release of endothelial microparticles (EMP), mediating a paracrine induction of senescence in naïve endothelial cells. SIRT1 level inversely correlated with EMP release and drives PT-ECFC vesiculation. Global transcriptomic analysis revealed changes in stress response pathways, specifically the MAPK pathway. We delineate a new epigenetic mechanism by which SIRT1 deficiency regulates MKK6/p38 MAPK /Hsp27 pathway to promote EMP biogenesis in senescent ECFC. These findings deepen our understanding of the role of ECFC senescence in the disruption of endothelial homeostasis and provide potential new targets towards the control of cardiovascular risk in individuals born preterm. Preterm (PT) birth is associated with an increased risk of vascular-related diseases during the neonatal period, such as bronchopulmonary dysplasia and retinopathy, as well as early in adulthood, including hypertension and emphysema 1–4. Adverse early programming may explain such association and influence cardiovascular risk over the life course by acting on the vascular bed. Vascular alterations are major determinants and include an increase in arterial stiffness, a reduction in microvascular density because of incomplete vasculogenesis, and an impairment of endothelial function 5, 6. Endothelial Colony Forming Cells (ECFC) are a relevant subset of endothelial progenitor cells that mainly reside in vessel wall, circulate at low frequency in the blood, and support vascular repair and de novo vessel formation 7–9. A growing body of evidence supports their role as potential biomarkers and therapeutic targets in PT birth 5, 10, 11. Among the factors that can alter cord blood ECFC functions in premature neonates, we recently demonstrated the
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Scientific Reports, Nature Publishing Group, 2017, 7 (1), pp.8277. 〈10.1038/s41598-017-08883-1〉
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Stephanie Simoncini, Anne-Line Château, Stéphane Robert, Dilyana Todorova, Catherine Yzydorzick, et al.. Biogenesis of Pro-senescent Microparticles by Endothelial Colony Forming Cells from Premature Neonates is driven by SIRT1-Dependent Epigenetic Regulation of MKK6. Scientific Reports, Nature Publishing Group, 2017, 7 (1), pp.8277. 〈10.1038/s41598-017-08883-1〉. 〈hal-01663685〉

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