The senescent status of endothelial cells affects proliferation, inflammatory profile and SOX2 expression in bone marrow-derived mesenchymal stem cells

Abstract

ABSTRACT Human aging is a physiological process characterized by a chronic low‐grade inflammation. Senescence may affect endothelial cells, subsequently involved in the most common age‐related diseases (ARDs), as well as mesenchymal stem cells (MSCs) with an impairment of their properties in tissues regeneration. Endothelial cells seem to be able to exert a paracrine effect on BM‐MSCs through the secretion of pro‐inflammatory factors. This work is aimed to evaluate if the senescent status of human umbilical vein endothelial cells (HUVECs) could affect bone marrow derived MSCs (BM‐MSCs) proliferative ability and stemness. HUVECs were cultured until the senescence status. Young (passage 3) and senescent HUVECs (passage 13) were indirectly co‐cultured with BM‐MSCs for 8 days in order to evaluate the effect of their senescence status on proliferative ability and stemness of MSCs. The co‐culture of senescent HUVECs with BM‐MSCs was associated with a reduced proliferative ability of BM‐MSCs, an enforced pro‐inflammatory phenotype of BM‐MSCs (increased synthesis of proinflammatory cytokines such as IL‐6 and TNF‐&agr;) and an increased expression of miR‐126a‐3p, in association with a significant decrease of SOX2, a stemmness‐ associated gene, targeted by miR‐126a‐3p. A more general IPA analysis, revealed as miR‐126a‐3p also modulates the expression of IRS1, IRS2, IL6ST and PIK3R2, all targets that enforce the hypothesis that senescent endothelial cells may reduce the proliferative ability and the stemness phenotype of bone marrow‐derived mesenchymal stem cells. HighlightsSenescent HUVECs affects proliferation of BM‐MSCs.Senescent HUVECs exert a paracrine effect on BM‐MSCs.IL‐6 and TNF‐&agr; and miR‐126a‐3p are up‐regulated by co‐culture with senescent HUVECs.miR‐126a‐3p targets SOX2, IRS1‐2, IL6ST and PIK3R2 all involved in stemness.BM‐MSCs stemness may be compromised by senescent microenvironment.