Abstract
Nowadays, paracrine regulation is considered as a major tool of mesenchymal stem cell (MSC) involvement in tissue repair and renewal in adults. Aging results in alteration of tissue homeostasis including neovascularization. In this study, we examined the influence of replicative senescence on the angiogenic potential of adipose-derived MSCs (ASCs). Angiogenic activity of conditioned medium (CM) from senescent and “young” ASCs was evaluated in chorioallantoic membrane (CAM) assay in ovo using Japanese quail embryos. Also, the formation of capillary-like tubes by human umbilical vein endothelial cells (HUVECs) in 3D basement membrane matrix “Matrigel” and HUVEC migration capacity were analyzed. Multiplex, dot-blot and gene expression analysis were performed to characterize transcription and production of about 100 angiogenesis-associated proteins. The results point to decreased angiogenic potential of senescent ASC secretome in ovo. A number of angiogenesis-associated proteins demonstrated elevation in CM after long-term cultivation. Meanwhile, VEGF (key positive regulator of angiogenesis) did not change transcription level and concentration in CM. Increasing both pro- (FGF-2, uPA, IL-6, IL-8 etc.) and antiangiogenic (IL-4, IP-10, PF4, Activin A, DPPIV etc.) factors was observed. Some proangiogenic genes were downregulated (IGF1, MMP1, TGFB3, PDGFRB, PGF). Senescence-associated secretory phenotype (SASP) modifications after long-term cultivation lead to attenuation of angiogenic potential of ASC.
Highlights
Mesenchymal stromal cells (MSCs) are a heterogeneous population of poorly differentiated stromal precursors with high proliferative activity and multilineage differentiation, which keeps them in demand for clinical use [1,2]
These effects are of particular interest for the treatment of ischemia, where the stimulation of vascularization is crucial for the preservation of alive tissue and, for the prevention of fibrosis [7]
Osteogenic and adipogenic potential were confirmed (Figure 1b). These data indicate that obtained cells are Adipose-derived MSCs (ASCs) according to International Federation for Adipose Therapeutics and Science (IFATS) and International Society for Cell and Gene Therapy (ISCT) statements [25,26]
Summary
Mesenchymal stromal cells (MSCs) are a heterogeneous population of poorly differentiated stromal precursors with high proliferative activity and multilineage differentiation, which keeps them in demand for clinical use [1,2]. These days, the positive effects of MSCs are mainly attributed to their ability to produce a number of biologically active factors, including cytokines, exosomes, and extracellular matrix components [3,4,5,6]. Neovascularization after administration of ASCs or conditioned medium (CM) was considered the main mechanisms of hepatic regeneration [18]
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