Abstract
BackgroundAdipose-derived MSC (AMSCs) possess angiogenic and immunomodulatory properties that may modulate kidney regeneration. Whether these properties are retained in older patients with atherosclerotic vascular disease is poorly understood. Hypoxic conditions are known to modify properties and growth characteristics of AMSCs. We tested the hypothesis that AMSCs from older patients with atherosclerotic renovascular disease (RVD) differ from normal kidney donors, and whether hypoxia changes their functional and molecular properties to promote angiogenesis.MethodsAMSCs from 11 patients with RVD (mean age =74.5 years) and 10 healthy kidney donors (mean age = 51.2 years) were cultured under normoxia (20 % O2) and hypoxia (1 % O2) for 3–4 days until they reached 80 % confluency. We analyzed expression of genes and microRNAs using RNA sequencing and real-time quantitative rt-PCR. Protein expression of selected angiogenic factors (VEGF, IGF, HGF and EGF) were quantified in conditioned media using ELISAs. Apoptosis was tested using Annexin IV staining.ResultsNormoxic AMSC from RVD patients grew normally, but exhibited increased DNA damage and reduced migration. VEGF protein secretion was significantly lower in the RVD AMSCs (0.08 vs 2.4 ng/mL/ cell, p <0.05) while HGF was higher. Both trends were reversed during growth under hypoxic conditions. Hypoxia upregulated pro-angiogenic mRNAs expression in AMSCs (VEGF, FGF, STC and ANGPTL4), and downregulated expression of many miRNAs (e.g., miR-15a, miR-16, miR-93, miR-424, 126, 132, 221) except miR-210.ConclusionsThus, although AMSC from patients with RVD had increased DNA damage and reduced migration, hypoxia stimulated pro-angiogenic responses via increased expression of angiogenic genes, VEGF secretion and induction of the hypoxia-inducible miR-210, while downregulating angiogenesis-related miRNAs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0389-x) contains supplementary material, which is available to authorized users.
Highlights
Adipose-derived MSC (AMSCs) possess angiogenic and immunomodulatory properties that may modulate kidney regeneration
vascular endothelial growth factor (VEGF) secretion in the supernatant of renovascular disease (RVD) adipose-derived mesenchymal stem/stromal cells (AMSCs) at normoxic conditions was markedly lower compared to healthy controls (p
These changes were mainly due to age rather than vascular disease, as cytokine secretion (IGF, HGF and epidermal growth factor (EGF)) was not different in RVD compared to older healthy subjects except for VEGF (Fig. 7)
Summary
Adipose-derived MSC (AMSCs) possess angiogenic and immunomodulatory properties that may modulate kidney regeneration Whether these properties are retained in older patients with atherosclerotic vascular disease is poorly understood. Occlusive atherosclerotic renovascular disease (RVD) reduces renal blood flow (RBF), eventually producing renal ischemia, tissue hypoxia, and oxidative stress [1, 2] These changes lead eventually to microvascular dysfunction, activation of inflammatory pathways, and fibrosis [3, 4]. Administration of AMSCs in the swine model of RVD is associated with increased vascular endothelial growth factor (VEGF) and suppression of inflammatory cytokines These changes are accompanied by increased RBF and glomerular filtration rate (GFR), and reduced fibrosis in the post-stenotic kidney [5]. The exact mechanisms have not yet been elucidated, regenerative characteristics of MSCs are widely attributed to paracrine effects mediated through secretion of bioactive molecules and chemokines [6]
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