We demonstrated that extracellular vesicles (EV) derived from mesenchymal stem cells (MSC) cultured in high glucose and/or hypoxia are able to enter the pericytes, causing their detachment from substrate and migration, and stimulating angiogenesis in vitro. In fact, they down-regulate miR-126 leading to increased expression of angiogenic molecules (VEGF and HIF-1α). Our present hypothesis is that circulating EV in diabetes may influence small vessel homeostasis, and that identification of molecular differences in EV from healthy controls and diabetic subjects, with/without microvascular complications, could represent a predictive option for diagnostic purposes. The aim of this study was the molecular characterization and comparative analysis of EV derived from healthy and diabetic subjects and their influence on pericyte detachment and angiogenesis. EV were extracted from plasma samples of 3 diabetic patients with microvascular complications (nephropathy and retinopathy) (DM) and 3 healthy age-matched controls (noDM). EV expression of surface molecules was measured by FACS. microRNA (miRNA) content was evaluated by Taqman Human MicroRNA Array, which allows detection of 377 different miRNAs. Human retinal pericyte (HRP) detachment was evaluated after 4 and 24 hr exposition to EV obtained from MSC, DM and noDM plasma. FACS analysis of surface molecules showed no significant changes between DM and noDM. We found differences between the two groups in six miRNAs: 4 of them, which have anti-angiogenic properties (miR-150, miR-155, miR-342-3p, let-7-g), were decreased, while 2 of them with a pro-angiogenic function (miR-17 and miR-106a) were increased in DM vs noDM (p<0.05). EV from DM patients induced HRP detachment (-19.6% after 4hrs, -31.4% after 24 hr exposure, p<0.05), similarly to EV derived from MSC in diabetic-like conditions, while noDM-EV had no effect. These observations suggest that diabetic patients may have different EV patterns in comparison with healthy subjects. In particular, an imbalance between miRNAs with pro- and anti-angiogenic functions could lead to abnormal microvessel proliferation, and consequently result in proliferative diabetic retinopathy. Further studies on this subject could potentially provide a useful therapeutic tool for the treatment of various types of vessel abnormalities.

Different miRNA patterns in extracellular vesicles from diabetic and healthy subjects. In: Abstracts from the 26th Meeting of the European Association for the Study of Diabetes Eye Complications Study Group (EASDec) | Manchester, UK | 23-25 June 2016

MAZZEO, AURORA;BELTRAMO, Elena;GAI, CHIARA;LOPATINA, Tatiana;PORTA, Massimo
2016

Abstract

We demonstrated that extracellular vesicles (EV) derived from mesenchymal stem cells (MSC) cultured in high glucose and/or hypoxia are able to enter the pericytes, causing their detachment from substrate and migration, and stimulating angiogenesis in vitro. In fact, they down-regulate miR-126 leading to increased expression of angiogenic molecules (VEGF and HIF-1α). Our present hypothesis is that circulating EV in diabetes may influence small vessel homeostasis, and that identification of molecular differences in EV from healthy controls and diabetic subjects, with/without microvascular complications, could represent a predictive option for diagnostic purposes. The aim of this study was the molecular characterization and comparative analysis of EV derived from healthy and diabetic subjects and their influence on pericyte detachment and angiogenesis. EV were extracted from plasma samples of 3 diabetic patients with microvascular complications (nephropathy and retinopathy) (DM) and 3 healthy age-matched controls (noDM). EV expression of surface molecules was measured by FACS. microRNA (miRNA) content was evaluated by Taqman Human MicroRNA Array, which allows detection of 377 different miRNAs. Human retinal pericyte (HRP) detachment was evaluated after 4 and 24 hr exposition to EV obtained from MSC, DM and noDM plasma. FACS analysis of surface molecules showed no significant changes between DM and noDM. We found differences between the two groups in six miRNAs: 4 of them, which have anti-angiogenic properties (miR-150, miR-155, miR-342-3p, let-7-g), were decreased, while 2 of them with a pro-angiogenic function (miR-17 and miR-106a) were increased in DM vs noDM (p<0.05). EV from DM patients induced HRP detachment (-19.6% after 4hrs, -31.4% after 24 hr exposure, p<0.05), similarly to EV derived from MSC in diabetic-like conditions, while noDM-EV had no effect. These observations suggest that diabetic patients may have different EV patterns in comparison with healthy subjects. In particular, an imbalance between miRNAs with pro- and anti-angiogenic functions could lead to abnormal microvessel proliferation, and consequently result in proliferative diabetic retinopathy. Further studies on this subject could potentially provide a useful therapeutic tool for the treatment of various types of vessel abnormalities.
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extracellular vesicles, diabetes, miRNAs, pericytes
Mazzeo, A.; Beltramo, E.; Gai, C.; Lopatina, T.; Porta, M.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1572536
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