title: Type 2 Diabetes Inhibited Human Mesenchymal Stem Cells Angiogenic Response by Over-Activity of the Autophagic Pathway.
abstract: The current study aimed to address the impact of serum from type 2 diabetes patients on the angiogenic properties of human bone marrow mesenchymal stem cells and its relationship to autophagy signaling. Human primary stem cells were enriched and incubated with serum from diabetic and normal subjects for 7 days. Compared to data from the control group, diabetic serum was found to induce a higher cellular death rate (P < 0.001) and apoptotic changes (P < 0.01). We also showed that diabetic condition significantly abolished angiogenesis tube formation on Matrigel substrate, decreased cell chemotaxis (P < 0.01) in response to SDF-1α, and inhibited endothelial differentiation rate (P < 0.0001). Western blotting showed autophagic status by high levels of P62 (P < 0.0001), beclin-1 (P < 0.0001), and increase in LC3II/I ratio (P < 0.001). In vivo Matrigel plug assay revealed that supernatant conditioned media prepared from cells exposed to diabetic serum caused a marked reduction in the recruitment of VE-cadherin- (P < 0.01) and α-SMA-positive (P < 0.0001) cells 7 days after subcutaneous injection. PCR expression array analysis confirmed the overexpression of autophagy and apoptosis genes in cultured cells in response to a diabetic condition (P < 0.05). Using bioinformatic analysis, we noted a crosstalk network between DM2, angiogenesis, and autophagy signaling. DM2 could potently modulate angiogenesis by the interaction of IL-1β with downstream insulin receptor and upstream androgen receptor. Corroborating to data, diabetic serum led to abnormal regulation of P62 during the angiogenic response. These data demonstrate that diabetic serum decreased human mesenchymal stem cell angiogenic properties directly on angiogenesis pathways or by the induction of autophagy signaling. J. Cell. Biochem. 118: 1518-1530, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Faculty of Pharmacy, Department of Pharmacology and Toxicology, Tabriz University of Medical Sciences, Tabriz, Iran.|Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.|Student Research Committee of Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Aysa
authors.initials: A
authors.lastname: Rezabakhsh
authors.affiliation: Faculty of Natural Sciences, Department of Biology, University of Tabriz, Tabriz, Iran.
authors.forename: Omid
authors.initials: O
authors.lastname: Cheraghi
authors.affiliation: Faculty of Medicine, Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Nourazarian
authors.affiliation: Faculty of Medicine, Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Hassanpour
authors.affiliation: Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Kazemi
authors.affiliation: Faculty of Advanced Medical Sciences, Department of Molecular Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Shahrooz
authors.initials: S
authors.lastname: Ghaderi
authors.affiliation: Faculty of Medicine, Department of Internal Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Esmaeil
authors.initials: E
authors.lastname: Faraji
authors.affiliation: Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.|Faculty of Advanced Medical Sciences, Department of Applied Cell Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Rahbarghazi
authors.affiliation: Faculty of Medicine, Department of Medical Biology, Ege University, Izmir, Turkey.
authors.forename: Çığır Biray
authors.initials: ÇB
authors.lastname: Avci
authors.affiliation: Faculty of Medicine, Department of Medical Biology, Ege University, Izmir, Turkey.
authors.forename: Bakiye Goker
authors.initials: BG
authors.lastname: Bagca
authors.affiliation: Faculty of Pharmacy, Department of Pharmacology and Toxicology, Tabriz University of Medical Sciences, Tabriz, Iran.|Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Garjani
mesh_terms: D000328:Adult; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000145:classification* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C491997:BECN1 protein, human; D000071186:Beclin-1; D017077:Culture Media, Conditioned; C118585:P62 protein, human; D016601:RNA-Binding Proteins
keywords: ANGIOGENESIS; AUTOPHAGY; DIABETES TYPE 2; DIFFERENTIATION; PARACRINE ACTIVITY; hMSCs