Type 2 Diabetes Inhibited Human Mesenchymal Stem Cells Angiogenic Response by Over‐Activity of the Autophagic Pathway

• Published in: Journal of cellular biochemistry Vol. 118; no. 6; pp. 1518 - 1530
• Main Authors: Rezabakhsh, Aysa, Cheraghi, Omid, Nourazarian, Alireza, Hassanpour, Mehdi, Kazemi, Masoumeh, Ghaderi, Shahrooz, Faraji, Esmaeil, Rahbarghazi, Reza, Avci, Çığır Biray, Bagca, Bakiye Goker, Garjani, Alireza
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.06.2017
• Subjects: Adult; Androgen receptors; ANGIOGENESIS; Apoptosis; AUTOPHAGY; Autophagy - drug effects; Beclin-1 - genetics; Beclin-1 - metabolism; Bone marrow; Cadherins; Cell death; Cell Differentiation - drug effects; Cells, Cultured; Chemotaxis; Chemotaxis - drug effects; Crosstalk; Culture Media, Conditioned - pharmacology; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; DIABETES TYPE 2; DIFFERENTIATION; hMSCs; Humans; Insulin; Male; Mesenchymal stem cells; Mesenchymal Stromal Cells - classification; Mesenchymal Stromal Cells - secretion; Neovascularization, Physiologic - drug effects; PARACRINE ACTIVITY; Phagocytosis; Receptors; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal transduction; Signaling; Stem cells; Substrates; Western blotting; Young Adult; PARACRINE ACTIVITY; hMSCs; AUTOPHAGY; DIABETES TYPE 2; DIFFERENTIATION; ANGIOGENESIS
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.25814

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. In summary, the results of current experiment showed that DM2 could directly or indirectly affect the angiogenic behavior in hMSCs over a period of 7 days. It seems that over‐expression of autophagic factor P62 in line with insulin, FGF2, FGF1, and IL‐1β signaling could hamper the angiogenic capacity in diabetic hMSCs.