| Metformin is commonly prescribed as a hypoglycemic agent following the onset of type 2 diabetes mellitus. This
study aimed to investigate pro- and/or anti-angiogenic effects of Metformin on human bone marrow mesenchymal
stem cells. Cells were incubated with different doses of Metformin including 0.5, 1, 10, 50, 100, 200
and 500 μM for 14 days. Cell viability and total fatty acids profile were examined by MTT and gas chromatography
methods. Differentiation of cells to endothelial lineage was studied by monitoring the expression of
VEGFR-2 and Tie-2 receptors and VE-cadherin via real-time PCR and western blotting. Angiogenic potential and
migration of cells were assessed by tubulogenesis and Transwell migration assays. PCR array was performed to
analyze mTOR signaling. CD133+ and VEGFR-2+ cells were detected in blood samples of non-diabetic control,
diabetic subjects and diabetics received Metformin. Metformin dose-dependently reduced cell survival.
Decreased content of palmitate and oleate coincided increased level of stearate, palmitoleate, and linoleate
(p < 0.05). Metformin decreased the angiogenic potential of cells by decreasing VEGFR-2 and Tie-2 expression
(p < 0.05). The protein level of VE-cadherin decreased in cells received Metformin. Compared to the control,
Metformin blunted the expression of VEGF subtypes and directed cells to energy status by induction of PRKAA1,
PRKAB2, and PRKAG1 genes (p < 0.05). Non-significant differences were observed regarding the number of
CD133 and VEGFR-2 cells in blood samples (p > 0.05). These data support a notion that Metformin could blunt
the angiogenic behavior of human mesenchymal stem cells by modulating mTOR signaling pathway. |