Angiogenic and Restorative Abilities of Human Mesenchymal Stem Cells Were Reduced Following Treatment With Serum From Diabetes Mellitus Type 2 Patients Jafar Rezaie, 1 Malek S. Mehranjani , 1 * Reza Rahbarghazi, 2,3 and Mohammad A. Shariatzadeh 1 1 Department of Biology, Faculty of Sciences, Arak University, Arak, Iran 2 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 3 Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran ABSTRACT This experiment investigated the impact of serum from patients with type 2 diabetes mellitus on the angiogenic behavior of human mesenchymal stem cells in vitro. Changes in the level of Ang-1, Ang-2, cell migration, and trans-differentiation into pericytes and endothelial lineage were monitored after 7 days. The interaction of mesenchymal stem cells with endothelial cells were evaluated using surface plasmon resonance technique. Paracrine restorative effect of diabetic stem cells was tested on pancreatic b cells. Compared to data from FBS and normal serum, diabetic serum reduced the stem cell survival and chemotaxis toward VEGF and SDF-1a (P < 0.05). Diabetic condition were found to decline cell migration rate and the activity of MMP-2 and -9 (P < 0.05). The down-regulation of VEGFR-2 and CXCR-4 was observed with an increase in the level of miR-1-3p and miR-15b-5p at the same time. The paracrine angiogenic potential of diabetic stem cells was disturbed via the changes in the dynamic of Ang-1, Ang-2, and VEGF. Surface plasmon resonance analysis showed that diabetes could induce an aberrant increase in the interaction of stem cells with endothelial cells. After treatment with diabetic serum, the expression of VE-cadherin and NG2 and ability for uptake of Dil-Ac-LDL were reduced (P < 0.01). Conditioned media prepared from diabetic stem cells were unable to decrease fatty acid accumulation in b-cells (P < 0.05). The level of insulin secreted by b-cells was not affected after exposure to supernatant from diabetic or non-diabetic mesenchymal stem cells. Data suggest diabetes could decrease angiogenic and restorative effect of stem cells in vitro. J. Cell. Biochem. 9999: 1–12, 2017. © 2017 Wiley Periodicals, Inc. KEY WORDS: HUMAN MESENCHYMAL STEM CELLS; DIABETES MELLITUS TYPE 2; DIFFERENTIATION AND PARACRINE ANGIOGENESIS PROPERTIES; RESTORATIVE ABILITY D iabetes mellitus type 2 (DM2) is a serious metabolic disease affecting human societies globally with common macro- and microvascular pathologies [Rezabakhsh et al., 2017]. Aberrant angiogenesis was found to cause vasculopathy in retina and kidneys, while deficient neovascularization could postpone wound healing in various tissues [El-Asrar et al., 2006; Golden, 2011]. Various scientific works provided evidence that DM2 had potential to affect the dynamic of different cells, especially stem cells (SCs) [Salabei et al., 2016]. Having the ability to release pro-angiogenic factors and transdifferentiate into endothelial phenotype, it was accepted that SCs and marrow-derived mesenchymal stem cells (hMSCs) actively participate in the promotion of vascularization, holding promise for regeneration of tissues during injuries [Rosser et al., 2007; Chou et al., 2002; Mizuno, 2010; Song et al., 2010]. With respect to hMSCs regenerative capacity on various pathologies, they can easily trigger the amelioration of diabetes-related complications [Park et al., 2010; Zhao et al., 2015]. In spite of SCs restorative function, there are very few studies on the adverse effects of DM2 on hMSCs to show adverse biological changes. For instance, in the great body of experiments, SCs were only exposed to high glucose content in vitro [Saki et al., 2013], while one of the causes of diabetes damage is correlated with the detrimental effect of glucose [Chen et al., 2013]. As a matter of fact, it is reasonable to elucidate many signaling pathways and factors causing MSCs damage during DM2 [Kollar et al., 2009]. Conflicts of interest: The authors have declared that no competing interests exist. Grant sponsor: Arak University; Grant sponsor: Tabriz University of Medical Sciences. *Correspondence to: Dr. Malek S. Mehranjani, PhD, Faculty of Sciences, Department of Biology, Arak University, P.O. Box: 38156-8-8349, Arak, Iran. E-mail: m-soleimani@araku.ac.ir Manuscript Received: 26 April 2017; Manuscript Accepted: 12 June 2017 Accepted manuscript online in Wiley Online Library (wileyonlinelibrary.com): 13 June 2017 DOI 10.1002/jcb.26211  © 2017 Wiley Periodicals, Inc. 1 ARTICLE Journal of Cellular Biochemistry 9999:1–12 (2017)