Unsaturated fatty acids induce mesenchymal stem cells to increase secretion of angiogenic mediators.

Mesenchymal stem cells (MSC) represent emerging cell-based therapies for diabetes and associated complications (Volarevic et al., 2011). Ongoing clinical trials are using exogenous MSC to treat type 1 and 2 diabetes, cardiovascular disease and non-healing wounds due to diabetes (Fotino et al., 2010; Ankrum and Karp, 2010). The majority of these trials are aimed at exploiting the ability of MSC to release soluble mediators that reduce inflammation and promote both angiogenesis and cell survival at sites of tissue damage due to diabetic complications (Ankrum and Karp, 2010). Translational studies targeting the pancreas are also taking advantage of the immunosuppressive properties of MSC (Fotino et al., 2010). Growing evidence suggests that MSC secretion of soluble factors is dependent on tissue microenvironment. To date, the majority of studies have investigated the effect of a hypoxic environment. Hypoxia has been shown to regulate MSC gene expression and protein secretion in vitro with reports of increased secretion of VEGF, FGF2, HGF, IGF-1, MCP1 and thymosin β4 (Annabi et al., 2003; Gnecchi et al., 2006; Hung et al., 2007; Potier et al., 2007) and reduced secretion of MMP2 (Annabi et al., 2003; Lee et al., 2009). Interestingly, hypoxic pre-conditioning appears to enhance the ability of MSC to mediate tissue repair in vivo. MSC-conditioned medium prepared under hypoxic conditions is more effective at accelerating wound closure (Lee et al., 2009) and improving cardiac function after myocardial infarction (Rosova et al., 2008). These studies clearly demonstrate that a hypoxic environment impacts MSC secretion and that these environment-induced changes have functional consequences in vivo. Although less is known about the effect of the metabolic environment of diabetes on MSC secretion, there are reports that MSC secretion of growth factors is affected by exposure to elevated glucose. High glucose was shown to up-regulate MSC secretion of TGF-β1 protein levels (Ryu et al., 2010) but had no effect on levels of secreted VEGF, HGF and FGF2 (Weil et al., 2009). Despite the contribution of fatty acids to the metabolic environment of type 2 diabetes, almost nothing is known about their effects on MSC secretion of growth factors and cytokines. In this study, we determined the effect of two unsaturated fatty acids, linoleic and oleic acids, on human bone marrow-derived MSC. Our results show that exposure to either unsaturated fatty acid changed the MSC secretome at the level of both gene expression and protein secretion. In addition, linoleic and oleic acids affected MSC proliferation and chemotaxis.