Diabetes impairs osteogenic differentiation of bone marrow mesenchymal stem cells

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Spanish Ministry of Science and Innovation (MICINN) Diabetes impairs osteogenic differentiation of bone marrow mesenchymal stem cells Background Diabetes is a severe metabolic condition that induces micro- and macrovascular disease, including atherosclerotic vascular disease, cutaneous lesions and bone necrosis. Whether it affects stem cell function is a matter of investigation. When the self-renewing capacity of mesenchymal stem cells (MSC) is compromised, their regenerative potential for cell therapy is impaired. Purpose We aimed to investigate the effects of diabetes on bone marrow- mesenchymal stem cells (BM-MSC) transcriptomics to evidence their potential for differentiation. Methods Bone marrow was extracted from femurs of Zucker rats, and BM-MSC were isolated by culturing adherent cells of extracted bone marrow in DMEM low glucose/ 20% FBS/ 1% P/S under hypoxic conditions (1% oxygen). After one week, MSC were characterized by flow cytometry. Gene expression arrays were used to analyse the expression of BM-MSC of Zucker rats with diabetes (ZD) compared to those of lean-normoglycemic controls (ZC) with the same genetic background (n=6). Results were analysed in silico to identify significantly modified signalling pathways. In addition, BM-MSC differentiation into endothelial, adipogenic and osteogenic cells was investigated in vitro. Results 95-99% of cells isolated from BM expressed CD90, a marker of MSC. Expression data analyses revealed a down-regulation of transcription factors related to the osteogenic pathway (Abcb1a, Adipoq, Fut1, Il1b, Kdr, Nes, Rhoa, Runx2, Tbx5, Tert and Tgfb3), and up-regulation of adipogenic- and angiogenic-related genes such as Bmp7, Casp3, Cd44, Csf2, Erbb2, Gdf7, Il10, Mcam, Nt5e, Pparg, Sox2, Vegfa and Vwf, in BM-MSC from animals with diabetes compared to lean controls. Concomitantly, BM-MSC from rats with diabetes showed impaired osteogenic differentiation in vitro compared to lean controls. No significant differences in adipogenesis or endothelial differentiation were observed between BM-MSC of rats with diabetes and lean controls. Conclusions Diabetes down-regulates several factors involved in the osteogenic differentiation pathway resulting in impaired osteogenesis. The imbalance in gene expression and MSC differentiation may partially explain the impaired regenerative capacity in diabetes.