1. The transcription factor Oct4 is critical to the pluripotency, self-renewal and differentiation of stem cells. The aim of the present study was to investigate the effects of high glucose (HG) on the cell cycle progression of bone marrow multipotent adult progenitor cells (MAPC) and Oct4 expression, as well as the underlying mechanisms. 2. Rat MAPC were cultured in normal (5.5 mmol/L D-glucose) and HG (25.5 mmol/L D-glucose) media for up to 14 days. L-Glucose served as a high osmolarity control. Culture in HG media substantially increased the number of cells in the G(0)/G(1) phase and decreased the number in the S phase without changing the cell population in the G(2) phase. Expression of the cell cycle regulatory protein p21CIP/WAF-1 (p21), but not that of p27KIP-1 (p27), was significantly upregulated in cells cultured in HG media. Significant increases were seen in transforming growth factor (TGF)-β1 levels in cells and MAPC-conditioned medium in the presence of HG, and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was enhanced in cells cultured in the presence of HG medium without any changes in Akt phosphorylation. 3. Neutralizing TGF-β1 antibody effectively prevented HG-induced increases in ERK1/2 phosphorylation, p21 expression and suppression of cell cycle progression of MAPC. Inhibiting ERK1/2 phosphorylation with PD98059 completely blocked HG-induced p21 expression and markedly reversed HG-induced inhibition of cell cycle progression in MAPC. The HG-induced suppression of cell cycle progression was not accompanied by inhibition of cell proliferation or Oct4 expression in these cells. 4. The data indicate that HG facilitates cell cycle arrest of rat MAPC through TGF-β1-induced activation of ERK1/2 signalling and p21 expression, and that Oct4 expression in MAPC is independent of the cell cycle and/or TGF-β1 or ERK1/2 signalling in HG medium.
© 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.