Endoplasmic reticulum stress inhibits adipocyte differentiation of mesenchymal stem cells

Endoplasmic reticulum (ER) stress due to aging is one of the critical factors that inhibit stem cell differentiation and cause differentiation failure. However, some ER stress-related proteins play important roles in the regulation of stem cell differentiation and are upregulated during differentiation. Thus, ER stress is associated with both positive and negative regulation of adipocyte differentiation. Nevertheless, it remains unclear whether the upregulation of ER stress-related proteins is a cause or an effect of differentiation. This study investigated the effect of the ER stress signaling pathway on mesenchymal stem cell (MSC) differentiation. Before stimulating their differentiation, MSCs were transiently treated with tunicamycin to induce a mild ER stress, which does not induce apoptosis. We found that activating transcription factor 4 (ATF4) was upregulated by ER stress and/or adi-pocyte differentiation stimulation. This increase in ATF4 expression resulted in either an increase or a decrease in tribbles-related protein 3 (TRB3) expression. Our findings suggest that TRB3 downregulation is required for adi-pocyte differentiation. These results indicate that TRB3 might be a key protein that switches on cells in response to ER stress or adipocyte differentiation.