Chronic restraint stress decreases the repair potential from mesenchymal stem cells on liver injury by inhibiting TGF-β1 generation

Chronic psychological stress has been demonstrated to play an important role in several severe diseases, but whether it affects disease therapy or not remains unclear. Mesenchymal stem cells (MSCs) have been demonstrated to have therapeutic potentials in treating tissue injury based on their multidifferentiation potential toward various cell types. We investigated the effect of chronic restraint stress on therapeutic potential of MSCs on carbon tetrachloride (CCl₄)-induced liver injury in mice. CCl ₄-induced mice were injected with enhanced green fluorescent protein-MSCs, which was followed by chronic restraint stress administration. Corticosterone and RU486, a glucocorticoid receptor (GR) antagonist, were employed in vivo and in vitro, too. In the present study, we illustrated that MSCs could repair liver injury by differentiating into myofibroblasts (MFs) which contribute to fibrosis, whereas stress repressed differentiation of MSCs into MFs displayed by reducing a-smooth muscle actin (α-SMA, a solid marker of MFs) expression. Whereas RU486 could maintain the liver injury reduction and liver fibrosis increases induced by MSCs in stressed mice and block the decrease of α-SMA expression induced by stress. Furthermore, chronic stress inhibited MFs differentiation from MSCs by inhibiting transforming growth factor-b1 (TGF-β1)/Smads signaling pathway which is essential for MFs differentiation. Chronic stress reduced autocrine TGF-β1 of MSCs, but not blunted activation of Smads. All these data suggested that corticosterone triggered by chronic stress impaired liver injury repair by MSCs through inhibiting TGF-β1 expression which results in reduced MFs differentiation of MSCs.