Effect of bone marrow mesenchymal stem cells on the TGF-β1/Smad signaling pathway of hepatic stellate

This study investigated the effect of bone marrow mesenchymal stem cells (BMCs) on the transforming growth factor-beta 1 (TGF-beta 1)-induced activation of the Smad signaling pathway in rat hepatic stellate cells (HSCs). There were four experimental groups: 1) a blank control group, 2) a TGF-beta 1 treatment group, 3) an MSC-combined group, and 4) an induced MSC-combined group. Isolation and culture of rat liver HSCs in vitro and the proliferation of HSCs in each group were detected by MTT method. The expression of alpha-SMA and the TGF receptors (T beta RI and II) were determined by immunohistochemical staining of HSCs in all groups, while Smad2/3, Smad4, and Smad7 mRNA expressions were detected by RT-PCR for HSCs in each group. TGF-beta 1 treatment significantly promoted the proliferation of HSCs (P < 0.01); it has different inhibition effects on the proliferation of HSCs in the MSC-combined group and in the induced MSC-combined group (P < 0.05). TGF-beta 1 treatment also enhanced the expression of alpha-SMA as compared to the control group (P < 0.01). Alternatively, when compared with the pure TGF-beta 1 group, the MSC-combined group and the induced MSC-combined group showed lower alpha-SMA expression (P < 0.05). Activation of HSCs induced by TGF-beta 1, T beta RI and T beta RII fluorescence was (+ + +); the fluorescences of TbRI and T beta RII in MSC-combined group and in induced MSC-combined group were (+ +) and (+/- similar to +), respectively. The expressions of T beta RI and T beta RII in activated HSCs induced by TGF-beta 1 were significantly decreased in the MSC-combined group (P < 0.05) and in the induced MSC-combined group (P < 0.01). The expression of HSC Smad2/3 and Smad4 was reduced in the MSC-combined group (P < 0.05) and in the induced MSC-combined group (P < 0.01), as compared to the TGF-beta 1 group. However, the expression of Smad7 in HSCs was upregulated in the MSC-combined group (P < 0.05) and in the induced MSC-combined group (P < 0.01). These results indicate that BMCs can inhibit the activation and proliferation of HSCs by downregulating the expression of T beta RI and T beta RII in the cell membrane of HSCs. Moreover, BMCs can upregulate the expression of Smad7 and downregulate the expression of Smad2/3 and Smad4 in the HSCs induced by TGF-beta 1, which resulted in an inhibition of HSC activation.