Human bone marrow mesenchymal stem cells suppress the proliferation of hepatic stellate cells by inhibiting the ubiquitination of p27

Abstract

Bone marrow mesenchymal stem cells (BMSCs) have considerable therapeutic potential for the treatment of end-stage liver disease. Previous studies have demonstrated that BMSCs secrete growth factors and cytokines that inactivate hepatic stellate cells (HSCs), which inhibited the progression of hepatic fibrosis. The aim of this study was to determine the mechanism by which BMSCs suppress the function of HSCs in fibrosis. Our results showed that co-culture of BMSCs and HSCs induced cell cycle arrest at the G10/G1 phase and cell apoptosis of HSCs, which finally inhibited the cell proliferation of HSCs. Consistent with the cell cycle arrest, co-culture of BMSCs and HSCs increased the abundance of the cell cycle protein p27. Mechanistically, we further uncovered that following the co-culture with BMSCs, the expression level of the E3 ligase S-phase kinase-associated protein 2 (SKP2) that is responsible for the ubiquitination of p27 was decreased, which attenuated the ubiquitination of p27 and increased the stability of p27 in HSCs. Collectively, our results indicated the potential involvement of the SKP2–p27 axis for the inhibitory effect of BSMCs on the cell proliferation of HSCs.

Strategies to improve the efficiency of mesenchymal stem cell transplantation for reversal of liver fibrosis

“…16 (SKP2) level, attenuating the ubiquitination of p27 and increasing the stability of p27. 18 Moreover, MSCs are demonstrated to produce various growth factors and cytokines with anti-inflammatory effects in vitro and in vivo to reverse the liver fibrotic state, as transplantation of MSCs increases the serum levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), IL-10 and MMP-9 in injured livers. 19 MSCs in vivo attenuated hepatic fibrosis as shown by decreased serum levels of collagen I, type III procollagen, collagen IV, hyaluronic acid and laminin, and down-regulated liver collagen proportionate area, hepatic hydroxyproline and liver αsmooth muscle actin (α-SMA); this progress is accompanied by reduced expression of serum TGF-β1 and reduced hepatic levels of TGF-β1, Smad3 and Smad4 but increased Smad7 expression.…”

Mesenchymal stem cell-based treatment in autoimmune liver diseases: underlying roles, advantages and challenges

“…Furthermore, co-culturing BM-MSCs with HSCs could induce apoptosis and inhibit the proliferation of HSCs. 81 Other mechanisms of MSC inhibition on liver fibrosis have also been uncovered. In a TAA-induced cirrhotic rat model, MSC administration significantly decreased the expression of TGF-β1, collagen-1, and α-smooth muscle actin (α-SMA) expression and inhibited Smad3 phosphorylation, which is a downstream effector of the TGF-β1 signaling pathway.…”

Novel insights into the impact of the SUMOylation pathway in hematological malignancies (Review)

“…There are two prerequisites for a protein to be SUMOylated: A direct interaction with the Ubc9-SUMO thioester and the recognition of a specific SUMO ligase in proximity with Ubc9 ( 2 ). Ubc9 acts as a hub protein of SUMOylation, and has been found to be upregulated in various types of cancer cells ( 48 - 50 ). Functionally, Ubc9 serves an important role in cell cycle regulation, DNA repair, transcription and nuclear transport ( 51 , 52 ).…”