Mesenchymal Stem Cells Promote Liver Regeneration and Prolong Survival in Small-For-Size Liver Grafts: Involvement of C-Jun N-Terminal Kinase, Cyclin D1, and NF-κB

Abstract

BackgroundThe therapeutic potential of mesenchymal stem cells (MSCs) has been highlighted recently for treatment of acute or chronic liver injury, by possibly differentiating into hepatocyte-like cells, reducing inflammation, and enhancing tissue repair. Despite recent progress, exact mechanisms of action are not clearly elucidated. In this study, we attempted to explore whether and how MSCs protected hepatocytes and stimulated allograft regeneration in small-for-size liver transplantation (SFSLT).MethodsSFSLT model was established with a 30% partial liver transplantation (30PLT) in rats. The differentiation potential and characteristics of bone marrow derived MSCs were explored in vitro. MSCs were infused transvenously immediately after graft implantation in therapy group. Expressions of apoptosis-, inflammatory-, anti-inflammatory-, and growth factor-related genes were measured by RT-PCR, activities of transcription factors AP-1 and NF-κB were analyzed by EMSA, and proliferative responses of the hepatic graft were evaluated by immunohistochemistry and western blot.ResultsMSCs were successfully induced into hepatocyte-like cells, osteoblasts and adipocytes in vitro. MSCs therapy could not only alleviate ischemia reperfusion injury and acute inflammation to promote liver regeneration, but also profoundly improve one week survival rate. It markedly up-regulated the mRNA expressions of HGF, Bcl-2, Bcl-XL, IL-6, IL-10, IP-10, and CXCR2, however, down-regulated TNF-α. Increased activities of AP-1 and NF-κB, as well as elevated expressions of p-c-Jun, cyclin D1, and proliferating cell nuclear antigen (PCNA), were also found in MSCs therapy group.ConclusionThese data suggest that MSCs therapy promotes hepatocyte proliferation and prolongs survival in SFSLT by reducing ischemia reperfusion injury and acute inflammation, and sustaining early increased expressions of c-Jun N-terminal Kinase, Cyclin D1, and NF-κB.

Activator protein 1 promotes gemcitabine-induced apoptosis in pancreatic cancer by upregulating its downstream target Bim

“…Significantly, the AP-1 transcription factor is at the hub of the signalling network. Jun proteins preferentially regulate genes involved in proliferation and apoptosis, including Bim (34), Bcl-3 (35) and cyclin D1 (36), whereas Fos proteins, including DNA (cytosine-5)-methyltransferase 1 (37) and matrix metalloproteinase 1, are often required for angiogenesis and invasion by malignant tumours (38). To clarify the factors involved in gemcitabine-induced apoptosis, we analysed c-Jun and c-Fos.…”

miR-214 suppresses the osteogenic differentiation of bone marrow-derived mesenchymal stem cells and these effects are mediated through the inhibition of the JNK and p38 pathways

“…Under different induction environments, they can differentiate into osteoblasts, adipocytes, chondroblasts and neuroblasts (2). Studies have indicated that BMSCs are the source of osteoblasts and osteocytes (3,4). Inducing BMSCs to differentiate directionally is of significance to curing inflammatory bone disease and repairing bone loss (3,4).…”

Stem Cell Therapeutics of Acute Liver Diseases, Transplantation, and Regeneration

“…[128]. MSCs accelerate liver regeneration through complement C3, EGFR and thioredoxin [129]. For restoration of portal vein hepatic circulation growth factors [hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), insulin-likegrowth factor 1 (IGF-1), insulin-like growth factor binging protein 3 (IGF-BP3), epidermal growth factor (EGF), transforming growth factor (TGFα), tumor necrosis factor (TNF)] and interleukins (IL2, -6, -8 and -10) play important role [130].…”