Human urokinase-type plasminogen activator gene-modified bone marrow-derived mesenchymal stem cells attenuate liver fibrosis in rats by down-regulating the Wnt signaling pathway

Ma, Zhigang; Lv, Xiaodan; Zhan, Lijun; Chen, Lan; Zou, Qi-Yuan; Xiang, J.; Qin, Jiao-Li; Zhang, Weiwei; Zeng, Zhaojing; Jin, Hui; Jiang, Hai‐Xing; Lv, Xiaoping

doi:10.3748/wjg.v22.i6.2092

Cited by 29 publications

(17 citation statements)

References 46 publications

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“…These capabilities allow MSCs to combat liver fibrosis regardless of etiological factors ( 25 – 28 ). Indeed, MSC therapy has been widely studied and suggested as an alternative novel method of treating liver fibrosis ( 29 – 30 ). Furthermore, the development of MSC therapy may bring hope to patients with end-stage liver fibrosis on the waiting list for a liver transplant ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, MSC therapy has been widely studied and suggested as an alternative novel method of treating liver fibrosis ( 29 – 30 ). Furthermore, the development of MSC therapy may bring hope to patients with end-stage liver fibrosis on the waiting list for a liver transplant ( 30 ). MSCs can be derived from a wide range of tissue sources, including the bone marrow, adipose tissue, dental pulp and umbilical cord blood ( 12 , 13 ).…”

Section: Discussionmentioning

confidence: 99%

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Comparison of bone marrow‑vs. adipose tissue‑derived mesenchymal stem cells for attenuating liver fibrosis

et al. 2017

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Mesenchymal stem cell (MSC) therapy has emerged as a potential novel method of treating liver fibrosis. To date, bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AD-MSCs) have not been analyzed with respect to their ability to combat liver fibrosis. The present study aimed to compare the capabilities of BM-MSCs and AD-MSCs in the treatment of liver fibrosis. BM-MSCs and AD-MSCs were taken from male Sprague-Dawley rats and cultured. Hepatic stellate cells (HSCs) were co-cultured with either BM-MSCs or AD-MSCs, and the effects of BM-MSCs or AD-MSCs on the proliferation, activation and apoptosis of HSCs were determined. The secretion of a selected group of cytokines by BM-MSCs and AD-MSCs was measured using enzyme-linked immunosorbent assays. Using a CCl4-induced liver fibrosis animal model, the anti-inflammatory and anti-fibrotic effects of BM-MSCs or AD-MSCs against liver fibrosis in vivo were evaluated. The morphological examination and analysis of specific surface markers confirmed the successful preparation of BM-MSCs and AD-MSCs. Furthermore, the proliferation, activation and apoptosis of HSCs were significantly inhibited by BM-MSCs and AD-MSCs, with statistically greater reductions achieved by AD-MSCs compared with BM-MSCs. Direct comparison of the secretion of selected cytokines by BM-MSCs and AD-MSCs revealed that significantly higher levels of nerve growth factor and transforming growth factor-β1 were secreted in the AD-MSC culture medium, whereas levels of vascular endothelial growth factor and interleukin-10 did not differ significantly between AD-MSCs and BM-MSCs. In vivo studies using a CCl4-induced liver fibrosis model demonstrated that inflammatory activity and fibrosis staging scores were significantly lower in the MSC-treated groups compared with controls. Although AD-MSCs improved anti-inflammatory and anti-fibrotic effects compared with BM-MSCs, these differences were not significant. Thus, the current study demonstrated that BM-MSCs and AD-MSCs are similarly effective at attenuating liver fibrosis by inhibiting the activation and proliferation of HSCs, as well as promoting the apoptosis of HSCs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comparison of bone marrow‑vs. adipose tissue‑derived mesenchymal stem cells for attenuating liver fibrosis

et al. 2017

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“…Necdin is a melanoma antigen family protein preferentially expressed in aHSCs that promotes myogenic and neuronal differentiation while suppressing adipogenesis. Notably, Necdin silencing restores PPARγ-mediated Wnt pathway inhibition to effectively reverse HSC activation[85,86]. In the canonical pathway, Wnt ligation to cell surface receptors elicits downstream signaling that stabilizes β-catenin, which can then translocate into the nucleus, bind T cell factor/lymphoid enhancer-binding factor (TCF/LEF) promoter, and induce gene expression to exert biological effects[87,88].…”

Section: Novel Therapeutic Targets In Liver Fibrosismentioning

confidence: 99%

Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

Zhang¹,

Yuan²,

He³

et al. 2016

WJG

466

327

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Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.

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“…MSCs infected with decorin‐expressing adenovirus more effectively impeded the development of thioacetamide (TAA)‐induced liver fibrosis in rat models than unmodified MSCs by inhibition of the TGF‐β/Smad signalling pathway . MSC administration significantly attenuates, and MSCs transfected with adenovirus‐mediated human urokinase plasminogen activator further reduced the extent of liver tissue fibrosis via down‐regulation of the Wnt signalling pathway . Knockout of androgen receptor in MSCs results in enhancement of self‐renewal and migration abilities of MSCs and consequently suppressed the infiltrating macrophages and HSC activation .…”

Section: Gene Modificationmentioning

confidence: 99%

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

Zhao

Duan

et al. 2019

J Cellular Molecular Medi

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End‐stage liver fibrosis frequently progresses to portal vein thrombosis, formation of oesophageal varices, hepatic encephalopathy, ascites, hepatocellular carcinoma and liver failure. Mesenchymal stem cells (MSCs), when transplanted in vivo, migrate into fibrogenic livers and then differentiate into hepatocyte‐like cells or fuse with hepatocytes to protect liver function. Moreover, they can produce various growth factors and cytokines with anti‐inflammatory effects to reverse the fibrotic state of the liver. In addition, only a small number of MSCs migrate to the injured tissue after cell transplantation; consequently, multiple studies have investigated effective strategies to improve the survival rate and activity of MSCs for the treatment of liver fibrosis. In this review, we intend to arrange and analyse the current evidence related to MSC transplantation in liver fibrosis, to summarize the detailed mechanisms of MSC transplantation for the reversal of liver fibrosis and to discuss new strategies for this treatment. Finally, and most importantly, we will identify the current problems with MSC‐based therapies to repair liver fibrosis that must be addressed in order to develop safer and more effective routes for MSC transplantation. In this way, it will soon be possible to significantly improve the therapeutic effects of MSC transplantation for liver regeneration, as well as enhance the quality of life and prolong the survival time of patients with liver fibrosis.

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Human urokinase-type plasminogen activator gene-modified bone marrow-derived mesenchymal stem cells attenuate liver fibrosis in rats by down-regulating the Wnt signaling pathway

Abstract: Transplantation of uPA gene modified BMSCs suppressed liver fibrosis and ameliorated liver function and may be a new approach to treating liver fibrosis. Furthermore, treatment with uPA gene modified BMSCs also resulted in a decrease in expression of molecules of the Wnt signaling pathway.

Cited by 29 publications

References 46 publications

Comparison of bone marrow‑vs. adipose tissue‑derived mesenchymal stem cells for attenuating liver fibrosis

Comparison of bone marrow‑vs. adipose tissue‑derived mesenchymal stem cells for attenuating liver fibrosis

Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

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

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