Signalling pathways involved in the process of mesenchymal stem cells differentiating into hepatocytes

Ye, Junsong; Su, Xiaohong; Stoltz, Jean‐François; Isla, Natalia de; Zhang, Lei

doi:10.1111/cpr.12165

Cited by 34 publications

(23 citation statements)

References 69 publications

(109 reference statements)

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“…Mesenchymal stem cells, which reside in various tissue, such as bone marrow, umbilical cord blood, adipose tissue and others, can differentiate into multiple cell lineages in vitro , including hepatocyte (Ye et al, 2015 ). Yet, few engraft human cells could be found in the liver after transplantation of human mesenchymal stem cells into the sublethally irradiated NOD/SCID mice exposed to acute or chronic CCl4 injury (di Bonzo et al, 2008 ).…”

Section: Transplantation Of Mesenchymal Stem Cells To Relieve Liver Fmentioning

confidence: 99%

Promising Therapy Candidates for Liver Fibrosis

et al. 2016

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Liver fibrosis is a wound-healing process in response to repeated and chronic injury to hepatocytes and/or cholangiocytes. Ongoing hepatocyte apoptosis or necrosis lead to increase in ROS production and decrease in antioxidant activity, which recruits inflammatory cells from the blood and activate hepatic stellate cells (HSCs) changing to myofibroblasts. Injury to cholangiocytes also recruits inflammatory cells to the liver and activates portal fibroblasts in the portal area, which release molecules to activate and amplify cholangiocytes. No matter what origin of myofibroblasts, either HSCs or portal fibroblasts, they share similar characteristics, including being positive for α-smooth muscle actin and producing extracellular matrix. Based on the extensive pathogenesis knowledge of liver fibrosis, therapeutic strategies have been designed to target each step of this process, including hepatocyte apoptosis, cholangiocyte proliferation, inflammation, and activation of myofibroblasts to deposit extracellular matrix, yet the current therapies are still in early-phase clinical development. There is an urgent need to translate the molecular mechanism of liver fibrosis to effective and potent reagents or therapies in human.

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Section: Transplantation Of Mesenchymal Stem Cells To Relieve Liver Fmentioning

confidence: 99%

Promising Therapy Candidates for Liver Fibrosis

et al. 2016

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“…Hepatocyte growth factor (HGF) played a critical role in the development and regeneration of the liver and induced expression of the hepatic phenotype in mesenchymal stem cells in vitro [ 11 , 12 ]. Mitogen-activated protein kinases (MAPKs) play important roles in the cellular response to growth factors, cytokines and chemicals, or environmental stress.…”

Section: Introductionmentioning

confidence: 99%

Zebularine Promotes Hepatic Differentiation of Rabbit Bone Marrow Mesenchymal Stem Cells by Interfering with p38 MAPK Signaling

Luo

Chen

Xiao

et al. 2018

Stem Cells International

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Demethylating agent zebularine is reported to be capable of inducing differentiation of stem cells by activation of methylated genes, though its function in hepatocyte differentiation is unclear. p38 signal pathway is involved in differentiation of hepatocytes and regulating of DNA methyltransferases 1 (DNMT1) expression. However, little is known about the impact of zebularine on bone marrow mesenchymal stem cells (BMMSCs) and p38 signaling during hepatic differentiation. The present study investigated the effects of zebularine on hepatic differentiation of rabbit BMMSCs, as well as the role of p38 on DNMT1 and hepatic differentiation, with the aim of developing a novel strategy for improving derivation of hepatocytes. BMMSCs were treated with zebularine at concentrations of 10, 20, 50, and 100 μM in the presence of hepatocyte growth factor; changes in the levels of hepatic-specific alpha-fetoprotein and albumin were detected and determined by RT-PCR, WB, and immunofluorescence staining. Expression of DNMT1 and phosphorylated p38 as well as urea production and ICG metabolism was also analyzed. Zebularine at concentrations of 10, 20, and 50 μM could not affect cell viability after 48 h. Zebularine treatment leads to an inhibition of DNMT activity and increase of hepatic-specific proteins alpha-fetoprotein and albumin in BMMSCs in vitro; zebularine addition also induced expression of urea production of and ICG metabolism. p38 signal was activated in BMMSCs simulated with HGF; inhibition of p38 facilitated the synthesis of DNMT1 and albumin in cells. Zebularine restrained DNMT1 and phosphorylated p38 which were induced by HGF. Therefore, this study demonstrated that treatment with zebularine exhibited terminal hepatic differentiation of BMMSCs in vitro in association with hepatocyte growth factor; p38 pathway at least partially participates in zebularine-induced hepatic differentiation of rabbit BMMSCs.

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“…. 40 MSC-derived HLCs express high levels of hepatic genes and have liver-specific metabolic activities after culture in medium containing HGF, nicotinamide and dexamethasone. 41 Hepatocyte nuclear factor (HNF)-4 plays a critical role in hepatogenic differentiation and can regulate liver regeneration.…”

Section: Tr An S Pl Anted Hlc S With Improved Liver Fun C Ti On Maymentioning

confidence: 99%

Pre‐treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases

Wang

2019

J Cellular Molecular Medi

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Liver diseases caused by viral infection, alcohol abuse and metabolic disorders can progress to end‐stage liver failure, liver cirrhosis and liver cancer, which are a growing cause of death worldwide. Although liver transplantation and hepatocyte transplantation are useful strategies to promote liver regeneration, they are limited by scarce sources of organs and hepatocytes. Mesenchymal stem cells (MSCs) restore liver injury after hepatogenic differentiation and exert immunomodulatory, anti‐inflammatory, antifibrotic, antioxidative stress and antiapoptotic effects on liver cells in vivo. After isolation and culture in vitro, MSCs are faced with nutrient and oxygen deprivation, and external growth factors maintain MSC capacities for further applications. In addition, MSCs are placed in a harsh microenvironment, and anoikis and inflammation after transplantation in vivo significantly decrease their regenerative capacity. Pre‐treatment with chemical agents, hypoxia, an inflammatory microenvironment and gene modification can protect MSCs against injury, and pre‐treated MSCs show improved hepatogenic differentiation, homing capacity, survival and paracrine effects in vitro and in vivo in regard to attenuating liver injury. In this review, we mainly focus on pre‐treatments and the underlying mechanisms for improving the therapeutic effects of MSCs in various liver diseases. Thus, we provide evidence for the development of MSC‐based cell therapy to prevent acute or chronic liver injury. Mesenchymal stem cells have potential as a therapeutic to prolong the survival of patients with end‐stage liver diseases in the near future.

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Signalling pathways involved in the process of mesenchymal stem cells differentiating into hepatocytes

Cited by 34 publications

References 69 publications

Promising Therapy Candidates for Liver Fibrosis

Promising Therapy Candidates for Liver Fibrosis

Zebularine Promotes Hepatic Differentiation of Rabbit Bone Marrow Mesenchymal Stem Cells by Interfering with p38 MAPK Signaling

Pre‐treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases

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