HNF-4α determines hepatic differentiation of human mesenchymal stem cells from bone marrow

Chen, Mong Liang; Lee, Kuan Der; Huang, Huei Chun; Tsai, Yue Lin; Wu, Yi; Kuo, Tzer Min; Hu, Cheng; Chang, Chung-Ming

doi:10.3748/wjg.v16.i40.5092

Cited by 29 publications

(33 citation statements)

References 37 publications

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“…Considering the hierarchical role of HNF-4α, it raised the possibility that the changes in HNF-4α expression level might lead to the alteration of HNF-3β expression. This idea is supported by our previous research in which we demonstrated that overexpression of HNF-4α significantly upregulates the transcription of HNF-3β [33]. Moreover, we showed that overexpression of HNF-4α could rescue the expression of 2.1–2.4 Kb HBV transcripts under TGF-β1 treatment (Fig.…”

Section: Discussionsupporting

confidence: 81%

Transforming Growth Factor-β1 Suppresses Hepatitis B Virus Replication by the Reduction of Hepatocyte Nuclear Factor-4α Expression

Hong

Chou

et al. 2012

PLoS ONE

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Several studies have demonstrated that cytokine-mediated noncytopathic suppression of hepatitis B virus (HBV) replication may provide an alternative therapeutic strategy for the treatment of chronic hepatitis B infection. In our previous study, we showed that transforming growth factor-beta1 (TGF-β1) could effectively suppress HBV replication at physiological concentrations. Here, we provide more evidence that TGF-β1 specifically diminishes HBV core promoter activity, which subsequently results in a reduction in the level of viral pregenomic RNA (pgRNA), core protein (HBc), nucleocapsid, and consequently suppresses HBV replication. The hepatocyte nuclear factor 4alpha (HNF-4α) binding element(s) within the HBV core promoter region was characterized to be responsive for the inhibitory effect of TGF-β1 on HBV regulation. Furthermore, we found that TGF-β1 treatment significantly repressed HNF-4α expression at both mRNA and protein levels. We demonstrated that RNAi-mediated depletion of HNF-4α was sufficient to reduce HBc synthesis as TGF-β1 did. Prevention of HNF-4α degradation by treating with proteasome inhibitor MG132 also prevented the inhibitory effect of TGF-β1. Finally, we confirmed that HBV replication could be rescued by ectopic expression of HNF-4α in TGF-β1-treated cells. Our data clarify the mechanism by which TGF-β1 suppresses HBV replication, primarily through modulating the expression of HNF-4α gene.

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Section: Discussionsupporting

confidence: 81%

Transforming Growth Factor-β1 Suppresses Hepatitis B Virus Replication by the Reduction of Hepatocyte Nuclear Factor-4α Expression

Hong

Chou

et al. 2012

PLoS ONE

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“…During the first stage of maturation, from 0 to 8 days, A-fetoprotein (AFP), cytokeratin 18 (CK18), cytokeratin 19 (CK19), and transthyretin (TTR) show increased levels [28, 64, 65]. During the second stage, from 9th to 14th day , albumin (ALB), ornithine transcarbamylase (TAT) as well as mRNA levels for VII clotting factor, asialoglycoprotein receptor 1 (ASGPR1), and CYP1A2 member of cytochrome P450 superfamily production are increased while AFP levels are reduced [65–68].…”

Section: Resultsmentioning

confidence: 99%

“…During the second stage, from 9th to 14th day , albumin (ALB), ornithine transcarbamylase (TAT) as well as mRNA levels for VII clotting factor, asialoglycoprotein receptor 1 (ASGPR1), and CYP1A2 member of cytochrome P450 superfamily production are increased while AFP levels are reduced [65–68]. The last stage of maturation process, from 15th to 21st day , presents hepatic-like cells with functional properties unique to hepatocytes such as increased detoxifying ability, lipid and glycogen storage capacity, urea production, and bile acid secretion [65–68]. …”

Section: Resultsmentioning

confidence: 99%

Mesenchymal Stem Cells Transplantation following Partial Hepatectomy: A New Concept to Promote Liver Regeneration—Systematic Review of the Literature Focused on Experimental Studies in Rodent Models

Papanikolaou

Katselis

Αποστόλου

et al. 2017

Stem Cells International

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Mesenchymal stem cells (MSCs) are an attractive source for regenerative medicine because they are easily accessible through minimally invasive methods and have the potential to enhance liver regeneration (LG) and improve liver function, following partial hepatectomy (PH) and acute or chronic liver injury. A systematic review of the literature was conducted for articles published up to September 1st, 2016, using the MEDLINE database. The keywords that were used in various combinations were as follows: “Mesenchymal stem cells”, “transplantation”, “stem cells”, “adipose tissue derived stem cells”, “bone marrow-derived stem cells”, “partial hepatectomy”, “acute liver failure”, “chronic liver failure”, “liver fibrosis”, “liver cirrhosis”, “rats”, “mice”, and “liver regeneration”. All introduced keywords were searched for separately in MeSH Database to control relevance and terminological accuracy and validity. A total of 41 articles were identified for potential inclusion and reviewed in detail. After a strict selection process, a total of 28 articles were excluded, leaving 13 articles to form the basis of this systematic review. MSCs transplantation promoted LG and improved liver function. Furthermore, MSCs had the ability to differentiate in hepatocyte-like cells, increase survival, and protect hepatocytes by paracrine mechanisms. MSCs transplantation may provide beneficial effects in the process of LG after PH and acute or chronic liver injury. They may represent a new therapeutic option to treat posthepatectomy acute liver failure.

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“…In addition to glucose metabolism, our unpublished data also suggest that miR-338-3p might play a role in hepatic lipogenesis. It was reported that HNF-4α played a vital role in regulating hepatic differentiation [37, 38]. Several studies demonstrated the major effect of HNF-4a in the control of genes involved in glucose and fat metabolism [39].…”

Section: Discussionmentioning

confidence: 99%

Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression

Dou

Wang

Sun

et al. 2017

Cell Physiol Biochem

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Objective: Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. Methods: The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. Results: miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Conclusions: Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression.

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HNF-4α determines hepatic differentiation of human mesenchymal stem cells from bone marrow

Abstract: Overexpression of HNF-4α improves the hepatic differentiation of human MSCs from bone marrow and is a simple way of providing better cell sources for clinical applications.

Cited by 29 publications

References 37 publications

Transforming Growth Factor-β1 Suppresses Hepatitis B Virus Replication by the Reduction of Hepatocyte Nuclear Factor-4α Expression

Transforming Growth Factor-β1 Suppresses Hepatitis B Virus Replication by the Reduction of Hepatocyte Nuclear Factor-4α Expression

Mesenchymal Stem Cells Transplantation following Partial Hepatectomy: A New Concept to Promote Liver Regeneration—Systematic Review of the Literature Focused on Experimental Studies in Rodent Models

Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression

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