Oct4 and Hnf4alpha-induced hepatic stem cells attenuated hepatic function in liver injury model
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ABSTRACT:
PROVIDER: PRJNA416344 | ENA |
REPOSITORIES: ENA
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Project description:Generation of expandable induce hepatic stem cells (iHSCs) has a potential for cell-based therapy and drug screening in liver disease. Recently many groups reported reprogramming of somatic cells into hepatocyte-like cells by direct conversion. However, the induced hepatocytes have limitations in proliferation, function and viability for cell therapy and drug development. We generated iHSCs which have properties including self-renewal and bipotency into hepatocytes and cholangiocytes. iHSCs-derived hepatocytes showed typical morphology and functions which include glycogen storage, low-density lipoprotein (LDL) uptake, Indocyanine green (ICG) metabolism, and Albumin secretion, and iHSCs-derived cholangiocytes also have functional characteristics of cholangiocytes, including cyst and tubules formation, cyst polarity, and the secretion of small substances by transmembrane channel protein. In addition, iHSCs attenuated liver injury, such as alcohol induced steatosis and carbon tetrachloride (CCl4) induced fibrosis models. Taken together, generation of functional iHSCs would be used in therapeutic applications.
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Project description:HNF4alpha is a master regulator of hepatic differentiation. In this study, HNF4alpha was deleted in adult mice using a Cre-LoxP system where Cre recombinase was delivered using an AAV8 virus.
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Project description:HNF4alpha is a master regulator of hepatic differentiation. In this study, HNF4alpha was deleted in adult mice using a Cre-LoxP system where Cre recombinase was delivered using an AAV8 virus. Total RNA was isolated from the livers of HNF4alpha-floxed mice (mixed backgournd) treated with either Control Virus or Cre-carrying virus at 3 months of age.
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Project description:Post-translational modification of proteins has been shown to control different aspects of protein biology. We have previously implicated a SUMO consensus motif in HNF4alpha’s carboxylic terminus as an important regulator of protein biology during stem cell differentiation. In this study, we have generated deletion and point mutants of HNF4alpha to precisely study the role of protein domains during hepatocyte specification. During mammalian development, liver differentiation is driven by signals which converge on multiple transcription factor networks. The hepatocyte nuclear factor signalling network is known to be essential for hepatocyte specification and maintenance. In these studies we demonstrate that nuclear HNF4 is essential for hepatic progenitor specification and the introduction of point mutations in HNF4alpha’s SUMO consensus motif leads to disrupted hepatocyte specification and maturation. Taking a multi-omics approach, we identified key deficiencies in cell biology which included; dysfunctional cell metabolism, cell adhesion, tricarboxylic acid cycle flux, mRNA transport and processing. In summary, the combination of genome editing and multi-omics analyses have provided new insight into the diverse functions of HNF4alphaprotein during human hepatocyte specification and maturation.
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Project description:Abnormalities in hepatic lipid metabolism are believed to play a critical role in the etiology of nonalcoholic steatohepatitis (NASH). Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol (TAG) synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis and knocking down Mogat1 improves insulin sensitivity, but whether increased MGAT activity plays a role in the etiology of NASH is unclear. To examine the effects of knocking down Mogat1 in the liver on the development of NASH, C57BL/6 mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were then injected with antisense oligonucleotides (ASO) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver, attenuated weight gain, improved glucose tolerance, and decreased hepatic TAG content compared to control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic DAG, cholesterol, or free fatty acid content, improve histologic measures of liver injury, or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves glucose tolerance and hepatic TAG accumulation without attenuating liver inflammation and injury. Total RNA obtained from liver of 4 control vs. 4 Mogat1 ASO treated higf-fat diet (HFD) fed mice.
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2023-09-05 | GSE220520 | GEO
Project description:A series of dual-channel gene expression profiles obtained using Rosetta/Agilent Whole Mouse Genome oligonucleotide microarrays, 4 x 44K format, was used to identify sex-dependent and HNF4alpha-dependent differences in gene expression in adult mouse liver. This series is comprised of four sex-genotype combinations: adult male wild-type liver (M-WT), adult female wild-type liver (F-WT), adult male liver-specific HNF4alpha knockout liver (M-KO) and adult female liver-specific HNF4alpha knockout liver (F-KO). Four pools, each comprised of 4 randomly selected individual liver RNAs, were prepared for each sex-genotype combination. The pools were paired randomly to generate 4 separate experimental comparisons: M-WT:F-WT (first array comparison), M-WT:M-KO (second array comparison), F-WT:F-KO (third array comparison), and M-KO:F-KO (fourth array comparison). A total of 4994 HNF4alpha-dependent genes were identified, of which ~1000 fewer genes responded to the loss of HNF4alpha in female liver as compared to male liver. Moreover, 90% of the genes showing sex-specific expression in the liver were shown to lose sex specificity in HNF4alpha-deficient liver. Keywords: genetic knockout and sex response
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Project description:We have found three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2 or Foxa3, could convert mouse embryonic fibroblasts (MEFs) into cells that closely resemble hepatocytes in vitro. Then we used ChIP-seq to explore the targets of the transduced Foxa and Hnf4alpha proteins in MEFs.
2020-08-06 | GSE143444 | GEO
Project description:Abnormalities in hepatic lipid metabolism are believed to play a critical role in the etiology of nonalcoholic steatohepatitis (NASH). Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol (TAG) synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis and knocking down Mogat1 improves insulin sensitivity, but whether increased MGAT activity plays a role in the etiology of NASH is unclear. To examine the effects of knocking down Mogat1 in the liver on the development of NASH, C57BL/6 mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were then injected with antisense oligonucleotides (ASO) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver, attenuated weight gain, improved glucose tolerance, and decreased hepatic TAG content compared to control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic DAG, cholesterol, or free fatty acid content, improve histologic measures of liver injury, or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves glucose tolerance and hepatic TAG accumulation without attenuating liver inflammation and injury.
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