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Oct4 and Hnf4alpha-induced hepatic stem cells attenuated hepatic function in liver injury model

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE106347 | GEO | 2019/08/21

REPOSITORIES: GEO

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Reprogramming fibroblasts into bi-potential hepatic stem cells by defined factors

Project description:Recent studies have demonstrated direct reprogramming of fibroblasts into a range of somatic cell types, but to date stem/progenitor cells have only been reprogrammed for the blood and neuronal lineages. We previously reported generation of induced hepatocyte-like (iHep) cells by transduction of Gata4, Hnf1α, and Foxa3 in p19 Arf null mouse embryonic fibroblasts (MEFs). Here, we show that Hnf1β and Foxa3, liver organogenesis transcription factors, are sufficient to reprogram MEFs into induced hepatic stem cells (iHepSCs). iHepSCs can be stably expanded in vitro and possess the potential of bi-directional differentiation into both hepatocytic and cholangiocytic lineages. In the injured liver of fumarylacetoacetate hydrolase (Fah)-deficient mice, repopulating iHepSCs become hepatocyte-like cells. They also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury. Lineage-conversion into bi-potential expandable iHepSCs provides a strategy to enable efficient derivation of both hepatocytes and cholangiocytes for use in disease modeling and tissue engineering. iHepSCs were converted form fibroblasts by transduction of Hnf1β and Foxa3. iHepSCs were induced to differentiate into hepatocyte-like cells and cholangiocytes in vitro. Totally, 9 samples including four clones of iHepSCS, one clone of LEPCs, two samples of MEFs and two samples of iHepSCs-derived cholangocytes were analyzed.

2013-07-19 | E-GEOD-48486 | biostudies-arrayexpress

STAT3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis

Project description:Background and aims: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6 type cytokine signaling required for hepatocyte proliferation and hepatoprotection but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. Methods: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2-/-) as a model for SC. Results: We demonstrate that conditional inactivation of stat3 in hepatocytes and cholangiocytes (stat3 delta hc) of mdr2-/- mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2-/- mice lacking IL-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both, hepatocytes and cholangiocytes. Loss of Stat3 in cholangiocytes led to increased expression of TNFÎ± which might reduce the barrier function of bile ducts. Loss of Stat3 in hepatocytes led to upregulation of bile acid biosynthesis genes and downregulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3deltahc mice were more sensitive to cholic acid-induced liver damage than control mice. Conclusions: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes. Affymetrix microarray analyses was performed to identify metabolic and molecular pathways in stat3Dhc mdr2-/- mice that lead to cholestasis and bile acid-induced liver injury. To avoid false positive results that are due to differential cellular composition, we defined the onset of fibrosis and expression of fibrogenic factors in stat3Dhc mdr2-/- mice.

2010-10-20 | E-GEOD-18759 | biostudies-arrayexpress

Reprogramming fibroblasts into bi-potential hepatic stem cells by defined factors

2013-07-19 | GSE48486 | GEO

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2014-09-01 | E-GEOD-55552 | biostudies-arrayexpress

Hepatocyte ductal metaplasia in chronic mouse liver injury

Project description:Expression profiling of hepatocytes-derived ductal cells with properties intermediate between mature hepatocytes and cholangiocytes

2014-09-01 | GSE55552 | GEO

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Visium spatial transcriptomics and proteomics identifies novel hepatic cell populations and transcriptomic signatures of alcohol-associated hepatitis

Project description:Background: Alcohol-associated hepatitis (AH) is the clinical manifestation of alcohol-associated liver disease (ALD). AH is a complex disease encompassing the dysregulation of many cells and cell subpopulations. This study used a hepatic spatial transcriptomic and proteomic approach (10X Genomics Visium) to identify hepatic cell populations and their associated transcriptomic and proteomic alterations in human AH. Methods: Formalin fixed parraffin embedded liver tissue from AH patients (n=2) and non-ALD controls (donors) (n=2) were used for Visium spatial transcriptomic and proteomic analysis. Results: AH cell clusters and cell markers were drastically different in regard to tissue pattern and number of cell type as compared to non-ALD controls. Cholangiocytes, endothelial cells, macrophages, and stellate cells were more profuse in AH relative to non-ALD controls. Transcriptionally, proliferating cell nuclear antigen positive (PCNA+) hepatocytes in AH more closely resembled cholangiocytes suggesting they were non-functional hepatocytes derived from cholangiocytes. Further, mitochondria protein coding genes were reduced in AH vs non-ALD control hepatocytes, suggesting reduced functionality and loss of regenerative mechanisms. Macrophages in AH exhibited elevated gene expression involved in exosomes as compared to non-ALD controls. The most upregulated macrophage genes observed in AH were those involved in exosome trafficking and cellular migration. Gene and protein signatures of disease associated hepatocytes (ANXA2+/CXCL1+/CEACAM8+) were elevated in AH and could visually identify a pre-malignant lesion. Conclusions: This study identified global cell type alterations in AH and distinct transcriptomic changes between AH and non-ALD controls. These findings characterizes cellular plasticity and profuse transcriptomic and proteomic changes that are apparent in AH and contributes to the identification of novel therapeutics.

2024-12-02 | GSE278662 | GEO

Prominin-1-expressing Hepatic Progenitor Cells Induce Fibrogenesis in Murine Cholestatic Liver Injury

Project description:Purpose: Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin-1 (Prom1/CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1-expressing HPCs promote fibrogenesis in cholestatic liver injury. Methods: Using Prom1CreERT2-nLacZ/+;Rosa26Lsl-GFP/+ mice, we traced the fate of Prom1-expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Results: Prom1-expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential towards both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1-expressing HPCs gave rise to both PROM1(+) and PROM1(-) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA-sequencing analysis of GFP(+) Prom1-expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor-b pathway activation. Conclusion: Our data indicate that Prom1-expressing HPCs promote biliary fibrosis by activation of myofibroblasts in cholestatic liver injury.

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Project description:Mutations in the coding region of hepatocyte nuclear factor 4alpha (HNF4alpha), and its upstream promoter (P2) that drives expression in the pancreas, are known to lead to maturity-onset diabetes of the young 1 (MODY1). HNF4alpha also controls gluconeogenesis and lipid metabolism in the liver, where the proximal promoter (P1) predominates. However, very little is known about the role of hepatic HNF4alpha in diabetes. Here, we examine the expression of hepatic HNF4alpha in two diabetic mouse models, db/db mice (type 2, insulin resistant) and streptozotocin-treated mice (type 1, insulin deficient). We found that the level of HNF4alpha protein and mRNA was decreased in the liver of db/db mice but increased in streptozotocin-treated mice. Because insulin increases the activity of sterol regulatory element-binding proteins (SREBP)-1c and -2, we also examined the effect of SREBPs on hepatic HNF4alpha gene expression and found that, like insulin, ectopic expression of SREBPs decreases the level of hepatic HNF4alpha protein and mRNA both in vitro in primary hepatocytes and in vivo in the liver of C57BL/6 mice. Finally, we use gel shift, chromatin immunoprecipitation, small interfering RNA, and reporter gene analysis to show that SREBP2 binds the human HNF4alpha P1 promoter and negatively regulates its expression. These data indicate that hyperinsulinemia down-regulates HNF4alpha in the liver through the up-regulation of SREBPs, thereby establishing a link between these two critical transcription factor pathways that regulate lipid and glucose metabolism in the liver. These findings also provide new insights into diabetes-associated complications such as fatty liver disease.

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