Upregulation of CYP 450s expression of immortalized hepatocyte-like cells derived from mesenchymal stem cells by enzyme inducers

Sa‐ngiamsuntorn, Khanit; Wongkajornsilp, Adisak; Kasetsinsombat, Kanda; Duangsa-ard, Sunisa; Nuntakarn, Lalana; Borwornpinyo, Suparerk; Akarasereenont, Pravit; Limsrichamrern, Somchai; Hongeng, Suradej

doi:10.1186/1472-6750-11-89

Cited by 38 publications

(51 citation statements)

References 60 publications

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“…Mesenchymal stem cells may be a suitable alternative to PHHs (Sa‐Ngiamsuntorn et al. ). Cell proliferation is maintained for 6 months in addition to hepatocyte‐like morphology and phenotype.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a novel PXR‐knockout in HepaRG^™ cells

Williamson

Lorbeer

Mitchell³

et al. 2016

Pharmacology Res & Perspec

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The nuclear pregnane X receptor (PXR) regulates the expression of genes involved in the metabolism, hepatobiliary disposition, and toxicity of drugs and endogenous compounds. PXR is a promiscuous nuclear hormone receptor (NHR) with significant ligand and DNA‐binding crosstalk with the constitutive androstane receptor (CAR); hence, defining the precise role of PXR in gene regulation is challenging. Here, utilising a novel PXR‐knockout (KO) HepaRG cell line, real‐time PCR analysis was conducted to determine PXR involvement for a range of inducers. The selective PXR agonist rifampicin, a selective CAR activator, 6‐(4‐chlorophenyl)imidazo[2,1‐b][1,3]thiazole‐5‐carbaldehyde O‐(3,4‐dichlorobenzyl)oxime (CITCO), and dual activators of CAR and PXR including phenobarbital (PB) were analyzed. HepaRG control cells (5F clone) were responsive to prototypical inducers of CYP2B6 and CYP3A4. No response was observed in the PXR‐KO cells treated with rifampicin. Induction of CYP3A4 by PB, artemisinin, and phenytoin was also much reduced in PXR‐KO cells, while the response to CITCO was maintained. This finding is in agreement with the abolition of functional PXR expression. The apparent EC50 values for PB were in agreement between the cell lines; however, CITCO was ~threefold (0.3 μmol/L vs. 1 μmol/L) lower in the PXR‐KO cells compared with the 5F cells for CYP2B6 induction. Results presented support the application of the novel PXR‐KO cells in the definitive assignment of PXR‐mediated CYP2B6 and CYP3A4 induction. Utilization of such cell lines will allow advancement in composing structure activity relationships rather than relying predominantly on pharmacological manipulations and provide in‐depth mechanistic evaluation.

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Section: Introductionmentioning

confidence: 99%

Evaluation of a novel PXR‐knockout in HepaRG^™ cells

Williamson

Lorbeer

Mitchell³

et al. 2016

Pharmacology Res & Perspec

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“…However, the expression levels of hepatic nuclear factor4α (HNF-4α), glucose-6-phosphatase (G-6Pase) and tyrosine aminotransferase (TAT), were still reduced with respect to human primary hepatocytes. In addition, CYP450 isoenzymes were clearly upregulated by inducers at a level that outperformed the HepG2 cells used as controls [114].…”

Section: Hepatocyte-like Differentiative Capa-city By Extrahepatic Msmentioning

confidence: 94%

Recent Advances in Derivation of Functional Hepatocytes from Placental Stem Cells

Iacono

Anzalone²,

Corrao

et al. 2013

TOTERMJ

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End-stage liver diseases are one of the leading causes of death in the world. Often orthotopic liver transplantation represents the final therapeutic choice. The limits of this approach are the scarcity of donor livers available, and the many side effects related to the administration of immune suppressants to the patients. Cellular therapy for liver diseases is increasingly being viewed as a promising strategy to provide hepatocytes to replenish the parenchymal cells of the organ. This technique suffers of some important limitations, such as the difficulty in isolating sufficient cell numbers (e.g. when adult or foetal hepatocytes are used for transplantation), the limited viability of isolated hepatocytes and, when applicable, the limited differentiation of stem cells (when hepatocyte-like cells are derived from hepatic or extra-hepatic progenitor populations).In recent years, perinatal stem cells have been proposed as reliable cellular populations which may be successfully used to derive hepatocyte-like cells. These cells feature key advantages over other adult stem cells: may be easily sourced from the tissues of origin, can be expanded ex vivo to obtain high cell numbers, may be differentiated towards hepatocyte-like cells. In addition, these cells feature relevant immunomodulatory and anti-inflammatory activities, and their sourcing is not limited by ethical concernsIn the present review we analyze the molecular basis of hepatocyte biology and development, and discuss the recent advances in deriving hapatocyte-like cells from perinatal stem cells. Very recent papers on mesenchymal stem cells derived from bone marrow and adipose tissues are also comparatively discussed as prototypes of the use of adult extrahepatic stem cells. In our opinion, perinatal stem cells do represent a promising tool for liver regenerative medicine, and recent research reports further strengthened this perception and fostered further efforts by multiple research groups worldwide.

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“…Human mesenchymal stromal cells (MSCs) were obtained and isolated from bone marrow of healthy volunteer or IVS2‐654/HbE thalassemic patient and maintained as described previously . For iPSC derivation, human MSCs (1 × 10 5 cells) were transduced with a polycistronic lentiviral vector encoding for human OCT4, KLF4, SOX2, MYC, and a fluorescent reporter, dTomato (pRRL.PPT.SF.hOKSM.idTomato.preFRT) at multiplicity of infection of 0.5 in the presence of 4 µg/ml Polybrene (Sigma‐Aldrich, St. Louis, MO, http://www.sigmaaldrich.com).…”

Section: Methodsmentioning

confidence: 99%

Enhancement of β-Globin Gene Expression in Thalassemic IVS2-654 Induced Pluripotent Stem Cell-Derived Erythroid Cells by Modified U7 snRNA

Phanthong¹,

Borwornpinyo²,

Kitiyanant³

et al. 2017

Stem Cells Translational Medicine

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The therapeutic use of patient‐specific induced pluripotent stem cells (iPSCs) is emerging as a potential treatment of β‐thalassemia. Ideally, patient‐specific iPSCs would be genetically corrected by various approaches to treat β‐thalassemia including lentiviral gene transfer, lentivirus‐delivered shRNA, and gene editing. These corrected iPSCs would be subsequently differentiated into hematopoietic stem cells and transplanted back into the same patient. In this article, we present a proof of principle study for disease modeling and screening using iPSCs to test the potential use of the modified U7 small nuclear (sn) RNA to correct a splice defect in IVS2‐654 β‐thalassemia. In this case, the aberration results from a mutation in the human β‐globin intron 2 causing an aberrant splicing of β‐globin pre‐mRNA and preventing synthesis of functional β‐globin protein. The iPSCs (derived from mesenchymal stromal cells from a patient with IVS2‐654 β‐thalassemia/hemoglobin (Hb) E) were transduced with a lentivirus carrying a modified U7 snRNA targeting an IVS2‐654 β‐globin pre‐mRNA in order to restore the correct splicing. Erythroblasts differentiated from the transduced iPSCs expressed high level of correctly spliced β‐globin mRNA suggesting that the modified U7 snRNA was expressed and mediated splicing correction of IVS2‐654 β‐globin pre‐mRNA in these cells. Moreover, a less active apoptosis cascade process was observed in the corrected cells at transcription level. This study demonstrated the potential use of a genetically modified U7 snRNA with patient‐specific iPSCs for the partial restoration of the aberrant splicing process of β‐thalassemia. Stem Cells Translational Medicine 2017;6:1059–1069

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Upregulation of CYP 450s expression of immortalized hepatocyte-like cells derived from mesenchymal stem cells by enzyme inducers

Cited by 38 publications

References 60 publications

Evaluation of a novel PXR‐knockout in HepaRG^™ cells

Evaluation of a novel PXR‐knockout in HepaRG^™ cells

Recent Advances in Derivation of Functional Hepatocytes from Placental Stem Cells

Enhancement of β-Globin Gene Expression in Thalassemic IVS2-654 Induced Pluripotent Stem Cell-Derived Erythroid Cells by Modified U7 snRNA

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Upregulation of CYP 450s expression of immortalized hepatocyte-like cells derived from mesenchymal stem cells by enzyme inducers

Cited by 38 publications

References 60 publications

Evaluation of a novel PXR‐knockout in HepaRG™ cells

Evaluation of a novel PXR‐knockout in HepaRG™ cells

Recent Advances in Derivation of Functional Hepatocytes from Placental Stem Cells

Enhancement of β-Globin Gene Expression in Thalassemic IVS2-654 Induced Pluripotent Stem Cell-Derived Erythroid Cells by Modified U7 snRNA

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Evaluation of a novel PXR‐knockout in HepaRG^™ cells

Evaluation of a novel PXR‐knockout in HepaRG^™ cells