Transdifferentiation of Mature Rat Hepatocytes into Bile Duct-Like Cells in Vitro

Nishikawa, Yuji; Doi, Yuko; Watanabe, Hitoshi; Tokairin, Takuo; Omori, Yasufumi; Su, Mu; Yoshioka, Toshiaki; Enomoto, Katsuhiko

doi:10.1016/s0002-9440(10)62328-0

Cited by 103 publications

(105 citation statements)

References 55 publications

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“…20,21 The recovery of albumin expression in transdifferentiated hepatocytes was enhanced by Dex, which has been shown to increase albumin and TAT expression in spheroidal aggregate cultures of newborn rat hepatocytes 18 and decrease CK 19 mRNA expression in monolayer-cultured rat hepatocytes. 7 Although the mechanism of the effect of Dex on hepatocytic phenotypes has not been elucidated, this study suggests that the inhibition of the MEK and JNK signaling pathways may be important. In a previous study, we also found that PD98059 inhibited aberrant CK 19 expression in hepatocytes cultured within the collagen gel matrix.…”

Section: Discussionmentioning

confidence: 84%

“…In situ two-step collagenase liver perfusion and cell isolation were performed as previously described. 7,8 Alb-DsRed2 rats, which express DsRed2 fluorescence under the control of the albumin enhancer/promoter, were used to monitor the level of albumin expression in hepatocytes. 15 The protocols for animal experimentation were …”

Section: Isolation Of Rat Hepatocytesmentioning

confidence: 99%

“…7 After being embedded within the gel, spheroidal aggregates were cultured in Williams' Medium E supplemented with 10 mM nicotinamide, 10% FBS, 10 -7 M insulin, 10 ng/ml EGF, and 10 ng/ml TNF-α (R&D Systems, Minneapolis, MN).…”

Section: Three-dimensional Collagen Gel Culture Of Rat Hepatocytesmentioning

confidence: 99%

“…Protein samples (30 µg of protein per lane) were subjected to SDS-PAGE using 10% polyacrylamide gels and were analyzed as described previously. 7 The primary antibodies …”

Section: Western Blot Analysismentioning

confidence: 99%

“…7,8 This phenotypic change is characterized by a loss of hepatocytic differentiation markers and the expression of bile ductular markers, but it is not associated with the re-expression of markers of hepatic progenitor cells, such as delta-like.…”

Section: Introductionmentioning

confidence: 99%

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Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Sone

Nishikawa

Nagahama

et al. 2012

The American Journal of Pathology

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We previously demonstrated that mature rat hepatocytes transdifferentiate to bile ductular cells when cultured in a three-dimensional collagen-rich matrix. Here, we show that the phenotype of transdifferentiated hepatocytes can be reversed by modulating culture conditions. Spheroidal aggregates of hepatocytes were cultured within a collagen gel matrix in the presence of serum and tumor necrosis factor-α. Spheroids transformed into ductular structures composed of small cuboidal cells, lost the expression of hepatocytic markers, while aberrantly expressed bile ductular markers. The transdifferentiated cells were then retrieved from the gels, plated on Matrigel-coated surfaces, and cultured in serum-free media. Cells spontaneously formed spheroidal aggregates and recovered hepatocytic phenotype. While Dexamethasone (Dex), which suppressed the phosphorylation of ERK and Jun N-terminal kinase, facilitated the recovery, the combination with interleukin-6 or oncostatin M resulted in the recovery of HNF-4α protein expression and the typical hepatocytic morphology and a decrease in the expression of bile ductular markers. A cDNA microarray analysis revealed that the hepatocyte-specific mRNA expression profile was recovered in these cells. Our results demonstrate that hepatocytes are able to recover their phenotypes following bile ductular transdifferentiation, suggesting that hepatocytic and bile ductular phenotypes may be mutually reversible.4

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Section: Discussionmentioning

confidence: 84%

Section: Isolation Of Rat Hepatocytesmentioning

confidence: 99%

Section: Three-dimensional Collagen Gel Culture Of Rat Hepatocytesmentioning

confidence: 99%

“…Protein samples (30 µg of protein per lane) were subjected to SDS-PAGE using 10% polyacrylamide gels and were analyzed as described previously. 7 The primary antibodies …”

Section: Western Blot Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Sone

Nishikawa

Nagahama

et al. 2012

The American Journal of Pathology

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Embedded Spheroids as Models of the Cancer Microenvironment

2017

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To more accurately study the complex mechanisms behind cancer invasion, progression, and response to treatment, researchers require models that replicate both the multicellular nature and 3D stromal environment present in an in vivo tumor. Multicellular aggregates (i.e., spheroids) embedded in an extracellular matrix mimic are a prevalent model. Recently, quantitative metrics that fully utilize the capability of spheroids are described along with conventional experiments, such as invasion into a matrix, to provide additional details and insights into the underlying cancer biology. The review begins with a discussion of the salient features of the tumor microenvironment, introduces the early work on non-embedded spheroids as tumor models, and then concentrates on the successes achieved with the study of embedded spheroids. Examples of studies include cell movement, drug response, tumor cellular heterogeneity, stromal effects, and cancer progression. Additionally, new methodologies and those borrowed from other research fields (e.g., vascularization and tissue engineering) are highlighted that expand the capability of spheroids to aid future users in designing their cancer-related experiments. The convergence of spheroid research among the various fields catalyzes new applications and leads to a natural synergy. Finally, the review concludes with a reflection and future perspectives for cancer spheroid research.

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TWEAK Signaling‐Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis

et al. 2023

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The malignant transformation of hepatic progenitor cells (HPCs) in the inflammatory microenvironment is the root cause of hepatocarcinogenesis. However, the potential molecular mechanisms are still elusive. The HPCs subgroup is identified by single‐cell RNA (scRNA) sequencing and the phenotype of HPCs is investigated in the primary HCC model. Bulk RNA sequencing (RNA‐seq) and proteomic analyses are also performed on HPC‐derived organoids. It is found that tumors are formed from HPCs in peritumor tissue at the 16th week in a HCC model. Furthermore, it is confirmed that the macrophage‐derived TWEAK/Fn14 promoted the expression of inhibitor of differentiation‐1 (ID1) in HPCs via NF‐κB signaling and a high level of ID1 induced aberrant differentiation of HPCs. Mechanistically, ID1 suppressed differentiation and promoted proliferation in HPCs through the inhibition of HNF4α and Rap1GAP transcriptions. Finally, scRNA sequencing of HCC patients and investigation of clinical specimens also verified that the expression of ID1 is correlated with aberrant differentiation of HPCs into cancer stem cells, patients with high levels of ID1 in HPCs showed a poorer prognosis. This study provides important intervention targets and a theoretical basis for the clinical diagnosis and treatment of HCC.

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Transdifferentiation of Mature Rat Hepatocytes into Bile Duct-Like Cells in Vitro

Cited by 103 publications

References 55 publications

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Embedded Spheroids as Models of the Cancer Microenvironment

TWEAK Signaling‐Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis

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