Embryoid Body–Mediated Differentiation of Mouse Embryonic Stem Cells Along a Hepatocyte Lineage: Insights from Gene Expression Profiles

Novik, Eric; Maguire, Timothy J.; Orlova, Ksenia; Schloss, Rene; Yarmush, Martin L.

doi:10.1089/ten.2006.12.1515

Cited by 26 publications

(12 citation statements)

References 30 publications

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“…Traditional differentiation strategies using embryoid bodies yield a mixture of spatially and temporally regulated cell types. 12,18 We and others have described the use of sodium butyrate to obtain a more uniform population of hepatocyte cells. After 4 days of incubation with 1% DMSO, followed by another 6 days in 2.5 mM sodium butyrate, an enriched population of hepatocyte-like cells was generated, which were positive for urea secretion, albumin expression, cytokeratin 18 expression, and glycogen storage.…”

Section: Discussionmentioning

confidence: 99%

“…Many investigators have designed embryonic stem cell differentiation strategies using growth factors or extracellular matrix protein supplementation, 2,12,17,25 most commonly in conjunction with embryoid body formation. 12,18 We and others have recently utilized directed differentiation approaches mediated with sodium butyrate, and demonstrated the expression of a variety of hepatocyte functions, including albumin and urea secretion, cytokeratin 18 expression, and cyp4507a mediated detoxification potential. 20,24 Regulation of the differentiation process and/or further stabilization of the differentiated phenotype require an additional level of control for future pharmaceutical and clinical applications.…”

Section: Introductionmentioning

confidence: 99%

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Functional Modulation of ES-Derived Hepatocyte Lineage Cells via Substrate Compliance Alteration

Sharma

Chippada

et al. 2008

Ann Biomed Eng

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Pluripotent embryonic stem cells represent a promising renewable cell source to generate a variety of differentiated cell types including hepatocyte lineage cells, and may ultimately be incorporated into extracorporeal bioartificial liver devices and cell replacement therapies. Recently, we and others have utilized sodium butyrate to directly differentiate hepatocyte-like cells from murine embryonic stem cells cultured in a monolayer configuration. However, to incorporate stem cell technology into clinical and pharmaceutical applications, and hopefully increase the therapeutic potential of these differentiated cells for liver disease treatment, a major challenge remains in sustaining differentiated functions for an extended period of time in their secondary culture environment. In the present work, we have investigated the use of polyacrylamide hydrogels with defined mechanical compliances as a cell culture platform for improving and/or stabilizing functions of these hepatocyte-like cells. Several functional assays, e.g., urea secretion, intracellular albumin content, and albumin secretion, were performed to characterize hepatic functions of cells on polyacrylamide gels with stiffnesses of 5, 46.6, and 230 kPa. In conjunction with the mechanical and cell morphological characterization, we showed that hepatic functions of sodium butyrate differentiated cells were sustained and further enhanced on compliant substrates. This study promises to offer insights into regulating stem cell differentiation via mechanical stimuli, and assist us with designing a variety of dynamic culture systems for applications in tissue and cellular engineering.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional Modulation of ES-Derived Hepatocyte Lineage Cells via Substrate Compliance Alteration

Sharma

Chippada

et al. 2008

Ann Biomed Eng

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“…On the other hand, the combination of VEGF to FGF1, FGF2, or HGF rather decreased the level of hepatocyte marker genes. Novik et al [17] had shown negative feedback regulation of FGF1 and HGF expression by these factors in cultured EBs. We assume that such negative feedback regulation decreases the effects of FGFs and HGF.…”

Section: Discussionmentioning

confidence: 99%

“…Because of this, EBs intrinsically differentiate into many different cell types. In fact, HLC differentiation takes place in various surrounding tissues and cells which may continuously induce proliferation and function of HLCs [9][10][11][12][13][14][15][16][17]. This intrinsic feature of EB differentiation has potential for use in bioartificial liver and drug testing.…”

Section: Introductionmentioning

confidence: 99%

Vascular endothelial growth factor promotes proliferation and function of hepatocyte-like cells in embryoid bodies formed from mouse embryonic stem cells

Fujimori

Asahina

Shimizu-Saito

et al. 2008

Journal of Hepatology

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“…At day12, the concentration of Urea in culture medium was 8.3 μmol/L. In an effort to promote ESCs commitment to the hepatocyte lineage, Novik et al [26] evaluated the effects of four culture conditions on ALB and gene expression in differentiating ESCs. Quantitative in situ immunofluorescence and cDNA microarray analyses suggested that spontaneous and collagen-mediated differentiation induced cells with the highest levels of ALB expression, while mature liver specific genes were only expressed in the spontaneous condition, which indicated that two distinct mechanisms may govern spontaneous and collagen-mediated differentiation.…”

Section: Hepatic Differentiation Of Mescsmentioning

confidence: 99%

Differentiation of human embryonic stem cells along a hepatocyte lineage and its application in liver regeneration

Pei¹,

Wang²,

Pei³

2008

Chin. Sci. Bull.

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Hepatocyte transplantation and bioartificial liver (BAL) as alternatives to liver transplantation offer the possibility of effective treatment for many inherited and acquired hepatic disorders. Unfortunately, the limited availability of donated livers and the variability of their derived hepatocytes make it difficult to obtain enough viable human hepatocytes for the hepatocyte-based therapies. Embryonic stem cells (ESCs), which could be isolated directly from the blastocyst inner cell mass, have permanent self-renewal capability and developmental pluripotency and therefore might be an ideal cell source in the treatment of hepatic discords. However, differentiation of hESCs into hepatocytes with significant numbers remains a challenge. This review updates our current understanding of differentiation of ESCs into hepatic lineage cells, their future therapeutic uses and problems in liver regeneration. embryonic stem cell, hepatocyte, differentiation, liver regeneration Liver is the largest organ in mammals and it exerts a variety of important functions, including metabolizing diverse dietary molecules, storing glycogen, detoxifying compounds and swallowing for defense. This organ also has hematopoietic function in embryonic/fetal stage. Since liver has so many pivotal roles, patients with acute hepatic failure or end-stage liver diseases are in great danger. Orthotopic liver transplantation remains the most successful treatment for many cases of end-stage liver disease. However, the efficacy of liver transplantation is limited by the shortage of available donor organs, risk of rejection, infections, and other complications caused by the lifelong immunosupression. Liver cell therapies, including hepatocyte transplantation and bioartificial liver (BAL), are considered promising new approaches to treatment of patients with end-stage liver disease. However, the usage of mature hepatocytes is also hampered by limited tissue source and inability to proliferate and maintain the function for a long term in vitro. Embryonic stem cells (ESCs) might serve as an ideal source for cell therapy because of their immortalization and unique ability to give rise to all somatic cell lineages. ESCs were first isolated from mouse embryos in 1981 [1] , and the establishment of the first human ESC line in 1998 [2] undoubtedly further expanded the potential of ESCs not only as an important tool for basic research but also as a promising source for cell therapy.

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Embryoid Body–Mediated Differentiation of Mouse Embryonic Stem Cells Along a Hepatocyte Lineage: Insights from Gene Expression Profiles

Cited by 26 publications

References 30 publications

Functional Modulation of ES-Derived Hepatocyte Lineage Cells via Substrate Compliance Alteration

Functional Modulation of ES-Derived Hepatocyte Lineage Cells via Substrate Compliance Alteration

Vascular endothelial growth factor promotes proliferation and function of hepatocyte-like cells in embryoid bodies formed from mouse embryonic stem cells

Differentiation of human embryonic stem cells along a hepatocyte lineage and its application in liver regeneration

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