ArticleBioResearch open access2016
Hepatic Differentiation of Human Induced Pluripotent Stem Cells in a Perfused Three-Dimensional Multicompartment Bioreactor.
Article in BioResearch open access, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 47 citations in OpenAlex.
- Three-dimensional organoid culture enhances functional maturation of human pluripotent stem cell-derived hepatocytes.Molecular biology reports · 2026Article
- Stem Cell-Based Strategies: The Future Direction of Bioartificial Liver Development.Stem cell reviews and reports · 2024Review
- Novel Approaches to Studying SLC13A5 Disease.Metabolites · 2024Review
- Modulation of human iPSC-derived hepatocyte phenotype via extracellular matrix microarrays.Acta biomaterialia · 2022Article
- Development of Liver-on-Chip Integrating a Hydroscaffold Mimicking the Liver's Extracellular Matrix.Bioengineering (Basel, Switzerland) · 2022Article
- Using liver models generated from human-induced pluripotent stem cells (iPSCs) for evaluating chemical-induced modifications and disease across liver developmental stages.Toxicology in vitro : an international journal published in association with BIBRA · 2022Review
- The Effect of miR-106b-5p Expression in The Production of iPS-Like Cells from Mice SSCs during The Formation of Teratoma and The Three Embryonic Layers.Cell journal · 2022Article
- Current Status and Challenges of Human Induced Pluripotent Stem Cell-Derived Liver Models in Drug Discovery.Cells · 2022Review
- Three-Dimensional Liver Culture Systems to Maintain Primary Hepatic Properties for Toxicological Analysis In Vitro.International journal of molecular sciences · 2021Review
- A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies.Frontiers in cell and developmental biology · 2021Review
- Differentiation of Human Pluripotent Stem Cells Into Definitive Endoderm Cells in Various Flexible Three-Dimensional Cell Culture Systems: Possibilities and Limitations.Frontiers in cell and developmental biology · 2021Article
- Self-Organizing Human Induced Pluripotent Stem Cell Hepatocyte 3D Organoids Inform the Biology of the PleiotropicHepatology communications · 2020Article
- Nevirapine Biotransformation Insights: An Integrated In Vitro Approach Unveils the Biocompetence andInternational journal of molecular sciences · 2020Article
- The importance of transporters and cell polarization for the evaluation of human stem cell-derived hepatic cells.PloS one · 2020Article
- Effect of inoculum density on human-induced pluripotent stem cell expansion in 3D bioreactors.Cell proliferation · 2019Article
- Chemically defined and xenogeneic-free differentiation of human pluripotent stem cells into definitive endoderm in 3D culture.Scientific reports · 2019Article
- Differentiation of human-induced pluripotent stem cell under flow conditions to mature hepatocytes for liver tissue engineering.Journal of tissue engineering and regenerative medicine · 2018Article
- Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions.Bioengineering (Basel, Switzerland) · 2018Article
- Hepatic differentiation of human iPSCs in different 3D models: A comparative study.International journal of molecular medicine · 2017Article
- Effects of Co-Culture Media on Hepatic Differentiation of hiPSC with or without HUVEC Co-Culture.International journal of molecular sciences · 2017Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The hepatic differentiation of human induced pluripotent stem cells (hiPSC) holds great potential for application in regenerative medicine, pharmacological drug screening, and toxicity testing. However, full maturation of hiPSC into functional hepatocytes has not yet been achieved. In this study, we investigated the potential of a dynamic three-dimensional (3D) hollow fiber membrane bioreactor technology to improve the hepatic differentiation of hiPSC in comparison to static two-dimensional (2D) cultures. A total of 100 × 10(6) hiPSC were seeded into each 3D bioreactor (n = 3). Differentiation into definitive endoderm (DE) was induced by adding activin A, Wnt3a, and sodium butyrate to the culture medium. For further maturation, hepatocyte growth factor and oncostatin M were added. The same differentiation protocol was applied to hiPSC maintained in 2D cultures. Secretion of alpha-fetoprotein (AFP), a marker for DE, was significantly (p < 0.05) higher in 2D cultures, while secretion of albumin, a typical characteristic for mature hepatocytes, was higher after hepatic differentiation of hiPSC in 3D bioreactors. Functional analysis of multiple cytochrome P450 (CYP) isoenzymes showed activity of CYP1A2, CYP2B6, and CYP3A4 in both groups, although at a lower level compared to primary human hepatocytes (PHH). CYP2B6 activities were significantly (p < 0.05) higher in 3D bioreactors compared with 2D cultures, which is in line with results from gene expression. Immunofluorescence staining showed that the majority of cells was positive for albumin, cytokeratin 18 (CK18), and hepatocyte nuclear factor 4-alpha (HNF4A) at the end of the differentiation process. In addition, cytokeratin 19 (CK19) staining revealed the formation of bile duct-like structures in 3D bioreactors similar to native liver tissue. The results indicate a better maturation of hiPSC in the 3D bioreactor system compared to 2D cultures and emphasize the potential of dynamic 3D culture systems in stem cell differentiation approaches for improved formation of differentiated tissue structures.
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