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Disease-Corrected Hepatocyte-Like Cells from Familial Hypercholesterolemia-Induced Pluripotent Stem Cells

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Abstract

The generation of human induced pluripotent stem cells (hiPSCs) from an individual patient provides a unique tool for disease modeling, drug discovery, and cell replacement therapies. Patient-specific pluripotent stem cells can be expanded in vitro and are thus suitable for genetic manipulations. To date, several genetic liver disorders have been modeled using patient-specific hiPSCs. Here, we present the generation of corrected hepatocyte-like cells (HLCs) from hiPSCs of a familial hypercholesterolemia (FH) patient with a homozygous mutation in the low-density lipoprotein receptor (LDLR) gene. We generated hiPSCs from a patient with FH with the mutated gene encoding a truncated non-functional receptor. In order to deliver normal LDLR to the defective cells, we used a plasmid vector carrying the normal receptor ORF to genetically transform the hiPSCs. The transformed cells were expanded and directed toward HLCs. Undifferentiated defective hiPSCs and HLCs differentiated from the defective hiPSCs did not have the ability to uptake labeled low-density lipoprotein (LDL) particles. The differentiated transformed hiPSCs showed LDL-uptake ability and the correction of disease phenotype as well as expressions of hepatocyte-specific markers. The functionality of differentiated cells was also confirmed by indo-cyanine green (ICG) uptake assay, PAS staining, inducible cyp450 activity, and oil red staining. These data suggest that hiPSC technology can be used for generation of disease-corrected, patient-specific HLCs with potential value for disease modeling and drug discovery as well as cell therapy applications in future.

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Acknowledgments

This study was funded by a grant provided from Royan Institute and the Iranian Council of Stem Cell Research and Technology.

Conflict of interest

We hereby confirm that any and all potential conflicts of interest have been fully and properly disclosed in the manuscript as outlined.

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Authors and Affiliations

  1. Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Faranak Fattahi & Ghasem Hosseini Salekdeh

  2. Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran

    Faranak Fattahi, Samira Asgari & Behshad Pournasr

  3. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, P.O. Box 19395-4644, Tehran, Iran

    Samira Asgari, Behshad Pournasr, Ali Seifinejad, Mehdi Totonchi, Adeleh Taei, Nasser Aghdami & Hossein Baharvand

  4. Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Nasser Aghdami

  5. Department of Systems Biology, Agricultural Biotechnology Research Institute of Iran, Karaj, Iran

    Ghasem Hosseini Salekdeh

  6. Department of Developmental Biology, University of Science and Culture, ACECR, Tehran, Iran

    Hossein Baharvand

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  1. Faranak Fattahi
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  2. Samira Asgari
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  8. Ghasem Hosseini Salekdeh
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  9. Hossein Baharvand
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Correspondence to Ghasem Hosseini Salekdeh or Hossein Baharvand.

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Fattahi, F., Asgari, S., Pournasr, B. et al. Disease-Corrected Hepatocyte-Like Cells from Familial Hypercholesterolemia-Induced Pluripotent Stem Cells. Mol Biotechnol 54, 863–873 (2013). https://doi.org/10.1007/s12033-012-9635-3

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