title: Disease-corrected hepatocyte-like cells from familial hypercholesterolemia-induced pluripotent stem cells.
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.
authors.affiliation: Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
authors.forename: Faranak
authors.initials: F
authors.lastname: Fattahi
authors.forename: Samira
authors.initials: S
authors.lastname: Asgari
authors.forename: Behshad
authors.initials: B
authors.lastname: Pournasr
authors.forename: Ali
authors.initials: A
authors.lastname: Seifinejad
authors.forename: Mehdi
authors.initials: M
authors.lastname: Totonchi
authors.forename: Adeleh
authors.initials: A
authors.lastname: Taei
authors.forename: Nasser
authors.initials: N
authors.lastname: Aghdami
authors.forename: Ghasem Hosseini
authors.initials: GH
authors.lastname: Salekdeh
authors.forename: Hossein
authors.initials: H
authors.lastname: Baharvand
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001709:Biotechnology; D017690:Cell Transplantation / Q000379:methods*; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000628:therapy*; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D059785:Karyotype; D009154:Mutation; D011973:Receptors, LDL / Q000235:genetics; D014162:Transfection
chemical_list: D015415:Biomarkers; D011973:Receptors, LDL