title: Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells.
abstract: Human induced pluripotent stem (iPS) cells hold great promise for advancements in developmental biology, cell-based therapy, and modeling of human disease. Here, we examined the use of human iPS cells for modeling inherited metabolic disorders of the liver. Dermal fibroblasts from patients with various inherited metabolic diseases of the liver were used to generate a library of patient-specific human iPS cell lines. Each line was differentiated into hepatocytes using what we believe to be a novel 3-step differentiation protocol in chemically defined conditions. The resulting cells exhibited properties of mature hepatocytes, such as albumin secretion and cytochrome P450 metabolism. Moreover, cells generated from patients with 3 of the inherited metabolic conditions studied in further detail (alpha1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease type 1a) were found to recapitulate key pathological features of the diseases affecting the patients from which they were derived, such as aggregation of misfolded alpha1-antitrypsin in the endoplasmic reticulum, deficient LDL receptor-mediated cholesterol uptake, and elevated lipid and glycogen accumulation. Therefore, we report a simple and effective platform for hepatocyte generation from patient-specific human iPS cells. These patient-derived hepatocytes demonstrate that it is possible to model diseases whose phenotypes are caused by pathological dysregulation of key processes within adult cells.
authors.affiliation: Laboratory for Regenerative Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: S Tamir
authors.initials: ST
authors.lastname: Rashid
authors.forename: Sebastien
authors.initials: S
authors.lastname: Corbineau
authors.forename: Nick
authors.initials: N
authors.lastname: Hannan
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Marciniak
authors.forename: Elena
authors.initials: E
authors.lastname: Miranda
authors.forename: Graeme
authors.initials: G
authors.lastname: Alexander
authors.forename: Isabel
authors.initials: I
authors.lastname: Huang-Doran
authors.forename: Julian
authors.initials: J
authors.lastname: Griffin
authors.forename: Lars
authors.initials: L
authors.lastname: Ahrlund-Richter
authors.forename: Jeremy
authors.initials: J
authors.lastname: Skepper
authors.forename: Robert
authors.initials: R
authors.lastname: Semple
authors.forename: Anne
authors.initials: A
authors.lastname: Weber
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
mesh_terms: D000328:Adult; D000368:Aged; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D007223:Infant; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases; D008297:Male; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D006003:Glycogen; D003577:Cytochrome P-450 Enzyme System