Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells

Abstract

. 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 (α 1 -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 α 1 -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.

Human induced pluripotent stem cells derived hepatocytes: rising promise for disease modeling, drug development and cell therapy

“…Patient iPSC lines were established followed by a three-step hepatic differentiation protocol to generate disease-specific hepatocytes. Remarkably, the iPSC derived hepatocytes exhibited the characteristic abnormalities in culture which recapitulate key pathological features of the diseases (Greenbaum, 2010;Rashid et al, 2010). The significance of this report is profound as it is the first proof-ofprinciple study demonstrating the feasibility of modeling hepatic diseases in which the pathological defects are only seen in terminally differentiated adult hepatocytes (late-onset disease).…”

“…Recently, a number of studies have reported the generation of patient-specific iPSC from individuals with inherited liver disease. Rashid et al (2010) reported the first success in modeling inborn liver metabolic disorders using human iPSC. The authors obtained skin fibroblasts from patients diagnosed with α1-antitrypsin deficiency, familiar hypercholesterolemia and glycogen storage disease type 1a, which represent three different mechanisms of liver disease respectively: defective protein secretion, lack of cell surface receptor and lack of a critical intracellular enzyme (Greenbaum, 2010).…”

“…Song et al (2009) described the first successful hepatic differentiation of human iPSC, closely followed by several other reports (Liu et al, 2010;Rashid et al, 2010;Si-Tayeb et al, 2010b;Sullivan et al, 2010). Similarly to the strategies developed in ESC differentiation, most reported studies of directed hepatic differentiation of human iPSC adopt multi-step protocols to mimic the liver embryogenesis by sequentially adding endodermal and hepatic inductive cytokines and small molecules.…”

Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase ( MAK ) as a cause of retinitis pigmentosa

“…Identifying additional affected individuals with mutations in the same gene will always strengthen the association of the gene with a given phenotype, but other emerging technologies can also contribute to such associations. For example, skin-derived induced pluripotent stem cells (iPSCs) can be used to investigate the function or dysfunction of a mutant gene product in tissues such as retina that are inaccessible to molecular analysis in living patients (9,10). In this study, we sequenced the exome of an individual with RP who had no family history of eye disease and only one living sibling, and we identified a likely disease-causing homozygous mutation.…”

Cellules souches embryonnaires humaines et iPS

“…Ainsi des études de fonctionnalité in vivo pourront être réalisées de façon comparative avec ces deux types de progéniteurs. Nous avons également montré que des iPS générées à partir de patients atteints de maladies métaboliques hépatiques reproduisaient, après différenciation en hépatocytes, le phénotype de la maladie [30].…”