Induced Pluripotent Stem Cells Can Be Used to Model the Genomic Imprinting Disorder Prader-Willi Syndrome

Abstract

The recent discovery of induced pluripotent stem cell (iPSC) technology provides an invaluable tool for creating in vitro representations of human genetic conditions. This is particularly relevant for those diseases that lack adequate animal models or where the species comparison is difficult, e.g. imprinting diseases such as the neurogenetic disorder PraderWilli syndrome (PWS). However, recent reports have unveiled transcriptional and functional differences between iPSCs and embryonic stem cells that in cases are attributable to imprinting errors. This has suggested that human iPSCs may not be useful to model genetic imprinting diseases. Here, we describe the generation of iPSCs from a patient with PWS bearing a partial translocation of the paternally expressed chromosome 15q11-q13 region to chromosome 4. The resulting iPSCs match all standard criteria of bona fide reprogramming and could be readily differentiated into tissues derived from the three germ layers, including neurons. Moreover, these iPSCs retain a high level of DNA methylation in the imprinting center of the maternal allele and show concomitant reduced expression of the disease-associated small nucleolar RNA HBII-85/SNORD116. These results indicate that iPSCs may be a useful tool to study PWS and perhaps other genetic imprinting diseases as well.

Conversion of genomic imprinting by reprogramming and redifferentiation

“…However, recent studies have suggested that iPSCs from PWS patients maintained their imprinting pattern even after reprogramming (Chamberlain et al, 2010;Yang et al, 2010). This discrepancy between mouse and human iPSCs may be attributable to differences in the pluripotent state of iPSCs: mouse ESCs and iPSCs appear to be in a developmentally less-advanced pluripotent state than human ESCs and iPSCs.…”

Neural progenitor cells from human induced pluripotent stem cells generated less autogenous immune response

“…NPC differentiation from hESCs and hiPSCs derived from both SFs and UCs was performed as described previously [26,30,35,36]. The typical neural rosettes were blown off and picked out to produce a neural sphere consisting of Figure 1A).…”

iPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery

“…Disease modeling based on iPSC technology has also been applied to many other neurological or psychiatry disorders, including Alzheimer's disease [32] , Huntington's disease [33,34] , Angelman and Prader-Willi syndromes [35,36] , schizophrenia [37] , and others (Table 1).…”