Premium
Investigating the utility of human embryonic stem cell‐derived neurons to model ageing and neurodegenerative disease using whole‐genome gene expression and splicing analysis
Author(s) -
Patani Rickie,
Lewis Patrick A.,
Trabzuni Daniah,
Puddifoot Clare A.,
Wyllie David J. A.,
Walker Robert,
Smith Colin,
Hardingham Giles E.,
Weale Michael,
Hardy John,
Chandran Siddharthan,
Ryten Mina
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07825.x
Subject(s) - biology , embryonic stem cell , induced pluripotent stem cell , neurodegeneration , stem cell , neural stem cell , directed differentiation , transcriptome , neuroscience , cellular differentiation , alternative splicing , gene expression profiling , adult stem cell , somatic cell , gene expression , genetics , gene , disease , exon , pathology , medicine
J. Neurochem. (2012) 122 , 738–751. Abstract A major goal in regenerative medicine is the predictable manipulation of human embryonic stem cells (hESCs) to defined cell fates that faithfully represent their somatic counterparts. Directed differentiation of hESCs into neuronal populations has galvanized much interest into their potential application in modelling neurodegenerative disease. However, neurodegenerative diseases are age‐related, and therefore establishing the maturational comparability of hESC‐derived neural derivatives is critical to generating accurate in vitro model systems. We address this issue by comparing genome‐wide, exon‐specific expression analyses of pluripotent hESCs, multipotent neural precursor cells and a terminally differentiated enriched neuronal population to expression data from post‐mortem foetal and adult human brain samples. We show that hESC‐derived neuronal cultures (using a midbrain differentiation protocol as a prototypic example of lineage restriction), while successful in generating physiologically functional neurons, are closer to foetal than adult human brain in terms of molecular maturation. These findings suggest that developmental stage has a more dominant influence on the cellular transcriptome than regional identity. In addition, we demonstrate that developmentally regulated gene splicing is common, and potentially a more sensitive measure of maturational state than gene expression profiling alone. In summary, this study highlights the value of genomic indices in refining and validating optimal cell populations appropriate for modelling ageing and neurodegeneration.