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Human iPSC-derived neurons and lymphoblastoid cells for personalized medicine research in neuropsychiatric disorders.

ABSTRACT: The development and clinical implementation of personalized medicine crucially depends on the availability of high-quality human biosamples; animal models, although capable of modeling complex human diseases, cannot reflect the large variation in the human genome, epigenome, transcriptome, proteome, and metabolome. Although the biosamples available from public biobanks that store human tissues and cells may represent the large human diversity for most diseases, these samples are not always sufficient for developing biomarkers for patient-tailored therapies for neuropsychiatric disorders. Postmortem human tissues are available from many biobanks; nevertheless, collections of neuronal human cells from large patient cohorts representing the human diversity remain scarce. Two tools are gaining popularity for personalized medicine research on neuropsychiatric disorders: human induced pluripotent stem cell-derived neurons and human lymphoblastoid cell lines. This review examines and contrasts the advantages and limitations of each tool for personalized medicine research.

SUBMITTER: Gurwitz D

PROVIDER: S-EPMC5067144 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Human iPSC-derived neurons and lymphoblastoid cells for personalized medicine research in neuropsychiatric disorders.

Gurwitz David D

Dialogues in clinical neuroscience 20160901 3

The development and clinical implementation of personalized medicine crucially depends on the availability of high-quality human biosamples; animal models, although capable of modeling complex human diseases, cannot reflect the large variation in the human genome, epigenome, transcriptome, proteome, and metabolome. Although the biosamples available from public biobanks that store human tissues and cells may represent the large human diversity for most diseases, these samples are not always suffi ...[more]

PMID: 27757061

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Project description:Our understanding of the molecular processes underlying Alzheimer's disease (AD) is still limited, hindering the development of effective treatments, and highlighting the need for human-specific models. Advances in identifying components of the amyloid cascade are progressing, including the role of the protein clusterin in mediating ?-amyloid (A?) toxicity. Mutations in the clusterin gene (CLU), a major genetic AD risk factor, are known to have important roles in A? processing. Here we investigate how CLU mediates A?-driven neurodegeneration in human induced pluripotent stem cell (iPSC)-derived neurons. We generated a novel CLU-knockout iPSC line by CRISPR/Cas9-mediated gene editing to investigate A?-mediated neurodegeneration in cortical neurons differentiated from wild type and CLU knockout iPSCs. We measured response to A? using an imaging assay and measured changes in gene expression using qPCR and RNA sequencing. In wild type neurons imaging indicated that neuronal processes degenerate following treatment with A?25-35 peptides and A?1-42 oligomers, in a dose dependent manner, and that intracellular levels of clusterin are increased following A? treatment. However, in CLU knockout neurons A? exposure did not affect neurite length, suggesting that clusterin is an important component of the amyloid cascade. Transcriptomic data were analyzed to elucidate the pathways responsible for the altered response to A? in neurons with the CLU deletion. Four of the five genes previously identified as downstream to A? and Dickkopf-1 (DKK1) proteins in an A?-driven neurotoxic pathway in rodent cells were also dysregulated in human neurons with the CLU deletion. AD and lysosome pathways were the most significantly dysregulated pathways in the CLU knockout neurons, and pathways relating to cytoskeletal processes were most dysregulated in A? treated neurons. The absence of neurodegeneration in the CLU knockout neurons in response to A? compared to the wild type neurons supports the role of clusterin in A?-mediated AD pathogenesis.

Dataset Information

Human iPSC-derived neurons and lymphoblastoid cells for personalized medicine research in neuropsychiatric disorders.

Publications

Human iPSC-derived neurons and lymphoblastoid cells for personalized medicine research in neuropsychiatric disorders.

Similar Datasets

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