Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors
Open accessAbstract
Large cohorts of human induced pluripotent stem cells (iPSCs) from healthy donors are a potentially powerful tool for investigating the relationship between genetic variants and cellular behavior. Here, we integrate high content imaging of cell shape, proliferation, and other phenotypes with gene expression and DNA sequence datasets from over 100 human iPSC lines. By applying a dimensionality reduction approach, Probabilistic Estimation of Expression Residuals (PEER), we extracted factors that captured the effects of intrinsic (genetic concordance between different cell lines from the same donor) and extrinsic (cell responses to different fibronectin concentrations) conditions. We identify genes that correlate in expression with intrinsic and extrinsic PEER factors and associate outlier cell behavior with genes containing rare deleterious non-synonymous SNVs. Our study, thus, establishes a strategy for examining the genetic basis of inter-individual variability in cell behavior.
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Outcomes are cell line dependent, as has been noted for other organoid models.
“The experimenters must be aware that outcomes are cell line dependent, as has been noted for other organoid models”
From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [74]
The Results (Identification of Outlier Cell Lines; page not supplied) report that 36 of 110 iPSC lines showed outlier behavior, supporting variation by cell line. But the paper assays cultured iPSCs, not organoid models, so it does not establish the claim specifically for other organoid models. (LLM, conf=0.86)
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- Authors
- Vigilante, A., Laddach, A., Moens, N., Meleckyte, R., Leha, A., Ghahramani, A., Culley, O. J., Kathuria, A., Hurling, C., Vickers, A., Wiseman, E., Tewary, M., Zandstra, P. W., Durbin, R., Fraternali, F., Stegle, O., Birney, E., Luscombe, N. M., Danovi, D., & Watt, F. M.
- Affiliations
- Guy's Hospital (GB)
- King's College London (GB)
- Wellcome Sanger Institute (GB)
- University of British Columbia (CA)
- University of Cambridge (GB)
- European Bioinformatics Institute (GB)
- The Francis Crick Institute (GB)
- Corresponding author
- Danovi, Davide
- Watt, Fiona M.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 26
- Issue
- 8
- Pages
- 2078-2087.e3
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6381787
- OpenAlex
- W2915808837
- Cited by
- 34
- References
- 48
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 5 · 2020: 6 · 2019: 4
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Discovery Research Portal (University of Dundee) (cc-by)
- The Francis Crick Institute (cc-by)
- Funders
- King’s College London
- Department of Health and Social Care
- Wellcome Trust
- Cancer Research UK (FC001110)
- Francis Crick Institute
- King's College London
- King's College Hospital NHS Foundation Trust
- National Institute for Health and Care Research
- Medical Research Council (WT098503)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- induced pluripotent stem cells, interindividual variability, cell behavior, external factors, peers, cell shape, cell proliferation, rare deleterious variants, gene expression, high-content imaging, healthy donors
- MeSH terms
- Biological Variation, Population, Animals, Cell Differentiation, Cell Line, Humans, Phenotype, Polymorphism, Single Nucleotide, Cell Proliferation, Mice, Induced Pluripotent Stem Cells, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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