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June 06, 2025
Harnessing Diversity: Redefining iPS Cell Standards for Global Health Equity
Reference iPS cell lines are essential in disease modeling, drug discovery, and regenerative medicine. However, most current lines—typically derived from healthy males of European ancestry—lack global genetic diversity. This bias not only limits the applicability of research but also affects how disease-associated variants are interpreted. The authors advocate for a new international framework to develop genetically diverse, exhaustively characterized iPS cell lines as more inclusive and reliable standards.
The article distinguishes between control lines, used for specific experimental comparisons, and reference lines, which serve as broadly applicable benchmarks. Reference lines should come from healthy individuals, be free of disease-associated or editing-induced mutations, and be validated across multiple laboratories. The authors outline several workflows for generating such lines, including selecting iPS cells optimized for gene editing, identifying low-risk donors with minimal pathogenic variants, and creating large-scale, population-based iPS cell cohorts. Notable examples of these efforts include KOLF2.1J, a line specifically optimized for high-efficiency gene editing; the PGPC lines from Canada, derived from individuals with low disease-associated variant loads; and a large-scale initiative in Japan that has produced over 650 iPS cell lines from healthy donors, deposited at the RIKEN BioResource Research Center. Together, these initiatives exemplify how diverse, well-characterized cell lines can serve as a foundation for more representative and globally applicable stem cell research.
With over 3 million single nucleotide variants per genome, even healthy individuals carry mutations that can affect disease risk and drug response. No single reference line can represent the full range of human biology, and relying on one may lead to biased or incomplete conclusions.
To address this, the authors outline three priority areas:
1. Diversity: Japan and Canada are generating iPS cell lines from ethnically diverse, healthy individuals.
These undergo rigorous genomic analysis and are shared through open science collaborations.
2. Disease Modeling and Drug Testing: Using only one genetic background can obscure critical biological responses. Incorporating multiple reference lines enhances the robustness and generalizability of findings.
3. Regenerative Medicine: Immune rejection is a major challenge. CiRA has developed clinical-grade iPS cell lines with HLA types matching 40% of the Japanese population. Hypoimmune iPS cell lines—engineered to evade immune detection—are also being developed to broaden treatment options and reduce reliance on immunosuppression.
The authors conclude that the question of "whose cells are used" will become increasingly important in future iPS cell research and therapies. They call for urgent global collaboration to establish a more inclusive and representative foundation for stem cell science—one that ensures future medical advances benefit all populations, not just a privileged few.
Paper Details
- Journal: Cell Stem Cell
- Title: Diversifying the Reference iPSC Line Concept
- Authors: James Ellis1*, Knut Woltjen2, Seema Mital3, Megumu K. Saito4, Akitsu Hotta4* and Jeanne F. Loring5*
*: Corresponding author - Author Affiliations:
- Developmental, Stem Cell and Cancer Biology, The Hospital for Sick Children
Dept. of Molecular Genetics, University of Toronto - Dept. of Life Sciences Frontiers, Centre for iPS Cell Research and Application, Kyoto University
- Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada; and Dept. of Pediatrics, University of Toronto
- Dept. of Clinical Application, Centre for iPS Cell Research and Application, Kyoto University
- Dept. Molecular Medicine, Scripps Research Institute
- Developmental, Stem Cell and Cancer Biology, The Hospital for Sick Children