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:

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.

• doi: 10.1016/j.stem.2025.05.004