Toward Inclusive Reference iPSC Lines: Enhancing Diversity in Disease Modeling and Therapeutics

The tools we use in research should reflect the full spectrum of genetic diversity, but they often do not. This is a gap that an international team of scientists is exploring through the lens of induced pluripotent stem cell (iPSC) lines. 

iPSCs are a type of stem cell that can differentiate into several different cell types and that can be created from a somatic cell. For a long time, researchers have relied on healthy control iPSC lines that they generate themselves. There are few high-quality lines that are shared across labs, and they mostly come from individuals of European or Japanese descent. A newly published perspective in Cell Stem Cell calls for the development of standardized, widely adopted models that better reflect global genetic diversity.

Inspired by the concept of reference standards such as the atomic clock, and by the advancements made to include diversity in the human genome reference sequence, the team defines what makes a reference iPSC line and proposes how they are used to improve diversity in disease modeling and therapeutic development.

Why Diversifying Reference iPSC Lines Matters 

iPSC lines are a foundation of disease modeling, drug testing, and the development of new cell-based therapies. Reference iPSC lines are needed to act as standardized controls in labs around the world, and their genomic ancestry has a direct impact on how widely applicable future medical advances will be. 

The issue is that existing cell lines do not adequately reflect global genetic diversity, and this gap could lead to treatments that are less effective for people from underrepresented populations. We have already seen this happen with clinical trials that excluded diverse participants, resulting in medications that fail or cause harm in real-world settings. The same risk exists in stem cell research if the models that we use are not representative of international diversity. 

A Global Collaboration with Canadian Roots 

The team combines expertise in genomics and translational iPSC research across a broad disease spectrum. At The Hospital for Sick Children (SickKids), Ted Rogers Centre for Heart Research and the University of Toronto in Canada, Dr. James Ellis and Dr. Seema Mital sought reference lines for disease modeling and drug screens. Dr. Akitsu Hotta and Dr. Knut Woltjen are Canadian-trained group leaders at the Centre for iPS Cell Research and Application (CiRA) in Kyoto—home to the discovery of iPSC and a hub for global stem cell innovation. With CiRA colleague Dr. Megumu Saito, they developed reference iPSC cohorts and hypoimmune lines for clinical applications. Dr. Jeanne Loring at the Scripps Research Institute in San Diego brought insights about reference standards and genomic diversity.

Together, this team is advocating for identification of genetically diverse stem cell lines that meet rigorous reference standards. While a few reference lines from European and Japanese donors provide an important foundation, large gaps remain—especially for smaller founder populations and even some major ethnicities. The goal is to build a toolkit of well-characterized iPSC lines that better reflect the genetic landscape of the world’s population. 

A New Standard for Regenerative Medicine 

The implications of the proposed research standards are far-reaching, as diverse iPSC lines could dramatically improve the safety and precision of emerging therapies in regenerative medicine, from treating inherited diseases to developing patient-specific cell therapies. Rather than waiting for problems to arise in clinical trials, researchers can use these inclusive models to anticipate and address them much earlier in the pipeline. 

“In the future, a diverse panel of Reference iPSC lines can be used in Village-in-a Dish experimental designs for drug testing” said Dr. Ellis.

This effort is not just about making better science. It is about ensuring that the next generation of treatments truly works for everyone.