In a recent study from UHN’s McEwen Stem Cell Institute (McEwen), Senior Scientist Dr. M. Cristina Nostro and her team identified key factors that drive the development of various pancreatic cell types, like insulin-producing beta cells. This work aims to improve how stem cells can be used to develop a cellular therapy for type 1 diabetes.

During fetal development, pancreatic progenitors (PPs) are precursor cells that give rise to multiple pancreatic cell types, including exocrine and endocrine cells. Exocrine cells produce digestive enzymes, and endocrine (islet) cells, like beta cells, produce the hormones important for controlling blood sugar levels. The endocrine or exocrine fate of PPs is regulated by a complex set of biological signals, including the duration and timing of exposure to these biological signals.

Reproducing the developmental conditions that results in endocrine cells, including beta cells, in the lab is essential to the study of diabetes and the generation of new, cell-based therapies that could be used to replace a patient’s lost and nonfunctional beta cells. To achieve this, scientists use a technique called in vitro differentiation, in which they expose human pluripotent stem cells—cells that can become any cell type in the body—to key biological factors to guide their development into pancreatic islet cells.

However, knowledge of how PPs develop into specific lineages, such as islet cells, is still limited. As a result, differentiation toward pancreatic beta cells remains difficult to control and frequently produces other cell types, such as intestinal enterochromaffin cells (ECs), as unintended and unwanted byproducts.

To address this challenge, Dr. Nostro’s team modulated key signals used during differentiation towards pancreatic beta-like cells and analyzed the characteristics of the resulting cells over time. They also collaborated with Dr. Gabriela Pavlínková from the Czech Academy of Sciences to compare the process of fetal pancreatic cell development in a lab model to the process of in vitro pancreatic cell differentiation.

Researchers found that distinct populations of PPs preferentially develop into beta cells or EC cells. They identified several key regulatory proteins—including NKX6-1 and Neurogenin 3 (NGN3)—that influenced the fate of the progenitors. 

Importantly, the McEwen showed that these PP populations respond differently to various developmental cues. By carefully adjusting these conditions in their differentiation protocol, the researchers were able to control which pancreatic cell type developed.

These findings may help refine stem cell differentiation protocols produce more consistent and defined cell populations. As cell-based therapies for type 1 diabetes advance to clinical trials, achieving precise control over differentiation outputs will be critical. “This work brings us closer to generating highly purified islet cell populations,” says Dr. Paraish Misra, first author of this study. “Purer populations can make this therapy safer and more effective for patients and streamline their production as they reduce the need to remove any non-beta cells from the cell population before transplantation into patients.” Overall, this work provides important insights that may support the development of more consistent and scalable cell-based therapies for diabetes.

The first author of this study is Dr. Paraish Misra, a former Postdoctoral Researcher in the Nostro Lab and currently an Assistant Professor and researcher at McGill University.

The senior author of this study is Dr. M. Cristina Nostro, a Senior Scientist at UHN’s McEwen Stem Cell Institute and Associate Professor in the Department of Physiology at the University of Toronto.

This work was supported by the Canadian Institutes of Health Research, the Howard Webster Foundation, the Kidney Foundation of Canada, the Canadian Society of Transplantation, the Temerty Faculty of Medicine at the University of Toronto, the Banting and Best Diabetes Centre, the Natural Sciences and Engineering Research Council of Canada, Breakthrough T1D International (formerly JDRF), The Leona M. and Harry B Helmsley Charitable Trust, Eli Lilly Canada, the Canadian Islet Research Training Network, the Canadian Clinical Trial Network, the Czech Science Foundation, the Grant Agency of Charles University, the Czech Academy of Sciences, and UHN Foundation. 

Drs. Misra, McGaugh, and Nostro are co-inventors on two patent applications related to this work.

Misra PS, McGaugh EC, Huang H, Cho A, Lin J, Sarangi F, Oakie A, Sambathkumar R, Song Y, Fabríciová V, Bohuslavová R, Pavlínková G, Nostro MC. Efficient control of enterochromaffin versus islet differentiation from human pluripotent stem cell-derived pancreatic progenitors. Nat Commun. 2026 Mar 18;17(1):4137. doi: 10.1038/s41467-026-70666-y. PMID: 41851084; PMCID: PMC13149693.