Stem cell–based therapies for diabetes hold enormous promise — but a persistent problem has stood in the way. Laboratory-grown pancreatic tissue intended to produce insulin often contains unwanted intestinal cells that reduce its purity.
, a Junior Scientist in the at The Institute, and colleagues at the University of Toronto have identified the molecular signals that control this critical cell fate decision, offering a practical framework for producing purer, more functional stem cell–derived islets for research and therapeutic applications. The findings were published in Nature Communications.
Key findings
Diabetes affects hundreds of millions of people worldwide, and cell replacement therapy is one of the most promising treatments for insulin-dependent forms of the disease. Because donor islets from deceased individuals are scarce, scientists have worked for years to generate them from pluripotent stem cells but preparations are frequently contaminated by enterochromaffin (EC) cells, a cell type normally found in the intestine, not the pancreas.
Dr. Misra and his collaborators systematically compared differentiation strategies and identified specific molecular signals that tip the balance between islet and EC cell fates. The work grew out of a practical challenge encountered during his doctoral research. “When I came across a stem cell line I absolutely needed for my thesis work that couldn’t differentiate into islet cells the way I wanted, I had no choice but to develop ways to better control stem cell differentiation,” said Dr. Misra. “What started as a practical problem led us to uncover something much more fundamental about how the pancreas forms – and how we can use that knowledge to build better cell therapies.”
The study identified the MAPK/ERK and BMP signalling pathways as molecular switches controlling islet versus EC cell fate. Early progenitor identity also proved critical – cells with high NKX6-1 expression preferentially became insulin-producing beta cells, while NKX6-1-deficient progenitors favoured EC, alpha, and delta cell fates. Using an optimized protocol, the team achieved beta cell enrichment of 50–60% and demonstrated significantly greater insulin secretion in response to glucose. The study also identified prolonged Neurogenin 3 (NGN3) expression as a conserved feature of EC-like cells, and unexpectedly uncovered conditions for generating delta cells – a rare islet cell type whose role remains poorly understood.
Looking ahead
“These findings lay the groundwork for a designer approach to cellular therapies for diabetes,” says Cristina Nostro, PhD, Scientist at the McEwen Stem Cell Institute and senior author of the study. Future work will focus on translating these findings to three-dimensional suspension culture systems used in clinical settings, and on further characterizing the functional role of delta cells and other rare islet subtypes.
About the study
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. Nature Communications. 2026;17:4137.
This work was conducted by Dr. Misra during his doctoral and postdoctoral studies at the University of Toronto, prior to joining The Institute.