Objective
This project will study the role of alternative splicing in beta cell maturation and test ways to enhance their functionality in lab-generated cells to help offer better therapies for type 1 diabetes.
Background Rationale
In diabetes, the body fails to maintain healthy blood sugar levels. This control depends on beta cells,
specialized pancreatic cells that release insulin in response to rising blood sugar. Beta cells develop their
identity in the embryo and continue to mature after birth to reach full functionality, essential for effective
blood sugar regulation. Although scientists can generate beta cells from stem cells in the lab, these cells
do not yet function as well as those from the human body. We found that beta cells and neurons share
gene arrangement patterns, known as alternative splicing, particularly involving small gene segments
called microexons. Microexons play a key role in insulin release, suggesting that tightly controlling these
segments is crucial for full beta cell maturation.
Description of Project
Type 1 diabetes (T1D) is a condition in which the body’s immune system attacks the insulin-producing beta cells in the pancreas. Without these cells, patients cannot regulate blood sugar and must rely on insulin injections for life. Stem cell-derived islets (SC-islets) offer hope as a potential cure, but current methods produce cells that are not fully mature and do not respond to glucose as efficiently as natural beta cells.
Beta cell maturation is the process after birth in which cells gain the ability to release insulin in response to glucose. While much is known about the genes that control beta cell identity, the role of alternative RNA splicing—a process that fine-tunes how genes are read—is less understood. Our research shows that beta cells use a neural-like splicing program, including very small “microexons,” to support their secretory function. SC-islets retain an immature version of this program, which may explain their incomplete function.
We aim to map how splicing changes during beta cell development, test how these splicing programs affect maturation using CRISPR and physiological assays, and explore small molecules that could promote full beta cell function. This work could provide crucial insights for improving stem cell therapies for T1D.
Anticipated Outcome
Type 1 diabetes (T1D) happens when the body destroys the cells in the pancreas that make insulin. Without these cells, people must take insulin every day to stay healthy. Scientists are working on a possible cure by creating new insulin-producing cells from stem cells. However, these lab-made cells still do not work as well as the real ones in the body.
One reason may be that these new cells are not fully “mature.” Mature beta cells can sense sugar in the blood and release insulin at exactly the right time. We know this maturing process happens after birth, but we still don’t understand it well.
Our research suggests that part of this problem may be linked to how cells process their own genes, through something called alternative splicing. This is a normal way cells fine-tune what proteins they make. Interestingly, early beta cells use patterns that look more like nerve cells, and these patterns normally decrease as beta cells grow up. But stem-cell-derived beta cells keep these immature patterns, which might explain why they don’t work properly.
In this project, we want to learn exactly how these splicing patterns change as beta cells grow and whether adjusting them can help stem-cell-derived cells become fully functional. To do this, we will:
Study how gene processing changes as beta cells develop.
Test what happens when we turn certain splicing patterns on or off.
Check whether specific medicines can help push the cells toward full maturity.
Our goal is to better understand how healthy insulin-producing cells develop and to use this knowledge to improve stem-cell-based therapies that could one day cure type 1 diabetes.
Relevance to T1D
People with type 1 diabetes lose the cells in the pancreas that make insulin, which means they must rely on insulin treatment for life. Replacing these lost cells with new ones made from stem cells is a promising approach to developing a long-term cure. However, the stem-cell–derived beta cells currently available do not work as well as the fully mature cells found in the body.
This project directly addresses this challenge by studying how beta cells normally mature and identifying what is missing in stem-cell–derived cells. By understanding and correcting these differences, we aim to produce stem-cell–derived islets that behave like healthy, natural beta cells. This would significantly improve future cell-based therapies, bringing us closer to a durable and potentially curative treatment for people with type 1 diabetes.