The scientists discovered a protein that activates the maturation process in vitro, overcoming this longstanding obstacle in diabetes therapy development.
“In a dish, with this one switch, it’s possible to produce a functional human beta cell that’s responding almost as well as the natural thing,” says senior author Ronald Evans of the Salk Institute. “This has been a major blockade, and overcoming it has been a major challenge to the field.”
To create different cell types in the lab, stem cells must be coaxed down the road of determination, the branching paths that fetal cells normally travel to become neurons, skin cells, muscle cells, or any number of other cell types. But there are many developmental points between a stem cell and a fully grown cell type, and for pancreatic beta cells, the stem cells have historically stalled out in an early stage when grown in the lab. “Everyone got stuck at this point,” says Evans.
To nail down the differences between fetal and adult beta cells and determine what might trigger the next step in the process, Evans and his colleagues analyzed human cells’ transcriptomes. They discovered that a nuclear receptor protein, estrogen-related receptor gamma (ERR gamma), occurred in much larger amounts in adult beta cells. Evans’ team had previously worked with the protein, which helps to promote endurance running.
When the researchers raised mice that lacked ERR gamma, the animals’ beta cells couldn’t produce insulin in response to blood glucose spikes. But when the team instructed human beta-like cells grown in the lab to produce more ERR gamma, “Voila,” says Evans. “Those cells in culture began to respond to glucose and release insulin.”
“I believe this work transitions us to a new era in creating functional beta cells at will,” says Evans. The researchers are planning to explore this process in more complicated models for treating diabetes.
The study appears in Cell Metabolism.