Generating functional pancreatic β (beta) cells in the lab has been a challenge for diabetes researchers. When human stem cells develop into beta cells in a dish, they only reach a precursor stage, unable to fully mature. Now an international team of scientists has discovered a nuclear receptor protein that activates the maturation process in vitro.
Postnatal maturation of pancreatic beta cells necessary for maximal glucosestimulated insulin secretion is coordinated by the estrogen-related receptor g (ERRg). ERRg drives a transcriptional program promoting mitochondrial oxidative metabolism, and its expression in iPSC-derived beta-like cells generates functional beta cells in vitro. Image credit: Eiji Yoshihara et al.
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.
To nail down the differences between fetal and adult beta cells and determine what might trigger the next step in the process, Dr. Ronald Evans of the Salk Institute for Biological Studies and his colleagues from the United States, Australia and Korea analyzed human cells’ transcriptomes.
They discovered that a nuclear receptor protein, estrogen-related receptor γ (ERRγ), occurred in much larger amounts in adult beta cells.
“In muscle, ERRγ induces greater mitochondrial growth and promotes oxidative use of sugars and lipids to generate energy,” explained Dr. Evans, senior author on a paper published this week in the journal Cell Metabolism.
“It was a little bit of a surprise to see that beta cells produce a high level of this regulator, but beta cells have to release massive amounts of insulin quickly to control sugar levels. It’s a very energy-intensive process.”
When the scientists raised mice that lacked ERRγ, the animals’ beta cells couldn’t produce insulin in response to blood glucose spikes.
“Mice deficient in beta cell-specific ERRγ expression are glucose intolerant and fail to secrete insulin in response to a glucose challenge,” they said.
But when they instructed human beta-like cells grown in the lab to produce more ERRγ, those cells began to respond to glucose and release insulin.
To further test the dish-matured cells, the team transplanted them into diabetic mice.
From the first day of transplantation, the cells produced insulin in response to glucose spikes in the mice’s blood, alleviating the modeled diabetes.
“We were very excited when we saw that,” Dr. Evans said. “Turning on the ERRγ switch alone is sufficient to mature the beta-like cells in vitro, with the power to rescue diabetes in vivo.”
The team is now planning to explore this process in more complicated models for treating diabetes.
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Eiji Yoshihara et al. 2016. ERRγ is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells. Cell Metabolism, vol. 23, no. 4, p622-634; doi: 10.1016/j.cmet.2016.03.005
