The researchers suggest that when a baby is born and takes its first breath, this oxygenation switches on the nuclear receptor protein ERRγ, which through its influence on mitochondria, helps to regulate insulin release in response to glucose.
Image credit: Yoshihara et al./Cell Metabolism 2016
A long-standing obstacle in developing a cell therapy for diabetes has been getting beta cells derived from human stem cells to mature beyond the precursor stage into fully-functioning insulin releasers.
Now, in the journal Cell Metabolism, researchers from the Salk Institute for Biological Studies, La Jolla, CA, explain how they got lab-grown beta cells to mature by activating a protein called estrogen-related receptor γ (ERRγ).
Senior author Ronald Evans, a professor and molecular biologist, says:
"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."
The self-renewing capacity of human pluripotent stem cells (hPSCs) and their ability to make most of our cell types - from neurons to skin cells, to muscles cells and insulin-producing pancreatic beta cells - has inspired many research teams to find ways to make glucose-responsive beta cells in the lab.
To create the different types of cell in the lab, researchers coax the hPSCs down the various branching paths that fetal cells normally travel to become the various cell types. However, Prof. Evans explains there are many developmental points in this process, and in the case of lab-grown pancreatic beta cells, research keeps getting stuck at an early stage.
Adult beta cells have more ERRγ protein
To try to discover what might trigger the next step in getting the cells to mature, the researchers compared the transcriptomes of adult and fetal beta cells. The transcriptome contains, among other things, the full catalog of molecules that switch genes on and off in the genome.
They discovered that the nuclear receptor protein ERRγ was more abundant in the adult beta cells. The team was already familiar with the protein's role in muscle cells and had studied its ability to enhance endurance running.
Prof. Evans says that in muscles, the protein promotes greater growth of mitochondria - the power generators inside cells - and they accelerate the burning of sugars and fats to make energy.
"It was a little bit of a surprise to see that beta cells produce a high level of this regulator," he adds, "but beta cells have to release massive amounts of insulin quickly to control sugar levels. It's a very energy-intensive process."
As such, the team decided to run some tests to look more closely at what role ERRγ might play in insulin-producing beta cells.
'New era in creating functional beta cells'
When they genetically engineered mice to lack ERRγ, the researchers found the animals' beta cells did not produce insulin in response to spikes in blood sugar.
The next thing they tried was to get beta cells made from hPSCs to produce more ERRγ, and this did the trick; the cells in culture began to respond to glucose and release insulin.
And finally, the team transplanted the lab-grown beta cells into diabetic mice and found from day 1, the cells produced insulin in response to glucose spikes in the animals' blood.
Prof. Evans says they were really excited by the results. It appears that just switching on the ERRγ protein is enough to get the lab-grown beta cells to mature and produce insulin in response to glucose - both in culture and in live animals.
Speculating on the implications of the findings, Prof. Evans suggests that when the fetus is developing, because it has a steady supply of glucose from the mother, it does not need to produce insulin to regulate its blood sugar, so the switch is inactive. But, when the baby is born and takes its first breath and takes in oxygen, this activates the switch.
The previous lab attempts to produce beta cells had got stuck at the fetal stage. This study has discovered how to take it to the adult stage, using the same protein that is switched on in nature. Prof. Evans concludes:
"I believe this work transitions us to a new era in creating functional beta cells at will."
He and his team now plan to look at how the switch might work in more complex models of diabetes treatments.
The study follows another study Medical News Today learned about recently where researchers generated mini-stomachs that produce insulin when transplanted into mice.