Fully functional pancreatic beta cells created from stem cells for the first time

Insulin is a vital hormone produced by pancreatic beta cells. Type 1 diabetes is caused by the destruction of these cells, which results in patients having to replace the lost insulin with multiple daily injections.

Insulin secretion can be restored in diabetic patients by transplanting beta cells isolated from the pancreas of a brain dead organ donor. However, this treatment has not been widely introduced, since cells from at least two donors are needed to cure one diabetic.

For a long time, attempts have been made to produce functional beta cells from stem cells, which could make this treatment increasingly common. However, the beta cells produced from stem cells have so far been immature, with poorly regulated insulin secretion. This may be a partial explanation for why no breakthroughs have been achieved in the clinical trials based on immature cells ongoing in the United States.

A research group headed by Professor Timo Otonkoski at the University of Helsinki, and carried out in collaboration with EMBO Postdoctoral Fellow Diego Balboa at the CRG, previously a PhD student in Professor Otonkoski’s lab, has carried out pioneering efforts to optimise the functionality of pancreatic cells produced from stem cells.

In a study published today in Nature Biotechnology, the group has demonstrated, for the first time, that stem cells can form cells that closely mimic normal pancreatic islets, in terms of both structure and function.

“In our study, insulin secretion was regulated as usual in cells, and the cells responded to changes in the glucose level even better than the pancreatic islets isolated from organ donors that were used as controls,” says Väinö Lithovius, a member of the research group at the University of Helsinki.

“Our work makes important advances in transfoming stem cells into spare pieces that could be used to replace the failing cells in the human pancreas that cause diabetes. Though there is more work to be done, these findings bring us one step closer to treating diabetes patients with stem-cell derived islet cells, something that is no longer in the realms of science-fiction,” says Diego Balboa.

The researchers demonstrated the function of stem cell–derived beta cells in both cell cultures and mice studies. In the latter, the researchers demonstrated that stem cell–derived beta cells transplanted into mice started effectively managing the glucose metabolism of the mice.

“Blood glucose levels are higher in mice than in humans, roughly 8–10 millimolar. After the cell transplantation, the level decreased to that seen in humans, roughly 4–5 millimolar. It remained at this level, proving that the stem cell–derived transplant was capable of regulating blood glucose levels in mice,” says University of Helsinki researcher Jonna Saarimäki-Vire, who was responsible for the cell transplantation.

The survey of beta cell function now published is the most comprehensive in the field: in addition to insulin secretion, the researchers investigated the functionality of systems that regulate insulin secretion, including metabolism and ion channels, also connecting the findings to gene expression occurring during development.

According to Diego Balboa, the stem cell-derived islets will also be useful to study the disease mechanisms behind diabetes. “We can generate millions of these cells in vitro in the lab and ask questions about what genes and cell machinery make the cells fail, helping us unravel the precise molecular causes of diabetes. We could also use the cells to explore the effects of potential new drugs to treat diabetes.”

“Our study will help further improve the production of stem cell islets, which will make it easier to utilise them in disease modelling and cell therapies,” concludes Timo Otonkoski.

IMAGE: Stem cell derived islet, insulin-producing beta cells marked in red, glucagon-producing alpha cells marked in green. Credit: Väinö Lithovius/University of Helsinki