New research shows how the Notch signalling pathway works when the pancreas forms as the fetus develops. This discovery may lead to new opportunities to cure people with diabetes and understand how pancreatic cancer develops.
Imagine doctors in the near future being able to cultivate stem cells that turn into the insulin-producing beta cells in the pancreas – and then implanting these in people with diabetes to replace their damaged beta cells and thus cure them.
This dream has just come a step closer, after researchers from the University of Copenhagen have revealed how a signalling pathway that guides the development of the pancreas works.
The discovery means that researchers now understand much better what they need to do to cultivate insulin-producing beta cells in a petri dish with the goal of curing people with diabetes.
“The interesting perspective is to take fetal stem cells and direct them to become insulin-producing cells. This requires knowing how nature does this normally, and we have come a step closer to understanding this,” says Palle Serup, Professor, Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, University of Copenhagen.
The research was published recently in Developmental Cell.
Curing people with diabetes using home-grown beta cells
Phase 1 clinical trials around the world are already trying to cure people with diabetes by inserting laboratory-grown insulin-producing beta cells into people’s pancreases.
So far, the trials have been oriented towards ensuring that this procedure is safe, but the idea is to be able to cure the first people with type 1 diabetes within a few years.
The researchers from the University of Copenhagen are at the forefront of this, and leading researchers can also determine how to optimally improve the various procedures.
This applies to the procedures the researchers use to develop the insulin-producing beta cells they implant in people.
The current laboratory-grown beta cells do not respond as well to glucose as they should, and the yield of the cultivation process is also relatively low.
“One reason is that we have not yet been able to fully replicate the natural process in the laboratory,” explains Palle Serup.
Current protocols do not exploit signalling pathways fully
Palle Serup and colleagues studied how the fetal pancreas develops.
Many signalling pathways play a role in the process of inducing the stem cells to become the various cells of a pancreas.
These signalling pathways ensure that insulin-producing beta cells, blood vessels and the ducts that secrete digestive enzymes are produced where they are needed.
The signalling pathways are communication tools between neighbouring cells, and the Notch signalling pathway that Palle Serup has now mapped is very important for the natural development of the pancreas.
“We did not know very much previously about this signalling pathway, and the protocols we use in cultivating pancreatic cells in the laboratory are therefore not very good at using the regulation of this pathway,” says Palle Serup.
Signal molecules oscillate
Notch has previously been linked to pancreatic development, and the new study explains this.
The research shows that the concentration of the signal molecule DLL1 oscillates from high to low and back again, with a 45-minute interval per direction.
Similarly, the oscillation activates the HES1 gene in the neighbouring cell, so the expression of this gene also begins to oscillate.
This is complicated, but Palle Serup’s research also shows that manipulating the oscillations causes the pancreas to grow more slowly.
“This gives us insight into how the cells act when the pancreas is formed, and we have to recreate that activity in the petri dishes,” explains Palle Serup.
Several signal molecules guide pancreatic development
The research also shows that DLL1 is not alone in controlling pancreatic growth during fetal development. The signal molecule JAG1 also plays a role.
Both molecules target the same receptors on neighbouring cells, but DLL1 stimulates pancreatic growth by promoting cell division in neighbouring cells, whereas JAG1 inhibits growth.
JAG1 also plays a role in the paths the cells take in their development. All pancreatic cells originate from two small groups of stem cells that can develop into all the different types of pancreatic cells.
During fetal development, cells develop in one direction or another. JAG1 influences the direction in which the cells develop.
When the researchers remove JAG1, too many cells develop towards cells that secrete digestive enzymes, and too few of the other types are formed. When JAG1 is present, a more appropriate number of the cells develop into insulin-producing beta cells.
To their surprise, the researchers could change the cell types by manipulating the oscillations. Attenuating the fluctuation in HES1 concentrations was equivalent to losing JAG1, whereas the opposite happened if the interval was increased from 45 to 60 minutes.
“Our experiments showed that removing JAG1 or artificially inhibiting oscillations makes the pancreas develop almost no insulin-producing beta cells. This is important to know for growing pancreatic cells in the laboratory,” says Palle Serup.
Improving protocols for developing pancreatic cells
Palle Serup says that the researchers are already looking towards the next step in investigating the role of the signalling pathways in developing the pancreas.
They want to confirm that these oscillations also occur in human pancreatic cells and not just in mice.
Then they will investigate the extent to which they can manipulate the oscillations to control cell development.
Specifically, the researchers would like to accelerate the first cell divisions that lead to a fully developed pancreas. This will make the process in the laboratory more efficient when the cells divide more than they do today.
Then the researchers will learn how to manipulate the individual steps in the process so that the finished product will resemble a natural pancreas as much as possible.
“Once the stem cells have become pancreatic cells, we need to determine whether we can make them divide more frequently and rapidly and become more normal types of cell compared with what is currently possible,” explains Palle Serup.
Discovery may also be relevant in cancer research
The research on pancreatic cells from mouse embryos also indicates new understanding of how pancreatic cancer develops.
Pancreatic cancer is very rare, but the mortality rate is very high.
Researchers know from studies of people with cancer that the JAG1, DLL1 and HES1 signalling pathway is important in developing pancreatic cancer.
This signalling pathway is shut down as the pancreas matures into adulthood, but among people with cancer, it is reactivated and causes uninhibited growth of cancer cells in the pancreas – and a hallmark of cancer cells is uncontrolled growth.
“Cancer may be caused by various mutations in components of this signalling pathway, and we have now begun collaborating with another researcher from the University of Copenhagen to try to understand how the signalling pathway specifically influences the development of pancreatic cancer. We do not know whether the oscillations play a role, but we will investigate these,” explains Palle Serup.
“Jag1 modulates an oscillatory Dll1-Notch-Hes1 signaling module to coordinate growth and fate of pancreatic progenitors” has been published in Developmental Cell. Palle Serup is Professor of Development Biology at the Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, University of Copenhagen. The Novo Nordisk Foundation has awarded research grants of nearly DKK 700 million to DanStem from 2010 to 2017.