Understanding how fetuses develop may cure diabetes

Breaking new ground 23. jan 2019 4 min Professor Anne Grapin-Botton Written by Kristian Sjøgren

Researchers have mapped how the pancreas is formed at the fetal stage. This is a step on the way to being able to create a pancreas from scratch to help to cure diabetes.

Imagine being able to cure diabetes by using stem cells to synthetically grow insulin-producing beta cells or an entire pancreas that can then be transplanted into a person with diabetes. Researchers are actually working on this right now, but this requires knowing all the tiny changes stem cells undergo to become mature beta cells as the fetus develops.

Researchers have now mapped many of these steps, and their discovery opens up a new way of understanding how diabetes develops and how it might be completely cured in the future.

“Understanding how the pancreas develops at the fetal stage is important for two reasons. First, we need to map all the tiny steps in the development process so that some day we can use stem cells to make a pancreas synthetically in the laboratory. Second, some types of diabetes already originate at the fetal stage, and for this, mapping the development of the pancreas is vital so we can determine what might go wrong,” says a co-author, Anne Grapin-Botton, Professor, Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, University of Copenhagen.

Anne Grapin-Botton and her colleagues at DanStem, at Novo Nordisk A/S and in France have recently published their latest results in Development.

How stem cells develop into all types of cells throughout the body

When an egg and a sperm cell develop into a fetus and then a child, all the organs also develop. The many cells of the organs develop from fetal stem cells that contain the genetic code to make all types of cells. This applies to cells for the liver, heart, skin, lungs and the pancreas, primarily comprising insulin-producing beta cells and glucagon-producing alpha cells.

Alpha cells and beta cells interact to regulate blood glucose. Beta cells produce insulin to lower blood glucose when it is high. Conversely, alpha cells produce glucagon to increase blood glucose when it is low.

When a stem cell develops and becomes a beta cell in the pancreas, for example, this happens in many tiny sequential steps that bring the cell closer and closer to becoming a beta cell. Stem cells are like a lump of modelling clay that can be turned into all sorts of things if the numerous steps are correctly carried out. This also applies to stem cells. These first develop into a type of cell that can still become many types of cells, but the more they develop, the more specialized they become until they ultimately become mature beta cells.

For a stem cell to know what it will develop into and how this differentiation will happen requires numerous signals comprising activating genes that influence a stem cell and its subsequent intermediate cells to develop increasingly in one direction or another. Depending on which genes are expressed, the stem cells and the intermediate cells differentiate to become, for example, liver cells. However, the expression of other genes induces cells to develop towards beta cells.

Reconstructing all the steps in beta cell development

In the new study, Anne Grapin-Botton and colleagues mapped what happens inside the cells at all the steps that induce a stem cell to differentiate into a beta cell and ultimately become a part of the pancreas. Thus, they have discovered which genes are expressed and when, enabling the cells to become their destination cells.

Researchers had previously mapped these steps in mice, but the Danish and French researchers mapped the process in human cells. This is a major breakthrough, because the process is usually hidden in the uterus.

The researchers examined pancreatic cells in a Petri dish and in actual pancreases that had been donated following abortions. This enabled them to compare and find differences between how cells develop in real life and in the laboratory.

In both cases, the researchers used bioinformatics to discover which genes were switched on and which were silenced at each step in cell development. They monitored the activity of about 100 genes that influence the development of the pancreas.

“We can reconstruct the steps cells undergo in their differentiation and determine which genes need to be activated or silenced to induce the cell to progress to the next development step. For example, we discovered that the differentiation of whether a cell becomes either an alpha or a beta cell happens very early as a stem cell develops into a fully formed cell. This does not happen immediately before these two cell types are fully formed. As a result, we can see that a cell’s ability to produce insulin develops very early, and knowing this is important to understand how congenital diabetes develops. We now know that one important step requires the fetus or the laboratory to nudge the cell in the right direction,” explains Anne Grapin-Botton.

The researchers also discovered that some steps in the differentiation are not as easy to replicate in the laboratory as they are in real life.

The synthetic pancreases are flat so far

Now that the researchers have new understanding of the many cellular development stages from stem cells to the pancreas, they can expand their ambitions of being able to make pancreases in the laboratory some day.

On paper this may sound simple.

Now that the researchers know the development steps of the genes involved, the right genes merely need to be activated at the right time to transform a stem cell into a beta cell. However, reality is not that simple.

• First, the researchers have only examined 100 genes so far. Although these 100 genes are assumed to be the most important ones, the researchers have not yet examined the activities of all the genes involved, which is required for full understanding.

• Second, a beta cell cannot be developed instantly. This takes a whole month in the laboratory, and many things can go wrong. The process takes even longer during fetal development.

• Third, the researchers are working on enabling cells to develop in an environment that will induce stem cells to end up as an entire pancreas.

“For now, we can induce cells to develop into something that resembles a pancreas based on the functions of individual cells. However, this pancreas is completely flat when we develop it in a Petri dish. The goal is to make one identical to the body’s own pancreas,” says Anne Grapin-Botton.

Anne Grapin-Botton explains that researchers in the United States are already conducting clinical trials in which synthetically developed beta cells are transplanted into people with diabetes.

Understanding human fetal pancreas development using subpopulation sorting, RNA sequencing and single-cell profiling” has been published in Development. Anne Grapin-Botton is a professor affiliated with the Novo Nordisk Foundation Center for Stem Cell Biology of the University of Copenhagen. The Novo Nordisk Foundation awarded research grants of almost DKK 700 million to the Center in 2010–2017.

Anne Grapin-Botton has a background in developmental biology and initially studied nervous system and endoderm development. Her laboratory is currentl...

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