Zebrafish reveal the secret origins of β-cells

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How can we improve the treatment and quality of life of diabetic patients? One possible approach involves the renewal of pancreatic β-cells, which are responsible for the production of insulin. A team from the GIGA Research Institute at the University of Liege, led by Isabelle Manfroid and Marianne Voz, has identified pancreatic progenitor cells in zebrafish that will make it possible to regenerate β-cells without the need for grafts or medicine.

The statistics are frightening: more than 340 million diabetics worldwide, more than 5 million deaths every year. Fortunately, an entire community of researchers is actively studying the disease and working to find new treatments. The members of the Zebrafish Development and Disease Models (ZDDM) laboratory, based at the GIGA Research Institute at the University of Liege, are part of this community: “For many years, we have been trying to understand how pancreatic β-cells are formed. These cells play a key role in the development of diabetes,” says Isabelle Manfroid, one of the heads of the ZDDM laboratory.

There are two main types of diabetes. Type 1 is caused by a deregulation of the immune system that destroys β-cells; these patients have to inject themselves with insulin for the rest of their lives. Type 2 is the result of insulin resistance: the tissues targeted by this hormone (such as muscle, liver and adipose tissue) no longer respond. The β-cells try to compensate for this resistance to insulin by producing more of it, but in the long term they become exhausted and die.

Apart from insulin injections (in the case of type 1 diabetes), other therapeutic options exist: “For serious cases, islets of Langerhans grafts are sometimes performed, but unfortunately, the lifespan of the transplanted islets is quite limited, and the disease stabilization is also short-lived,” Manfroid says. “At first, the patients no longer need insulin injections for a period of several months or even years, but then the graft no longer works and they need to revert to daily injections. Another avenue of research that is currently in the development phase aims to inject β-cells generated from human stem cells. However, all of these therapies have significant limitations, and none of them actually cure the disease.”

Regeneration of the zebrafish pancreas

“Another approach, which we have been actively working on, is to stimulate the regeneration of the patient’s β-cells,” Manfroid continues. “To do this, pancreatic stem cells or progenitor cells capable of regenerating the β-cells could be harnessed. However, the existence of pancreatic stem cells in humans and even in mice is shrouded in controversy because it’s deviously difficult to demonstrate their existence.”

We want to understand how regeneration works in zebrafish, so that we can apply this to humans.

How do pancreatic β-cells form in the zebrafish, not only during embryonic development but also in the adult fish? This question has occupied the ZDDM laboratory for several years. The freshwater fish of tropical origin is renowned for its ability to regenerate its own tissues, and this property has sparked the interest of the GIGA researchers. “This regeneration does not happen spontaneously in mice or humans, and it is incomplete,” Manfroid says. “We want to understand how regeneration works in zebrafish, so that we can apply this to humans. Of course, this could take a long time. We need to clarify these regeneration mechanisms and, in time, learn to activate them in diabetic patients.”

The hunt for pancreatic precursors

In an article published in BMC Biology (1), the researchers provided a demonstration of pancreatic progenitors, which are not exactly pancreatic stem cells; they correspond to a slightly later stage in the differentiation of β-cells. Marianne Voz has identified these cells in the embryo: She showed that the cells that express nkx6.1 give rise to β-cells during embryogenesis. Manfroid and her team then looked at the adult: “We saw that the nkx6.1-expressing cells were pancreatic duct cells and that they have the ability to form pancreatic β-cells. We showed that regenerated β-cells, or at least some of them, originate from nkx6.1-expressing cells in the pancreatic ducts.”

By combining and comparing their information, Voz and Manfroid discovered that the nkx6.1-expressing cells can form β-cells at both stages of life and that they share gene expression patterns. “We find ‘embryonic’ properties in the pancreatic duct cells of adult organisms,” Manfroid says. “This explains an array of genes present in the embryo which we know are necessary for the formation of β-cells. This was the first time that we were able to demonstrate this property.”

Over to the mouse?

To carry out this work, the GIGA researchers created a tool that makes it possible to irreversibly mark cells: “We made the progenitor cells fluorescent and, based on their fluorescence, were able to isolate them from the embryo or the adult. We then analyzed their transcriptome over time or in different conditions, like regeneration. Thanks to this very powerful tool, we can mark cells, monitor them and see what happens at a molecular level. It’s a real breakthrough,” says a delighted Voz.
Now that these progenitor cells have been demonstrated, how do the two researchers plan to continue their work? “In the adult model, as far as I am concerned,” Manfroid says. “Now that we have identified the cells that enable regeneration, we need to understand why and how. Once we understand these mechanisms, or at least some of them, we will be able to use mice to see whether we can stimulate these mechanisms. Over the next five years, the main task will be to really elucidate these mechanisms. The transition to using mice as a model could take up to five or six years. Demonstrating that it is possible to transpose the procedure to mammals is a key point.”
“What is important for us to understand is what role nkx6.1 plays in the ducts in the embryo,” Voz adds. “We need to understand how it works in terms of the development of the organism.”


Adapted from reflexions, ULG.

(1) Ghaye, Aurélie P., et al. “Progenitor potential of nkx6.1-expressing cells throughout zebrafish life and during beta cell regeneration.” BMC biology 13.1 (2015): 70.