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Body and mind

Stem cell mystery solved: sense of direction determines their destiny

If researchers can control the maturation of stem cells into fully developed cells, they may be able to cure such diseases as diabetes and blindness. By discovering the signals that control these processes in the developing organism, scientists can now mimic them in a test tube. They find that cells’ sense of direction and their surroundings determine their destiny.

How a fertilized egg can divide and develop into a complete human being is a mystery to most people. Stem cell researchers try not to merely understand but also to re-create the process that forms cells, tissue and organs in the laboratory. A Danish research group examined how the body creates the complex piping system that transports fluids and gases through the circulatory system and organs. These groundbreaking results have been published in the latest issue of Nature Cell Biology.

“When you compare the complexity of the human organism to the number of genes in our genome, it seems obvious that our body must reuse many of them in a context-dependent manner.Nevertheless, we were stunned when we realized that the same signal system that controls the creation of tubular systems also regulates the destiny of stem cells,” explains Henrik Semb, Professor and Executive Director, Novo Nordisk Foundation Center for Stem Cell Biology, DanStem.

Initially, the researchers were pretty sure that different signals would have evolved to regulate the creation of tubes and the destiny of stem cells in the same organ. They expected to find a complex system enabling the two processes, but they were wrong.

“We found that the body’s biological piping system influences the structure of an organ – and furthermore that changes in these structures affect the destiny of stem cells within the pipes. We thus came up with the idea that perhaps a common trait of the stem and precursor cells influences both processes.”

Same signal but different effects

Together with international collaborators, Henrik Semb and his co-workers Zarah Löf-Öhlin and Pia Nyeng found that it was the cells polarity – the cell’s ability to sense what is up and down. Whether the cell is facing the lumen of tubes or facing the internal environment is critical at an early stage in the developing pancreas for making the tubular system.

“At a later stage the polarity is crucial for instructing precursor cells to become insulin-producing beta cells. Intriguingly we found that the very same signalling pathway – epidermal growth factor (EGF) signalling – governs both the formation of pipes and the maturation of beta cells by modulating cell polarity. This is a really fantastic and simple mechanism.”

Although both processes are controlled by EGF signalling, they were also able to explain how the pathway is specifically induced to first regulate the tubular system and later the destiny of precursors.

“The fact that many human organs consist of polarized cells suggests that the mechanism they have discovered will also apply to other organs. We are convinced that the dynamic regulation of cell polarity is a key cellular process to control destiny decisions by stem and precursor cells in many organs, such as the nervous system, during embryonic development.”

Striving to cure diabetes

To ensure that the mechanism behind the development of the pancreas is not unique to mice, the researchers decided to examine whether it is conserved in human cells.

“We found that the same mechanism applies to the human pancreas. This emphasizes the significance of this discovery. For many years, we have become better and better at cultivating stem cells and inducing them into insulin-expressing beta cell–like cells. However, the process needs to be made more robust and cost-effective.”

Their discovery addresses both challenges and will contribute to the immense task of making future stem cell–based replacement therapies in diabetes available to everyone who needs them.

“It is obvious that, if we can fully understand the body’s effectiveness and robustness in developing the insulin-producing beta cells, we will improve our ability to copy this process to cultivate human stem cell–derived beta cells in the laboratory. The basic idea is to use human stem cell–derived beta cells to replace lost or dysfunctional beta cells among people with diabetes.”

EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity” has been published in Nature Cell Biology. Henrik Semb, Executive Director, Novo Nordisk Foundation Center for Stem Cell Biology, University of Copenhagen, is a main author. The Novo Nordisk Foundation has awarded grants of almost DKK 700 million to the Center in 2010–2017.

Henrik Semb
Professor
Henrik Semb is professor of stem cell and developmental biology of the pancreas and Executive Director of the Novo Nordisk Foundation Center For Stem Cell Biology at the Faculty of Health and Medical Sciences, University of Copenhagen. His research during the past 15+ years has been focused on elucidating basic mechanism in morphogenesis and cell differentiation during organogenesis using a combination of in vivo and in vitro genetic and cell biological experimental tools. In parallel, Professor Semb is heading a translational research program with particular interest to make human pluripotent stem cells usable as a source for mature insulin-producing beta cells for cell therapy in diabetes. In that area, he recently entered into a strategic partnership and became Director for Translational Stem Cell Research at the Helmholtz Diabetes Center, Helmholtz Zentrum München, in spring 2018. The current focus of the translational program lies on GMP adaptation of differentiation protocols, and establishment of new strategies for efficient expansion of beta cell pancreatic progenitors, towards the first stem cell-based clinical cell replacement . Professor Semb holds several patents and has previously acted as a co-founder and scientific advisor for the Gothenburg based company Cellartis AB that was bought by Takara Bio Inc in 2014. More recently he was involved in the start-up company Pancryos aiming to develop a next generation stem cell derived allogeneic cell therapy for type 1 diabetes. More information about Professor Semb’s ongoing basic and translational research projects can be found at: https://danstem.ku.dk/research1/semb_laboratory/