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Body and mind

New study sorts out how the destiny of cells is determined

Both inheritance and environment determine a person’s fate, but what determines the fate of a cell? Does inheritance predetermine the fate of a cell at birth or does its fate depend on the environment in which a cell develops? This knowledge is vitally important for inducing stem cells to differentiate into certain types of cells and has been the subject of many scientific discussions. Now researchers have found an answer, which might ultimately help treat both cancer and diabetes.

Many diseases are caused by the loss of certain types of cells, such as the insulin-producing beta cells in diabetes – or dysfunction of cells, as in cancer. Stem cell researchers have struggled for years to excel at restoring the normal healthy cell types. Henrik Semb’s group at the Novo Nordisk Foundation Center for Stem Cell Biology, DanStem studies the mouse pancreas to find out how the insulin-producing beta cells are formed naturally in the body and how stem cells can be induced to behave the same way in a petri dish.

“We examined how much immature cells – progenitor cells – move around as the pancreas develops in the embryo. And whether their journey to distinct niches within the organ can explain what they eventually will become. We discovered that, before the progenitors have decided their fate, they move around a lot and that their movement is determined by how much of the P120ctn protein they produce. By understanding this mechanism, we can improve our methods for making the correct cell type for future cell-replacement therapy for diseases such as type 1 diabetes and get new insight into how to prevent cancer from spreading,” explains Henrik Semb, Professor and Executive Director, Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, University of Copenhagen.

A cell’s fate is dictated by how sticky it is

Restoring the function of dysfunctional organs requires understanding how organ shape emerges and how it influences the fate of cells. Previous research has generated conflicting results. Some results suggest that the future fate of progenitor cells is predetermined, with their fate being decided by inheritance before they end up in their final niche, whereas other results suggest the opposite: that their destiny is determined at their final destination, the environment.

“We therefore decided to take a closer look at this problem by examining in greater detail how progenitor cells move around and whether their movements correlate with their final fate. By recording three-dimensional movies of fluorescently labelled individual progenitor cells within the early pancreas, we realized that the progenitor cells, before their fate decision, continue to change their positions to shape the architecture of the pancreas,” explains first author Pia Nyeng, Assistant Professor, DanStem.

This observation strongly indicates that the fates of cells do not appear to be predetermined but rather determined by the particular niche at their final destination. To examine how the final positioning of cells in the organ is controlled, the researchers found that the P120ctn signalling protein plays an important role.

“This protein affects adhesion – stickiness – between the cells. Cells with high expression of P120ctn are more adhesive than cells with low expression of P120ctn. We observed that cells with high expression of P120ctn remain in the central part of the pancreas, whereas cells with low expression of P120ctn migrate toward the peripheral part of the pancreas. The cells are sorting based on their level of p120ctn.”

Both inheritance and environment

The fetal pancreas has two separate domains – a domain in the centre where the insulin-producing beta cells develop and a peripheral domain where the enzyme-producing acinar cells emerge. To test their theory, the researchers reduced adhesion in a few progenitors within the central part of the pancreas by inactivating the gene encoding P120ctn.

“By using movies to analyse the behaviour of these cells, we saw that they migrated to the peripheral part of the pancreas and developed into enzyme-producing acinar cells.”

Thus, the progenitor cells’ final environment is undoubtedly crucial for the direction in which the cells develop, and the amount of p120ctn in a given cell dictates the destination.

“One can say that adhesion predetermines the fate of progenitor cells, even before they reach their niche. In other words, both inheritance – the level of p120ctn – and the environment – the niche – dictate the final fate.”

Towards treatments for diabetes and cancer

The researchers also observed another very interesting phenomenon: P120ctn also influences the differentiation of specific types of endocrine cells later in the development of the pancreas.

“If we remove p120ctn from cells after they have been directed towards a hormone-producing fate, most of them become glucagon-secreting cells rather than insulin-secreting cells. This important new knowledge helps us to control the fate of stem cell–derived pancreatic progenitors in the laboratory for disease modelling and cell therapy applications,” explains Henrik Semb.

Spreading of cancer is strongly connected to a decrease in the adhesive properties of cancer cells. Decreased adhesion enables the cancer cells in an organ to leave the niche from which they came and invade the surrounding tissues, including the blood vessels, to metastasize to other organs. Cancer research has therefore focused on trying to prevent the decrease in adhesion or to reinstate high adhesion in cancer cells without worrying so much about whether this could lead to higher adhesion than in the healthy cells.

“Our experiments show that what drives the segregation of cells is their intrinsic differences in adhesion. This suggests that it is not the cells’ adhesive characteristics per se but rather their relative adhesion to the neighbouring cells that dictates whether they will segregate – invade neighbouring tissue in cancer. To counteract metastasis, cancer therapy should therefore try to reinstate normal levels of adhesion.”

P120ctn-mediated organ patterning precedes and determines pancreatic progenitor fate” has been published in Developmental Cell. Henrik Semb, Professor and Executive Director, Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, University of Copenhagen, is the last author. Pia Nyeng, Assistant Professor, DanStem, is the first author. The Foundation has awarded grants of almost DKK 700 million (€92 million) to DanStem for research between 2010 and 2018.

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/
Pia Nyeng
Assistant professor
My main research interest is formation and maintenance of the 3D architecture of epithelial organs during embryonic development. I have identified mechanisms for how the resulting 3D environment regulates stem cell maintenance and cell fate determination. In order to address these questions I have studied the embryonic lung, intestine, stomach and pancreas of transgenic mouse models and developed novel live imaging methods.