The marker Flattop subdivides the insulin-producing beta cells of the pancreas into those that maintain glucose metabolism and into immature cells that divide more frequently and adapt to metabolic changes. This could provide a starting point for regenerative diabetes therapies, as scientists of the Technical University of Munich (TUM), in collaboration with colleagues of Helmholtz Zentrum München and the German Center for Diabetes Research (DZD), report in ‘Nature’.
The beta cells of the pancreas produce the metabolic hormone insulin when blood glucose levels rise, in order to keep glucose levels in equilibrium. If the beta cells are destroyed or lose their function, this can lead to serious diseases such as diabetes. However, not all beta cells are identical. “It has long been known that there are different subpopulations of beta cells,” says Professor Heiko Lickert, professor for Beta-Cell-Biology at TUM and director of the Institute of Diabetes and Regeneration Research at Helmholtz Zentrum München. “But until now, the underlying molecular mechanisms have remained elusive.”
Flattop is a marker for mature beta cells
In the current study, the researchers led by Lickert searched for molecular markers subdividing the respective subgroups. One molecule, in particular, captivated their attention: the protein Flattop.* It was present in about 80 percent of all beta cells. These cells effectively determined the glucose concentration of their environment and secreted the corresponding amount of insulin, thus showing the metabolic properties of mature beta cells.
Conversely, the team of researchers observed that beta cells in which no Flattop was measurable showed a particularly high rate of proliferation. “In our experimental model, these cells proliferated up to four times more often than the Flattop-positive cells,” says study leader Lickert.
A type of precursor cells?
To pursue the hypothesis that the actively dividing cells (without Flattop) could be precursors of metabolically active cells, the scientists made use of a genetic trick to map the fate of single cells. This so called lineage tracing revealed that the proliferative progenitor cells were able to develop into mature beta cells with metabolic properties. This was also the case, when the scientists placed them in an artificial mini-organ-like 3D environment. Moreover, genetic analyses confirmed that in beta cells without Flattop, primarily genes responsible for sensing the environment were expressed, while in cells with Flattop primarily classic metabolic programs took place.
“Our results suggest that the Flattop-negative cells are a kind of immature reserve pool, which constantly renews itself and can replenish the mature beta cells,” Lickert says. According to the study leader this new possibility of subdividing these two subgroups allows a comprehensive analysis of the signaling pathways involved. The results of the researchers raise hopes for the development of regenerative therapies: “The heterogeneity of the beta cells has been studied for more than 50 years, now with enabling technologies it looks like we are beginning to understand how the cells behave,“ says Lickert.
In the future, the scientist will focus on two major aspects: on the one hand in terms of regenerative therapy their goal would be to regenerate endogenous beta cells in a targeted manner to replace dysfunctional or lost cells in patients. On the other hand the findings are a milestone in the generation of functional beta cells from stem cells in cell culture for cell replacement therapy, which was not possible so far.
Prof. Dr. Heiko Lickert
Chair of Beta-Cell-Biology
Technical University of Munich (TUM)
Tel. +49 89 3187 3867
Bader, E. et al. (2016). Identification of proliferative and mature β-cells in the islet of Langerhans, Nature, DOI: 10.1038/nature18624
Migliorini, A. et al. (2016). Impact of islet architecture on beta cell heterogeneity, plasticity and function, Diabetologia, DOI: 10.1007/s00125-016-3949-9
Roscioni, S. et al. (2016). Impact of islet architecture on beta cell heterogeneity, plasticity and function, Nature Reviews Endocrinology, in press
The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. www.helmholtz-muenchen.de
Institute of Diabetes and Regeneration Research
The research activities of the Institute of Diabetes and Regeneration Research (IDR) focus on the biological and physiological study of the pancreas and/or the insulin producing beta cells. Thus, the IDR contributes to the elucidation of the development of diabetes and the discovery of new risk genes of the disease. Experts from the fields of stem cell research and metabolic diseases work together on solutions for regenerative therapy approaches of diabetes. The IDR is part of the Helmholtz Diabetes Center (HDC). www.helmholtz-muenchen.de/idr
German Center for Diabetes Research
The German Center for Diabetes Research (DZD) is a national association that brings together experts in the field of diabetes research and combines basic research, translational research, epidemiology and clinical applications. The aim is to develop novel strategies for personalized prevention and treatment of diabetes. Members are Helmholtz Zentrum München – German Research Center for Environmental Health, the German Diabetes Center in Düsseldorf, the German Institute of Human Nutrition in Potsdam-Rehbrücke, the Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Medical Center Carl Gustav Carus of the TU Dresden and the Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard-Karls-University of Tuebingen together with associated partners at the Universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich. www.dzd-ev.de