Next step towards replacement therapy for type 1 diabetes

Scientists have discovered the signals that determine the fate of immature cells in the pancreas. Research shows that they are very mobile and that their destiny is strongly influenced by their immediate environment. This breakthrough published in the journal Nature will facilitate the manufacture of pancreatic islet cells from stem cells and could contribute to the fight against type 1 diabetes. Professor Henrik Semb, who led the study, recently joined Helmholtz Zentrum München. Follow the link to see Henrik Semb explain the paper in one word: https: //vimeo.com /303012751

Type 1 diabetes is an autoimmune disease that destroys insulin-producing beta cells in the patient's pancreas. Current approaches to alternative therapies aim to generate insulin-producing beta cells from human pluripotent stem cells. Until now, the engineering of specialized cells from pluripotent stem cells was largely based on an empirical knowledge of what works. "We have now been able to map the signal that determines whether the pancreatic progenitor cells will become endocrine, such as insulin-producing beta cells or channel cells," explains Professor Henrik Semb. He is Director of the Stem Cell Translational Research Institute at Helmholtz Zentrum München as well as Professor and Executive Director of the Center for Stem Cell Biology of the Novo Nordisk Foundation (DanStem) at the University of Copenhagen.

"The cells are analogous to pinballs, whose final score is based on the sum of pine encounters.They move constantly in the developing pancreas, causing frequent environmental changes.We show that exposure to specific components extracellular matrix determines the ultimate fate of cells, "Semb explains.

Progenitor cells are similar to stem cells because they can both self-renew and differentiate into mature cell types. However, their ability to self-renew is usually limited compared to that of stem cells. The dynamic behavior of progenitors during organ formation makes them difficult to study. To overcome this obstacle, the scientist has seeded progenitors derived from human stem cells on microbatched glass slides with different matrix proteins. Using this approach, researchers could study how each progenitor, without the influence of neighboring cells, reacts to its environment. "This allowed us to discover something very surprising.Our investigation revealed that interactions with different components of the extracellular matrix modify the state of the mechanical force within the progenitor.These forces result from interactions between the matrix. extracellular, located on the outside of the cell, and the actin cytoskeleton, which is in the cell. "

Pancreatic endocrine cells include all hormone-producing cells, such as insulin-producing beta cells and glucagon producing alpha cells, in the islet of Langerhans, whereas the cells of the channels are cells. epithelial lining of the pancreatic ducts. "Experiments show that exposure to matrix extracellular laminin orients progenitor cells to an endocrine fate by reducing mechanical forces in the cells.Inversely, exposure to fibronectin results in a fate in the ducts." because of the increase in mechanical forces. "

Through detailed analyzes done by the first two authors of DanStem Drs. Researchers Anant Mamidi and Christy Prawiro then discovered the molecular details of the corresponding signaling pathway * and even validated the physiological relevance in vivo during pancreas development. "We can now replace a large number of empirically derived substances, whose mode of action in state-of-the-art differentiation protocols is largely unknown, with small molecule inhibitors targeting components. of the newly identified mechano-localization route, "explains Henrik Semb.

With this new strategy, insulin-producing beta cells can now be produced more cost-effectively and robustly from human pluripotent stem cells for future diabetes treatments. "Our discovery is innovative as it explains how multipotent progenitor cells transform into different types of cells during organ formation," Semb said. "It also gives us the tools to recreate lab processes to more accurately create lost or damaged cells for serious diseases, such as type 1 diabetes and neurodegenerative diseases, for future cell replacement therapies." . "

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* They showed that components of the extracellular matrix trigger a signal in the cell via an integrin receptor, resulting in changes in the mechanical forces transmitted by the actin cytoskeleton. The yes-associated protein (YAP) then detects these forces to activate and deactivate specific genes. This cascade determines the ultimate destiny of the progenitor cell. "Perhaps the most surprising result is that our data respond to an enigma that has been baffling the field for decades," said Henrik Semb. "How some progenitors mature in the cells of the channels, while others become endocrine cells via Notch signals." Researchers have shown that the apparently stochastic regulation of Notch function is in fact induced by progenitor encounters with extracellular matrix interactions via the regulatory protein of the YAP gene, a force sensor.

Original publication:
Mamidi, A. and Prawiro, C. et al. (2018): Mechanosignalization via integrins orients the decisions of fate of pancreatic progenitors. Nature, DOI: 10.1038 / s41586-018-0762-2

Helmholtz Zentrum München, the German research center for environmental health, pursues the goal of developing personalized medical approaches for the prevention and treatment of major common diseases such as diabetes, allergies and lung diseases. To do this, he studies the interactions between genetics, environmental factors and lifestyle. Helmholtz Zentrum München is headquartered in Neuherberg, north of Munich, with approximately 2,300 employees. He is a member of the Helmholtz Association, a community of 18 scientific, technical and medico-biological research centers with a total of 37,000 staff members. http: // www.Helmholtz-muenchen.fromin

The Stem Cell Translational Research Institute (STI) aims to develop stem cell-based alternative therapy in type 1 diabetes. Scientists aim to develop safe approaches to large-scale production of insulin-producing beta cells from human pluripotent stem cells (hPSC). An important short-term step is the proper production of the cells according to the defined standards of good manufacturing practice (GMP). To this end, ITS collaborates closely with the University of Copenhagen. http: // www.Helmholtz-muenchen.fromhis

Media Contact:
Department of Communication, Helmholtz Zentrum München – German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg – Tel. +49 89 3187 2238 – E-mail: [email protected]

Scientific contact at Helmholtz Zentrum München:
Dr. Tor Henrik Semb, Helmholtz Zentrum München – German Center for Environmental Health Research, Institute for Translational Stem Cell Research, Ingolstädter Landstr. 1, 85764 Neuherberg – Tel. +49 89 3187-49133 – E-mail: [email protected]