Next step towards replacement therapy in type 1 diabetes – ScienceDaily

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 badogous to pinballs, whose final score is based on the sum of encounters between pines.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.

The matrix determines the destiny

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 glbad 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. "

The mechanism facilitates the exploitation

Through detailed badyzes 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 manipulate lost or damaged cells during serious diseases, such as type 1 diabetes and neurodegenerative diseases, for future cell replacement therapies." . "