Scientists have discovered the signals that determine the fate of immature cells in the pancreas.
New research shows that these cells are very mobile and that their destiny is strongly influenced by their immediate environment.
The hope is this breakthrough will facilitate the manufacturing of pancreatic islet cells from stem cells which might help to combat type 1 diabetes.
Type 1 diabetes is an autoimmune disease destroying the insulin-producing beta cells in the patient’s pancreas.
Current approaches for replacement therapies aim to generate insulin-producing beta cells from human pluripotent stem cells.
Until now, the engineering of specialized cells from pluripotent stem cells has largely been based on knowledge of what works.
“We have now been able to map the signal that determines whether pancreatic progenitor cells will become endocrine, such as insulin-producing beta cells or duct cells,” explains Dr. Henrik Semb, who led the study.
Semb is the director of the Institute of Translational Stem Cell Research at Helmholtz Zentrum München as well as professor and executive director of the Novo Nordisk Foundation Center for Stem Cell Biology at the University of Copenhagen.
“The cells are analogous to pinballs, whose ultimate score is based on the sum of pin encounters,” he says, “They are constantly moving around within the developing pancreas, leading to frequent environmental changes. We show that the exposure to specific extracellular matrix components determines the ultimate destiny of the cells.”
How does the matrix determine destiny?
The researcher’s investigation showed that interactions with different extracellular matrix components change the mechanical force state within the progenitor.
These forces result from interactions between the extracellular matrix, outside the cell, and within the cell.
Pancreatic endocrine cells include all hormone-producing cells, such as insulin-producing beta cells and glucagon-producing alpha cells, within the islet of Langerhans, whereas the duct cells are epithelial cells that line the ducts of the pancreas.
Semb and his team’s experiments show that exposure to the extracellular matrix laminin instructs the progenitor cells towards an endocrine fate by reducing mechanical forces within the cells.
And vice versa: exposure to fibronectin results in a duct fate because of increased mechanical forces.
“We can now replace significant numbers of empirically derived substances, whose mode of action in current state-of-the-art differentiation protocols is largely unknown, with small molecule inhibitors that target specific components of the newly identified mechano-signaling pathway,” Semb explains.
With this new strategy, insulin-producing beta cells can now be more cost-effectively and robustly produced from human pluripotent stem cells for future treatments against diabetes.
“Our discovery breaks new ground because it explains how multipotent progenitor cells mature into different cell types during organ formation,” Semb says.
“It also gives us the tools to recreate the processes in the laboratory, to more precisely engineer cells that are lost or damaged in severe diseases, such as type 1 diabetes and neurodegenerative diseases, for future cell replacement therapies.”
The research has been published in the journal Nature.
Image Credit: DanStem ©. Image of an embryonic pancreatic bud cultured ex vivo.
Next step towards replacement therapy in type 1 diabetes. 2018, November 28. EurekAlert! Retrieved: https://www.eurekalert.org/pub_releases/2018-11/hzm–nst112718.php