Engineering the development of the pancreas

To the point:

Tissue engineering the pancreas: Working with three-dimensional pancreatic models (organoids), derived from mouse cells, researchers combined computer simulations with experiments to find out what controls the shape of lumens (fluid-filled cavities) during the development of the pancreas.

Proliferation, Pressure, Permeability: The shape of the lumen depends on the balance between the cell proliferation rate and the pressure in the lumen. Low pressure and high proliferation produce more complex or ‘star-shaped’ lumens. The pressure in lumens remain low because the surrounding pancreatic tissue is permeable. 

Implications for organ development and disease: The discovered mechanisms can be potentially relevant to other organs with complex ductal systems and to common cystic diseases. Furthermore, these findings could be used to develop new therapeutic strategies, including testing the effects of drugs for diseases.

Organs often have fluid-filled spaces called lumens, which are crucial for organ function and serve as transport and delivery networks. Lumens in the pancreas form a complex ductal system, and its channels transport digestive enzymes to the small intestine. Understanding how this system forms in embryonic development is essential, both for normal organ formation and for diagnosing and treating pancreatic disorders. Despite their importance, how lumens take certain shapes is not fully understood, as studies in other models have largely been limited to the formation of single, spherical lumens. Organoid models, which more closely mimic the physiological characteristics of real organs, can exhibit a range of lumen morphologies, such as complex networks of thin tubes.
 
Researchers in the group of Anne Grapin-Botton, director at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany, and also Honorary Professor at TU Dresden, teamed up with colleagues from the group of Masaki Sano at the University of Tokyo (Japan), Tetsuya Hiraiwa at the Institute of Physics of Academia Sinica (Taiwan), and with Daniel Rivéline at the Institut de Génétique et de Biologie Moléculaire et Cellulaire (France) to explore the processes involved in complex lumen formation. Working with a combination of computational modeling and experimental techniques, the scientists were able to identify the crucial factors that control lumen shape. 

Star-shaped lumen resembles real panceas
“Three-dimensional pancreatic structures, also called pancreatic organoids, can form either large spherical lumen or narrow complex interconnected lumen structures, depending on the medium in the dish,” says Byung Ho Lee, postdoctoral researcher in the group of Anne Grapin-Botton and lead author of the study. “By adding specific chemical drugs altering cell proliferation rate and pressure in the lumen, we were able to change lumen shape. We also found that making the epithelial cells surrounding the lumen more permeable reduces pressure and can change the shape of the lumen as well.”
 
“Our model can measure and predict which parameters account for the transitions of the lumen shapes, enabling feedback into the experiments themselves” says Kana Fuji, doctoral student in the research group of Masaki Sano. To understand how individual cells grow and divide and how this affects the formation of the lumen, the research team used a mathematical model in addition to the experiments to simulate the process.

“Our study shows that the shape and structure of the lumen in pancreatic organoids depend on three main factors: how fast cells proliferate, the pressure inside the lumen, and how permeable the cells around the lumen are,” says Anne Grapin-Botton, who supervised the study together with Byung Ho Lee. “This discovery could help us understand how other organs with narrow interconnected ducts develop and how common cystic diseases affect them. Our model system could further research in the field of organ development and tissue engineering and also potentially be used to test how different drugs affect diseases, which could lead to new treatments. This could help us better understand and treat diseases that affect the pancreas and other organs with branching ducts.”