Researchers from the Organoid group (previously Clevers group) at the Hubrecht Institute have developed a new organoid that mimics the human fetal pancreas, offering a clearer view of its early development. The researchers were able to recreate a complete structure that includes the three key cell types in the pancreas, which previous organoids couldn't fully mimic. Notably, the team identified a new stem cell that develops into the three cell types. These findings, published in Cell on December 2nd, could help researchers better understand the pancreas and develop new treatments for pancreatic diseases in the future.
The pancreas has two main jobs: to help digest food and to manage blood sugar levels. For each of these tasks, the organ uses different types of cells. Scientist can study how the pancreas works by looking at organoids — tiny organs, about 1 mm in size that are grown in the lab. However, most organoids up until now could only exist of one type of cell at a time. This makes it harder for scientists to understand the pancreas as a whole. "We wanted to create an organoid that includes all the cell types found in a real pancreas", explains Amanda Andersson Rolf, first author of the study. "With such an organoid, we could study how these different cells interact and gain a deeper understanding of how the pancreas develops."
Creating a complete organoid
Andersson Rolf and her fellow researchers used tissue from the pancreas to create a new three-dimensional organoid that imitates the human pancreas in its fetal stage. This organoid contained the three main types of pancreas cells: acinar cells, ductal cells, and endocrine cells. Each of these cells plays a vital role. Acinar cells release enzymes that help break down food, while ductal cells form channels to carry the enzymes to the gut. Finally, endocrine cells produce hormones like insulin to control sugar levels in the blood.
"In our organoid, we discovered and characterized a new type of stem cell that has the unique ability to develop into all three cell types", Andersson Rolf continues. "We saw that the three cell types not only formed but also performed their expected functions. The acinar cells released digestive enzymes and the endocrine cells produced hormones."
Pancreas organoid gives new clues
Using these organoids, the researchers discovered new information about how the pancreas develops. "The stem cell of the fetal pancreas is present longer than scientists have seen in earlier studies with mice", Andersson Rolf says. Interestingly, the organoids grown from one of these stem cells can grow rapidly over several years while still being able to produce the three main cell types of the pancreas. Andersson Rolf and her colleagues also found another crucial difference between mouse and human pancreatic development. "We saw the presence of a protein called LGR5, which marks stem cells across different tissues. This protein appears in human pancreatic stem cells but not in mice", Andersson Rolf explains. "Our research highlights the importance of studying human biology, as we couldn't have discovered this using animal cells", she notes.
Future perspective
The new organoid that mimics the fetal pancreas can give scientists new ways to study how genes and the environment affect the development and health of the pancreas. Ultimately, studying these organoids could help develop regenerative therapies and new drugs to treat pancreatic diseases. "However, we first need to fully understand how the cells and molecules in the human pancreas work together during development and in disease", Andersson Rolf explains. "We are just starting to scratch the surface."
Publication
Long-term in vitro expansion of a human fetal pancreas stem cell that generates all three pancreatic cell lineages. Amanda Andersson-Rolf, Kelvin Groot, Jeroen Korving, Harry Begthel, Maaike A.J. Hanegraaf, Michael VanInsberghe, Fredrik Salmén, Stieneke van den Brink, Carmen Lopez-Iglesias, Peter J. Peters, Daniel Kruger, Joep Beumer, Maarten H. Geurts, Anna Alemany, Helmuth Gehart, Françoise Carlotti, Eelco J.P. de Koning, Susana M. Chuva de Sousa Lopes, Alexander van Oudenaarden, Johan van Es, Hans Clevers. Cell 2024.
About the Hubrecht Institute
Research at the Hubrecht Institute is pioneering in developmental and stem cell biology. The institute encompasses 20 research groups that perform fundamental, multidisciplinary research on healthy and diseased cells, tissues and organisms.The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences ( KNAW ), situated on the Utrecht Science Park. Since 2008, the Hubrecht is affiliated with the UMC Utrecht. This allowed the institute to grow into an internationally renowned research institute and facilitated the link with (pre)clinical research. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory ( EMBL ) based on shared institutional goals, scientific synergy and complementarity.
About Hans Clevers
Hans Clevers is advisor/guest researcher at the Hubrecht Institute for Developmental Biology and Stem Cell Research ( KNAW ) and at the Princess Máxima Center for Pediatric Oncology. He holds a professorship in Molecular Genetics from the Utrecht University and is Investigator at Oncode Institute. Hans Clevers has been the Head of Pharma Research and Early Development (pRED) at Roche since 2022. He previously held directorship/President positions at the Hubrecht Institute, the Royal Netherlands Academy of Arts and Sciences and the Princess Máxima Center for pediatric oncology.
