Hans Clevers, PhD, has been working on organoids from the beginning. He was group leader for twenty years at the Hubrecht Institute and has been head of pharma research and early development (pRED) of Roche, since March 2022.
The latest advance from Clevers and his group is the development of a new organoid that mimics the human fetal pancreas, offering a clearer view into its early development. The complete structure includes the three key cell types in the pancreas, which previous organoids couldn’t fully mimic. The team also identified a new stem cell that develops into the three cell types.
These findings are published in Cell in the paper, “Long-term in vitro expansion of a human fetal pancreas stem cell that generates all three pancreatic cell lineages.”
The pancreas consists of three epithelial compartments which derive from a common pancreatic progenitor: the acini and ducts of the exocrine pancreas and the endocrine islets of Langerhans. 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.
Most pancreatic organoids (up until now) contained only one type of cell. But Amanda Andersson-Rolf, PhD, and colleagues were able to create an organoid that contained the three main types of pancreas cells.
“We wanted to create an organoid that includes all the cell types found in a real pancreas,” explained Andersson-Rolf, a postdoctoral researcher in the Clevers lab. “With such an organoid, we could study how these different cells interact and gain a deeper understanding of how the pancreas develops.”
More specifically, the researchers report “derivation of 18 human fetal pancreas organoid lines from gestational weeks 8–17 fetal pancreas samples. Four of these lines, derived from 15 to 16 gestational weeks samples, generate acinar-, ductal-, and endocrine-lineage cells while expanding exponentially for >2 years under optimized culture conditions.”
In addition, the team used single-cell RNA sequencing to identify rare LGR5+ cells in the fetal pancreas and in human fetal pancreas organoids as the root of the developmental hierarchy. Moreover, the “organoids derived from the single LGR5+ organoid-derived cells recapitulated the tripotency in vitro.”
“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 continued. “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.”
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 said. 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 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 explained. “Our research highlights the importance of studying human biology, as we couldn’t have discovered this using animal cells,” she noted.
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 said. “We are just starting to scratch the surface.”
