Image of a section of the pancreatic organoid, visible through a microscope. The cell nucleus is in blue, somatostatin is in green and C-peptide is in magenta. Source: Dr. Amanda Andersson-Rolf.
You most likely have heard of beta cells due to their role in diabetes. Beta cells are endocrine cells that release insulin, which signals cells to intake glucose from the blood. Alpha cells, which I like to think of as the opposite of beta cells, release glucagon, signalling cells to release glucose into the blood. Both are in a delicate balance. Other pancreatic endocrine cells, such as somatostatin and ghrelin, regulate glucose homeostasis and satiety signalling.
Unlike endocrine cells, which release hormones directly into the bloodstream, acinar cells release their enzymes into a tubular network of ductal cells. They are transported through ductal tubules and land in the small intestine to digest our food. The digestive enzymes, such as amylase, lipase and trypsin, help break down sugars, fats and peptides, respectively.
Organoids are 3D miniature organs that grow from stem cells that can produce all or some of the different kinds of organ-specific cells as part of their progeny. Therefore, some organoids reflect the diversity of cell types found in a single organ, as well as the interconnective network between the various cell types. Observing how different cell types interact with each other and the environment helps scientists understand what makes a healthy functional organ.
If organoids are created by a human stem cell (rather than a mouse stem cell) it offers a way to model 3D human organs. Organoids have become a popular model system in the scientific community because these self-organizing 3D structures can mimic human organ generation and they have the potential to overcome the limitations of using animal models for drug discovery (for example, high failure rates in clinical trials and ethical concerns). Intestinal organoids and brain organoids have been successfully cultured and grown for a while now. However, there is something about the pancreas organ that has made it extremely difficult to model in its entirety in the lab.
Previously, scientists have only been able to create pancreatic organoids made exclusively of endocrine cells or organoids made entirely of duct cells. Since these organoids do not contain all three pancreatic cell types (or the progenitors that make all three of them), they do not reflect the cellular heterogeneity found in the human pancreas organ.
Dr. Amanda Andersson-Rolf
Creating a pancreatic organoid with all three cell types has not been possible until now. Dr. Amanda Andersson-Rolf, who was a post-doctoral fellow in the Hans Clevers lab (at Hubrecht Institute, Netherlands) and her team, have finally created an organoid that has all three differentiated cell types. To establish their organoid, the group took cells directly from the human fetal pancreas (from the first and second trimester).
Depending on what media you give the organoid, it will produce more endocrine cells or more acinar cells.
These endocrine cells and acinar cells can produce their corresponding hormones and digestive enzymes, which is great, but can these cells also release them? The answer is yes! The researchers were successful in showing that beta cells release C-peptide (this shows that they most likely also release insulin) and that acinar cells can release their corresponding enzymes.
This fact is important because being able to actually release the hormones and digestive enzymes is indicative of a more mature, differentiated functional cell. In the long term, the ability to generate endocrine and acinar cells provides scientists with the possibility to study Type 1 diabetes (which affects endocrine beta cells) as well as pancreatic acinar cell carcinoma (which affects acinar cells). The ultimate goal is to be able to generate these cell types for regenerative therapies and identify drug targets for pancreatic cancers. Although far off into the future, scientists would also like to someday use the whole organoid as a tool for organ transplantation due to organ donor shortages.
For the pancreas, we may be a long way off from being able to transplant the whole organ, especially since even the mature cells within the organoid created by the Hans Clevers lab still resemble the first/second-trimester fetal stage rather than adult cells. However, being able to create the pancreas organ with all its cell types inside a dish means we can study how all these cell types interact with each other, develop, and ultimately create the human pancreas. It could also help us understand which types of cells to use to grow a pancreas organoid.
Furthermore, it appears that these organoids, made of tens of thousands of cells, originate from a single stem cell and that this stem cell has a stem cell marker called LGR5 (a type of receptor on the cell surface). Since this stem cell can ultimately differentiate into all three cell types of the pancreas – endocrine, acinar, and duct – we call it tripotent. Knowing that LGR5 labels the human embryonic pancreatic stem cell will make it easier to repeatedly isolate not only the pancreatic stem cell, but its downstream beta cell or acinar cell, which may make it easier to conduct future clinically relevant repeatable studies.
It is interesting to note that for mice, LGR5 expression does not seem to be a pancreatic stem cell or progenitor marker during development or in adulthood under normal conditions (although when the adult mouse pancreas is injured, ductal cells will express LGR5 and act as stem/progenitor cells).
There are many other differences between a mouse pancreas and the human pancreas on a cellular and developmental level. “As a result, it is not always possible to extrapolate from mouse to human. The processes of pancreatic development are slightly different. Timeline-wise, […] we wouldn’t have expected to find tripotent stem cells so late in human development as we do [based on previous studies in mice],” Dr. Andersson-Rolf explained in an interview with me.
That is why one of the main advantages of Dr. Andersson-Rolf’s and her team’s pancreatic organoid is that we can study human pancreas development and how a single human LGR5+ stem cell creates all three differentiated cell types. Although mouse models have been extremely useful, there are inherent species-specific differences between the mouse and human pancreas. For example, organ morphology, the proportion of the endocrine cells, and certain events in development.
Having an organoid that reflects the diversity of human pancreatic cells reduces our reliance on animal models or using pure populations of one homogenous pancreatic cell type (which have little resemblance to human organs) to study disease, developmental processes, or drug therapies that could potentially be used to promote human beta cell regeneration for Type 1 diabetes or reverse human pancreatic cancer.
Specifically, understanding how a human pancreatic stem cell decides to become a beta cell, duct cell, or acinar cell through human organoids will provide insight into how diseases related to the human pancreas develop. Further, organoids derived from human cells that reflect the architecture of the human pancreas would be one of the best ways for scientists to predict how humans will respond to new therapies and to test for the safety and efficacy of pharmaceutical drugs before they reach human clinical trials.
Dr. Andersson-Rolf is now transitioning to becoming a Principal Investigator of her own lab and will continue to investigate pancreas development and disease.
Krystal Jacques
Latest posts by Krystal Jacques (see all)
- Biodegradable electrodes stimulate neural precursor cells to expand and migrate - May 29, 2025
- The first pancreatic organoid with all pancreatic cell types - April 3, 2025
- Freeze-thawing neural stem cells - February 19, 2025
Comments