Blog Series with the 3RCC, part 6: Unlocking Growth Secrets: Radially Dispersed Stem Cells Transform Organoid Expansion

Researchers around the globe are investigating innovative techniques for tissue analysis to deepen our understanding of diseases and accelerate the development of new treatments. These efforts also aim to reduce and replace the use of animals in experiments. One promising approach that has emerged involves the use of stem cells, which are unique in their ability to differentiate into various specialized cell types. These cells serve as a foundational building block in the body, capable of transforming into anything from muscle cells to neurons. This versatility allows scientists to study the development and function of specific tissues, offering new insights into disease mechanisms and potential therapeutic applications. By harnessing this capability, scientists can also create mini organs called organoids, which closely mimic human tissues and diseases, providing a valuable and ethical tool for advancing research and medicine.        

A common way to grow stem cells is by placing them in small drops of a three-dimensional gel. However, a big problem with this method is that nutrients can’t easily reach the center of the gel drop, which causes the cells in the middle to die. This limits the ability to use stem-cell-derived mini-organs for longer studies or to create more complex organ structures. As organoids grow, their energy needs increase, requiring more nutrients and oxygen. Current methods can only support their growth for about 10 days, necessitating frequent dissociation and redistribution of cells to continue growing. These steps prevent the formation of more mature organoids needed for studying organ development and performing large-scale drug screenings. To solve this, Sunghee Estelle Park and her colleagues from Dan Huh’s research group in the Department of Bioengineering at the University of Pennsylvania have developed a new method to better distribute nutrients to the cells.

In a groundbreaking study published in Nature Methods, they demonstrated that radially dispersing intestinal organoids derived from mouse cells on a disc-shaped device, named OCTOPUS (Organoid Culture-based Three-dimensional Organogenesis Platform with Unrestricted Supply of soluble signals), allowed organoids to access nutrients and oxygen more effectively, sustaining their growth for up to 21 days. This method helped create more consistent organoids and promoted the development of structures similar to those found in the small intestine.

The researchers then replicated their experiment using cells from the adult human intestine, discovering that the new system excelled at growing enterocytes, the cells responsible for nutrient absorption. This finding is significant because traditional methods tend to favor the growth of cells involved in secretion rather than absorption. The OCTOPUS system’s ability to create these more effective enterocytes makes it valuable for developing human models of the small intestine. The researchers also used cells from children with Crohn’s disease (a type of inflammatory bowel disease) to study this condition in the lab. They were able to reproduce key features of the disease, like tissue damage and inflammation, which helps in understanding and researching treatments for irritable bowel disease.

With OCTOPUS, Sunghee Estelle Park and her colleagues have provided a novel means to facilitate long-term organoid cultures with functionally and physiologically relevant features for the small intestine. This innovative approach has the potential to be adapted for the development of other organoid systems, advancing our understanding of various tissues and diseases. Moreover, it holds promise for revolutionizing drug development and regenerative medicine.

Authors: Christopher Cederroth, Jessica Lampe & Robbie I’Anson Price, Swiss 3R Competence Centre 

Reference:  Park, S.E., Kang, S., Paek, J. et al. (2022) Geometric engineering of organoid culture for enhanced organogenesis in a dish.Nat Methods 19, 1449–1460. https://doi.org/10.1038/s41592-022-01643-8