A group led by Matthias Lütolf, PhD, Professor at EPFL’s Institute of Bioengineering, have developed a concept to guide stem cells to form functional intestinal organoids. The complexity of these organoids is an important step towards personalised medicine.
Over the past decade, one of the most exciting advancements in stem cell research has been the development of organoid systems. Organoids are three-dimensional cell cultures that are capable of recapitulating some of the key features of their represented organ. The value of organoids is evident across research and medicine. This extends from basic drug discovery and testing, to tissue and even organ replacement in the future. A key drawback of organoids is the fact that stem cells typically have a short lifespan and are restricted in size. As a result, this limits experimental manipulation and prohibits homeostasis.
Guiding stem cells
In this study, published in Nature, researchers from EPFL used tissue engineering and the intrinsic self-organisation properties of cells to induce intestinal stem cells to organise themselves into tube-shaped epithelia that mimic the surface of the native tissue.
The team generated a scaffold that would be permeable to gases, nutrients and macromolecules. They also created the scaffold to facilitate intestinal stem cell adherence, proliferation and differentiation. They integrated hydrogels into a perfusable platform to generate a hybrid microchip system.
Microscopy revealed rapid establishment of a continuous layer of cells and a tightly-packed epithelium expressing high levels of E-cadherin. They found that the tissues remained open and free of cells at both ends; thus, enabling the delivery of fluid and removal of dead cells from the lumen. Consequently, this established a long-lived homeostatic organoid system. These mini intestines consisted of rare, specialised cell types, not often found in conventional organoids. They also retained key physiological hallmarks of the intestine.
“It looks like the geometry of the hydrogel scaffold, with its crypt-shaped cavities, directly influences the behaviour of the stem cells so that they are maintained in the cavities and differentiate in the areas outside, just like in the native tissue.”
The team illustrated that these mini intestines share many functional features with their in vivo counterparts. For example, they found that these tissues could regenerate after tissue damage. Importantly, they found that researchers could use these mini intestines to model inflammatory processes or host-microbe interactions, in a manner not previously possible in other model systems. Researchers could broadly apply this approach to other miniature tissues from stem cells derived from other organs, e.g. the lung.
“Our work shows that tissue engineering can be used to control organoid development and build next-gen organoids with high physiological relevance, opening up exciting perspectives for disease modelling, drug discovery, diagnostics and regenerative medicine.”
Image credit: By Jose Luis Calvo Martin and Jose Enrique Garcia-Mauriño Muzquiz – canva.com