New Method Creates Organoids with High Physiological Relevance

Established methods of making organoids come with considerable drawbacks that often result in overall anatomical and/or physiological inconsistency with real-life organs.

Now, scientists from EPFL's Institute of Bioengineering have found a way to "guide" stem cells to form an intestinal organoid that looks and functions just like a real tissue. Their method, which is described in a paper published today in Nature, exploits the ability of stem cells to grow and organize themselves along a tube-shaped scaffold that mimics the surface of the native tissue, placed inside a microfluidic chip.

The EPFL researchers used a laser to sculpt this gut-shaped scaffold within a hydrogel. Aside from being the substrate on which the stem cells could grow, the hydrogel also provides the form or "geometry" that would build the final intestinal tissue. Once seeded in the gut-like scaffold, within hours, the stem cells spread across the scaffold, forming a continuous layer of cells. The scientists also found that, the stem cells just "knew" how to arrange themselves in order to form a functional tiny gut.

"It looks like the geometry of the hydrogel scaffold, with its crypt-shaped cavities, directly influences the behavior of the stem cells so that they are maintained in the cavities and differentiate in the areas outside, just like in the native tissue," explains study leader Matthias Lütolf. The stem cells didn't just adapt to the shape of the scaffold, they produced all the key differentiated cell types found in the real gut, with some rare and specialized cell types normally not found in organoids.

The researchers demonstrate that these miniature intestines share many functional features with their in vivo counterparts. For example, they can regenerate after massive tissue damage and they can be used to model inflammatory processes or host-microbe interactions in a way not previously possible with any other tissue model grown in the laboratory.

In addition, this approach is broadly applicable for the growth of miniature tissues from stem cells derived from other organs such as the lung, liver or pancreas, and from biopsies of human patients. "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," adds Lütolf.