The field of regenerative medicine holds great promise, propelled by a growing understanding of how stem cells differentiate themselves into many of the body’s different cell types. But clinical applications in the field have been slow to materialize, partially owing to difficulties in replicating the conditions these cells naturally experience.

Now, a team of researchers, including Jason Burdick, an associate professor of bioengineering in the School of Engineering and Applied Science (SEAS), Christopher Chen, the Skirkanich Professor of Innovation at SEAS, and former SEAS graduate student Sudhir Khetan, has generated new insight into the importance of a stem cell’s three-dimensional environment.

“We’re trying to understand how material signals can dictate stem cell response,” Burdick says. “Rather than considering the material as an inert structure, it’s really guiding stem cell fate and differentiation—what kind of cells they will turn into.”

The team worked with mesenchymal stem cells, which are found in bone marrow and can turn into fat, cartilage, or bone cells. When this type of stem cell is grown on top of a two-dimensional gel film, the gel’s stiffness has an effect on how the cells differentiate. Softer environments produce more fat-like cells, while more rigid environments, where the cells can pull on the gel harder, produce more bone-like cells.

However, when encapsulated in a three-dimensional gel matrix, the researchers found this principle did not apply; they produced fat-like cells regardless of the gel’s stiffness. The researchers reasoned that the cells couldn’t get a “grip” on their surrounding environment because they couldn’t spread past the bonds that held the gel together.

To test this hypothesis, Burdick’s team made a gel that contained bonds that the stem cells could naturally degrade, enabling them to spread out as they grew. The researchers were able to track how much the cells were pulling on the surrounding gel, and saw that the better grip they had, the more likely they were to become bone-like cells.

For another test, the researchers made an additional type of gel; this one had the same degradable bonds, but also had a separate kind of bond that the cells could not break down, and only formed when the gel was exposed to light. When the researchers generated these bonds after the stem cells had spread, they ended up as fat-like cells.

Burdick and his colleagues believe these results will help to develop a better fundamental understanding of how to engineer tissues using stem cells. 

“This is a model system for showing how the microenvironment can influence the fate of the cells,” Burdick says.