Using embryonic tissue explants, finite element modeling, and 3D cell-patterning techniques, a research team have shown that mechanical compaction of the extracellular matrix during mesenchymal condensation is sufficient to drive tissue folding along programmed trajectories.
Many of the complex folded shapes that form mammalian tissues can be recreated with very simple instructions.
By patterning mechanically active mouse or human cells to thin layers of extracellular matrix fibers, the researchers could create bowls, coils, and ripples out of living tissue. The cells collaborated mechanically through a web of these fibers to fold themselves up in predictable ways, mimicking natural developmental processes.
Labs already use 3D printing or micro-molding to create 3D shapes for tissue engineering, but the final product often misses key structural features of tissues that grow according developmental programs. The Gartner lab's approach uses a precision 3D cell-patterning technology called DNA-programmed assembly of cells (DPAC) to set up an initial spatial template of a tissue that then folds itself into complex shapes in ways that replicate how tissues assemble themselves hierarchically during development.
"We're beginning to see that it's possible to break down natural developmental processes into engineering principles that we can then repurpose to build and understand tissues," says first author Alex Hughes, a postdoctoral fellow at UCSF. "It's a totally new angle in tissue engineering."
"It was astonishing to me about how well this idea worked and how simply the cells behave," Gartner says. "This idea showed us that when we reveal robust developmental design principles, what we can do with them from an engineering perspective is only limited by our imagination. Alex was able to make living constructs that shape-shifted in ways that were very close to what our simple models predicted."
Gartner and his team are now curious to learn whether they can stitch the developmental program that control tissue folding together with others that control tissue patterning. They also hope to begin to understand how cells differentiate in response to the mechanical changes that occur during tissue folding in vivo, taking inspiration from specific stages of embryo development.