In the journey from egg to embryo to mature organism, our bodies stretch and wrinkle and fold like a fabulously intricate piece of origami. Now UC San Francisco bioengineers have shown that many of the complex folded shapes that form mammalian body plans and internal tissue structures can be re-created with very simple instructions, setting the stage for future applications ranging from lab-grown organs to soft biological robots.
In their new paper – published Dec. 28, 2017, in the journal Developmental Cell – the researchers found that specialized cells called mesenchymal cells play a special role in folding some tissues during development. Like spiders pulling on their webs, these cells can reach out to tug on the network of ropelike extracellular matrix (ECM) fibers that cells naturally secrete around themselves for structural support.
When mesenchymal cells in different parts of a tissue pull on the web of ECM fibers in tandem, the researchers found, they create forces within the tissue that can cause it to bend and fold into a variety of shapes, from the finger-like villi that line the gut and aid in digestion to the buds that eventually form an animal’s hairs or feathers.
The researchers then demonstrated that they could apply these natural developmental processes to re-create tissue folding in tissue samples in the laboratory. By laying down specific patterns of mouse or human mesenchymal cells, the researchers could cause thin slabs of living tissue to fold themselves into bowls, coils, and ripples, as well as more abstract shapes like cubes not typically found in nature.
“Development is starting to become a canvas for engineering, and by breaking the complexity of development down into simpler engineering principles, scientists are beginning to better understand, and ultimately control, the fundamental biology. In this case, the intrinsic ability of mechanically active cells to promote changes in tissue shape is a fantastic chassis for building complex and functional synthetic tissues,” said senior author Zev Gartner, PhD, an associate professor of pharmaceutical chemistry in the UCSF School of Pharmacy, a Chan Zuckerberg Biohub investigator, and co-director of the UCSF Center for Cellular Construction, a collaborative center whose aim is to “turn biology into an engineering discipline.
One goal of the work, Gartner said, is to improve biologists’ ability to create tissue “organoids” – tiny lab-grown tissues typically grown from stem cells taken from a human patient – which have become an increasingly popular tool in precision medicine, for example to allow researchers to screen drugs effective against a specific patient’s disease.
Labs already use 3-D printing or micro-molding to create 3-D shapes for tissue engineering, but the final product often misses key structural features of tissues that grow according to developmental programs. The Gartner lab’s approach uses a precision 3-D 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.
“Our sense is that you can’t print a final living structure directly with a bioprinter,” Gartner said. “You need to print a template that will evolve over time through a kind of artificial development, or what you might call 4-D bioprinting.”
Gartner and his team are now curious to learn whether they can stitch the developmental program that controls 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. In the future, Gartner imagines using these principles to inform techniques for growing transplantable human organs in the lab or designing soft robots constructed from living, active materials.
“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,” said first author Alex Hughes, PhD, a postdoctoral scholar in Gartner’s lab. “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 said. “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.”
This work was funded by a Jane Coffin Childs postdoctoral fellowship, the National Institutes of Health, the Department of Defense Breast Cancer Research Program, the NIH Common Fund, the Chan Zuckerberg Biohub Investigator Program, the National Science Foundation, the UCSF Program in Breakthrough Biomedical Research, and the UCSF Center for Cellular Construction. See published paper online for full list of authors and contributions.
UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, transitional and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.