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Creating mammal tissue from simple instructions
Many of the complex folded shapes that form mammalian tissues can be recreated from very simple instructions. University of California San Francisco (UCSF) bioengineers reported the results of their efforts this past December 28 in the journal Developmental Cell. By injecting active mouse and human cells into thin layers of an extracellular matrix of fibers, researchers recreated the bowls, coils, and ripple shapes found in living tissues. Cells then collaborated with other cells through that web of fibers to fold into the predictable shapes mimicking natural ones found in fetal development.
"Development is starting to become a canvas for engineering. By breaking the complexity of development into simpler engineering principles, scientists are beginning to understand and control fundamental biology," explains senior author Zev Gartner, Center for Cellular Construction, University of California, San Francisco. "In this case, the intrinsic ability of active cells to promote change in shape, is a fantastic chassis for building complex and functional synthetic tissues."
Labs already use 3D printing, or micro-molding, to create 3D shapes in tissue engineering, but the final product often misses key structural features that grow according to developmental programming. The Gartner lab approach uses a precision 3D cell-patterning technology called DNA-Programmed Assembly of Cells (DPAC) to set up an initial spatial template. The tissue then folds itself into complex shapes in ways that replicate how tissues assemble hierarchically during actual 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. It's a totally new angle in tissue engineering."
"It was astonishing how well this idea worked and how simply cells behave," says Gartner. "This idea showed that robust developmental design principles, from an engineering perspective, are only limited by imagination."."
Gartner and his team now want to see if they can stitch together programs controlling tissue folding with programs that control tissue patterning. They want to know how cells differentiate in response to mechanical changes occurring during tissue folding in vivo — taking inspiration from the stages of embryo development.
• Mesenchymal condensation involves myosin II-dependent compaction of ECM
• Reconstituted condensates compact ECM and drive curvature at tissue interfaces
• Finite element modeling of condensation mechanics predicts tissue folding patterns
• Arrays of condensates encode complex curvature profiles of reconstituted tissues
Many tissues fold into complex shapes during development. Controlling this process in vitro would represent an important advance for tissue engineering. We use embryonic tissue explants, finite element modeling, and 3D cell-patterning techniques to show that mechanical compaction of the extracellular matrix during mesenchymal condensation is sufficient to drive tissue folding along programmed trajectories. The process requires cell contractility, generates strains at tissue interfaces, and causes patterns of collagen alignment around and between condensates. Aligned collagen fibers support elevated tensions that promote the folding of interfaces along paths that can be predicted by modeling. We demonstrate the robustness and versatility of this strategy for sculpting tissue interfaces by directing the morphogenesis of a variety of folded tissue forms from patterns of mesenchymal condensates. These studies provide insight into the active mechanical properties of the embryonic mesenchyme and establish engineering strategies for more robustly directing tissue morphogenesis ex vivo.
Authors: Alex J. Hughes, Hikaru Miyazaki, Maxwell C. Coyle, Jesse Zhang, Matthew T. Laurie, Daniel Chu, Zuzana Vavrušová, Richard A. Schneider, Ophir D. Klein4, Zev J. Gartner
Developmental Cell, published by Cell Press, is a bimonthly, cross-disciplinary journal that brings together the fields of cell biology and developmental biology. Articles provide new biological insight of cell proliferation, intracellular targeting, cell polarity, membrane traffic, cell migration, stem cell biology, chromatin regulation and function, differentiation, morphogenesis and biomechanics, and regeneration and cellular homeostasis. Visit: http://www.cell.com/developmental-cell. To receive Cell Press media alerts, contact firstname.lastname@example.org.
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Shapes made from living tissue after mechanically patterning active mouse and human cells onto thin layers of extracellular fibers making bowls, coils, and ripple shapes. Image credit: Alex Hughes.