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June 18, 2018

Optogenetic Hack Advances Synthetic Morphogenesis

Three examples of the tissue shapes the team created. The black and white square, circle, and triangle on the left correspond to the cells that were illuminated. On the right, three fruit fly embryos are shown in cyan, magenta, and yellow, demonstrating how the illuminated cells folded inward after the light activation. [Stefano De Renzis/EMBL]

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    Example of optogenetics-guided tissue folding. The top image shows an embryo 10 minutes after illumination and the bottom one 13 minutes afterward. Light-activated cells have folded inward and thus moved downward, creating a furrow. [Stefano De Renzis/EMBL]

    A living organism, says the synthetic biologist, is the output generated by a tangle of interconnected subprograms. Naturally, the synthetic biologist wants to disentangle these programs and—to the extent possible—modularize them, so that they may be plucked from their ordinary, living contexts and put to work, harnessed for applications such as regenerative medicine. Adding to the synthetic biologist’s collection of parts, scientists based at the European Molecular Biology Laboratory (EMBL) have isolated a signaling mechanism that helps determine tissue shapes.

    "We've uncoupled the link between the shape and function of a cell,” said the EMBL’s Stefano De Renzis, Ph.D. “This allows us to, for the first time, build tissues in a certain shape without affecting the cell's expertise."

    Dr. De Renzia and colleagues have used optogenetics to reconstruct a fundamental developmental process called epithelial folding. Epithelial folding causes cells to move inward and fold into the embryo, eventually giving rise to internal tissues like muscles, for example. Remarkably, De Renzia’s EMBL team triggered epithelial folding in cells that normally do not undergo this process.

    Details of the work appeared June 18 in the journal Nature Communications, in an article entitled “Guided Morphogenesis through Optogenetic Activation of Rho Signalling during Early Drosophila Embryogenesis.” The article expresses the hope that by isolating the components of living systems such as the epithelial folding process, synthetic biologists may learn how to drive tissue remodeling and even reconstruct morphogenesis.

    “We show that precise spatial and temporal activation of Rho signaling is sufficient to trigger apical constriction and tissue folding,” wrote the article’s authors. “Induced furrows can occur at any position along the dorsal–ventral or anterior–posterior embryo axis in response to the spatial pattern and level of optogenetic activation.”

    Constructing biological tissues, such as skin, muscle, or bone, in customized shapes is now one step closer. Researchers at EMBL have succeeded in guiding the folding and thus shape of tissues with optogenetics—a technique that controls protein activity with light. Nature Communications published their results, with implications for regenerative medicine, on June 18.

    The research was done in developing fruit flies, but since epithelial folding is a conserved process across evolution, Dr. De Renzis expects these methods to also be applicable in other organisms and ex vivo stem cell culture systems. In that case, optogenetics could be an ideal technique for reconstructing and directing tissue development, which could be used to (re)build artificial tissues in regenerative medicine.

    The changing of tissue shapes in an embryo is essential for healthy development. Dr. De Renzis and his team members are interested in the mechanisms behind these shape transitions, also called morphogenesis.

    To demonstrate that epithelial folding is, essentially, a modularized process, Dr. De Renziz and colleagues used optogenetics, which involves the illumination of cells that have been engineered to respond to light. Optogenetically stimulated cells activate selected molecularly driven programs. By intervening optogenetically, the scientists achieved the localized activation of Rho signaling at the apical surface of cells that are otherwise not programmed to invaginate.

    “Our data argue that while normally tissue differentiation and tissue shape are intimately linked, it is possible to direct tissue shape without interfering with complex layers of gene regulatory network and tissue differentiation programs,” the article’s authors concluded. "This might have important implications also for tissue engineering, where it might be desirable to shape any given tissue of interest without changing its fate.”

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