In what looks more like a post-impressionist painting than a scientific achievement, a transgenic zebrafish is revealing how hundreds of its cells regenerate in a bouquet of colors. Thanks to a genetically engineered line of technicolor zebrafish, scientists can now watch – in real time – how hundreds of individual cells work together to maintain and regenerate wounded skin tissue.
Each cell on the surface of the fish is genetically programmed to glow with a slightly different hue (theoretically up to 5,000 different hues). Thus, each cell from the center of the eye to the tip of each scale can essentially be distinguishable from the other. So, the colors sort of effectively stamp each cell with a permanent barcode, letting scientists track its movements in a live animal for days or even weeks at a time. This system called “Skinbow” by the researchers definitely serves a much deeper purpose than lighting up an aquarium.
“It’s a spectacular-looking fish,” says Kenneth Poss, who studies tissue regeneration at Duke University in Durham, North Carolina, and who led the research, published in Developmental Cell.” He also added, “Before we can fully understand tissue regeneration, we need to be able to monitor what individual cells are doing. This is a cutting-edge way to visualize hundreds or thousands of cells at once in a regenerating tissue.”
The original idea of imparting Skinbow’s cells with their technicolor hues comes from a technology called “Brainbow”. Published in 2007, Brainbow was originally created to label individual neurons in the brain with distinct colors. Using the same concept, skin cells in the Skinbow zebrafish were designed to express mixtures of red, green and blue fluorescent proteins, resulting in over 70 hues that can be reliably distinguished under a microscope. However, these colors are only expressed in the outermost layer of skin cells, and remain permanent throughout each cell’s lifetime.
“It is like you have given each cell an individual barcode,” said Chen-Hui Chen, a postdoctoral fellow in Poss’s lab and lead author on the study. “You can precisely see how individual cells collectively behave during regeneration.” In addition, to track the individual cells over time, the team designed their own software. This allowed them to compile full “biographies” of many different cells together.
Poss’s team followed the movements and the changes in hundreds of individual skin cells over three weeks of normal skin turnover. They also monitored the behaviors of skin cells after different types of injury, from a scrape or a fin amputation. Their studies revealed some astonishing diversity in how the cells respond to injury. For instance, when a fin is amputated, three distinct processes are employed to keep regenerating tissue. Neighbouring cells were initially recruited from below the amputation plane to cover the wound. Then, new cells were generated at a rapid pace, and finally some cells at the tip of the regrown tissue temporarily grew in size to provide surface coverage.
“These are quite different cellular mechanisms, and one would not be able to detect the sequence or the appearance of these mechanisms without being able to track all or most of the cells on the surface of the fin,” Poss said. “The interesting thing about this kind of study,” he adds, “is you don’t know what to expect, but you have a great way to visualize it.”
To fully tap into this remarkable system, his team hopes to combine the Skinbow system with other imaging techniques to paint a more complete picture of skin tissue regeneration. They also want to expand its application to how other biological stressors, such as drugs, infection or cancer, impact the cellular mechanisms underlying tissue healing.