Salamanders and zebrafish can grow new limbs and fins, but chop off your own finger, and it’s not going to grow back. Now researchers in San Diego have been able to regenerate wings in chicken embryos, which can’t normally grow new limbs. The findings move scientists one step closer to understanding how to induce regenerative powers in humans.
“Regeneration likely involves a combination of factors,” says Stephen Badylak, a scientist at the McGowan Institute for Regenerative Medicine, in Pittsburgh, PA, who is not involved in the research. “If we can identify the key ones and put them together, we can probably induce regeneration.”
When a salamander loses a leg, specialized epithelial cells cover the wound, forming a multilayered structure. These cells then trigger the muscle, nerve, and connective-tissue cells below to dedifferentiate (essentially, lose the specialized characteristics that make them a neuron or muscle cell), divide, and form a ball of stem-cell-like cells. The ball of cells begins to develop the way a normal limb does, forming new muscle and bone to produce an entirely new limb.
While many animals have this capacity–within the animal kingdom, more species can regenerate limbs than cannot–mammals have largely lost it. For reasons not yet clear, they instead form scars when wounded. But many developmental biologists believe that if they can understand the regeneration process, they will be able to induce it in humans. The process could potentially repair damaged tissue, such as occurs in cardiac muscle after a heart attack, or even spur the growth of new limbs.
Researchers have now identified a genetic “on” switch that triggers regeneration at developmental stages when the animal normally lacks the capacity. Yasuhiko Kawakami and colleagues at the Salk Institute for Biological Studies, in La Jolla, CA, performed experiments in chickens and frogs in which they overactivated a set of genes, called the Wnt pathway, known to be involved in regular development and thought to be involved in regeneration. When the genes were turned on in chicken embryos that had had their developing wings removed, the action triggered the growth of a new limb. In frogs, which can regenerate limbs when they are tadpoles but not as adults, activating the genes extended the period of time that tadpoles could regenerate.
“We think that controlling activity of Wnt may have the potential for making tissue regenerate which normally does not regenerate,” says Kawakami, a developmental biologist who carried out the study with Juan Carlos Izpisua Belmonte, also at the Salk.
Kawakami cautions that both the timing and the duration of gene expression are crucial. If the genes were turned on for too long, abnormal limbs developed. And if the genes were expressed too late in development, new limbs were unable to grow.
Experts say the findings are exciting, but they caution that much remains to be done before new limbs can be grown in mammals. The studies took place in still-developing animals, whose cells are likely much more flexible when it comes to inducing regeneration, says Hans-Georg Simon, a developmental biologist at Northwestern University, in Chicago, who studies limb and heart regeneration. Even mammals, including humans, show some regenerative capabilities. Under some circumstances, children as old as five can grow a new fingertip if the wound is treated correctly. But that ability is lost as we age.
“This pathway is undoubtedly a critical one,” says Simon. “But other unknown factors are probably needed to reactivate adult, fully differentiated tissue to reconstruct a new structure.”
Badylak adds that regeneration in mammals will likely require inhibition of our normal immune response, which triggers inflammation at the site of a wound. None of the animals that can regenerate limbs show this type of immune response.
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