Fight or Flight—and Grow a New Limb
Study reveals how salamanders rely on sympathetic nervous system to regenerate body parts
By Kermit Pattison / Harvard Staff Writer
Biologists have long been fascinated by the ability of salamanders to regrow entire limbs. Now Harvard researchers have solved part of the mystery of how they accomplish this feat—by activating stem cells throughout the body, not just at the injury site.
In a paper [LINK WILL ACTIVATE WHEN EMBARGO LIFTS 11am 10/24] published in the journal Cell, researchers documented how this bodywide response in axolotl salamanders is triggered by the sympathetic nervous system—the iconic "fight or flight" network. The study raises the possibility that these mechanisms might one day be manipulated to regenerate human limbs and organs.
"We've shown the importance of the adrenaline stress signaling hormone in getting cells ready for regeneration," said Duygu Payzin-Dogru , lead author of the new study and a postdoctoral researcher in the Department of Stem Cell and Regenerative Biology (SCRB). "Because adrenaline exists in humans, this tells us we can coopt some of the things we found in the axolotl to perhaps improve regenerative outcomes in humans. We have some of the same components and just have to figure out the right way to implement them."
The new study culminates several years of research by the lab of Jessica Whited , associate professor in SCRB, who studies limb regeneration in axolotls, a species native to Mexico. Axolotls are often examined as model organisms of limb regeneration because they are among the fastest-breeding species of salamanders.
Some invertebrates such as planarian flatworms can regrow entire bodies from small bits of tissue. But salamanders are the only vertebrates that can regenerate full limbs.
When an appendage is severed, salamanders sprout a blastema—a lump that contains the precursor cells that become increasingly specialized to form a new arm, leg, or tail.
This remarkable ability has long intrigued biologists because it may provide insights for regenerative medicine. Some researchers suspect that the ancient common ancestor of all tetrapods (the group of four-limbed vertebrates that includes amphibians, birds, and mammals) was able to regenerate limbs, but this ability was subsequently lost in most evolutionary lineages—but not salamanders.
In 2018, the Whited team reported that limb amputation triggered a proliferation of cells throughout the body—even in limbs and organs that remained unharmed—but it remained unclear what mechanisms governed this response. The team spend more than six years deciphering those processes—an investigation that ultimately involved 38 coauthors.
They discovered that the systematic response was coordinated by the adrenergic signaling network, part of the sympathetic nervous system that also controls involuntary responses such as heart rate, breathing, and blood flow during times of extreme stress. (This system became well-known due to the pioneering studies of Harvard physiologist Walter Bradford Cannon , who coined the term "fight or flight response" more than a century ago). Adrenergic signaling also involves the well-known hormones noradrenaline and adrenaline, both of which also can act as neurotransmitters.
The systemic activation of stem cells and other progenitor cells "primes" the other uninjured limbs to regenerate more quickly—an ability that may help salamanders survive in the wild because they often lose multiple limbs to predators or cannibalism. The researchers discovered that the activated cells reconfigured their DNA architecture to make some genes easier to turn on—thus readying them for future regeneration.
"The animal seems to form a short-term memory of the injury, bodywide," said Payzin-Dogru. "There is something that senses the injury and kind of goes into 'getting ready' mode for a subsequent injury so it can respond faster."
But the priming was short lived: the researchers found that systemic activation persisted only a few cell cycles, perhaps because the high metabolic costs could only be sustained for brief periods. After four weeks, there was no difference in the speed of limb regeneration.
The study parsed the roles of different elements of this system: one pathway known as alpha-adrenergic signaling is required to prime distant cells for limb regeneration while another pathway known as beta-adrenergic signaling promotes regrowth at the amputation site. The adrenergic signaling also triggered cascades of downstream processes essential for limb regeneration such as activation of the mTOR signaling pathway that promotes cell growth and division.
For two centuries, scientists have known that nerve supply was necessary to regenerate limbs, but many suspected the process involved sensory or motor nerves. "I heard very few people talking about sympathetic nerves," said Whited.
Until now, many biologists have viewed limb regeneration as a local phenomenon at the injury site. But Whited said growing evidence suggests that it should be viewed as a whole-body event.
"I think it's paradigm-shifting," she said of the new study. "I think it's going to inspire a lot of future work to try to figure out not just how this works in an axolotl but also how it works in other systems."
