A team of researchers identified common genes in salamanders, mice, and zebrafish to develop a novel gene therapy to regrow digit tips in mice, which has the potential to eventually be used regrow limbs in humans.
“This significant research brought together three labs, working across three organisms to compare regeneration,” said Josh Currie, PhD, an assistant professor in biology at Wake Forest University whose lab studies the Mexican axolotl. “It showed us that there are universal, unifying genetic programs that are driving regeneration in very different types of organisms, salamanders, zebrafish and mice.”
The work included David A. Brown, MD, PhD, a plastic surgeon who studies digit regeneration in mice at Duke University, and Kenneth D. Poss, PhD, who studies fin regeneration in zebrafish at the University of Wisconsin-Madison.
The scientists chose to study these three animals in comparison because of specific characteristics of each one. The axolotl excels at regeneration, with the ability to regrow complete limbs, tails, including the spinal cord, parts of the heart, brain, liver, lungs, and jaw. Zebrafish offer one of the best models for appendage regeneration because their tail fins regrow rapidly and have unlimited capacity for regrowth. The zebrafish also can regenerate its heart, spinal cord, brain, retinas, kidneys, and pancreas. Mice represent mammals like humans, and they already can regenerate the tips of their digits. Humans can regrow the flesh, skin, and bone of their fingertips when an injury preserves the nailbed.
The researchers discovered that SP genes are vital for limb regeneration and shared by the mouse, zebrafish and axolotl.
Currie said that once the scientists determined the regenerating epidermis of all three species expressed the SP genes SP6 and SP8, they set out to test what the genes do and how they work.
In salamanders, SP8 does the work in regenerating limbs. Using CRISPR gene-editing technology, Currie’s lab removed SP8 from the axolotl genome. Without SP8, the axolotl could not properly regenerate the limb bones; a similar result occurred with the mouse digits missing SP6 and SP8.
With that information in hand, Brown’s lab used a tissue regeneration enhancer found in zebrafish to develop a viral gene therapy.
That therapy delivered a secreted molecule called FGF8, a gene that is usually turned on by SP8, to encourage digit bone regrowth and partially restore the regenerative effects of the missing SP genes in mice.
Human limbs don’t have that kind of regenerative power, but a future therapy could emulate the abilities of SP genes.
“We can use this as a kind of proof of principle that we might be able to deliver therapies to substitute for this regenerative style of epidermis in regrowing tissue in humans,” Currie said. He called the study foundational in the search for therapies to regrow limbs after injury or disease.
“Scientists are pursuing many solutions for replacing limbs, including bioengineered scaffolds and stem cell therapies,” he said. “The gene-therapy approach in this study is a new avenue that can complement and potentially augment what will surely be a multidisciplinary solution to one day regenerate human limbs.”
Editor’s note: This story was adapted from materials provided by Wake Forest University.
The study, “Enhancer-directed gene delivery for digit regeneration based on conserved epidermal factors,” was published in the Proceedings of the National Academy of Sciences.
