The USC researchers' experiments help inform efforts to improve wound healing in humans. Lizards can re-grow severed tails, making them the closest relatives to humans who can regenerate lost appendages. But the alternative structure is an imperfect cartilage tube, rather than a primitive tail that includes the spine and nerves. Now, for the first time, a study led by the University of Southern California has described in Nature Communications how stem cells help lizards regenerate better tails.
Thomas Lozito, corresponding author of the study and assistant professor of orthopedic surgery and stem cell biology and regenerative medicine at the Keck School of Medicine at the University of Southern California, said: "This is one of the only cases in which any reptile, bird or mammal has significantly improved accessory regeneration through stem cell therapy, and it provides a reference for improving wound healing in humans. "
"These new and improved lizard tails exhibit what is known as a 'dorsal-ventral pattern' – meaning they have bone and nerve tissue in the upper or dorsal side, and cartilage tissue in the lower or ventral side," Lozito identifies. Lizards have been around for more than 250 million years, and in all of that time, never have a lizard re-grown a tail with a dorsal-ventral shape until now. My lab has created the first regenerated lizard tail with a patterned skeleton. ”
To achieve this, a team of scientists from the University of Southern California and the University of Pittsburgh School of Medicine analyzed how lizard tails form during adult regeneration, compared to embryonic development. In both cases, neural stem cells, or NSCs — stem cells that build the nervous system — play a central role.
Adult NSCs produce a molecular signal that blocks the formation of bones and nerves and encourages the growth of cartilage, effectively "ventralizing" the sides of the tail, which brings with it the typical cartilaginous tubes that regenerate the tail.
The histology of a fully regenerated mournful gecko's tail. Muscles are white, cartilage is red, proliferating cells are green, and nuclei are blue. Source: University of Southern California/Lozito Lab
Even in the absence of this ventral signal, adult NSCs are unable to generate new neural tissue for the dorsal side of the tail.
In contrast, embryonic NSCs produce this "ventralized" signal only in the cartilage region that becomes the lower part of the tail or ventrally. At the same time, in the absence of such signals, bone and nerve tissue develop on the upper or dorsal side. Thus, the tail acquires the intricate dorsal-ventral pattern of the original embryonic appendages.
However, if embryonic NSCs are implanted at the stump of an adult tail, they respond to ventral signals and cannot develop into dorsal structures.
To overcome these obstacles, Lozito's team used gene-editing tools to make embryonic NSCs unresponsive to ventralization signals and surgically implant these cells into the adult tail stump, enabling the regeneration of the perfect tail.
Histology of the grieving gecko cyst. Muscles are white, cartilage is red, proliferating cells are green, and nuclei are blue. Source: University of Southern California/Lodstow Lab
"This study provides us with basic practices on how to increase the regenerative potential of organisms," Lozito said. "Perfecting imperfect regenerative lizard tails gives us a blueprint to improve the healing of wounds that cannot regenerate naturally, such as broken human limbs and spinal cords." In this way, we hope that our lizard research will bring about a medical breakthrough in the treatment of injuries that are difficult to heal. "