Wed. Oct 27th, 2021

Grieving gecko

image: A lizard species known as a mourning echo can regenerate the tail, but the replacement is an imperfect copy of the original.
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Credit: USC / Lozito Lab

Lizards can re-cut tails, making them the closest relative to humans that can generate a lost pendant. But instead of the original tail, which includes a spine and nerves, the replacement structure is an imperfect cartilage tube. Now, for the first time, a USC-led study in Nature communication describes how stem cells can help lizards regenerate better tails.

“This is one of the only cases where regeneration of a pendant has been significantly improved through stem cell-based therapy in any reptile, bird or mammal, and it informs efforts to improve wound healing in humans,” said study co-author Thomas Lozito, assistant professor. in orthopedic surgery and stem cell biology and regenerative medicine at the Keck School of Medicine in USC.

These new and improved lizard tails exhibit what is known as the “dorsoventral pattern” – meaning they have skeletal and nerve tissue on the upper or dorsal side and cartilage tissue on the lower or ventral side.

“The lizard has been around for more than 250 million years, and during that time no lizard has ever regrown a tail with a dorsoventral pattern, until now,” Lozito said. “My lab has created the first regenerated lizard tails with patterned skeletons.”

To achieve this, the research team from the medical schools at USC and the University of Pittsburgh analyzed how lizard tails are formed during adult regeneration, compared to embryonic development. In both cases, neural stem cells or NSCs – the stem cells that make up the nervous system – play a key role.

Adult NSCs produce a molecular signal that blocks skeletal and nerve formation and encourages cartilage growth and effectively “ventralizes” both sides of the tail. This results in the cartilage tube being typical of regenerated tails.

Even in the absence of this ventralization signal, adult NSCs are unable to generate new nerve tissue to the dorsal side of the tail.

In contrast, embryonic NSCs produce only this “ventralizing” signal in the cartilage area, which becomes the lower or ventral side of the tail. Meanwhile, in the absence of this signal, the upper or dorsal side develops skeletal and nerve tissue. Thus, the tail gets the intricate dorsoventral pattern that is characteristic of original embryonic pendants.

However, if embryonic NSCs are implanted in adult tail stumps, they respond to the ventralizing signal and fail to develop into dorsal structures.

To overcome these obstacles, Lozito’s team used gene editing tools to make embryonic NSCs unresponsive to the ventralizing signal and implanted these cells surgically in adult tail stumps — leading to regeneration of perfect tails.

“This study has provided us with significant practice on how we can improve the regenerative potential of an organism,” Lozito said. “Perfecting the imperfectly regenerated lizard tail gives us a plan to improve the healing of wounds that do not naturally regenerate, such as severed limbs and spinal cord. In this way, we hope that our lizard research will lead to medical breakthroughs in the treatment of difficult to heal injuries. ”

Additional co-authors include Ricardo Londono and Aaron X. Sun of the University of Pittsburgh School of Medicine and Megan L. Hudnall of USC.

The work was made possible by grant R01GM115444 from the National Institute of General Medical Sciences, one of the National Institutes of Health.

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