Getting jellyfish, flies and mice to regenerate body parts

Caltech researchers have discovered certain conditions that allow different lab animals to regenerate amputated appendages. After consuming a diet rich in sugar and essential amino acids, three different species – the moon jellyfish Aurelia coerulea, the fruit fly Drosophila melanogaster, and common lab mice – all demonstrated some ability to regenerate appendages after amputation.

While some animals are known to systematically regenerate amputated body parts – some tapeworms even grow back their entire heads – none of the species in the study were ever shown to regrow limbs after certain injuries. The work suggests that the ability to regenerate is somehow innate in various species and can be triggered under the right conditions.

An article describing the research, mainly carried out in the laboratory of Lea Goentoro, professor of biology, appears in the journal eLife December 7.

In 2015, while conducting other experiments with the lunar jellyfish Aurelia coerulea, former graduate student Michael Abrams (PhD ’18) and former lab tech Ty Basinger noticed that on rare occasions jellyfish would show small growths where one of their arms had been amputated.

Further study indicated that four environmental conditions helped prompt jellyfish to regrow an amputated appendix. First, the animals had to swim; in the laboratory, they moved actively in a conical bubble tank. Second, they need a high level of nutrients, provided by the daily diet of plankton. Third, the provision of two nutrient system activators, insulin and leucine, an essential amino acid, dramatically increased the frequency and extent of regeneration, as did the fourth factor, an oxygen-poor environment.

“Insulin and leucine are not exotic molecules,” says Abrams, who is now a postdoctoral fellow at UC Berkeley. “Most of the current regeneration studies focus on specific developmental signals. But what we have found are simple nutrient factors, administered in a straightforward manner, which can promote regeneration. We asked ourselves: could this work in other animals? “

The team then examined whether similar dietary conditions might prompt normally non-regenerative lab animals to regenerate appendages after injury. Graduate student Fayth Tan led a team that developed a protocol for amputations in Drosophila melanogaster fruit flies, optimized insulin and leucine additions to the fly food, and subsequently observed the first signs of limb regrowth. Next, a team led by graduate students Yutian Li and Anish Sarma set up time-lapse imaging to measure the extent of regrowth over a period of several weeks.

Although drosophila were never shown to repel limbs, the team found that an increase in insulin and leucine in fly food resulted in regrowth in 49% of the flies.

drosophila are known for specifically not regenerating – not just limbs, but all parts of the body – so we were thrilled to see that, ”Li says.“ Regrowth is not just random growth; it is a structured reconstruction of the cuticle, sensory hairs and joint. “

Finally, led by Tan and former technician Martin Heithe, the team turned to lab mice to test whether the same factors were inducing regeneration of mouse fingers. The mice have shown the ability to push back the fingertips, but only if the injury is above the nail. (Human children have also demonstrated this ability in some instances.)

The team performed amputations under the nail, through the distal part of the bone, and gave the mice leucine and sugars in their drinking water. Ten percent of the mice were then able to regrow at least part, and in a few cases almost all, of the amputated finger.

In future work, the team aims to understand the mechanism underlying how these common and relatively simple molecules are able to stimulate the regrowth of very different complex structures – what types of cells are involved, etc. These results open new questions and present new models to study how to induce regeneration.

The article is titled “A conserved strategy to induce appendix regeneration”. Abrams, Tan and Li are co-first authors. In addition to Goentoro, other co-authors are Basinger, Heithe, Sarma, undergraduate student Iris T. Lee, graduate student Zevin J. Condiotte, former undergraduate student Misha Raffiee (BS ‘ 15), centenary professor of aeronautics and mechanical engineering John O. Dabiri (MS ’03, PhD ’05) and former postdoctoral fellow David A. Gold.

Funding was provided by the National Science Foundation Graduate Student Research Fellowship Program, the James E. and Charlotte Fedde Cordes Postdoctoral Fellowship in Biology, the James S. McDonnell Foundation, and the following Caltech organizations and programs: the Center for Environmental Microbial Interactions, the Center for Evolutionary Sciences, Undergraduate Summer Research Fellowships, Charles Trimble and the Caltech Chair of Biology and Biology Board.

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