Building better frogs’ legs

Scientists in the US have successfully trialled a new model for testing “electroceuticals” – devices that treat ailments with electrical impulses.

They were able to induce partial hind limb regeneration in African clawed frogs (Xenopus laevis) by kick-starting tissue repair using bioreactors that released the hormone progesterone over 24 hours at amputation sites.

This resulted, over the following nine months or so, in the development of a paddle-like formation closer to a fully formed limb than unaided regeneration could create.

“At best, adult frogs normally grow back only a featureless, thin, cartilaginous spike,” says Michael Levin, a developmental biologist at the Allen Discovery Centre at Tufts University in Massachusetts.

“Our procedure induced a regenerative response they normally never have, which resulted in bigger, more structured appendages. The bioreactor device triggered very complex downstream outcomes that bioengineers cannot yet micromanage directly.”

Levin says the bioreactor created a supportive environment for the wound that allowed the tissue to grow as it did during embryogenesis, the early stages of prenatal development.

The regenerating limbs of the treated frogs were thicker than those in the control groups, with more developed bones, nerves, and blood vessels. The treated frogs also swam more like unamputated specimens.

RNA sequencing and transcriptome analysis revealed that the bioreactor had altered the gene expression occurring in cells at the amputation site. Scarring and immune responses also were downregulated in the treated frogs, suggesting that the added progesterone dampened the body’s natural reaction to injury in a way that benefited the regeneration process.

Progesterone is best known for its role in preparing the uterus for pregnancy, but also has been shown to promote nerve, blood vessel and bone tissue repair.

Neuroscientist Celia Herrera-Rincon sees some bigger picture implications.

“In both reproduction and its newly discovered role in brain functioning, progesterone’s actions are local or tissue-specific,” she says.

“What we are demonstrating with this approach is that maybe reproduction, brain processing and regeneration are closer than we think. Maybe they share pathways and elements of a common – and, so far, not completely understood – bioelectrical code.”

Levin hopes to replicate the team’s experiments with mammals. Previous research suggests mice can partially regenerate amputated fingertips in the right conditions, but their life on land hinders this process.

“Almost all good regenerators are aquatic,” he says. “You can imagine why this matters: a mouse that loses a finger or hand, and then grinds the delicate regenerative cells into the flooring material as it walks around, is unlikely to experience significant limb regeneration.”

Levin also plans to add sensors to the device for remote monitoring and optogenetic stimulation, which he hopes will improve control over cellular decision making after injury.

The research is published in the journal Cell Reports.

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