Limb regeneration is a frontier in biomedical science. Organisms such as the African clawed frog (Xenopus laevis) — whose limited regenerative capacities in adulthood mirror those of humans — are important models with which to test interventions that can restore form and function. In new research, a team of scientists at Tufts University demonstrated long-term (18 months) regrowth, marked tissue repatterning, and functional restoration of an amputated Xenopus laevis hindlimb following a 24-hour exposure to a five-drug cocktail delivered by a silicone wearable bioreactor.
An African clawed frog (Xenopus laevis) swimming in a tank. Image credit: Celia Herrera-Rincon / Tufts University.
“Many creatures have the capability of full regeneration of at least some limbs, including salamanders, starfish, crabs, and lizards,” said Dr. Nirosha Murugan, a researcher with the Allen Discovery Center at Tufts University, and colleagues.
“Flatworms can even be cut up into pieces, with each piece reconstructing an entire organism.”
“Humans are capable of closing wounds with new tissue growth, and our livers have a remarkable, almost flatworm-like capability of regenerating to full size after a 50% loss.”
“But loss of a large and structurally complex limb — an arm or leg — cannot be restored by any natural process of regeneration in humans or mammals.”
“In fact, we tend to cover major injuries with an amorphous mass of scar tissue, protecting it from further blood loss and infection and preventing further growth.”
The authors triggered the regenerative process in African clawed frogs by enclosing the wound in a wearable bioreactor (‘BioDome’) containing silk protein infused with five small-molecule compounds.
Each compound fulfilled a different purpose, including tamping down inflammation, inhibiting the production of collagen which would lead to scarring, and encouraging the new growth of nerve fibers, blood vessels, and muscle.
The combination and the bioreactor provided a local environment and signals that tipped the scales away from the natural tendency to close off the stump, and toward the regenerative process.
The researchers observed dramatic growth of tissue in many of the treated frogs, re-creating an almost fully functional leg.
The new limbs had bone structure extended with features similar to a natural limb’s bone structure, a richer complement of internal tissues (including neurons), and several ‘toes’ grew from the end of the limb, although without the support of underlying bone.
The regrown limb moved and responded to stimuli such as a touch from a stiff fiber, and the frogs were able to make use of it for swimming through water, moving much like a normal frog would.
Twenty-four-hour multidrug treatment delivered by bioreactor improves repatterning in regenerates. Image credit: Murugan et al., doi: 10.1126/sciadv.abj2164.
“It’s exciting to see that the drugs we selected were helping to create an almost complete limb,” Dr. Murugan said.
“The fact that it required only a brief exposure to the drugs to set in motion a months-long regeneration process suggests that frogs and perhaps other animals may have dormant regenerative capabilities that can be triggered into action.”
The scientists explored the mechanisms by which the brief intervention could lead to long-term growth.
Within the first few days after treatment, they detected the activation of known molecular pathways that are normally used in a developing embryo to help the body take shape.
Activation of these pathways could allow the burden of growth and organization of tissue to be handled by the limb itself, similar to how it occurs in an embryo, rather than require ongoing therapeutic intervention over the many months it takes to grow the limb.
“We’ll be testing how this treatment could apply to mammals next,” said Professor Michael Levin, director of the Allen Discovery Center at Tufts University.
“Covering the open wound with a liquid environment under the BioDome, with the right drug cocktail, could provide the necessary first signals to set the regenerative process in motion.”
“It’s a strategy focused on triggering dormant, inherent anatomical patterning programs, not micromanaging complex growth, since adult animals still have the information needed to make their body structures.”
The team’s work appears today in the journal Science Advances.
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Nirosha J. Murugan et al. 2022. Acute multidrug delivery via a wearable bioreactor facilitates long-term limb regeneration and functional recovery in adult Xenopus laevis. Science Advances 8 (4); doi: 10.1126/sciadv.abj2164
Source link: https://www.sci.news/biology/biodome-10494.html
