Science & Technology

Scientists regenerate a frog’s lost paw with a five-agent cocktail

The frog, which was easily treated with a five-drug cocktail administered to the stump by a wearable bioreactor, was able to regenerate a functional, almost complete limb.

For millions of patients who have lost their limbs due to reasons ranging from diabetes to trauma, the possibility of regaining function through natural regeneration is still out of reach. Leg and arm regrowth remains in the realm of salamanders and superheroes.

However, in a study published in the journal Science Advances, Scientists at the Wis Institute at Tufts University and Harvard University have taken us one step closer to the goal of regenerative medicine.

In adult frogs that are unable to regenerate their limbs naturally, researchers have used a five-agent cocktail applied to a silicon wearable bioreactor dome that seals Elixil on a stump for only 24 hours, and the lost leg. Could cause regrowth. Its simple treatment begins an 18-month regeneration period that restores functional legs.

Many creatures have the ability to fully regenerate at least some of their limbs, such as salamanders, starfish, crabs, and lizards. Flatworms can also be chopped, and each fragment reconstructs the entire organism. Humans can close wounds with the growth of new tissue, and our liver has an amazing, almost flatworm-like ability to regenerate to full size after a 50% loss.

However, the loss of large and structurally complex limbs (arms and legs) cannot be recovered by the natural regeneration process of humans and mammals. In fact, we tend to cover large injuries with an amorphous mass of scar tissue, which protects it from further blood loss and infection and prevents further growth.

Xenopus laevis

Normal Xenopus laevis. Credit: Pouzin Olivier

Kick start of playback

Researchers at Tufts University have triggered the process of regenerating Xenopus laevis by surrounding the wound with a silicon cap (called BioDome) containing a silk protein gel filled with a five-agent cocktail.

Each drug served a variety of purposes, including reducing inflammation, suppressing the production of collagen, which leads to scarring, and promoting new growth in nerve fibers, blood vessels, and muscles. The combination and bioreactor provided a local environment and signal to scale towards the regeneration process from the natural tendency to close the stump.

Researchers have observed dramatic tissue growth in many of the treated frogs, recreating almost fully functional legs. The new limbs have an expanded bone structure with features similar to the bone structure of the natural limbs, a richer complement of internal tissues (including neurons), and some “without the support of the underlying bone”. The “toes” have grown from the ends of the limbs.

The regrown limbs moved and responded to stimuli such as contact from hard fibers, allowing the frog to move like a normal frog and use it to swim in the water.

Regeneration of frog limbs

The soft tissues of MDT animals were consistently longer than BD or ND from 8mpa. [F(2,19) = 61.9, P < 0.05].. Credits: Murugan, et. al. , Science Advances 2022, DOI: 10.1126 / sciadv.abj2164

Nirosha Murgan, a research affiliate at the Allen Discovery Center at Tufts University and the lead author of the paper, said: “The fact that only a short exposure to the drug was required to initiate the one-month regeneration process has the ability to regenerate during dormancy, allowing frogs and possibly other animals to take action. It suggests that there is a possibility. ”

Researchers have investigated the mechanisms by which short-term interventions lead to long-term growth. Within the first few days after treatment, they detected activation of known molecular pathways commonly used in developing embryos to help shape the body.

Activation of these pathways puts the burden of tissue growth and organization on the same as that in the embryo, without the need for months of continuous therapeutic intervention to grow the limbs. , You will be able to process with the limbs themselves.

How BioDome works

Animals that can regenerate naturally live mainly in aquatic environments. The first stage of growth after the loss of a limb is the formation of a mass of stem cells called blasts at the ends of the stump. It is used to gradually reconstruct lost body parts. The wound is rapidly covered by skin cells within the first 24 hours after injury and protects the underlying reconstructed tissue.

“Mammals and other regenerated animals usually expose their injuries to the air or touch the ground. It can take days or weeks to close with scar tissue,” said Stern Family Engineering, University of Tufts. Professor David Kaplan said. The author of the study. “Using the BioDome cap in the first 24 hours helps to mimic an amnion-like environment, which allows the reconstruction process to proceed with the appropriate medication and without scar tissue interference.”

The next step for frogs and mammals

Previous studies by the Tufts team have shown a significant degree of limb growth caused by the single drug progesterone using BioDome. However, the resulting limbs grew as spikes, far from the more normal-shaped functional limbs achieved in current studies.

The five-drug cocktail represents an important milestone in the recovery of fully functional frog limbs, and further investigation of drug and growth factor combinations reveals normal fingers, webbing, and a more detailed skeleton. It suggests that it may lead to a more functionally complete regrowth limb with. Muscle characteristics.

“Next, we’ll test how this treatment can be applied to mammals,” said corresponding author Michael Levin, Professor Vannevar Bush of the Faculty of Arts and Sciences, and Allen Discovery of Tufts University. Director of the center and Wyss Institute.

“By using the appropriate drug cocktail to cover the open wound in a liquid environment under BioDome, we can provide the first signal needed to initiate the regeneration process,” he said. “This is a strategy focused on triggering a unique anatomical patterning program during dormancy, rather than fine-grained control of complex growth. Adult animals are responsible for building the structure of the body. I still have the information I need. “

Reference: “Acute multidrug delivery via wearable bioreactor promotes long-term limb regeneration and functional recovery in adult Xenopus laevis” Nirosha J. Murugan, Hannah J. Vigran, Kelsie A. Miller, Annie Golding , Quuang L. Pham, Megan M. Sperry, Cody Rasmussen-Ivey, Anna W. Kane, David L. Kaplan, Michael Levin, January 26, 2022, Science Advances..
DOI: 10.1126 / sciadv.abj2164

Scientists regenerate a frog’s lost paw with a five-agent cocktail Scientists regenerate a frog’s lost paw with a five-agent cocktail

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