Tag Archives: Regrowth

Alligators can regrow their tails, and it could help us heal our own wounds better

Young alligators sometimes lose their tails, but they can grow them back to a certain extent, a new study reports. Each animal can regrow around three-quarters of a foot of tail, roughly equivalent to one fifth of their total body length.

Image via Pixabay.

The team used advanced imaging techniques to determine whether alligators have the same type of regenerative tissues known in smaller species of reptiles. Lizards, for example, have evolved to have detachable tails that can regrow, which they use to escape predators. But alligators are very large animals, potentially reaching up to 14 feet, and it was unknown how that difference in scale reflects on their regenerative abilities.

Taily tales

“The spectrum of regenerative ability across species is fascinating, clearly there is a high cost to producing new muscle,” said Jeanne Wilson-Rawls, co-senior author and associate professor with Arizona State University’s (ASU) School of Life Sciences.

“What makes the alligator interesting, apart from its size, is that the regrown tail exhibits signs of both regeneration and wound healing within the same structure,” said Cindy Xu, lead author of the paper. “Regrowth of cartilage, blood vessels, nerves, and scales were consistent with previous studies of lizard tail regeneration from our lab and others,” she said. “However, we were surprised to discover scar-like connective tissue in place of skeletal muscle in the regrown alligator tail.”

Alligators and humans both belong to the amniote group, related species who all have a spine or backbones. Lizards do, as well. Understanding more about the natural regeneration processes of these species could point the way towards better ways of repairing our own bodies after damage.

By studying the anatomy and tissue organization of regrown alligator tails, the team found that they were made up of a central skeleton of cartilage surrounded by connective tissue. The tails were fully irrigated with blood vessels and had nerve bundles, meaning they were fully-functional tails. The sheer scale and complexity of these regrown body parts after were surprising, the team adds, and goes a long way towards our understanding of regeneration processes in larger amniotes. It also raises questions about the history of such processes, and about their possibilities in the future.

For example, the team notes that alligators and birds both split off from dinosaurs around 250 million years ago, but birds lost their ability to regenerate while alligators did not. We’re not exactly sure when, or why, this happened. The authors note that existing literature makes no mention of dinosaur fossils with regrown tails.

But perhaps of more immediate concern for most of us is whether the findings have practical use. The team says it lays the groundwork for new therapies meant to heal wounds or treat diseases such as arthritis.

“If we understand how different animals are able to repair and regenerate tissues, this knowledge can then be leveraged to develop medical therapies,” said Rebecca Fisher, co-author of the paper.

The paper “Anatomical and histological analyses reveal that tail repair is coupled with regrowth in wild-caught, juvenile American alligators (Alligator mississippiensis)” has been published in the journal Scientific Reports.

Frog pre-amputation.

Experimental bioreactor helps frogs regenerate lost limbs

We’re one leg closer to developing functional limb regeneration.

Frog pre-amputation.

Xenopus laevis pre-amputation
Image credits Celia Herrera-Rincon / Tufts University.

A team of researchers from the Tufts University wishes that everyone could lose a foot and have it, too. The group successfully “kick-started” partial tissue regrowth in adult African clawed frogs (Xenopus laevis) through the use of a bioreactor and electroceutical (electrical cell-stimulating) techniques.

The cradle of life

“At best, adult frogs normally grow back only a featureless, thin, cartilaginous spike,” says senior author Michael Levin, developmental biologist at the Tufts University’s Allen Discovery Center.

“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.”

The scientists split up the frog models into three groups — one experimental, one control, and one ‘sham’ group. Each animal had one of its hindlimbs amputated for the trial. Next, they 3D printed a “wearable bioreactor” out of silicon and filled it with hydrogel (a tissue-like mix of water and polymers). This hydrogel was mixed with certain silk proteins that provided a “pro-regenerative environment” and “enhanc[ed] bone remodeling”, according to the authors.

Next came the trial proper: frogs in the experimental and sham groups received the bioreactor (which was sutured on) immediately after the amputation procedure. The difference between the two is that the hydrogel for the experimental group was further laced with progesterone. Progesterone is a hormone that works to prepare the body for pregnancy but has also been shown to promote tissue repair, from nerves to bone. The control group received no treatment. Twenty-four hours later, the devices were removed.

Observations carried out at various times over the following nine-and-a-half months show that the bioreactor induced a degree of regeneration in the experimental group that had no counterpart in the other two groups. Instead of the typical spike-like structure, frogs treated with the bioreactor-progesterone combo re-grew a paddle-like structure — closer to a fully formed limb than what unaided regeneration processes created.

Results comparison.

Image credits Celia Herrera-Rincon et al., 2018, Cell Reports.

“The bioreactor device created a supportive environment for the wound where the tissue could grow as it did during embryogenesis,” says Levin. “A very brief application of bioreactor and its payload triggered months of tissue growth and patterning.”

The regenerated structures of the experimental groups were thicker, had better-developed bones, nerve bundles, and blood vessels. Video footage of the frogs in their tanks also showed that these frogs could swim more like un-amputated ones, the team adds. Scarring and immune responses were also dampened in the bioreactor-treated frogs, suggesting that the progesterone limited the body’s natural reaction to injury in a way that benefited the regeneration process.

So, why exactly did the device work? Genetic tests performed by the team showed that the bioreactor-progesterone combo altered gene expression in cells at the amputation site. Genes involved in oxidative stress, serotonergic signaling, and white blood cell activity were upregulated, while some other signaling-related genes were downregulated.

Regeneration results 2.

Anatomical outcome (bottom) and X-ray images (top) of regenerates formed in adult Xenopus hindlimb amputation after no treatment (Ctrl, A) and after 24-hr combined treatment of drug-loaded device (Prog-device, B–D).
Image credits Celia Herrera-Rincon et al., 2018, Cell Reports.

“In both reproduction and its newly discovered role in brain functioning, progesterone’s actions are local or tissue-specific,” says first author Celia Herrera-Rincon, neuroscientist in Levin’s lab at Tufts University.

“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.”

The team plans to expand their research in mammal subjects. Previous research hinted that mice can partially regenerate tissue (such as amputated fingertips) under the right conditions. Life on land, however, hinders this process. “Almost all good regenerators are aquatic,” Levin explains, adding that “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.” Still, let’s keep our fingers crossed that the team finds an elegant and efficient solution to this problem — it may, after all, be our limbs that we regrow one day!

But there’s much work to be done until then. Levin says the next step is to add sensors to the device for remote monitoring and optogenetic stimulation, which should give the team a degree of control over how tissues regenerate in the bioreactor. They also plan to expand on their work with bioelectric processes in the hopes of successfully inducing regeneration in the spinal cord, and to the merits of this approach for tumor reprogramming

The paper “Brief Local Application of Progesterone via a Wearable Bioreactor Induces Long-Term Regenerative Response in Adult Xenopus Hindlimb” has been published in the journal Cell Reports.

Fungus-derived molecule enables axon regrowth — potentially treating brain and spinal chord injuries

One family of proteins that plants use to combat fungal infections could have an unexpected use: repairing axons — the long thread-like parts of a nerve cell.

Fluorescent bundles of axons.
Image credits Minyoung Choi / Wikipedia.

Axons are the large projections that neurons use to ferry signals to other parts of the body. They’re the main component of white matter, and without them, the nervous communication in the body would grind to a halt. Axonal damage can also lead to a host of disabilities associated with conditions such as spinal cord injury or stroke.

Andrew Kaplan, a PhD candidate at the Montreal Neurological Institute and Hospital of McGill University, was trying to find a substance that could help undo the damage for people suffering these conditions as part of Dr. Alyson Fournier’s team, professor of neurology and neurosurgery and senior author on the study. During his research, he found one family of proteins with neuroprotective functions known as 14-3-3 which could hold the key to creating axon-repairing drugs.

This family of proteins takes on a surprising role in plants which are fighting off a certain fungal strain. The fungus releases a marker molecule called fusicoccin-A. When exposed to this molecule, the plants’ leaves will wilt but their roots grow longer. This happens because fusicoccin-A affects 14-3-3’s normal interaction with other proteins, promoting growth.

“While 14-3-3 is the common denominator in this phenomenon, the identity of the other proteins involved and the resulting biological activities differ between plants and animals,” says Kaplan.

Kaplan’s theory was that fusicoccin-A could be used to harness 14-3-3 for use in repairing axons. He and his team placed mechanically damaged neurons in a culture with the substance and waited to see what happened.

“When I looked under the microscope the following day the axons were growing like weeds, an exciting result that led us to determine that fusicoccin-A can stimulate axon repair in the injured nervous system,” says Kaplan.

Beyond brain or spinal chord injuries, axonal damage also plays a central role in other disorders and diseases, such as multiple sclerosis or neurodegenerative conditions. Fusicoccin-A and similar molecules could become the starting point for a new class of drugs to treat and repair this damage. Kaplan says future research should aim to better understand the underlying mechanism by which fusicoccin-a improves axonal repair, which can be used to develop even more powerful medication.

One protein called GCN1 holds particular promise. The team found that GCN1 and 14-3-3 bonding can be an important factor in the fusicoccin-A-induced growth.

“We have identified a novel strategy to promote axon regeneration with a family of small molecules that may be excellent candidates for future drug development,” says Fournier.

“This is an exciting advance because the field has struggled to find treatments and identify targets for drugs that stimulate axon repair.”

The full paper “Small-Molecule Stabilization of 14-3-3 Protein-Protein Interactions Stimulates Axon Regeneration” has been published in the journal Neuron.

 

 

Teeth

An Alzheimer’s drug could become the unlikely replacer of fillings

An Alzheimer’s drug could spell the end of fillings after scientists discovered that it causes teeth to regrow dentite, potentially repairing cavities from the inside out.

Teeth

Image credits dreverton9 / Pixabay.

King’s College, London researchers have found that Tideglusib, a drug investigated as a potential Alzheimer’s cure, stimulates the stem cells in teeth’s pulp so they construct new dentine — the mineralized layer under enamel. Teeth can naturally regrow dentine, but only if the pulp — the soft squishy bit inside the tooth — becomes exposed. Even so, they can only regrow a very thin layer, enough to protect the pulp but not enough to form a workable tooth. Tideglusib switches off an enzyme known as GSK-3 which inhibits the further formation of dentine.

The team showed that by soaking a biodegradable sponge with the drug and inserting it into a cavity, it triggers the growth of dentine and repairs the damage within six weeks.

“The simplicity of our approach makes it ideal as a clinical dental product for the natural treatment of large cavities, by providing both pulp protection and restoring dentine,” said Professor Paul Sharpe of the Dental Institute, KCL and lead author of the study.

“In addition, using a drug that has already been tested in clinical trials for Alzheimer’s disease provides a real opportunity to get this dental treatment quickly into clinics.”

No filler

Dentists currently treat cavities by filling them with artificial cements or calcium and silicon-based products. While fillings are very effective way of repairing large cavities, these materials don’t disintegrate so the tooth can’t regenerate its mineral layers. They’re also porous, fostering infection, and often need to be replaced quite a few times. In both cases, dentists have to remove an area larger than what is affected, then fill it back up. After a few such treatments, the tooth may need to be extracted.

Tideglusib offers a novel alternative that could represent a big step-up in dental care. Motivating our teeth to heal themselves would not only remove the issues associated with fillings, but create a less intrusive option for treatment. A laser method that can help regenerate dentine was developed a few months ago but is comparatively more invasive than the Tideglusib. As dental phobia is still very common, such a treatment would do wonders for patients who would otherwise have to overcome a lot of anxiety to go to the dentist’s.

The drug was shown to “fill the whole injury site” in mouse trials, and it been proven safe for human use in clinical trials with Alzheimer’s patients. So we might be seeing it in dentists’ offices pretty soon.

The full paper “Promotion of natural tooth repair by small molecule GSK3 antagonists” has been published in the journal Scientific Reports.