Tag Archives: regeneration

These adorable mice can regenerate their kidneys without scarring

This tiny mouse has Wolverine-like regeneration abilities. Image credits: Marcel Burkhard.

Spiny mice are a group of rodents with scaled tails. Their coats have stiff guard hairs similar to the spines of a hedgehog — hence the name “spiny” mice.

These mice are well-known for their ability to heal severe skin wounds without even a scar. In a new study, researchers wanted to see if their regeneration abilities also extend to other organs.

No scars allowed

It wasn’t easy to set the study up. Researchers had to establish a spiny mouse colony at Seattle Children’s Research Institute, says Mark W. Majesky of the Seattle Children’s Research Institute from the University of Washington. But thanks to initial funding from the W. M. Keck Foundation, researchers were able to get going.

They exposed spiny mice to conditions that cause serious kidney injuries in other types of mice (non-spiny ones). The researchers found that although initially, spiny mice suffer damage just like their counterparts, they were able to completely regenerate — furthermore, they showed no signs of fibrosis (or scarring).

“We used experimental kidney injuries that are known to produce extensive renal fibrosis leading to complete kidney failure in laboratory mice. Using the same kidney injury models, we found that spiny mice naturally repair the injury-induced damage to the kidney and fully regenerate kidney function with no signs of renal fibrosis,” Majesky told ZME Science.

This is the first time this type of regenerative ability has been demonstrated in a mammal and it could have big implications for human research.

Researchers compared the genes that spiny mice express in the healing process, compared to the genes of “regular” mice, which don’t have the ability to regenerate. They found differences in 843 genes in six clusters — it’s likely here that the ‘magic’ is happening.

The study also found a delayed response by macrophages — specialized cells involved in the detection and destruction of pathogens. These macrophages are known to play a role in fibrosis, so essentially, the mice are delaying an immune response to avoid scarring.

“When we looked closer at gene expression in these experiments, we found that the spiny mouse genome appears to be poised to initiate a regenerative wound healing response at the time of organ injury. By contrast, laboratory mice initiate a proinflammatory response leading to interstitial cell activation, extensive organ fibrosis, and loss of organ function,” the researcher added.

Tackling renal problems in humans

Millions of people on the globe are affected by kidney issues. In the US alone, there are 600,000 patients with kidney failure and over 450,000 patients (including children) currently on dialysis, says Majesky. Most of those patients have progressive kidney fibrosis leading to kidney failure.

“We conducted our research with those individuals in mind. Since there are very few effective therapies for progressive renal fibrosis, our objective was to look to nature for a different way to approach the problem of fibrosis-driven kidney failure,” Majesky told ZME Science.

“The global health burden for loss of vital organ function due to progressive tissue fibrosis is enormous,” says Mark Majesky, a principal investigator at Seattle Children’s Research Institute and professor of pediatrics at the University of Washington. “Very few treatment options are currently available for patients with end-stage kidney disease or similar degenerative fibrotic diseases of the heart, lungs, liver, or reproductive organs. Our group took a different approach to this problem and looked to nature to provide clues that might lead to novel therapies.”

When they learned about the ability of spiny mice to regenerate skin damage without scarring, Majesky and colleagues immediately wanted to see if that ability extends to other organs.

“Our initial experiments were designed to test the possibility that scarless wound healing might extend to
internal vital organs, such as the kidney,” Majesky notes.

If researchers can zoom in on the mechanisms through which the mice achieve this regeneration, perhaps they can also replicate it on humans. While that’s still a ways off, for now, it’s still an avenue well worth investigating.

“We have opened a new window on the development of possible therapies for chronic kidney disease, that may perhaps apply to other organs that similarly exhibit loss of function due to progressive tissue fibrosis,” Majesky says.

“Our goal is to learn what nature has done in evolving a mammalian genome that heals tissue injury by regeneration without fibrotic scarring and apply the lessons learned to the development of new therapies for kidney disease,” adds Daryl M. Okamura, also of Seattle Children’s Research Institute, and co-author of the study.

Researchers are also hopeful that, with work also progressing in related fields of medicine, the findings could be soon applied in human treatment.

“Given that other investigators in many different fields are developing small molecule drugs to target key regulators of the mammalian epigenome, it may be that in the not too distant future we will be able to apply the lessons learned from nature and the remarkable spiny mouse to human kidney disease,” Majesky concludes.

Journal Reference: iScience, Okamura et al.: “Spiny mice activate unique transcriptional programs after severe kidney injury regenerating organ function without fibrosis” https://www.cell.com/iscience/fulltext/S2589-0042(21)01238-4 

Injectable bone gel.

New “bone spackling” that can fix injuries with a simple injection shows promise in mice

Researchers at the University of Michigan want to make it possible for doctors to heal large bone injuries using a simple injection.

Injectable bone gel.

Nick Schott, graduate student research assistant at BME and one of the paper’s co-authors, working with the new compound.
Image credits Robert Coelius / Michigan Engineering.

Large or complex bone fractures are a nightmare to fix for patients and doctors both. They often require grafts and multiple surgeries to properly address, which is a long, expensive, and quite stressful process for everyone involved. So Jan Stegemann a professor of biomedical engineering at the University of Michigan and his team are working on reprogramming progenitor cells so they can be injected directly into a wound and grow into solid bone. Progenitor cells are adult bone marrow stem cells that can differentiate into several functions (i.e. morph into other cell types).

Bone-a-fide bone fixer

We’re targeting large, complex defects, where a lot of bone has been lost and the tissue around the bone has been damaged,” Stegemann explains. “These wounds don’t always heal, and they can be highly debilitating. Sometimes the muscle and surrounding blood vessels have been disturbed.”

“There are treatments to stabilize the bone and even fillers you can put in to try to help the bone regenerate, but these options are not suitable in all cases and current treatments are not ideal — they don’t work for some of the most serious cases.”

Right now, the only treatment option for patients with this kind of injury is to receive a graft from another part of their body. For example, doctors will harvest bone from a patient’s hip, crush it up, and plaster it into the wound to help that bone regenerate. It works, but it involves several rounds of surgery (one to collect the material, one to graft it in if no complications arise).

The team wanted to devise a way to actually regenerate living bone, and for that, they needed living cells. You could do it in much the same way as with the bone — graft these cells from other areas of the body and use them to regenerate the bone. However, that still poses the same problems and unpleasantness. What the team did instead was to harvest progenitor cells from the patient, grow them in the lab, and nudge them into creating bone tissue. They are then used like a drug — injected into the damaged area.

This approach, the team explains, is intended to make the cells more likely to survive and regenerate bone where it is needed. Progenitor cells can be “derived from the bone marrow or other tissues” according to Stegemann, “even from liposuctioned fat”.

“You can isolate those cells and then expand their number until you have many multiples of the initial number of cells that you took from the body,” he explains. “You can also treat them so that they form the type of tissue you are interested in.”

The researchers treat these cells with specific biological molecules that make them differentiate into bone cells. Furthermore, specialized biomaterial is used to bind the progenitor cells together and further coax them into creating bone. These “microtissues” as the team calls them are essentially small beads of proteins containing tens to hundreds of cells inside each. The microtissues are meant to feed and promote the survival and function of the cells after they’re transplanted into the bone, as this is a kind of tissue that doesn’t get a sizable blood supply and tends to trigger inflammation in surrounding tissues when damaged. This makes it likely that the injected cells will die or migrate away before they actually begin regenerating the tissue.

Through the combination of these two approaches, the cells are made to “to really potently regenerate new tissue”. Millions of these microtissues can be produced in a single batch, the team explains. Overall, the end product looks like a slurry — Stegemann likens it to spackling compound that can be used to repair damaged drywall — which is injected directly into the damaged bone. Because the delivery can be performed with a simple needle, there is a good chance that doctors can avoid having to perform a surgery.

Right now, the team is testing their approach on mice.

“The work that we’ve accomplished so far has shown very clearly that our biomaterials-based approach has a lot of merit,” Stegemann explains. “We are able to consistently control cell function and cell phenotype to regenerate tissue types that we’re interested in — most specifically bone right now.”

“We’ve shown that the idea of creating these little microtissues, culturing them outside the body and priming them to regenerate bone before we transplant, has merit as well. And we’ve validated that the culturing process, and delivering them in conjunction with a biomaterial, very significantly increases the amount of bone that you can regenerate.”

The team says that their method can be further developed to work with other types of tissues.

The paper “Injectable osteogenic microtissues containing mesenchymal stromal cells conformally fill and repair critical-size defects” has been published in the journal Biomaterials.

Researchers map the genetic mechanisms that makes hydras ‘immortal’

Researchers are especially interested in hydra’s ability to regenerate its nervous system, which could new therapeutics for treating trauma or degenerative disease in humans.

Image credits Stefan Siebert / UC Davis.

The tiny freshwater invertebrate known as the hydra, while definitely less scary than its mythological counterpart, regenerates damaged cells and tissues. This ability is so poignant that, were you to cut a hydra in half, it would regrow its body and nervous system in a matter of days.

Trying to understand exactly how it does this, researchers at the University of California have traced the evolution of the hydra’s cells throughout its life, finding three lines of stem cells that differentiate into nerves, muscles, or other tissues.

Life renewed

“The beauty of single-cell sequencing and why this is such a big deal for developmental biologists is that we can actually capture the genes that are expressed as cells differentiate from stem cells into their different cell types,” says Celina Juliano, assistant professor in the UC Davis Department of Molecular and Cellular Biology and lead author of the study.

Juliano’s team sequenced RNA transcripts of 25,000 single hydra cells to follow the genetic trajectory of nearly all of the animal’s differentiated cell types. The study thus creates a high-resolution map of the entire developmental path of the hydra’s cells.

Hydras continuously renew their cells from stem cell populations, the team explains. Based on the analysis of sets of messenger RNA molecules (transcriptomes) retrieved from individual cells and groups of cells (based on shared expressed genes), the team separated these stem cells into three different lineages. They could then build a decision tree showing how each lineage matures into different cell types and tissues. For example, the interstitial stem cell lineage produces nerve cells, gland cells, and the stinging cells in the animal’s tentacles.

“By building a decision tree for the interstitial lineage, we unexpectedly found evidence that the neuron and gland cell differentiation pathway share a common cell state,” said Juliano. “Thus, interstitial stem cells appear to pass through a cell state that has both gland and neuron potential before making a final decision.”

The molecular map also allowed Juliano and colleagues to identify the genes that influence these decision-making processes, which will be the focus of future studies.

The team hopes that their work will allow developmental biologists to understand regulatory gene networks that control the early evolution of the hydra, networks that they say are shared among many animals, including humans. Understanding how the hydra regenerates its entire nervous system could thus help us better understand neurodegenerative diseases in humans.

“All organisms share the same injury response pathway but in some organisms like hydra, it leads to regeneration,” said coauthor and graduate student Abby Primack. “In other organisms, like humans, once our brain is injured, we have difficulty recovering because the brain lacks the kind of regenerative abilities we see in hydra.”

The paper “Stem cell differentiation trajectories in Hydra resolved at single-cell resolution” has been published in the journal Science.

Scientists heal wounds without scarring

Only a few of us can brag about having the perfect skin, with no scars. Some of the rest of world’s population might think about removing nasty-looking scar tissue if they had a chance. Alas, for existing scars, science has no proper solution yet.

But, for scars which have yet to form, there might be a chance. Researchers at the Perelman School of Medicine at the University of Pennsylvania, in connection with the Plikus Laboratory for Developmental and Regenerative Biology at the University of California, Irvine, found a way to heal wounds without scarring. Their secret? Hair follicles.

Regular tissue repair by scarring Via: Wikipedia

Scar tissue lacks two main components of regular skin: hair follicles and fat cells. The most common cells found in healing wounds are myofibroblasts, which were thought to only form scars. Researchers discovered that the already present myofibroblasts could change into fat cells that do not cause scarring. Until now, scientists thought that this biological phenomenon couldn’t be reproduced in mammals, only in amphibians.

“Essentially, we can manipulate wound healing so that it leads to skin regeneration rather than scarring,” said George Cotsarelis, MD, the chair of the Department of Dermatology and the Milton Bixler Hartzell Professor of Dermatology at Penn, and the principal investigator of the project in a press statement. “The secret is to regenerate hair follicles first. After that, the fat will regenerate in response to the signals from those follicles.”

The progression of the wound during healing when hair follicles are present. Credits: Penn Medicine

Researchers carried out experiments on mice and human skin cultures and found that hair follicles and fat cells developed separately, but not independently. The hair follicle develops first, then releases biochemical signals that change the surrounding myofibroblasts in adipocytes. A key role in fat cell development is played by a factor called Bone Morphogenetic Protein (BMP).

“Typically, myofibroblasts were thought to be incapable of becoming a different type of cell,” Cotsarelis said. “But our work shows we have the ability to influence these cells, and that they can be efficiently and stably converted into adipocytes.” This was shown in both the mouse and in human keloid cells grown in culture.

Credit: Maksim V. Plikus et. al./Science

Maksim Plikus, an assistant professor of Developmental and Cell Biology at the University of California and the study’s lead author, says that now dermatologists now have the opportunity to fully regenerate wounds, and not leave any scar tissue behind. Plikus began this research as a postdoctoral fellow in the Cotsarelis Laboratory at Penn, and the two institutions have continued to collaborate ever since.

These findings are truly remarkable for dermatology and might not only improve wound healing but also lead to new cosmetic procedures. Fat cells are lost in different situations, such as during treatment for HIV or because of aging — the natural loss of adipocytes, especially in the facial skin, produces permanent, deep wrinkles. So, ladies, you might just want to keep at least some fat cells.

“Our findings can potentially move us toward a new strategy to regenerate adipocytes in wrinkled skin, which could lead us to brand new anti-ageing treatments,” Cotsarelis added.

The ground-breaking dermatology paper was published in the journal Science.

Scientist decode the largest genome so far – and it belongs to the axolotl

The Mexican axolotl Ambystoma mexicanum. Credit: IMP.

The Mexican axolotl Ambystoma mexicanum. Credit: IMP.

The axolotl (Ambystoma mexicanum), also known as the Mexican salamander, is one of the most peculiar animals on Earth. Its superpower is similar to that of Wolverine’s: extreme regeneration. Axolotl, this smily-faced amphibian, can regrow missing limbs, spinal chord segments, brain tissue, nerves, and retina.

Scientists have long been fascinated about this creature’s mysterious abilities. Now, a team composed of researchers from Vienna, Dresden, and Heidelberg has successfully decoded the entire genetic information of the axolotl. This data may help decipher the miracle of limb re-growth.

For quite some time, salamanders such as axolotl have been intensely studied because of their remarkable regeneration ability. If the amphibian loses a limb, in a few weeks, it will grow a new one, from scratch. The limb will be just like the old one, with no scar tissue whatsoever. These salamanders can also receive implants from their kin with no problems. A research team even performed axolotl head transplants in 1968. One of the animals lived up to 65 weeks with two functioning heads.

A key factor in understanding this type of regeneration is the animal’s genome (genetic material). So far, scientists couldn’t sequence all of it due to its length — at 32 billion base pairs, it is more than ten times larger than the human genome.

Male albino axolotl. Source: Pixabay/Tinwe

Researchers used the PacBio-platform, a sequencing technology that produces long reads to span large repetitive regions. A total of 72.435.954 reads were sequenced. Next, Gene Myers and Siegfried Schloissnig together with colleagues developed software systems that can assemble the genome from the 72 million pieces.

This is how they found that the uniqueness of the axolotl resides in its genes — the salamander only shares several genes expressed in regenerating limb tissue with other amphibian species. An essential developmental gene that plays key roles in neural and muscle development — PAX3 — is completely missing. Another gene, named PAX7, has taken over its functions.

“We now have the map in our hands to investigate how complicated structures such as legs can be re-grown”, says Sergej Nowoshilow, co-first author of the study. “This is a turning point for the community of scientists working with axolotl, a real milestone in a research adventure that started more than 150 years ago.”

Because of their incredible regenerative abilities, axolotls are of great interest to scientists. Because they can not only regenerate limbs and organs, but also brain tissue, many researchers hope that they might one day be able to do the same for human tissue in certain conditions. The implications in medical practice would be immensenly beneficial.  One challenging aspect has always been the axolotl’s huge genome size but now that it’s been sequenced, a whole new avenue of discoveries await.

Scientific reference: The axolotl genome and the evolution of key tissue formation regulators. Sergej Nowoshilow, Siegfried Schloissnig, Ji-Feng Fei, Andreas Dahl, Andy W.C. Pang, Martin Pippel, Sylke Winkler, Alex R. Hastie, George Young, Juliana G. Roscito, Francisco Falcon, Dunja Knapp, Sean Powell, Alfredo Cruz, Han Cao, Bianca Habermann, Michael Hiller, Elly M. Tanaka, and Eugene Myers. Nature, doi: 10.1038/nature25458.

planaria

After being decapitated, flatworms not only grow back their head but also regain memories

Research on nematodes have always been convenient for scientists. For one, they grow and breed really fast, making them ideal for work pertaining to genetics. Some of them have amazing properties, like  the planaria or “flatworm”, which some scientists believe it possesses the indefinite ability to regenerate its cells and thus practically never grow old. It soon became the object of intense research as scientists are trying to unravel the key to its longevity and whether or not it could be possible to transfer it to humans.

The planaria’s startling regenerative abilities don’t end here apparently. Researchers at Tufts University have determined that the small, yellow worm is able to grow back a lot more than just its lost body parts: it can regain its memories too!

The idea was first suggested sometimes in the 1960s, however it was extremely cumbersome for scientists to prove at the time. Now, Tal Shomrat and Michael Levin at Tufts University built a computerized apparatus for training planarians that allowed them to to study planarian memory with less error and greater numbers of worms.

planaria

These small worms detest open spaces and bright lights, however some of them were trained by the researchers to ignore these stimuli and make their way through them to reach food. After decapitating specimens and after the worms grew back their heads, they were inserted back in the experimental set-up. Even after decapitation, worms that had gone through training were able to overcome their fears and start eating much faster than worms that hadn’t been trained. The scientists made certain that no bit of brain survived during the decapitation process.

It’s worth nothing, however, that the memories didn’t come back immediately. The researchers still had to teach them to ignore the bothersome stimuli, but only once, like a sort of reminder if you will. How is such a thing possible though? It’s still unclear how, but the scientists suggest the planaria might store their memories in various parts of their bodies, not just in the head. Alternatively, they suggest that the worms’ original brain may have modified their nervous systems, and their nervous systems may have then altered how the new brains formed during regrowth.

Levin says epigenetics may play a role—modifications to an organism’s DNA that dial certain genes up or down—”but this alone doesn’t begin to explain it.”

“We don’t have an answer to this,” he says. “What we do show evidence of is the remarkable fact that memory seems to be stored outside the brain.”

The study was reported in The Journal of Experimental Biology

Stem Cell therapy could help us grow back fingers

Mammals can naturally regenerate the very top of their fingers and toes after amputation; starting from this idea, researchers have demonstrated the mechanism that describes this process, and explain how stem cells from nails could play a pivotal role in future regeneration of entire fingers.

fingers

A study conducted on mice showed that the chemical signal that triggers stem cells to develop into new nail tissue also attracts nerves that promote bone and nerve regeneration. The study suggests that nail stem cells could be used to develop new regeneration treatments for amputees.

Mice are pretty similar to humans in thhis regard – in both species, regenerating a finger starts with regenerating the nail. But whether the amputated portion of the digit actually takes place depends on exactly where the amputation occurs – if the stem cells in the nails are amputated as well, then no regeneration takes place. But if a small portion of the nail still remains in place, then it does regenerate. To understand exactly why these stem cells are so important, researchers turned to mice.

The two unfortunate groups of mice were separated into two groups – one control group, and one which was treated with a drug that made them unable to make the signals for new nail cells to develop. The second group was unable to regenerate, while the first one did this just fine, in time. When the signal was replenished, the second group resumed regeneration.

Limb regeneration is a very interesting field for biologists at the moment; a vast number of animals can regenerate lost limbs, most notably amphibians – aquatic salamanders can regenerate complete limbs, and even parts of their heart, by a process which involves their immune system. By studying species which are close to us and understanding the mechanism through which they regenerate, we could some day apply the same techniques to humans.

Via Discovery