Spiny Mice Appear to Regenerate Damaged Kidneys
https://www.the-scientist.com/news-opinion/spiny-mice-appear-to-regenerate-damaged-kidneys-69375
Apeculiar rodent called the spiny mouse seems to be able to regenerate kidney tissue, according to research published today (November 3) in iScience. After damaging their kidneys to simulate kidney disease, the scientists found that the spiny mice not only regenerated the structure and function of nephrons, the tiny filters that make up the kidney, but they did so without the dangerous scarring that normally occurs in mammals.
Spiny mice, a collection of several species in the genus Acomys, are famous for their stiff coats of hair that resemble a hedgehog’s quills. The critters were already important to scientists studying regeneration, as they have an unusual defense mechanism in which they shed their skin to escape predators. A 2012 study in Nature revealed that spiny mice regenerate all of the tissue they give up, including vasculature and hair follicles, without any scarring, a process that subsequent research found may stem from a reduced inflammatory immune response to injuries. In the new study, researchers set out to determine whether the mice could pull the same regenerative trick with their internal organs.
Lead study author and regenerative medicine researcher Mark Majesky and his team at the University of Washington and Seattle Children’s Research Institute contrasted how spiny mice and house mice (Mus musculus) responded to kidney injuries. To do so, they operated on the mice to obstruct urine flow into the kidney and also directly damaged tissue, then watched to see whether organ structure and function returned. The process seems to trigger “scarless, regenerative wound healing” in the spiny mice, Majesky tells The Scientist in an email.
The same injuries from which the spiny mice seemingly escaped unscathed led to scarring in the house mice. As in human organ damage, that scarring can build up over time and cause fatal organ failure down the road—suggesting that unlocking the secrets of mammalian regeneration could someday prove invaluable to medicine.
“We used the term ‘functional regeneration’ because spiny mice sustain severe kidney injury initially but then completely restore kidney function within two weeks. This differs from many kinds of ‘repair’ responses, including fibrotic repair, that restore tissue continuity but do so with variable degrees of loss of organ function,” Majesky writes in his email.
“It sounds as if this new paper does show true restoration of injured Acomys kidney tissue, which I would explain by the immunodeficient status of this unusual species allowing patterning of new nephrons rather than scarring,” Anthony Mescher, an emeritus professor of anatomy and cell biology at Indiana University School of Medicine who didn’t work on the new study, emails The Scientist. The discovery, he adds, is “rather remarkable.”
Spiny mice aren’t the only mammals with regenerative capabilities, explains Rachel Sarig, a molecular cell biologist and regeneration expert at the Weizmann Institute of Science in Israel who didn’t work on the paper. They’re joined by animals like deer, which can grow new antlers, and MRL mice, which can regrow skin, hair, ears, and even some organs all without scarring. Even neonate mice can regenerate heart tissue but lose the ability during the first week of life.
Still, regeneration is typically not mammals’ forte, and examples of the phenomenon in these animals are so rare that they’re inevitably met with excitement. Regeneration is far more common among animals like the zebrafish, which can regrow pieces of its heart even after 20 percent has been removed, and salamanders, which famously regrow entire limbs. But fish, reptiles, and amphibians rely on a different biological process to regenerate lost limbs or tissue than do mammals, and more work is needed to uncover the exact mechanisms at play in spiny mice and what other organs or tissues they might apply to.
“In our lab, we definitely will try to see what else these mice can regenerate—maybe their hearts,” Sarig says. “Maybe we can learn from them what is missing for us”—that is, why humans don’t have the same regenerative capacity.
Multiple researchers tell The Scientist that getting to the bottom of mammalian regeneration could prove invaluable for developing new treatments for organ damage, whether it stems from severe injury or disease.
However, University of Kentucky animal regeneration researcher Ashley Seifert, who was not involved in the new study but was one of the researchers behind the 2012 skin regeneration paper, says that some key aspects of the paper gave him pause, and he will be interested to see what happens when other researchers attempt to replicate the study.
One potential issue, Seifert notes, is that it’s particularly difficult to conduct a surgical procedure on two different animal species and ensure that the same injury produces the same initial effect in both.
“One thing that troubled me about this particular paper . . . is that it almost looks like they never caused any damage whatsoever” to the spiny mice, Seifert tells The Scientist. Seifert points out that the researchers found almost no collagen buildup in the spiny mice after injury. The authors pointed to that lack of collagen as a sign that the mice were healing without forming scars, but collagen is an expected part of healing and recovery that even other regenerating animals experience, Seifert explains.
Seifert adds that the paper’s methodology lacks details that would be helpful in evaluating and replicating the work. For instance, the study authors say they experimented on adult spiny and house mice, but because the species have significantly different lifespans, a spiny and house mouse of the same age may be at different stages of life. Perhaps the authors controlled for that discrepancy—and Seifert adds that he believes the authors’ methods were sound—but without clarification in the paper, it’s impossible to tell whether there were issues or errors.
“At the end of the day, science needs to be reproduced to be worthwhile,” Seifert says.
Similarly, Sarig adds that she hopes researchers will conduct a more precise analysis of the genetic and epigenetic mechanisms responsible for the apparent regeneration in order to paint a clearer picture of what’s going on at a molecular level.
While much research remains to be done before the finding might be translated to anything of clinical relevance to humans, Sarig says papers of this sort give her hope for a future where regenerative medicine can treat diseases or perhaps prevent organ failure in people.
“A decade ago, when [scientists] started to study heart regeneration, it was like science fiction; it seemed impossible,” Sarig says. “Now we know it is possible. During those ten years, we found several factors, several strategies, which we can use to induce adult mammalian heart repair. So we know it is possible, we just need to find the right factors—the right signal.”
Seifert adds that even if future researchers and clinicians never quite figure out true regeneration for human tissue, taking lessons from the spiny mouse or other animals with incredible healing abilities could still prove valuable for emergency medicine situations. Finding new ways to induce healing, whether or not that involves scarless regeneration of tissue, could lead to therapeutics that keep hospitalized heart failure patients alive, he explains.
“We [know] that over 600,000 Americans have kidney failure and over 450,000 patients, including children, are currently on dialysis,” Majesky writes. “Most of those patients have progressive kidney fibrosis leading to kidney failure. We conducted our research with those individuals in mind.”
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