Research conducted by an international team and led by biologists at the University of Kentucky has found that the ability to regenerate complex tissue may be more widespread in mammals than previously thought — an important step towards figuring out why many most mammals, and humans in particular, have poor regenerative ability. Basic research studies like this hold promise for developing novel regenerative therapies in humans.
Vertebrate regeneration is most commonly found in reptiles, amphibians and fish. In mammals it's usually a limited ability — deer regrowing antlers in the late spring or mice regrowing lost digit tips.
This latest study builds upon previous work using spiny mice by Ashley W. Seifert, Ph.D., a professor in the Department of Biology in the UK College of Arts and Sciences, and his research group. These rodents are known for their unique ability to regrow lost skin, restore function to a severed spinal cord and even repair damaged heart tissue.
The paper titled "Complex tissue regeneration in Lophuromys reveals a phylogenetic signal for enhanced regenerative ability in deomyine rodents" was recently published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
The study focused on a group of African rodents called brush-furred mice (Lophuromys), which the team uncovered could regrow musculoskeletal tissue as opposed to healing injuries with scar tissue. Seifert and the team of researchers wanted to learn whether these close relatives of spiny mice and other murid rodents might also have enhanced regenerative ability. Researchers examined ear injuries in a range of rodent species found in Kenya. They also studied non-murid rodents for comparison.
"This project establishes an evolutionary framework to study complex tissue regeneration in mammals. Our study found that only spiny mice and brush-furred mice could regenerate complete tissue," Seifert said. "Because these two types of mice are from the same subfamily of murid rodents, our discovery provides a phylogenetic signal for enhanced regenerative ability suggesting that specific features in their common ancestor provided the foundation for regeneration to emerge."
Seifert said he's been collecting data on this project for years. It was paused due to the pandemic but saw renewed interest thanks to Ph.D. student Brennan Riddell. He shared how important this work is to our understanding of the world around us.
"Understanding regeneration is a monumental undertaking. Discovering a unique instance of regeneration in a poorly characterized mammalian lineage should encourage people to ask questions and be both curious and protective of our biodiversity," Riddell said. "While our study only describes the presence of the trait, it shows just how interesting a simple mouse or rodent can be. In a fast-paced world, it is essential to slow down and appreciate the wonder of the natural world and all its mysteries."
Seifert worked with colleagues in the Department of Biology as well as researchers in the Department of Pharmacology and Nutritional Sciences in the UK College of Medicine, Yale University, Chicago State University, the Field Museum of Natural History and long-time collaborators at the University of Nairobi where Seifert is also a visiting professor.
"The collaboration between the University of Nairobi and University of Kentucky has brought together skills from the two institutions which has assisted in discovering two mammals from the wild that are able to heal by regeneration. This study provides yet another animal model for scar-free wound healing," said Stephen Kiama, Ph.D., the vice-chancellor of the University of Nairobi and professor in the Department of Veterinary Anatomy and Physiology.
The research team has a shared interest in understanding complex tissue regeneration in mammals, specifically rodents, and recognize the doors this opens for future discoveries.
"Documenting musculoskeletal regeneration in brush-furred mice gets us one step closer to understanding the shared evolutionary history of this truly unique lineage of rodents. As if shedding skin, regenerating musculoskeletal tissues and possessing tail osteoderms is not cool enough, it appears these phenomena could be shared among the entire subfamily and I'm looking forward to finding out," said Adam Ferguson, Ph.D., collection manager at the Gantz Family Collection Center at the Field Museum of Natural History in Chicago.
"Studies like this highlight why it is so important to understand natural history traits across the tree of life. Combining trait data with phylogeny we can begin to elucidate the origins of potentially adaptive traits, such as musculoskeletal tissue regeneration," said Molly McDonough, Ph.D., an assistant professor at Chicago State University and a research associate at the Field Museum of Natural History.
This study also highlights the importance of comparative studies across multiple species to understand the diversity of regenerative abilities and how they evolved.
"Future work can use this multi-species system to study the mechanisms underlying mammalian regeneration and its emergence using broader species coverage to make more evolutionarily informed conclusions," Riddell said. "There remain many deep, unanswered questions in the field, and we can use the evolutionary relationships between these types of rodents to gain a deeper understanding of the 'why' of it all."
Researchers say further studies are needed to explore the mechanisms and cellular features that facilitate regeneration in these mice.
"Importantly, this study provides the foundation to test the degree to which specific cellular, genetic and physiological features are or are not correlated with regenerative ability which will pave the way for subsequent studies," Seifert said. "These rodents offer important clues for how regeneration may be activated in tissues or species where it does not normally occur."
This research and others of its type across the tree of life provide a series of blueprints that could one day help scientists develop new therapies for wound healing, tissue repair and organ regeneration.
The full paper is available online here.
This research was supported by a grant from the National Geographic Society (Grant No. 9699-15).
Research reported in this publication was supported by the U.S. National Science Foundation (NSF) and the Office for International Science and Engineering under Award No. IOS-1353713. The opinions, findings, and conclusions or recommendations expressed are those of the author(s) and do not necessarily reflect the views of the U.S. National Science Foundation.
