For generations, science has accepted that humans and salamanders have very different approaches to injury: salamanders regrow entire limbs, while humans form scar tissue and complain about it. New research from the Texas A&M College of Veterinary Medicine and Biomedical Sciences (VMBS) suggests that this limitation might not be as hardwired as we thought - the ability to regenerate may be hiding inside our own healing machinery, just waiting for the right nudge.
"Why some animals can regenerate and others, particularly humans, can't is a big question that has been asked since Aristotle," said Dr. Ken Muneoka, a professor in the VMBS' Department of Veterinary Physiology & Pharmacology (VTPP). "I've spent my career trying to understand that." Aristotle, for the record, did not have access to modern growth factors.
In a study published in Nature Communications, Muneoka and colleagues describe a two-step treatment that successfully regenerated bone, joint structures, and ligaments in mammals. The regrown tissues weren't perfect replicas, but they were close enough to suggest that the approach could eventually reduce scarring and improve tissue repair after amputations.
The key was redirecting the healing process away from fibrosis - the body's default response where fibroblast cells quickly close wounds with scar tissue. In regenerating animals like salamanders, similar cells gather into a blastema, a structure that serves as a foundation for new growth. The Texas A&M team wanted to see if they could push mammalian fibroblasts toward blastema instead of scar.
"It's as if these cells can move in two different directions," Muneoka said. "They could either make a scar or make a blastema. Our research focused on redirecting the behavior of fibroblasts already present at the injury site."
The treatment uses two well-known growth factors in sequence. First, they applied fibroblast growth factor 2 (FGF2) after the wound had healed over - letting the body respond normally before intervening. This encouraged the formation of a blastema-like structure, which doesn't normally occur in mammals after such injuries. Several days later, they applied bone morphogenetic protein 2 (BMP2), which told those cells to start building new tissues.
"This is really a two-step process," Muneoka said. "You first shift the cells away from scarring, and then you provide the signals that tell them what to build."
One of the study's most encouraging findings is that regeneration doesn't require adding stem cells from outside the body - a common approach in regenerative medicine. "You don't have to actually get stem cells and put them back in," Muneoka said. "They're already there - you just need to learn how to get them to behave the way you want."
Dr. Larry Suva, another VTPP professor involved in the study, said the results challenge long-standing assumptions. "The cells that we thought to be unprogrammable, in fact are," Suva said. "The capacity is not absent - it's just obscured."
The researchers also found evidence that cells can be redirected to create structures outside their usual location - a process called positional re-specification. In practical terms, cells that would normally help form one type of tissue can be instructed to rebuild something entirely different after an injury.
Although the regenerated tissues weren't exact matches to the original anatomy, the team successfully restored all major structures removed during amputation, including bone, tendon, ligament, and joint tissue. "We regenerated what you would expect to see at that level of injury," Muneoka said. "The structures are there - just not in a perfect form."
The findings also suggest that regeneration depends on multiple biological pathways working together, making it far more complex than activating a single mechanism. But the scientists believe the approach could have practical applications long before complete regeneration becomes possible - even shifting the response slightly away from scarring could improve healing outcomes.
The path toward clinical testing may also be more straightforward than with many experimental therapies. BMP2 already has FDA approval for certain medical applications, and FGF2 is currently being evaluated in multiple clinical trials.
The study adds to growing evidence that regeneration in mammals may not be a completely lost trait - just a dormant capability that normally stays inactive during healing. "This changes the way we think about what's possible," Suva said. "Once you show that regeneration can be activated, it opens the door to asking entirely new questions."
For Muneoka, those questions have driven decades of research, and now they have a promising new framework. "Regenerative failure in mammals can be rescued," he said. "Now we have a model to begin figuring out how."