For generations, scientists have considered the inability to regenerate lost body parts as one of the fundamental limitations of humans and other mammals. While creatures like salamanders can regenerate entire limbs, humans often heal injuries by forming scar tissue.
However, new research from the Texas A&M College of Veterinary Medicine and Biomedical Sciences (VMBS) suggests that regenerative capabilities may not be completely absent in mammals. Instead, they could be hidden within the body’s normal healing machinery, waiting to be activated under the right conditions.
“Why some animals can regenerate and others, particularly humans, cannot, is a big question that has been asked since Aristotle,” said Dr. Ken Muneoka, professor in the Department of Veterinary Physiology and Pharmacology (VTPP) at VMBS. “I’ve spent my career trying to understand that.”
In a study published in Nature CommunicationsMuneoka and his colleagues describe a new two-step treatment that allowed the regeneration of bones, joint structures and ligaments. Although the regenerated tissues were not perfect replicas of the originals, the researchers believe the approach could eventually help reduce scarring and improve tissue repair after amputations.
Redirect healing away from scar formation
When mammals are injured, the body often responds with fibrosis. During this process, fibroblast cells quickly close the wound and create scar tissue. While this response helps prevent infection and further damage, it also limits the body’s ability to rebuild what was lost.
Animals capable of regenerating follow a different path. In salamanders, for example, similar cells gather together in a structure called a blastema, which serves as the basis for the growth of new tissues.
“It’s like these cells can move in two different directions,” Muneoka said. “They could leave a scar or a blastema. Our research focused on redirecting the behavior of fibroblasts already present at the injury site.”
To explore whether mammalian healing could be driven toward regeneration, the research team developed a treatment that uses two well-known growth factors in sequence.
The first step involved applying fibroblast growth factor 2 (FGF2) after the wound had already healed. By waiting until the initial healing process was complete, the researchers allowed the body to respond normally before intervening.
According to Muneoka, the team “changed what happens next.”
FGF2 promoted the formation of a blastema-like structure, something that does not typically occur in mammals after this type of injury. Several days later, the researchers applied a second growth factor, bone morphogenetic protein 2 (BMP2), which prompted those cells to begin building new tissues.
“This is really a two-step process,” Muneoka said. “You first move the cells away from the scars and then you give them the signals that tell them what to build.”
Rethinking the role of stem cells
One of the most important findings of the study is that regeneration may not require the addition of stem cells from outside the body, an approach commonly explored in regenerative medicine.
“You don’t actually have to get stem cells and put them back in,” Muneoka said. “They’re already there; you just have to learn how to get them to behave the way you want them to.”
Dr. Larry Suva, another VTPP professor involved in the study, said the results challenge long-held assumptions about what mammalian cells are capable of.
“Cells that we thought were not programmable actually are,” Suva said. “The capacity is not absent, it is simply obscured.”
The researchers also found evidence that cells can be redirected to create structures outside their usual location. This process, known as positional respecification, is an important part of development.
In practical terms, cells that would normally help form one type of tissue can be instructed to rebuild a different structure after an injury.
Regrowing bones, tendons, ligaments and joints
Although the regenerated tissues did not exactly match the original anatomy, the researchers successfully restored all major structures that had been removed during the amputation, including bones, tendons, ligaments and joint tissues.
The regenerated areas contained skeletal components and connective tissues arranged in patterns that resembled natural anatomy.
“We regenerated what you would expect to see with that level of injury,” Muneoka said. “The structures are there, but not in perfect shape.”
The findings also suggest that regeneration depends on multiple biological pathways working together. Reconstructing tissue appears to be much more complex than activating a single mechanism.
Potential benefits for wound healing
While the research is still in its early stages, scientists believe it could have practical applications long before full regeneration is possible.
Rather than focusing solely on replacing missing structures, the approach can help improve healing outcomes by reducing scar formation and improving tissue repair.
“People should start thinking about using these signals during the healing process,” Muneoka said. “Even slightly diverting the scar response could have real benefits.”
The path to clinical trials may also be simpler than that of many experimental therapies. BMP2 already has FDA approval for certain medical applications and FGF2 is currently being evaluated in multiple clinical trials.
A new vision of mammalian regeneration
The study adds to growing evidence that regeneration in mammals may not be a completely lost trait. Instead, it may be a latent ability that normally remains dormant during healing.
“This changes the way we think about what is possible,” Suva said. “Once it is shown that regeneration can be activated, it opens the door to asking completely new questions.”
For Muneoka, those questions have fueled decades of research and now have a promising new framework.
“Regenerative failure in mammals can be overcome,” he said. “Now we have a model to start figuring out how to do it.”