Researchers have successfully regenerated skeletal and connective tissue—even if not perfectly formed—demonstrating the next, critical step in limb regeneration.
For centuries, the inability to regrow lost body parts has been considered a defining limitation of humans and other mammals. While animals like salamanders can regenerate entire limbs, humans are left with scar tissue.
But new research suggests that this limitation may not be permanent.
“This changes the way we think about what’s possible.”
Instead, the capacity for regeneration may still exist—hidden within the body’s normal healing process.
“Why some animals can regenerate and others, particularly humans, can’t is a big question that has been asked since Aristotle,” says Ken Muneoka, a professor in the Texas A&M University College of Veterinary Medicine and Biomedical Sciences (VMBS)’ veterinary physiology and pharmacology department (VTPP).
“I’ve spent my career trying to understand that.”
In their study in Nature Communications, Muneoka and his colleagues detail a newly developed two-step treatment that led to the regeneration of bone, joint structures, and ligaments.
While the results were imperfect, the team believes this approach could be used more immediately to reduce scarring and improve tissues repair after amputations.
Redirecting the body’s natural response
In mammals, injuries typically trigger fibrosis, a process in which fibroblast cells rapidly close the wound and form scar tissue. This response prioritizes survival by sealing the injury quickly, but also limits the body’s ability to rebuild missing structures.
In regenerative species, like salamanders that can regrow lost limbs, those same types of cells organize into a blastema, a temporary structure that enables tissue regrowth.
“It’s as if these cells can move in two different directions,” Muneoka says. “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.”
To test whether mammalian healing could be shifted toward regeneration, researchers developed a sequential treatment using two well-studied growth factors.
The first step involved applying fibroblast growth factor 2 (FGF2) after a wound had already closed. This timing allowed the body to complete its typical healing response, and then the team “changed what happens next,” Muneoka says.
FGF2 stimulated the formation of a blastema-like structure—something that does not normally occur in mammals following this type of injury; several days later, a second treatment—using bone morphogenetic protein 2 (BMP2)—was applied, triggering those cells to begin forming new structures.
“This is really a two-step process,” Muneoka says. “You first shift the cells away from scarring, and then you provide the signals that tell them what to build.”
Challenging assumptions
A key implication of the study is that regeneration does not depend on adding external stem cells, as many current approaches in regenerative medicine attempt to do.
“You don’t have to actually get stem cells and put them back in,” Muneoka says. “They’re already there—you just need to learn how to get them to behave the way you want.”
Larry Suva, a VTPP professor who worked on the study, says the findings shift how researchers think about the limits of mammalian healing.
“The cells that we thought to be unprogrammable, in fact are,” Suva says. “The capacity is not absent—it’s just obscured.”
The study also showed that cells can be redirected to form structures beyond their original location—a concept known as positional re-specification, which plays a critical role in development.
This means cells that would normally contribute to one part of the body can be instructed to rebuild a different structure after injury.
Not perfect
Although the regenerated structures were not exact replicas of the original anatomy, researchers were able to restore all the expected components removed during amputation, such as the bone, tendon, ligament, and joint.
The results included both skeletal elements and connective tissues, organized in a way that reflects the natural structure.
“We regenerated what you would expect to see at that level of injury,” Muneoka says. “The structures are there—just not in a perfect form.”
The findings also revealed that regeneration occurs through multiple biological pathways, indicating that rebuilding tissue is more complex than relying on a single mechanism.
Potential applications for humans
While the research is still in early stages, it may have more immediate applications in improving how wounds heal.
Rather than focusing solely on regrowing entire structures, researchers believe the approach could first be used to reduce scarring and improve tissue repair.
“People should start thinking about using these signals during the healing process,” Muneoka says. “Even shifting the response slightly away from scarring could have real benefits.”
Because BMP2 is already FDA approved for certain medical uses and FGF2 is in multiple clinical trials, the pathway to clinical exploration may be more accessible for entirely new therapies.
The study represents a shift in how scientists understand regeneration in mammals—not as a lost ability, but as one that remains present but inactive.
“This changes the way we think about what’s possible,” Suva says. “Once you show that regeneration can be activated, it opens the door to asking entirely new questions.”
For Muneoka, those questions have guided decades of research—and now, finally, have a new foundation.
“Regenerative failure in mammals can be rescued,” he says. “Now we have a model to begin figuring out how.”
Source: Texas A&M University
