For generations, scientists have considered the inability to regenerate lost body parts to be one of the fundamental limitations of humans and other mammals. Creatures like salamanders can regenerate entire limbs, while humans typically heal injuries by forming scar tissue.
But new research from the Texas A&M College of Veterinary and Biomedical Sciences (VMBS) suggests that mammals may not be completely without regenerative abilities. Instead, they may be hidden within the body’s normal healing mechanisms, waiting to be activated under the right conditions.
“Why some animals can regenerate while others, especially humans, cannot is a big question since Aristotle,” said Dr. Ken Muneoka, professor in the VMBS Department of Veterinary Physiology and Pharmacology (VTPP). “I’ve spent my career trying to figure that out.”
In a study published in nature communicationsMuneoka et al. describe a new two-step treatment that allows bone, joint structures, and ligaments to regenerate. Although the regenerated tissue was not a perfect replica of the original tissue, the researchers believe this approach may ultimately help reduce scarring and improve tissue repair after amputation.
Changing the direction of healing from scar formation
When a mammal is injured, the body usually responds with fibrosis. During this process, fibroblasts quickly close the wound and create scar tissue. This response helps prevent infection and further damage, but it also limits the body’s ability to rebuild what is lost.
Animals with the ability to regenerate take a different path. For example, in salamanders, similar cells gather into structures called blastocytes and serve as the basis for new tissue growth.
“It’s almost as if these cells can move in two different directions,” Muneoka says. “They can either create a scar or create a blastoma. Our study focused on redirecting the behavior of fibroblasts already present at the injury site.”
To explore whether healing in mammals could be driven toward regeneration, the researchers developed a treatment that uses two well-known growth factors in sequence.
The first step is to apply fibroblast growth factor 2 (FGF2) after the wound has already healed. By waiting until the initial healing process was complete, the researchers allowed the body to react normally before intervening.
According to Muneoka, the team’s development changed after that.
FGF2 promoted the formation of blastoid structures, which do not normally occur in mammals with such lesions. After a few days, the researchers applied a second growth factor, bone morphogenetic protein 2 (BMP2), to encourage these cells to start building new tissue.
“This is actually a two-step process,” Muneoka said. “First, it moves the cells away from the scar, and then it sends signals that tell the cells what to build.”
Rethinking the role of stem cells
One of the study’s most important findings is that regeneration may not require the addition of stem cells from outside the body, an approach commonly considered in regenerative medicine.
“There’s no need to actually obtain the stem cells and put them back together,” Muneoka says. “They’re already there. You just need to learn how to get them to do what you want them to do.”
Dr. Larry Suba, another VTPP professor involved in the study, said the results challenge long-held assumptions about the capabilities of mammalian cells.
“The cells we thought were unprogrammable were actually programmable,” Suba said. “It’s not that the ability doesn’t exist, it’s just that it’s vague.”
The researchers also found evidence that cells can change their orientation to create structures outside of their normal locations. This process, known as relocation, is an important part of development.
In fact, cells that normally help form one type of tissue can be directed to rebuild another structure after injury.
Regeneration of bones, tendons, ligaments, and joints
Although the regenerated tissue did not perfectly match the original anatomy, the researchers were able to restore all the major structures that were removed during the amputation, including bones, tendons, ligaments, and joint tissue.
The regenerated area contained both skeletal components and connective tissue arranged in a pattern resembling natural anatomy.
“He made a level of recovery that you would expect for an injury of that level,” Muneoka said. “The structure is there, but it’s not fully formed.”
This finding also suggests that regeneration relies on multiple biological pathways working in concert. Tissue remodeling appears to be much more complex than activating a single mechanism.
Potential benefits for wound healing
Although the research is still in its early stages, scientists believe it could be put into practice long before full regeneration becomes possible.
This approach may help improve healing outcomes by reducing scar formation and enhancing tissue repair, rather than focusing solely on replacing missing structures.
“People should start thinking about using these signals in the healing process,” Muneoka says. “Even slightly shifting the response away from scarring can have significant benefits.”
The path to clinical trials may be easier than for many experimental treatments. BMP2 already has FDA approval for certain medical uses, and FGF2 is currently being evaluated in multiple clinical trials.
A new perspective on mammalian regeneration
This study adds to the growing body of evidence that regeneration in mammals may not be a completely lost trait. Instead, it may be a dormant ability that normally remains inactive while healing.
“This changes the way we think about what is possible,” Suba says. “Showing that regeneration can be activated opens the door to entirely new questions.”
For Muneoka, these questions have fueled decades of research that now yields a promising new framework.
“Regenerative failure in mammals can be rescued,” he said. “Now we have a model to start thinking about how to do that.”
