Mammalian regeneration could occur by use of sequential growth factor signalling

A two-step treatment using fibroblast growth factor 2 and bone morphogenetic protein 2 has restored complex tissue structures in mammals, which challenges long-held assumptions about the limits of human healing

The inability to regrow lost body parts defines the biological limits of humans and other mammals. By contrast to regenerative species such as salamanders – which can restore entire limbs – mammalian injury has typically resulted in fibrotic scar formation and not structural replacement. Now, research from Texas A&M College of Veterinary Medicine and Biomedical Sciences, College Station, Texas, USA, has suggested that this limitation is latent biological programming that remains inactive in normal wound healing rather than the absence of regenerative capacity.

The study has described a two-step therapeutic strategy that has induced regeneration of bone, joint structures and connective tissues in a mammalian model. Although the reconstructed anatomy did not fully replicate the original structures, the findings have indicated that complex tissue restoration may be achievable through controlled manipulation of endogenous repair mechanisms.

“Why some animals can regenerate and others – particularly humans – cannot is a … question that has been asked since Aristotle’s [time],” said Dr. Ken Muneoka, professor in the department of veterinary physiology and pharmacology at Texas A&M, whose career in research has focused on the mechanisms that underpin this divergence in healing capacity.

In mammals, injury typically triggers fibrosis, in which fibroblast cells rapidly close wounds and deposit scar tissue. This response has prioritised rapid sealing of damaged tissue, which reduces infection risk but constrains the ability to rebuild complex anatomical structures. By contrast, regenerative organisms form a blastema, a transient cellular structure that supports coordinated tissue regrowth.

“It’s as if these cells can move in two different directions,” said Muneoka.

“They could either make a scar or make a blastema. Our research focused on redirecting the behaviour of fibroblasts already present at the injury site.”

To test this hypothesis, researchers developed a sequential intervention based on two well-characterised growth factors. The first phase involved administration of fibroblast growth factor 2 after wound closure. This approach allowed the initial healing response to proceed before subsequent modulation of cellular behaviour. The treatment has stimulated formation of a blastema-like structure, a phenomenon that does not normally occur in mammals following comparable injury.

Several days later, investigators applied bone morphogenetic protein 2, which has triggered differentiation within the newly formed cellular structure and initiated tissue reconstruction.

“This is really a two-step process. You first shift the cells away from scarring, and then you provide the signals that tell them what to build,” said Muneoka.

A notable implication of the work has been the demonstration that regeneration may not require transplantation of external stem cells, a strategy that has dominated much of regenerative medicine research. Instead, the findings have indicated that resident cells at the injury site retain intrinsic plasticity.

“You don’t have to actually get stem cells and put them back in. They’re already there – you just need to learn how to get them to behave the way you want,” Muneoka added.

Dr. Larry Suva, also a professor in the department of veterinary physiology and pharmacology, said the results have challenged prevailing assumptions about the rigidity of mammalian cell fate.

“The cells that we thought to be unprogrammable, in fact are [programmable]. The capacity is not absent – it’s just [been] obscured,” said Suva.

The study has also demonstrated positional re-specification, a developmental principle in which cells adopt identities appropriate to a different anatomical location. This capacity has allowed cells that would ordinarily contribute to one tissue type to participate in reconstruction of another following injury.

Although the regenerated structures did not achieve complete anatomical fidelity, researchers reported restoration of the full complement of expected components at the injury site, including bone, tendon, ligament and joint elements. These tissues have organised into arrangements that resemble native architecture, albeit with some structural imperfections.

“We regenerated what you would expect to see at that level of injury. The structures are there – just not in a perfect form,” said Muneoka.

The findings have also indicated that regeneration proceeds through multiple interacting biological pathways, which underscores the complexity of tissue reconstruction beyond a single signalling mechanism. This insight has reinforced the need for coordinated modulation of cellular processes rather than reliance on isolated molecular targets.

While the research remains at an early stage, investigators have suggested that near-term clinical applications may focus on improvement of wound healing rather than full limb regeneration. Even partial modulation of fibrotic responses could reduce scarring and enhance functional recovery after injury or surgery.

“People should start thinking about using these signals during the healing process. Even shifting the response slightly away from scarring could have real benefits,” said Muneoka.

The translational potential of the approach has been supported by the existing clinical status of its components. Bone morphogenetic protein 2 has already received regulatory approval for certain medical applications, while fibroblast growth factor 2 has entered multiple clinical trials. This context may facilitate progression towards clinical evaluation without the regulatory barriers associated with entirely novel therapeutics.

Taken together, the findings have reframed limb regeneration in mammals not as a lost evolutionary trait but as a suppressed biological capability that can be reactivated under defined conditions.

“This changes the way we think about what’s possible. Once you show that regeneration can be activated, it opens the door to asking entirely new questions,” said Suva.

For Muneoka, whose work has spanned decades, the study has provided a conceptual and experimental foundation to address those questions.

“Regenerative failure in mammals can be rescued. Now we have a model to begin figuring out how,” he concluded.

For further reading please visit: 10.1038/s41467-026-72066-8