Two-Step Growth Factor Treatment Unlocks Hidden Regenerative Capacity in Mammals
核心洞察
Researchers at Texas A&M University developed a two-step treatment using FGF2 and BMP2 growth factors that successfully regenerated bone, joint structures, tendons, and ligaments in mice.
The treatment redirects fibroblast cells away from scar formation toward forming a blastema, a transient cellular structure typically seen in regenerating species like salamanders.
Findings challenge the assumption that mammalian cells are unprogrammable, suggesting regenerative capacity is dormant rather than absent and can be activated without external stem cells.
A research team at Texas A&M University has demonstrated that mammals possess a hidden regenerative capacity that can be activated through a sequential two-step growth factor treatment, challenging centuries-old assumptions about the limits of human healing. The findings, published in Nature Communications, show that bone, joint structures, tendons, and ligaments can be regrown following amputation in mice—not perfectly, but with all major structural components restored.
"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 Texas A&M College of Veterinary Medicine and Biomedical Sciences' Department of Veterinary Physiology & Pharmacology. "I've spent my career trying to understand that."
Redirecting Healing Away From Scar Formation
When mammals sustain injuries, the body typically responds with fibrosis—fibroblast cells rapidly close the wound and create scar tissue. While this prevents infection and further damage, it forecloses the possibility of rebuilding what was lost. In contrast, animals like salamanders and axolotls gather similar cells into a blastema, a mass of multiplying, unprogrammed cells that serves as the foundation for new tissue growth.
"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 research team developed a treatment protocol with three distinct phases. First, they waited for the wound to heal over naturally after amputation of part of a mouse's finger. "The wound actually has the highest potential to regrow right when the skin closes and the body's natural inflammation peaks," Muneoka explained.
Second, they implanted a tiny bead containing fibroblast growth factor 2 (FGF2). While FGF2 does not cause full regrowth on its own in adult mice, it successfully stops the body from forming a scar and instead tricks wound cells into forming a blastema. Third, after the blastema formed, the researchers applied bone morphogenetic protein 2 (BMP2), which prompted those cells to begin building new tissues—specifically, an entirely new, complete bone at the tip of the finger.
"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."
Rethinking the Role of Stem Cells
One of the study's most significant findings is that regeneration may not require adding stem cells from outside the body, an approach commonly explored 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 professor in the department involved in the study, emphasized that the results challenge long-standing assumptions about what mammalian cells are capable of doing. "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 of positional re-specification, a process in which cells can be redirected to create structures outside their usual location. In practical terms, cells that would normally help form one type of tissue can be instructed to rebuild a different structure following an injury.
Regrown Structures and the Role of the Blueprint
Although the regenerated tissues were not exact replicas of the original anatomy, the researchers successfully restored all major structures that had been 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 tissue rebuilding far more complex than activating a single mechanism.
Muneoka noted that the human body uses a developmental blueprint to form limbs in the embryo, and his team found evidence that this same blueprint is re-utilized when regeneration is stimulated by their treatment. "If the 'blueprint' is intact, then the expectation is that the regeneration should be possible," he said. This has implications for congenital conditions: someone whose limb was underdeveloped due to external factors in utero, such as alcohol or drug exposure, might see better results than someone whose underdevelopment was caused by a genetic modification that damaged the blueprint.
Broader Applications and Limitations
The potential applications may extend beyond limbs. Muneoka pointed to studies showing that lung formation and limb formation share similar genetic requirements, and research in salamanders demonstrating that proteins important for limb regeneration are also important for regeneration of other structures such as gills.
"This suggests that the regenerative process may have universal characteristics, which gives us hope that our strategy for stimulating digit regeneration could have broad application," Muneoka said. "We believe that our study outlines a general strategy for enhancing regenerative capabilities in humans. The specific details for this strategy will likely differ between organ systems, and that needs to be determined empirically."
However, organ regeneration presents unique challenges. Unlike limbs, organs often cannot be taken offline during the regeneration period. "Organ regeneration requires time that may not be possible if the organ's use is required to stay alive," Muneoka cautioned. Depending on the extent of organ damage, a donor transplant may still be necessary.
Regeneration is also unlikely to confer immortality. Muneoka referenced a 2021 mouse study he worked on that found blastema formation and the quality of the regenerative response decline with age. "If individuals could regenerate organs throughout their lives, it would improve the quality of life, and it may enhance lifespan," he said, but it would not stop aging itself.
Path Toward Clinical Translation
The path toward clinical testing may be more straightforward than with many experimental therapies. BMP2 already holds FDA approval for certain medical applications, and FGF2 is currently being evaluated in multiple clinical trials.
"People should start thinking about using these signals during the healing process," Muneoka said. "Even shifting the response slightly away from scarring could have real benefits."
"Regenerative failure in mammals can be rescued," he concluded. "Now we have a model to begin figuring out how."