Can mammals regrow lost limbs? This new treatment could be the first step

Could humans regrow tissue like salamanders or sea stars? This is the question a new study has us asking, as researchers take an early step toward digit regeneration in mice.

Introducing a novel two-step treatment, scientists from Texas A&M College of Veterinary Medicine and Biomedical Sciences (TX, USA) report the regeneration of skeletal and connective tissue, albeit imperfectly, in mice. Although in its early days, the research expands our understanding of mammalian healing and could be used to reduce scarring and improve tissue repair for human patients.

The question of why regeneration occurs in some animals but not in others was first posed by Aristotle over 2000 years ago, and yet we still don’t have a definitive answer. While mammals have poor regenerative capabilities, some creatures, like the salamander, are able to regrow lost limbs by a process called epimorphic regeneration. This involves the formation of a blastema, a mass of undifferentiated, multipotent fibroblast cells that undergo morphogenesis and differentiate the structures removed by amputation. Meanwhile, the mammalian response to limb loss results in fibrosis, whereby fibroblasts form scar tissue to facilitate wound healing.

“It’s as if these cells can move in two different directions. They could either make a scar or make a blastema,” study author Ken Muneoka explained. This is what led the team to investigate whether, with a nudge in the right direction, fibroblasts could be rerouted toward regeneration during mammalian healing.

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In their new paper, the researchers report a protocol for attempting just that, using two well-studied growth factors: FGF2 and BMP2. First, they applied FGF2 – which is known to stimulate cell proliferation, migration and survival, as well as regeneration of the chick limb bud – by implanting a bead containing the protein into an amputated mouse digit 4 days post-op. After a further 21 days, the removed limbs were analyzed by micro-computed tomography (µCT) and compared with control limbs treated with BSA beads. While the control beads did not induce regeneration, FGF2 implants stimulated a minimal regeneration response.

Histological analysis of the FGF2-treated digit revealed the formation of a blastema-like accumulation of mesenchymal cells at the amputation site; however, this structure failed to differentiate and eventually regressed. Encouragingly, applying BMP2 – a protein implicated in bone and cartilage formation – 5 days after the initial FGF2 treatment resulted in imperfect digit regeneration, including ectopic bone formation, according to µCT imaging and subsequent histological analyses.

These findings demonstrate that sequential treatment with FGF2 and BMP2 can induce an epimorphic regenerative response in mammals. “You first shift the cells away from scarring, and then you provide the signals that tell them what to build,” Muneoka explained.

As well as reshaping our understanding of mammalian healing and providing a starting point for future research into rescuing regenerative failure in mammals, in the shorter term, the work could have clinical implications for the treatment of scarring and tissue repair. “People should start thinking about using these signals during the healing process,” Muneoka continued. “Even shifting the response slightly away from scarring could have real benefits.”