Digit regeneration in mice is stimulated by sequential treatment with FGF2 and BMP2

Epimorphic regeneration in mice is stimulated at a non-regenerative digit amputation by sequential treatment with FGF2 and BMP2 (FGF2→BMP2). FGF2 stimulates digit amputation wound cells to form a blastema and BMP2 induces blastema differentiation to regenerate the amputated distal phalangeal element, albeit imperfectly. The formation of a phalangeal growth plate suggests that the induced regenerate recapitulates embryonic development and cell lineage studies show that wound cells that enter the blastema cells are positionally re-specified during regeneration. FGF2→BMP2 treatment also stimulates a blastema-independent response that regenerates a synovial joint complex containing stump-derived tendon, ligament and a sesamoid-like bone. Together the blastema-dependent and blastema-independent responses can result in the regeneration of all skeletal structures removed by amputation. The induced regeneration response demonstrates the availability of regeneration competent cells at a non-regenerating wound, and that FGF and BMP signaling is sufficient to trigger a regenerative outcome at wounds that heal by fibrosis. Wound fibrosis after amputation in mammals is replaced with regeneration of amputated structural elements by sequential FGF2/BMP2 treatment. Regenerated tissues include phalangeal/sesamoid bones, tendon/ligament, synovial joint, articular cartilage.