BMP signaling induces digit regeneration in neonatal mice

Abstract

SUMMARYThe regenerating digit tip of mice is a novel epimorphic response in mammals that is similar to fingertip regeneration in humans. Both display restricted regenerative capabilities that are amputation-level dependent. Using this endogenous regeneration model in neonatal mice, we have found that noggin treatment inhibits regeneration, thus suggesting a bone morphogenetic protein (BMP) requirement. Using non-regenerating amputation wounds, we show that BMP7 or BMP2 can induce a regenerative response. BMP-induced regeneration involves the formation of a mammalian digit blastema. Unlike the endogenous regeneration response that involves redifferentiation by direct ossification (evolved regeneration), the BMP-induced response involves endochondral ossification (redevelopment). Our evidence suggests that BMP treatment triggers a reprogramming event that re-initiates digit tip development at the amputation wound. These studies demonstrate for the first time that the postnatal mammalian digit has latent regenerative capabilities that can be induced by growth factor treatment.

Getting nervous about regeneration

“…While candidates PDGF-AA and OSM both showed efficacy in promoting regeneration after denervation, these two ligands accompany other ligands which have previously been demonstrated to promote regeneration, including BMP 2, BMP4, BMP7, SDF1a, and Flightless I (18)(19)(20)(21). PDGF-AA was also found to be expressed in blastema cell types other than SPCs, and may be additionally supplied by platelets and macrophages recruited to the wound environment, so precise delineation of the contribution of each of these ligands and their cellular source to normal regeneration will require cell type-specific deletion of each.…”

Mechanisms of urodele limb regeneration

“…Such a mechanism would explain why the stylopodium is able to regenerate after grafting a mature hand to the mid‐stylopodium of axolot limbs, whereas more distal structures fail to be intercalated (Bryant & Iten, 1977; Pescitelli & Stocum, 1981), and why the stylopodium is not regenerated when undifferentiated blastemas derived from the distal stylopodium are grafted to the dorsal fin (Stocum, 1968a) or when supernumerary limbs are evoked from the stylopodium in the Lheureux model (Makanae, Mitogawa, & Satoh, 2014b). Also explained would be why BMP2 or 7 can stimulate adult mouse digits amputated through the second phalange to complete that phalange but not regenerate the distal‐most phalange, and stimulate neonatal mouse forelimbs amputated through the mid‐zeugopodium to regenerate the zeugopodium but not the autopodium (Ide, 2012; Masake & Ide, 2007; Yu, Han, Yan, Lee, & Muneoka, 2012; Yu et al., 2010). Clearly, there is much more to learn about blastema patterning from investigation of these phenomena.…”

Looking Ahead to Engineering Epimorphic Regeneration of a Human Digit or Limb

“…In the regenerative case, ECM remodeling includes intensive bone erosion to expose the bone marrow cavity to the wound site, 15 where much less remodeling and no marrow exposure occurs in the absence of regeneration. Also, in the more commonly occurring nonregenerative response, the wound epidermis covers the injury *4-5 DPA in the neonatal model 93 and 8-13 DPA in the adult model. 90 This is followed by collagen deposition between the epidermal layer and the transected bone, which impedes communication between the surface layer and most underlying tissues, 90,93 leading to scar formation and 254 QUIJANO ET AL.…”