Limb regeneration in higher vertebrates: Developing a roadmap

Abstract

We review what is known about amphibian limb regeneration from the prospective of developing strategies for the induction of regeneration in adult mammals. Prominent in urodele amphibian limb regeneration is the formation of a blastema of undifferentiated cells that goes on to reform the limb. The blastema shares many properties with the developing limb bud; thus, the outgrowth phase of regeneration can be thought of as cells going through development again, i.e., redevelopment. Getting to a redevelopment phase in mammals would be a major breakthrough given our extensive understanding of limb development. The formation of the blastema itself represents a transition phase in which limb cells respond to injury by dedifferentiating to become embryonic limb progenitor cells that can undergo redevelopment. During this phase, rapid wound closure is followed by the dedifferentiation of limb cells to form the blastema. Thus, the regeneration process can be divided into a wound-healing/dedifferentiation phase and a redevelopment phase, and we propose that the interface between the wound-healing response and gaining access to developmentally regulated programs (dedifferentiation) lies at the heart of the regeneration problem in mammals. In urodele amphibians, dedifferentiation can occur in all of the tissues of the limb; however, numerous studies lead us to focus on the epidermis, the dermis, and muscle as key regulators of regeneration. Among higher vertebrates, the digit tip in mammals, including humans, is regeneration-competent and offers a unique mammalian model for regeneration. Recent genetic studies in mice identify the Msx1 gene as playing a critical role in the injury response leading to digit tip regeneration. The results from regeneration studies ranging from amphibians to mammals can be integrated to develop a roadmap for mammalian regeneration that has as its focus understanding the phenomenon of dedifferentiation.

BMP signaling induces digit regeneration in neonatal mice

“…These results clearly show that the BMP7-induced response is distinct from endogenous regeneration and that it involves modification of the amputation wound in a way that allows cells to reactivate differentiation programs that restore the amputated structure. The reactivation of developmental programs effectively represents a reprogramming event that has obvious parallels with the process of dedifferentiation in limb regeneration (Brockes and Kumar, 2005;Gardiner, 2005;Han et al, 2005). Overall, the finding that developmental programs can be reactivated at a postnatal mammalian injury site provides some promise that similar reprogramming events might be inducible in adult tissues.…”

Mature osteoblasts dedifferentiate in response to traumatic bone injury in the zebrafish fin and skull

“…Bone is a major element of appendages, and the ability to regenerate bony structures during fin and limb regeneration appears to be essentially unlimited (Hall, 2005;Han et al, 2005). Bone repair also occurs in adult mammals, but internal bone defects can only be healed below a critical size (Hall, 2005), and regeneration of bony elements lost due to amputation does not occur.…”

Reptile genomes open the frontier for comparative analysis of amniote development and regeneration

“…Amphibians and teleost fish are spectacular examples of limb and tail regeneration (Stocum, Cameron, 2011). Many lizards are capable of tail regeneration following tail amputation and/or autotomy, and tail regeneration in alligators has been reported in the field (Han et al, 2005). Birds and mammals have limited regenerative capacity in comparison, though some neonatal and juvenile mammals can regenerate digit tips, and African spiny mice can autotomize and regenerate skin (Han et al, 2008).…”