In contrast to all other vertebrates, salamanders can regenerate their limbs throughout their lives, and thus they provide a unique window to observe how this can be done. Successful limb regeneration in a salamander is a two-step process (Fig. 1), consisting of an early phase that begins with wound healing and ends with the formation of a regeneration blastema. This is followed by the second, re-development phase that is a recapitulation of the events that occurred during limb development in the embryo.
Although the later phase of limb regeneration is equivalent to limb development, the early phase that results in genesis of the blastema is unique to regeneration.
The unique events of regeneration include the rapid closure of the wound by epidermal cells, interactions between the wound epidermis and underlying stump cells that stimulate dedifferentiation, and cell migration and proliferation that give rise to the blastema. Dedifferentiation of stump cells to give rise to the relatively undifferentiated blastema cells, though not well understood mechanistically, is a necessary step for limb regeneration.
Understanding the biphasic nature of salamander limb regeneration is important for two reasons. (1) The fact that we developed limbs as embryos means that we have the genetic program to regenerate them as adults. Since the second phase of regeneration corresponds to limb development, we can be reasonably confident that if we can induce an amputated limb to progress through Phase I (make a blastema), we will find that we have the genetics to progress through Phase II. (2) Therefore we need to focus our research efforts on how to induce Phase I.