Regeneration Basics

Written by David M Gardiner


     Although we cannot regenerate our limbs today, when we were embryos we likely could regenerate many of our tissues, including our limbs. Like other vertebrates, our impressive regenerative abilities were lost during embryogenesis, leaving us with a limited ability to repair tissue damage. This phenomenon of regenerative decline has been well studied in frogs. In contrast, adult salamanders can reactivate the embryonic regeneration response, and thus allow us to discover the mechanisms of tissue and organ regeneration. One important lesson we have learned from salamanders is that regeneration occurs in two steps. While the second step is comparable to limb development, the first step is unique and leads to the formation of a regeneration blastema through the process of dedifferentiation. An important early molecular event associated with dedifferentiation is the early expression of homeobox genes. A second lesson is that connective tissue fibroblasts control regeneration, and that the unique regenerative ability of salamanders is a consequence of the ability of fibroblasts to dedifferentiate and give rise to blastema cells. Although mammals (including humans) cannot regenerate an entire limb, they do possess some regenerative abilities, and we should recognize that regeneration is a basic biological process exhibited in all animals. It is just that salamanders are exceptionally good at regeneration. The most important difference between salamanders and mammals appears to be in the functioning of fibroblasts. In mammals fibroblasts respond to injury by forming scars. In salamanders they function to control regeneration of the other cell types in the limb. Thus regenerative failure is a consequence of the failure of mammalian fibroblasts to carry out this function. The challenge is to identify the signals that fibroblasts use to regulate cellular behavior. To study regeneration, we have developed a new assay (the Accessory Limb Model) that allows us to study each of the stages of limb regeneration, and identity the signals that control the behavior of limb cells. The ALM has demonstrated that successful limb regeneration requires a specialized wound epidermis, an adequate nerve supply and interactions between fibroblasts. The development of genomic resources for the axolotl (salamander) is allowing rapid progress in identifying the signals controlling limb regeneration. The most important lesson is that we possess the genetic program for limb regeneration within our genome, and we used this program to make our arms and legs when we were embryos. The challenge for regenerative medicine is to learn how to reactivate this intrinsic regeneration program.


Stages of axolotl limb regeneration