Ontogenetic decline of regenerative ability and the stimulation of human regeneration.

Although we cannot regenerate our limbs today, it is likely that when we were embryos we could regenerate many of our tissues, including our limbs. Like other vertebrates, our impressive regenerative abilities were lost during embryogenesis, leaving us with a relatively limited ability to repair tissue damage. In contrast, adult salamanders can reactivate the embryonic regeneration response, and thus they provide the opportunity to discover the principles and 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 shares the mechanisms of growth control and pattern formation with limb development, the first step is unique and leads to the formation of a regeneration blastema. A second lesson is that connective tissue fibroblasts control regeneration, and that the unique regenerative ability of salamanders (the first step of regeneration) is a consequence of the ability of fibroblasts to dedifferentiate and give rise to blastema cells. Since we all developed limbs as embryos, we all possess the genetic program for making a limb (the second step of regeneration). Therefore, the challenge for inducing limb regeneration in humans is to discover how to induce fibroblast dedifferentiation.