Why only certain species can regenerate their appendages (e.g. tails and limbs) remains one of the biggest mysteries of nature. Unlike anuran tadpoles and salamanders, humans and other mammals cannot regenerate their limbs, but can only regrow lost digit tips under specific circumstances. Numerous hypotheses have been postulated to explain regeneration-incompetency in mammals. By studying model organisms that show varying regenerative abilities, we now have more opportunities to uncover what contributes to regeneration-incompetency and functionally test which perturbations restore appendage regrowth. Particularly, Xenopus laevis tail and limb, and mouse digit tip model systems exhibit naturally occurring variations in regenerative capacities. Here, we discuss major hypotheses that are suggested to contribute to regeneration-incompetency, and how species with varying regenerative abilities reflect on these hypotheses.
| INTRODUCTIONAppendage regeneration has fascinated biologists for centuries, 1 as uncovering the molecular and cellular players regulating this process holds potential for therapies aimed at regenerating human limbs. While there are many different model organisms (e.g. zebrafish, salamander, deer) and appendage regeneration models (e.g. tail, digit tip, antler), each with unique characteristics, the bulk of our understanding of appendage regeneration has been derived from studies investigating amphibian limb and tail regeneration. 2 Amputations of appendages in these animals induce certain lineages to show a morphologically identified dedifferentiation phenotype and co-currently a simple wound epidermis covers the amputation plane. 3,4 This simple wound epithelium progresses into becoming a specialised wound epithelium called the apical-epithelial-cap (AEC). The AEC then functions as the key signalling centre during regeneration enabling expansion of lineage-restricted stem and progenitor populations, that are collectively termed the blastema. [5][6][7][8] The continuous interaction between the AEC and the blastema restores the lost appendage. Meanwhile, amputation of the mammalian limb fails to form an AEC or a blastema, and instead results in fibrotic scar formation and regenerative failure. 9Although mice, and in general amniotes including chickens 10 and lizards, 11 cannot perform limb regeneration, mouse digit tip amputations result in regrowth through formation of a blastema. 12,13 Interestingly, unlike limb regeneration in amphibians, there is no reported evidence that an AEC forms during digit tip regeneration, although the wound epidermis is suggested to be important for digit tip regrowth. 7 Instead of a signalling center AEC, nail bed stem cells were proposed to act as a signalling center population enabling expansion of progenitor cells during digit tip regeneration. 14,15 Nonetheless, it remains unclear why mammals, and amniotes in general, cannot perform full limb regeneration.