Common Themes in Tetrapod Appendage Regeneration: a Cellular Perspective Bess M

Miller et al. EvoDevo (2019) 10:11 https://doi.org/10.1186/s13227-019-0124-7 EvoDevo REVIEW Open Access Common themes in tetrapod appendage regeneration: a cellular perspective Bess M. Miller, Kimberly Johnson and Jessica L. Whited* Abstract Complete and perfect regeneration of appendages is a process that has fascinated and perplexed biologists for centuries. Some tetrapods possess amazing regenerative abilities, but the regenerative abilities of others are exceedingly limited. The reasons underlying these diferences have largely remained mysterious. A great deal has been learned about the morphological events that accompany successful appendage regeneration, and a handful of experimental manipulations can be reliably applied to block the process. However, only in the last decade has the goal of attain- ing a thorough molecular and cellular biological understanding of appendage regeneration in tetrapods become within reach. Advances in molecular and genetic tools for interrogating these remarkable events are now allowing for unprecedented access to the fundamental biology at work in appendage regeneration in a variety of species. This information will be critical for integrating the large body of detailed observations from previous centuries with a mod- ern understanding of how cells sense and respond to severe injury and loss of body parts. Understanding commonali- ties between regenerative modes across diverse species is likely to illuminate the most important aspects of complex tissue regeneration. Keywords: Appendage, Regeneration, Tetrapod, Limb, Tail, Antler, Digit tip Introduction Appendage regeneration is a complex process, which Regeneration is the replacement of lost parts with a relies on multiple cell types to act in harmony. Recent perfect copy following injury. Many vertebrate species advances allowing tracking and manipulation both of are capable of impressive feats of complete regenera- separate cell types and of individual cells have permitted tion; salamanders are particularly gifted in this regard, a much fner view of the cellular basis of regeneration. as they are able to replace lost limbs, tails, parts of their Tis review will examine appendage regeneration in tet- brain, and more. In mammals, regeneration in which rapods with a specifc focus on limb regeneration in sala- the structure of lost tissue is recapitulated appears to be manders, tail regeneration in lizards, antler regeneration limited to the distal tip of the digit. Although the liver in deer, and digit tip regeneration in mice to highlight grows new tissue following tissue loss, the original liver common cellular mechanisms employed across regen- structure is not reformed in this process, and it is thus erative modalities and consider potential reasons that not considered true complete regeneration. Terefore, may underlie the restriction of regenerative abilities in examining common themes in appendage regeneration mammals. While wound healing is intimately connected ofers a potentially unique platform to directly compare to the complex events underlying regeneration, heal- regenerative mechanisms across tetrapods, from amphib- ing of wounds restricted to cutaneous tissue has been ians to mammals, and to consider how common themes extensively reviewed elsewhere (e.g., [1–6]) and will not might be used to improve overall regenerative abilities in be covered per se in this review. Although deer antler mammals. replacement is not strictly speaking true regeneration, as it is prompted by seasonal changes in hormone lev- *Correspondence: [email protected] els rather than injury, it remains a rare case of complete Department of Stem Cell and Regenerative Biology, Harvard University, 7 replacement of a full appendage in mammals and will be Divinity Ave, Cambridge, MA 02138, USA © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Miller et al. EvoDevo (2019) 10:11 Page 2 of 13 instructive as to innate mechanisms of mammalian post- gills, and liver upon experimentation. Even when experi- developmental appendage replacement. mentally forced to undergo metamorphosis by thyroxine administration, metamorphosed axolotls retain the abil- Overview of appendage regeneration and its ity to regenerate skin and limbs, albeit at a signifcantly limitations in tetrapods reduced rate [20]. Metamorphosed axolotls (“paedo- Complete regeneration of complex body parts in verte- morphs”) tend to regenerate improperly patterned limbs brates manifests in many lineages and structures. Gen- more often than their neotenic counterparts [20]. Te erally, in vertebrates, regeneration is “unidirectional,” overall trend toward more restricted regenerative abil- meaning that the missing piece is replaced by the body, ity with organismal aging appears to exist but is cur- but the piece itself does not regrow the rest of the organ- rently poorly understood [21–23]. Future work will be ism. Te most readily appreciated structures which required to determine if mature animals are lacking an undergo regeneration in tetrapods are appendages, for essential component, cellular or otherwise, that juveniles example, limbs, tails, and antlers. Tese structures can be have, or if adults have an increased repertoire of antago- lost to predation, autotomy, or seasonal shedding, after nistic components. Tese possibilities are not mutually which they are regenerated with full or partial fdelity, exclusive. depending on these species. Many examples of append- One potential underexplored restriction is the possi- age regeneration are amenable to laboratory study fol- bility that even in strong regenerators, the regeneration lowing experimental amputation. program may not be repeatedly deployable with complete While many vertebrates have remarkable regenerative success. While still an underexplored topic, the major- abilities, these abilities are not infnite, and they are sub- ity of newt limbs reportedly either do not regenerate or ject to both spatial and temporal restrictions. In mice and regenerate with defects following as few as fve amputa- humans, limb regeneration is naturally restricted to the tions [24]. For axolotls, some evidence now exists that distal-most portion of the digits ([7–10] and reviewed in multiple regenerative events can be supported in juvenile [11]). Furthermore, human digit tip regeneration is anec- animals provided they are rather closely spaced in time dotally more successful in children and young adults, and [25]; however, other evidence indicates that the regen- it has only been documented in the medical literature up erative program can ultimately be pushed to exhaustion to age 13 [7]. Fetal mice possess the ability to regenerate by repeated sequential amputations performed over the a signifcantly larger fraction of the developing digit than course of a year [26]. In contrast, zebrafsh have been their post-natal counterparts. documented to regenerate tails up to 27 times [27], Frogs are more successful regenerators as tadpoles than though some permutations on the proximo-distal axis they are as adults. As frogs undergo metamorphosis, they patterning can occur in this context [28]. While these regenerate increasingly imperfect limbs culminating in examples involve experimental injury, in the wild, many either the regeneration of only a cartilage spike encased deer naturally undergo seasonal antler shedding followed in skin or complete loss of regeneration, depending on by complete regeneration (reviewed in [29]). the species of frog (reviewed in [12]). Imperfect regeneration is also a feature of lizard tails following autotomy, Vertebrate appendage regeneration follows the spontaneous release of the appendage in response to a common morphological pattern predation (reviewed in [13]). Following regeneration of Appendage regeneration is a complex process requir- lizard tails, the vertebra is replaced with an unsegmented ing the regrowth of multiple tissue types in an organized hollow cartilage section [14]. Dorsal root ganglia and gray pattern. In a general sense, all of the current models of matter of the spinal cord are not regenerated; rather, the vertebrate appendage regeneration undergo a stereotypi- regenerated tail is innervated by nerves extending from cal order of events to replace the lost tissue: epithelial the proximal intact tissue [15–17]. Furthermore, the frac- closure of the wound site, dediferentiation or activation ture planes seen in the intact tail, which permit autotomy of cells located at the injury plane to form a zone of pro- at precise locations, are not regenerated (reviewed in liferating cells at the amputation plane, and reformation [18]). Tus, lizards are distinctively better regenerators of the lost appendage through progenitor cell prolifera- than other amniotes, but they have limited appendage tion, diferentiation, and directed outgrowth (Fig. 1 for regenerative abilities beyond this imperfect tail, and they detailed illustration of this sequence in salamanders). do not regenerate

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