A Call for More Study of Exceptionally Regenerative Species
A range of higher animal species are capable of regrowing organs and limbs, such as the zebrafish and axolotl. Research groups have for some years investigated the differences between the biochemistry of these species and mammals, and given the promising progress to date, the authors of this commentary call for an increased investment in this field:
Increasingly more studies of nontraditional vertebrate model organisms with extraordinary regenerative capacities are providing valuable insight into the mechanisms of complex tissue regeneration. For example, the zebrafish (Danio rerio) can regenerate many tissues after injury including cardiac, fin appendages and spinal cord. Another ray-finned fish, the bichir (Polypterus senegalus) can also regenerate cardiac and fin appendages. Urodeles (salamanders and newts), such as the axolotl (Ambystoma mexicanum), can regenerate whole limbs. Studies of models with robust regenerative capacities have advanced our understanding of regenerative mechanisms by identifying genes that are necessary and sufficient for regeneration in vivo. Regenerative biology has historically focused on defining the cellular and molecular mechanisms within individual species. Within the last 15 years, rapid advances in genome sequencing technology and gene editing strategies have advanced the understanding of the molecular and cellular processes that define tissue regeneration. Unfortunately, they have also unintentionally created silos that encase individual animal models and discourage examination of regenerative capacity in nontraditional model systems.
Comparative studies of regeneration can be framed in a phylogenetic context where model organisms are selected to identify conserved gene regulatory mechanisms for regeneration. These limb regeneration traits are in stark contrast to mammals where it is limited to the very ends of digits in mice, rats, monkeys, and humans. Given that urodele taxa can regenerate limbs, it suggests that limb regeneration is an ancestral trait of urodeles. Furthermore, it is plausible that appendage regeneration is an ancestral trait of all jawed vertebrates as both ray-finned fish and urodele taxa can regenerate appendages. Alternatively, limb regeneration may be a derived trait. No reports of appendage regeneration have been published among cartilaginous fishes (chondrichthyes). The last common ancestor of jawed vertebrates appeared approximately 420 million years ago providing for an opportunity to find common mechanisms for appendage regeneration.
With increasing knowledge of proregenerative mechanisms, the next challenge is to identify small molecules to enhance regeneration following injury in humans. A target-based strategy where compounds are identified to target particular genes, proteins or pathways is a complementary strategy. Proregenerative lead compounds could then be tested in nonregenerative models, such as the mouse, to determine whether they promote regeneration. The demonstrated benefits of studying the genetic pathways for regeneration in highly regenerative species should motivate us to re-examine the allocation of research funds. Additional investment to create genetic and molecular resources to study nontraditional models, such as the zebrafish and axolotl, are needed to accelerate these comparative studies. The zebrafish represents a good start, its genome was characterized in 2003 and many genetic tools have been developed to work with it, which are already yielding fruit. The progress on therapies for heart regeneration, for instance, has been 'spectacular', according to researchers who discovered in 2002 that zebrafish can regenerate heart tissue after 20% of the ventricle has been removed.
Other model organisms are still unexploited, however. High levels of research funding using mouse models over several decades have built a vast repertoire of tools and resources for the mouse. Currently, over 70% of traditional research grants involve mouse studies. Increasing funding for studies that involve a broader set of model organisms, like the zebrafish and axolotl, across all biomedical fields would result in more tools and resources for these diverse models. In turn, these investments would provide the critical genetic and molecular tools and resources for nontraditional model organisms needed to accelerate comparative studies of regeneration.