Searching the Lizard Genome for Regenerative Factors

Some of the research aimed at understanding - and potentially replicating - the greater regenerative capacity of lizards is fairly reductionist in nature. The genome is sequenced for a lizard species, the proteome cataloged, and then compared with mammalian biochemistry in search of possibly interesting differences for further examination. This open access paper summarizes one such finding, and the background behind it:

It is likely that all animals have the capacity to regenerate damaged body parts, although the degree of regeneration seems to be different in different species. Regeneration is more vigourous in invertebrates than it is in vertebrates. Indeed, many invertebrates, such as hydra, planarians, and starfish, have bidirectional regeneration capcity, so they can generate two sets of the same animal by regrowing missing parts, while regeneration processes in vertebrates occur unidirectionally, in which the animal reproduces only damaged parts at the site of injury. Amongst vertebrates, fishes and amphibians have the greatest regenerative capacities, and amniotes such as reptiles, birds, and humans, seem to have lost the capability to regenerate, although many lizards can reproduce their tails.

In lower vertebrates, natural regeneration occurs mainly by virtue of the intrinsic plasticity of mature tissues, which involves cellular proliferation, migration of remaining parts, and regrowth of damaged or missing parts. The most prominent event in tissue regeneration in lower vertebrate may be formation of a blastema. The blastema shares many characteristics with stem cells, and can eventually redevelop into various tissues, including muscle, skin, bone, and blood vessels, that were originally present at the damaged site. The blastema is formed through the dedifferentiation process, and this step is omitted in the higher vertebrates such as birds and mammals. Thus, it could be that the lack of regenerative capacity in birds and mammals may be evolutionarily related to loss of the capacity to dedifferentiate.

In fact, mammals share many key factors for regeneration with lower animals, such as fibroblast growth factor (FGF), Wnt/beta-catenin, and bone morphogenic protein (BMP)/Msx signaling, which are known to be involved in wound healing and cellular proliferation. Through such processes, mammals can repair damaged tissues to some extent. Nevertheless, mammals have little regenerative capacity compared to lower animals, probably because they lack the capability to dedifferentiate. Damage to human organs, such as the heart, brain, and liver, often leads to serious pathological conditions. Although stem cell-based transplantation could be clinically performed, additional strategies may be required for proper treatment of organ injuries in humans. Thus, study of the mechanisms of blastema formation and the development of protocols for mammalian dedifferentiation will be a breakthrough for regenerative medicine and stem cell biology.

Mammalian cells have been known to undergo dedifferentiation in vitro by enforced expression of Oct4, Sox2, Klf4, and c-Myc. Although this induced pluripotent stem cell (iPSC) strategy is an innovative tool in human tissue regeneration and stem cell therapeutics, it has drawbacks including low efficiency and uncertain safety. For example, use of oncogenes such as Klf4 and c-Myc in iPSC generation raised concerns about the safety of iPSCs for practical applications. Although other substitutes such as Nanog and Lin28 have been suggested, these oncogenes may be regarded as indispensable to the efficiency of dedifferentiation. The first gene identified as a dedifferentiation factor from proteomic studies in lizards was a lactoferrin. Recent discoveries showed that lactoferrin can substitute for Klf4, and even provide greater efficiency for dedifferentiation of human fibroblasts. Although lactoferrin by itself is not enough to replace all the oncogenes necessary for dedifferentiation of human cells, and further identification of other factors should be performed, this finding indicates that comparative studies of lizards would be a promising strategy to reveal the mechanisms of regeneration.



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