Exceptional regeneration can be found in some higher animals, such as zebrafish and salamanders. These species are capable of completely regenerating non-lethal injuries and large loss of tissue from internal organs and limbs, producing an organ that is indistinguishable in function from the original, and doing so repeatedly. In mammals, with very few exceptions that occur in only a few species and a few tissues, such injuries only scar with no proficient regeneration. Why is this case? That is the question that many research groups seek to answer, as finding a way to spur regeneration of organs and limbs in our species is obviously a very desirable goal.
The authors of today's paper argue for the use of garfish as an animal model for the investigation of regeneration, based on the fact that they can regrow fins and have a genome that is closer to that of humans than is the case for zebrafish. The question all along regarding proficient regeneration is whether all of the relevant mechanisms are still in place in humans, just dormant and waiting for the right cues to be activated. Some research makes this seem plausible, but the scientific community is still some unknown distance from a definitive understanding of what needs to be accomplished in human biochemistry to allow limb or organ regrowth. It seems likely that cellular senescence and macrophage function are quite different in highly regenerative species, and some cancer suppression genes are similarly important. We can only speculate at this point as to whether any of these items can be safely changed in human biochemistry.
Researchers have studies how gar and other fish regenerate entire fins. More importantly, the researchers focused on how they rebuild the endochondral bones within their fins, which are the equivalents of human arms and legs. Garfish has been called a "bridge species," as its genome is similar to both zebrafish - often used as a genetic model for human medical advances - and humans. Gar evolve slowly and have kept more ancestral elements in their genome than other fish. This means that along with serving as a bridge species to people, gar also are great connectors to the deep past.
So, by studying how fish regenerate fins, researchers pinpointed the genes and the mechanisms responsible that drive the regrowth. When they compared their findings to the human genome, they made an interesting observation. "The genes responsible for this action in fish also are largely present in humans. What's missing, though, are the genetic mechanisms that activate these genes in humans. It is likely that the genetic switches that activate the genes have been lost or altered during the evolution of mammals, including humans."
Evolutionary speaking, this suggests that the last common ancestor of fish and tetrapods, or four-legged vertebrates, had already acquired a specialized response for appendage regeneration, and that this program has been maintained during evolution in many fish species as well as salamanders. Continuing research into these key genes and missing mechanisms could eventually lead to some revolutionary medical advances. "The more we study these commonalities among vertebrates, the more we can home in on prime targets for awakening this program for regenerative therapies in humans."
Salamanders and lungfishes are the only sarcopterygians (lobe-finned vertebrates) capable of paired appendage regeneration, regardless of the amputation level. Among actinopterygians (ray-finned fishes), regeneration after amputation at the fin endoskeleton has only been demonstrated in polypterid fishes (Cladistia). Whether this ability evolved independently in sarcopterygians and actinopterygians or has a common origin remains unknown. Here we combine fin regeneration assays and comparative RNA-sequencing (RNA-seq) analysis of Polypterus and axolotl blastemas to provide support for a common origin of paired appendage regeneration in Osteichthyes (bony vertebrates).
We show that, in addition to polypterids, regeneration after fin endoskeleton amputation occurs in extant representatives of 2 other non-teleost actinopterygians: the American paddlefish (Chondrostei) and the spotted gar (Holostei). Furthermore, we assessed regeneration in 4 teleost species and show that, with the exception of the blue gourami (Anabantidae), three species were capable of regenerating fins after endoskeleton amputation: the white convict and the oscar (Cichlidae), and the goldfish (Cyprinidae).
Our comparative RNA-seq analysis of regenerating blastemas of axolotl and Polypterus reveals the activation of common genetic pathways and expression profiles, consistent with a shared genetic program of appendage regeneration. Comparison of RNA-seq data from early Polypterus blastema to single-cell RNA-seq data from axolotl limb bud and limb regeneration stages shows that Polypterus and axolotl share a regeneration-specific genetic program. Collectively, our findings support a deep evolutionary origin of paired appendage regeneration in Osteichthyes and provide an evolutionary framework for studies on the genetic basis of appendage regeneration.