Regeneration, Regengrow and Tissue Repair in Animals: Evolution Indicates That No Regeneration Occurs in Terrestrial Environments but Only Recovery Healing

Abstract

The present, brief review paper summarizes previous studies on a new interpretation of the presence and absence of regeneration in invertebrates and vertebrates. Broad regeneration is considered exclusive of aquatic or amphibious animals with larval stages and metamorphosis, where also a patterning process is activated for whole-body regeneration or for epimorphosis. In contrast, terrestrial invertebrates and vertebrates can only repair injury or the loss of body parts through a variable "recovery healing" of tissues, regengrow or scarring. This loss of regeneration likely derives from the change in genomes during land adaptation, which included the elimination of larval stages and intense metamorphosis. The terrestrial conditions are incompatible with the formation of embryonic organs that are necessary for broad regeneration. In fact, no embryonic organ can survive desiccation, intense UV or ROS exposition on land, and rapid reparative processes without embryonic patterning, such as recovery healing and scarring, have replaced broad regeneration in terrestrial species. The loss of regeneration in land animals likely depends on the alteration of developmental gene pathways sustaining regeneration that occurred in progenitor marine animals. Terrestrial larval stages, like those present in insects among arthropods, only metamorphose using small body regions indicated as imaginal disks, a terrestrial adaptation, not from a large restructuring process like in aquatic-related animals. These invertebrates can reform body appendages only during molting, a process indicated as regengrow, not regeneration. Most amniotes only repair injuries through scarring or a variable recovery healing, occasionally through regengrow, the contemporaneous healing in conjunction with somatic growth, forming sometimes new heteromorphic organs.

Keywords: development; evolution; healing; metazoans; regeneration.

Figure 1

Summarizing image reporting the distribution of regenerative abilities among extant aquatic (light-blue background) and terrestrial (pale-brown background) animals. The colored bars associated with the different animal phyla represent the progressive phases of their main life cycles (embryo phase in pale blue, larval phase in green, metamorphic phase in vermillion, juvenile and growing phase in brown, adult phase in deep blue, and aging phase in grey). Phyla including metamorphosis (vermillion color segment inside their life cycle bars) also show large regenerative ability and are generally marine. Among arthropods, one or more metamorphic transitions occur in insects, but these are mainly body growths through molting in heterometabolous insects and large changes derived from localized imaginal disks in holometabolous insects (see text for further explanation). In minor phyla (Tardigrada, Onychophora, Priapulida but also Phoronida, Ectoprocta and Rotifera), no or insufficient information on regeneration is available.

Figure 2

Schematic drawing showing the indicative evolution of the main phyla of animals, from a primitive planula and/or aceloid progenitor in the marine environment (light-blue background) to a marine or a terrestrial environment (light-brown background). Dots along the evolutionary lines indicate elapsed time (millions of years) to evolve new animals. Each representative animal form is associated with an idealized simple genome network of different extension, according to the animal complexity (small in simple invertebrates and larger in more complex marine or terrestrial invertebrates and vertebrates). The final genome network of extant animals is invariant and includes developmental genes (or groups of genes), some of which can be re-activated in adult animals after injury, promoting regeneration. All terrestrial animals (light-brown background) lost a larval phase or evolved a terrestrial adapted larva (insects) and also lost metamorphosis and broad regenerative ability. Terrestrial restrictions imposed the evolution of a rapid healing process, generally through scarring.

Figure 3

Schematic drawing for vertebrate evolution in relation to regeneration. From a basic embryonic form at the base of the tree, different embryos were derived and gave rise to cyclostomes and different types of fish (light-blue background), then amphibians (green background), and finally terrestrial vertebrates, reptiles, birds and mammals (pale-brown background). Each embryo or adult form is associated with an idealized gene network of different complexity. Dots along the evolutionary lines indicate elapsed time (millions of years) to evolve new animals. Numerous fish and amphibians possess one or more larval phases with one or more metamorphic transitions and, after an injury as adults, can often broadly regenerate. This is not the case for amniotes (terrestrial vertebrates) that lost a larval form and related metamorphosis during land adaptation and also do not regenerate after injury or have limited healing recovery, regengrow or heteromorphic regeneration in rare cases and generally scar.

Figure 4

Schematic drawing illustrating few examples of regengrow or of recovery healing after loss (small arrows) of appendages in terrestrial animals (myriapods, insects and arachnids), eyed-peduncles in the head (gastropod mollusks), or posterior sections of the body (earthworms). Within the associated gene networks for each animal, in light-blue colored areas, are indicated the idealized region of the genome utilized for the development of the specific appendages (left) or regions of the body that are later lost (small arrows) and regenerated (large arrows and genomes on the right). Regenerated organs are colored in red. Note that in these simple examples, the light-blue areas of the genome utilized for regeneration (on the right) are smaller than those utilized for the development of the same organs (on the left). This ideally indicates that not all developmental genes can be re-activated for regenerating the lost organs, but they are, however, sufficient to restitute all or most of the lost organ (see text and Alibardi, 2023 a–c, for more explanation).

Figure 5

Schematic drawing featuring a few examples of different healing abilities among amphibians (light-blue background) and amniotes (light-brown background). The light-blue areas within the gene networks for each embryo or adult animals ideally represent genes utilized for development (on the left) and for recovery healing after injury or loss of the same organs (arrows on the right). The regenerated organs are colored in red. Ample regeneration is present in freshwater anuran tadpoles, but regeneration is lost at metamorphosis, and, rarely, heteromorphic appendages (arms or digits) are regenerated/regengrown. The light-blue area present in the gene network associated to tadpoles ideally indicates genes utilized during development that, in combination with genes utilized for metamorphosis, also determine regeneration. Heteromorphic but large regeneration occurs in lizard tail and, occasionally, in growing crocodilians (regengrow). In mammals, aside from the prevalent scarring outcome and physiological tissue regeneration, three examples of “recovery healing” are shown: cyclical bony regeneration in deer or reindeers after drop of antlers in previous cycles, ear hole recovering in hares, and digit tips regengrow in rodents (see text for further explanation). Within the gene networks associated with each animal, the light-blue areas ideally indicate those sections of the genome utilized for developing the specific organ or appendage (on the left) and those re-activated for healing or regenerate the same organ (arrows on the right). Note the smaller light-blue areas utilized for healing or regeneration in each idealized gene network, in comparison to those utilized for development (on the left), an indication of limited re-activation of the same or closely related genes.