Metamorphosis and regeneration

Appendage regeneration is restricted to a small number of vertebrates including some bony fish, frogs, and salamanders. It has been known for decades that frogs lose their ability to regenerate limbs upon metamorphosis and evidence suggests that regenerative ability declines in aged fish. These observations suggest that fundamental processes such as age, body size, or metamorphosis may have an effect on regenerative ability. In collaboration with four other researchers at the University of Florida, we have started to address such questions in the Mexican axolotl salamander. Our recent review shown below explores how fundamental traits may effect an animal’s ability to regenerate appendages at the tissue, cellular, and genomic levels.

The influence of fundamental traits on mechanisms controlling appendage regeneration.

Seifert AW, Monaghan JR, Smith MD, Pasch B, Stier AC, Michanneau F, Maden M.
Biol Rev Camb Philos Soc. 87(2):330-45.

Abstract

One of the most compelling questions in evolutionary biology is why some animals can regenerate injured structures while others cannot. Appendage regeneration appears to be common when viewed across the metazoan phylogeny, yet this ability has been lost in many taxa to varying degrees. Within species, the capacity for regeneration also can vary ontogenetically among individuals. Here we argue that appendage regeneration along the secondary body axis may be constrained by fundamental traits such as body size, aging, life stage, and growth pattern. Studies of the molecular mechanisms affecting regeneration have been conducted primarily with small organisms at early life stages. Such investigations disregard the dramatic shifts in morphology and physiology that organisms undergo as they age, grow, and mature. To help explain interspecific and intraspecific constraints on regeneration, we link particular fundamental traits to specific molecular mechanisms that control regeneration. We present a new synthesis for how these fundamental traits may affect the molecular mechanisms of regeneration at the tissue, cellular, and genomic levels of biological organization. Future studies that explore regeneration in organisms across a broad phylogenetic scale, and within an ontogenetic framework, will help elucidate the proximate mechanisms that modulate regeneration and may reveal new biomedical applications for use in regenerative medicine.

Skin regeneration in adult axolotls: A blueprint for scar-free healing in vertebrates.

Seifert AW, Monaghan JR, Voss SR, Maden M. (2012)PLoS ONE 7(4): e32875.

Abstract

While considerable progress has been made towards understanding the complex processes and pathways that regulate human wound healing, regenerative medicine has been unable to develop therapies that coax the natural wound environment to heal scar-free. The inability to induce perfect skin regeneration stems partly from our limited understanding of how scar-free healing occurs in a natural setting. Here we have investigated the wound repair process in adult axolotls and demonstrate that they are capable of perfectly repairing full thickness excisional wounds made on the flank. In the context of mammalian wound repair, our findings reveal a substantial reduction in hemostasis, reduced neutrophil infiltration and a relatively long delay in production of new extracellular matrix (ECM) during scar-free healing. Additionally, we test the hypothesis that metamorphosis leads to scarring and instead show that terrestrial axolotls also heal scar-free, albeit at a slower rate. Analysis of newly forming dermal ECM suggests that low levels of fibronectin and high levels of tenascin-C promote regeneration in lieu of scarring. Lastly, a genetic analysis during wound healing comparing epidermis between aquatic and terrestrial axolotls suggests that matrix metalloproteinases may regulate the fibrotic response. Our findings outline a blueprint to understand the cellular and molecular mechanisms coordinating scar-free healing that will be useful towards elucidating new regenerative therapies targeting fibrosis and wound repair.