Model systems for regeneration: salamanders

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Abstract

Salamanders have been hailed as champions of regeneration, exhibiting a remarkable ability to regrow tissues, organs and even whole body parts, e.g. their limbs. As such, salamanders have provided key insights into the mechanisms by which cells, tissues and organs sense and regenerate missing or damaged parts. In this Primer, we cover the evolutionary context in which salamanders emerged. We outline the varieties of mechanisms deployed during salamander regeneration, and discuss how these mechanisms are currently being explored and how they have advanced our understanding of animal regeneration. We also present arguments about why it is important to study closely related species in regeneration research. Summary: This Primer provides an overview of salamanders as a model system for studying regeneration, outlining the mechanisms deployed during salamander regeneration and highlighting how the study of salamanders has increased our understanding of regeneration more broadly.

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Macrophages are required for adult salamander limb regeneration.

James W Godwin, Alexander R Pinto, Nadia Rosenthal (2013)

The failure to replace damaged body parts in adult mammals results from a muted growth response and fibrotic scarring. Although infiltrating immune cells play a major role in determining the variable outcome of mammalian wound repair, little is known about the modulation of immune cell signaling in efficiently regenerating species such as the salamander, which can regrow complete body structures as adults. Here we present a comprehensive analysis of immune signaling during limb regeneration in axolotl, an aquatic salamander, and reveal a temporally defined requirement for macrophage infiltration in the regenerative process. Although many features of mammalian cytokine/chemokine signaling are retained in the axolotl, they are more dynamically deployed, with simultaneous induction of inflammatory and anti-inflammatory markers within the first 24 h after limb amputation. Systemic macrophage depletion during this period resulted in wound closure but permanent failure of limb regeneration, associated with extensive fibrosis and disregulation of extracellular matrix component gene expression. Full limb regenerative capacity of failed stumps was restored by reamputation once endogenous macrophage populations had been replenished. Promotion of a regeneration-permissive environment by identification of macrophage-derived therapeutic molecules may therefore aid in the regeneration of damaged body parts in adult mammals.

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Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate.

Luis Garza, Dwayne Godwin, Jeremy Brockes … (2007)

The limb blastemal cells of an adult salamander regenerate the structures distal to the level of amputation, and the surface protein Prod 1 is a critical determinant of their proximodistal identity. The anterior gradient protein family member nAG is a secreted ligand for Prod 1 and a growth factor for cultured newt blastemal cells. nAG is sequentially expressed after amputation in the regenerating nerve and the wound epidermis-the key tissues of the stem cell niche-and its expression in both locations is abrogated by denervation. The local expression of nAG after electroporation is sufficient to rescue a denervated blastema and regenerate the distal structures. Our analysis brings together the positional identity of the blastema and the classical nerve dependence of limb regeneration.

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Single-cell analysis uncovers convergence of cell identities during axolotl limb regeneration

Tobias Gerber, Prayag Murawala, Dunja Knapp … (2018)

Amputation of the axolotl forelimb results in the formation of a blastema, a transient tissue where progenitor cells accumulate prior to limb regeneration. However, the molecular understanding of blastema formation had previously suffered from the inability to identify and isolate blastema precursor cells in the adult tissue. Here we use a combination of Cre-loxP reporter lineage tracking and single-cell (sc) RNA-seq to molecularly track mature connective tissue (CT) cell heterogeneity and its transition to a limb blastema state. We uncover a multi-phasic molecular program where CT cell types found in the uninjured adult limb revert to a relatively homogenous progenitor state that recapitulates an embryonic limb bud-like phenotype including multipotency within the CT lineage. Together, our data illuminates molecular and cellular reprogramming during complex organ regeneration in a vertebrate.