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Differentiation
2014 Jan 01; doi: 10.1016/j.diff.2014.02.002.
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Scar-free wound healing and regeneration in amphibians: Immunological influences on regenerative success.
Godwin JW
,
Rosenthal N
.
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Salamanders and frogs are distinct orders of Amphibians with very different immune systems during adult life, exhibiting varying potential for scar free repair and regeneration. While salamanders can regenerate a range of body parts throughout all stages of life, regeneration is restricted to early stages of frog development. Comparison of these two closely related amphibian orders provides insights into the immunological influences on wound repair, and the different strategies that have evolved either to limit infection or to facilitate efficient regeneration. After injury, cells of the immune system are responsible for the removal of damaged cells and providing a cohort of important growth factors and signaling molecules. Immune cells not only regulate new vessel growth important for supplying essential nutrients to damaged tissue but, modulate the extracellular matrix environment by regulating fibroblasts and the scarring response. The profile of immune cell infiltration and their interaction with local tissue immune cells directly influences many aspects of the wound healing outcomes and can facilitate or prevent regeneration. Evidence is emerging that the transition from wound healing to regeneration is reliant on immune cell engagement and that the success of regeneration in amphibians may depend on complex interactions between stem cell progenitors and immune cell subsets. The potential immunological barriers to mammalian regeneration are discussed with implications for the successful delivery of stem cell therapeutic strategies in patients.
Fig. 1.
Xenopus laevis (African clawed frog) and Ambystoma mexicanum (Axolotl, or Mexican salamander) are common laboratory model amphibians with unusual appearance. A post-metamorphic xenopus is shown on the left and neotenic adult wild type axolotl shown right. Xenopus image courtesy of LHG creative Photography Under licence CC BY-NC-ND 2.0.
Fig. 2.
Scar-free healing and regeneration is inversely correlated with development in anuran amphibians but is maintained in adult life in urodeles. (A) The development of sophisticated adult adaptive immunity begins at the onset of frog metamorphosis and is associated with a progressive loss of patterned regeneration where the number of digits that can be regenerated gradually declines between stage 55 to stage 60. While amputation at stage 53 results in a perfectly patterned limb, at stage 60 regeneration results in a “non-patterned spike”. Tail regeneration is transiently lost during a “refractory period” (stage 45–47, marked with dotted line), which coincides with early immune cell development in the absence of regulatory T cells (T-regs). Restoration of functional regenerative potential in the tail is correlated with T-reg cell development. Scar-free wound healing is lost in adult anuran amphibians. (B) Scar free wound healing and regeneration is maintained throughout all life stages in salamanders. Metamorphosis is linked to relatively minor changes in adaptive immunity and regenerative capacity is maintained. Most salamander species transition through metamorphosis; however some species like the axolotl may have neotenic life cycles that do not normally transition through metamorphosis but can be chemically induced to do so. Unlike frogs, scar-free healing is maintained in adult life in salamanders. Various axolotl natural pigment mutants are available. (Common laboratory “white mutant” shown). Xenopus images courtesy of David Bay and the National Science Foundation.
Fig. 3.
Hypothetical model for monocyte/macrophage (MΦ) regulation of progenitor cell activation, survival, growth and differentiation in the salamander. Within the influx of various white blood cells types that invade the damaged tissue monocyte/macrophage cell types are critical for regenerative success. Monocyte/macrophage populations regulate the resolution of inflammation, provide growth factors and signaling molecules important for angiogenesis and may influence the differentiation of progenitor cells. Monocyte/macrophage populations may also play a role in facilitating dedifferentiation and the regulation of cell mediated lysis.
