Abstract
Tissue and organ regeneration, unlike development, involves an injury that in postembryonic animals triggers inflammation followed by resolution. How inflammation affects epimorphic regeneration is largely uninvestigated. Here we examine inflammation and its resolution in Xenopus laevis hindlimb regeneration, which declines during larval development. During the first 5 days postamputation, both regeneration-competent stage 53 and regeneration-deficient stage 57 hindlimbs showed very rapid accumulation of leukocytes and cells expressing interleukin-1β and matrix metalloproteinase 9. Expression of genes for factors mediating inflammatory resolution appeared more persistent at stages 55 and 57 than at stage 53, suggesting changes in this process during development. FoxP3, a marker for regulatory T cells, was upregulated by amputation in limbs at all three stages but only persisted at stage 57, when it was also detected before amputation. Expression of genes for cellular reprogramming, such as SALL4, was upregulated in limbs at all 3 stages, but markers of limb patterning, such as Shh, were expressed later and less actively after amputation in regeneration-deficient limbs. Topical application of specific proinflammatory agents to freshly amputated limbs increased interleukin-1β expression locally. With aqueous solutions of the proinflammatory metal beryllium sulfate, this effect persisted through 7 days postamputation and was accompanied by inhibition of regeneration. In BeSO4-treated limbs expression of markers for both inflammation and resolution, including FoxP3, was prolonged, while genes for cellular reprogramming were relatively unaffected and those for limb patterning failed to be expressed normally. These data imply that in Xenopus hindlimbs postamputation inflammation and its resolution change during development, with little effect on cellular dedifferentiation or reprogramming, but potentially interfering with the expression of genes required for blastema patterning. The results suggest that developmental changes in the larval anuran immune system may be involved in the ontogenetic loss of epimorphic regeneration in this system.
Highlights
Best developed among certain teleost fishes and urodele amphibians, the capacity of vertebrates to regenerate appendages shows both considerable phylogenetic variation and a general decline during ontogeny [1]
The causes of this ontogenic loss of regenerative capacity remain unknown, but we have suggested that that major changes in the premetamorphic anuran immune system [6] may produce local changes in the inflammatory response to injury that interfere with epimorphic regeneration [7]
Developmental stages 53 through 57 cover most of the period during which Xenopus hindlimbs lose their capacity for epimorphic regeneration: amputated stage 53 limbs produce well-patterned regenerates typically lacking only the most anterior digit, while the larger stage 57 limb stumps are regeneration-deficient, forming at most small, skin-covered cartilaginous spikes
Summary
Best developed among certain teleost fishes and urodele amphibians, the capacity of vertebrates to regenerate appendages (epimorphic regeneration) shows both considerable phylogenetic variation and a general decline during ontogeny [1]. Tail regeneration in Xenopus laevis occurs throughout larval development except during a transient ‘‘refractory period’’ from stages 45 to 47, and occurs more slowly and imperfectly at late larval stages [4,5]. The causes of this ontogenic loss of regenerative capacity remain unknown, but we have suggested that that major changes in the premetamorphic anuran immune system [6] may produce local changes in the inflammatory response to injury that interfere with epimorphic regeneration [7]. When the inflammation-inducing injury includes grafting genetically disparate cells or stem cells that express new proteins, the adaptive response can result in rejection of the transplanted cells [14]
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