Regeneration of Vertebrate Appendages

Abstract

Some vertebrates can faithfully replace complex parts of their body, a feature that is more commonly observed in invertebrates. They can perform this remarkable task because of their capacity to recruit progenitor cells and activate developmental programmes that largely parallel those used during embryogenesis. Tailed amphibians (urodeles), fish and deer provide the most striking examples of regeneration of appendages in adult animals. Frogs (anurans) can regenerate their limbs only at larval stages and can provide valuable models for studying loss of regenerative capability in the same species. Although birds and mammals cannot regenerate their limbs, digit tips display notable regenerative capability. The most striking example of mammalian appendage replacement is antler regeneration. Information on molecular landmarks of mature cell reprogramming in response to amputation is rapidly building up together with insights into the complex regulatory machinery controlling subsequent proliferation, differentiation and patterning of regenerating appendages.

Key Concepts:

  • Appendage regeneration can occur in some lower vertebrates, fish and amphibians.

  • Wound healing modality and appropriate inflammatory responses are crucial for regeneration.

  • Regeneration of vertebrate appendages occurs via formation of a growth zone, the blastema.

  • Blastema formation in adult lower vertebrates involves a reversal of the differentiated state.

  • Resident progenitor cells can contribute to regeneration.

  • Blastemal cells in regenerating limbs largely maintain their original identity.

  • The presence of a specialized wound epidermis is essential for regeneration throughout the process.

  • The presence of the nerve is crucial for the initial stages of limb and fin regeneration and also for mammalian digit tip regeneration.

  • Limb regeneration becomes nerve dependent after the developing limb is innervated.

  • Redeployment of certain developmental mechanisms underlies patterning in regenerating appendages.

  • Although, by and large, the same key signalling pathways are involved in regenerative responses across species, existence of speciesā€specific molecules may provide some rationale for differences in adult appendage regenerative capability.

Keywords: antler; amphibia; blastema; fin; fish; limb; mouse; regeneration

Figure 1.

Schematic representation of a limb regeneration blastema, a mound of undifferentiated progenitor cells covered by a specialised wound epithelium, the apical epithelial cap (AEC). The blastema gives rise to the amputated part of the appendage; after a rapid proliferation phase its differentiation progresses in a proximal to distal direction as indicated. Abbreviations: B, bone; M, muscle and N, nerve.

Figure 2.

Successive stages of regeneration and their approximate time course after limb amputation in the adult newt, N. viridescens. An appropriate inflammatory response is crucial for wound healing and underlies limb regeneration. Following wound healing, blastemal cells accumulate at the tip of the stump by a process of dedifferentiation, and they start to proliferate under the influence of the nerve and the thickened wound epithelium within 1 week after amputation. A clear blastema is usually visible by 2 weeks. Between 2 and 3 weeks after amputation, proliferation becomes nerve independent and differentiation begins. Some of the signalling pathways important at different stages of limb regeneration are indicated (red triangles) as well as one of the pathways regulated by retinoic acid unique to urodele limb regeneration. Abbreviations: d, day after amputation and w, weeks after amputation.

Figure 3.

Schematic representation of a normal pectoral fin skeleton (a) and of lepidotrichia in longitudinal (b) and cross‐section (c). (d) Schematic representation of ray stump and blastema. (e) Micrographs of cross‐ and longitudinal sections of normal fin and regenerating fins 1 and 5 days after amputation. Abbreviations: B, bone and bv, blood vessel.

Figure 4.

Schematic summary of interactions between different signalling pathways believed to regulate growth, differentiation and patterning in regenerating fins.

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Further Reading

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Ferretti P and Géraudie J (eds) (1998) Cellular and Molecular Basis of Regeneration: From Invertebrates to Humans. Chichester, UK: John Wiley and Sons, Ltd.

Géraudie J, Akimenko MA and Smith M (1998) The dermal skeleton. In: Ferretti P and Géraudie J (eds) Cellular and Molecular Basis of Regeneration: From Invertebrates to Humans, pp 167–185. Chichester, UK: John Wiley and Sons, Ltd.

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Ferretti, Patrizia(Oct 2013) Regeneration of Vertebrate Appendages. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001099.pub3]