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While urodele amphibians (newts and salamanders) can regenerate limbs as adults, other tetrapods (reptiles, birds and mammals) cannot and just undergo wound healing. In adult mammals such as mice and humans, the wound heals and a scar is formed after injury, while wound healing is completed without scarring in an embryonic mouse. Completion of regeneration and wound healing takes a long time in regenerative and non-regenerative limbs, respectively. However, it is the early steps that are critical for determining the extent of regenerative response after limb amputation, ranging from wound healing with scar formation, scar-free wound healing, hypomorphic limb regeneration to complete limb regeneration. In addition to the accumulation of information on gene expression during limb regeneration, functional analysis of signaling molecules has recently shown important roles of fibroblast growth factor (FGF), Wnt/beta-catenin and bone morphogenic protein (BMP)/Msx signaling. Here, the routine steps of wound healing/limb regeneration and signaling molecules specifically involved in limb regeneration are summarized. Regeneration of embryonic mouse digit tips and anuran amphibian (Xenopus) limbs shows intermediate regenerative responses between the two extremes, those of adult mammals (least regenerative) and urodele amphibians (more regenerative), providing a range of models to study the various abilities of limbs to regenerate.
Fig. 1. Skeletal pattern and regenerative
capacity of tetrapod
forelimbs. While the limb skeletal
pattern is well conserved among
tetrapods, limb regenerative
capacity differs from animal to animal.
Salamanders can regenerate their
limbs completely, but amnoites
(lizards, birds and mammals)
cannot regenerate their limbs.
Frogs exhibit different degrees of
limb regenerative capacity at
different stages of their life cycles.
Fig. 2. Wound healing in mammal
skin versus limb regeneration of
amphibians. (A) Wound healing
process of mammalian adult skin.
I Wounded skin immediately after
injury. II The clot is formed and
platelets are trapped in the clot.
The clot has dried at the surface
to form a scab (stippled). III
Neuroptophils and then monocytes
(which transform into macrophages)
enter the wound, re-epithelization
begins, and angiogenesis is initiated.
IV Re-epithelization is almost
completed and an extensive capillary
network develops. Fibroblasts
invade the wound, proliferate,
and start synthesizing collagen,
resulting in the formation of
granulation tissue. V The temporal matrix of collagen is broken down and remodeled into thick bundles of collagen (dark lines).
c, collagen d, dermis; e, epidermis; fb, fibroblast; m, macrophage; n, neurotrophil; p, platelet; v, blood vessel. (B) Limb regeneration
process of urodele amphibians. I The limb stump immediately after amputation. II Wound epithelium is formed very soon after
amputation. Mesenchymal tissues of the stump secret matrix metalloproteinases (MMPs) and the wound epithelium thickens to form
an apical epithelial cap (AEC). III Secreted MMPs and the AEC promote the formation of blastema composed of undifferentiated
mesenchymal cells. IV The blastema continues to grow distally through interactions between the mesenchyme and the AEC. It starts
re-differentiation and re-patterning. V A complete limb is regenerated. bs, blastema.
Fig. 3. Wnt/β-catenin is essential for limb regeneration.
(A) Map of the heat shock-inducible Dkk1GFP transgene. (B) Bright field and (C) fluorescent view of transgenic tadpoles carrying this transgene 3–4 h after heat shock. No green fluorescent protein (GFP) expression was detected in the same tadpole before heat shock (inset). (D) A wild-type tadpole heatshocked prior to amputation regenerated the limb completely. (E) The hs-Dkk1GFP tadpole heatshocked prior to amputation did not regenerate the limb. Note that un-amputated rightlimb buds developed normally (black arrows). Arrowheads show the presumptive knee level (amputation level). Bar, 500 μm.
Fig. 4. The stepwise model for
limb regeneration and a strategy
to identify predicted signals. (A)
The stepwise model predicts when
signals from nerves (N signals)
and those from fibroblasts (F
signals) will be released during
limb regeneration. The points of
divergence of the three pathways
(wound healing, bump formation,
and limb formation) are represented
by vertical lines. Regen, regeneration;
Dediff, dedifferentiation;
Synth, synthesis; Form, formation
[Reprinted from Developmental
Biology, 270, Endo, T., Bryant, S. V.
& Gardiner. D. M., A stepwise model
system for limb regeneration,
135â145., Copyright (2004), with
permission from Elsevier.] . (B) To
identify the signals predicted by
the stepwise model, a heat shock
inducible-transgenic technique
may prove invaluable. Transgenic
animals harboring heat shockinducible
inhibitors for candidate
signaling pathways that function in the stepwise model must be prepared. If the stepwise signals are mediated by such candidates,
limb regeneration will be significantly blocked by heat shock at the time point when the stepwise signals are required for the promotion
of limb regeneration but will not be blocked significantly at other time points.
Fig. 5. Range of regenerative
responses of tetrapods to limb
amputation. There is a large gap
between the lowest regenerative
response with scar formation
in adult mice (mammals) and
complete limb regeneration in
newts and salamanders. Embryonic
mice, digit tips of the mouse and
Xenopus tadpoles are located in
the intermediate between the
extremes and can be excellent
models to fill the large gap between
them. Attempts to improve the
extent of regenerative response
step-by-step using such models
will ultimately enable adult
mammals of complete limb regeneration. Signaling in parentheses has been shown to control regenerative capacity in such models by
functional analysis.
