Yokoyama H (2008), Initiation of limb regeneration: the critical s...

XB-ART-36762

Dev Growth Differ 2008 Jan 01;501:13-22. doi: 10.1111/j.1440-169X.2007.00973.x.

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Initiation of limb regeneration: the critical steps for regenerative capacity.

Yokoyama H .

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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.

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GO keywords: regeneration [+]

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	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 right limb 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, 135–145., 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.