Lizard tail regeneration as an instructive model of enhanced healing capabilities in an adult amniote - PubMed (original) (raw)

Review

Lizard tail regeneration as an instructive model of enhanced healing capabilities in an adult amniote

Thomas P Lozito et al. Connect Tissue Res. 2017 Mar.

Abstract

The ability to regenerate damaged or lost tissues has remained the lofty goal of regenerative medicine. Unfortunately, humans, like most mammals, suffer from very minimal natural regenerative capabilities. Certain non-mammalian animal species, however, are not so limited in their healing capabilities, and several have attracted the attention of researchers hoping to recreate enhanced healing responses in humans. This review focuses on one such animal group with remarkable regenerative abilities, the lizards. As the closest relatives of mammals that exhibit enhanced regenerative abilities as adults, lizards potentially represent the most relevant model for direct comparison and subsequent improvement of mammalian healing. Lizards are able to regenerate amputated tails and exhibit adaptations that both limit tissue damage in response to injury and initiate coordinated regenerative responses. This review summarizes the salient aspects of lizard tail regeneration as they relate to the overall regenerative process and also presents the relevant information pertaining to regrowth of specific tissues, including skeletal, muscular, nervous, and vascular tissues. The goal of this review is to introduce the topic of lizard tail regeneration to new audiences with the hope of expanding the knowledge base of this underutilized but potentially powerful model organism.

Keywords: Cartilage; lizard; muscle; peripheral nerve; regeneration; salamander; spinal cord.

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Figures

Fig. 1

Fig. 1

Examples of limb and tail regeneration in amphibians and lizards. (A, B) Morphological comparison of (A) salamander (Ambystoma mexicanum) and (B) frog (Xenopus laevis) forelimbs before (left) and 8 weeks after (right) amputation. Salamanders regenerate new limbs, while frogs regenerate cartilage spikes. (C, D) Histological analysis (pentachrome) of regenerated (C) salamander and (D) frog limbs. Salamanders regenerate all the skeletal elements of the upper arm and hand, while frogs regenerate a single cartilage spike. (E, F) Histological (pentachrome) and (E, F Insets) morphological analysis of (E) salamander tail 5-weeks post amputation and (F) lizard (Anolis carolinensis) tail 2 weeks post-amputation. (G) Salamander (top) and lizard (bottom) tails 10 weeks after amputation analyzed by micro computed tomography. The regenerated salamander, but not lizard, skeleton segments. Pentachrome stains cartilage green, bone orange, muscle red, and spinal cord and epidermis purple. Dashed lines denote amputation planes. c, carpal; cr, cartilage rod; cs, cartilage spike; ct, cartilage tube; h, humerus; m, muscle; mc, metacarpal; nc, notochord; p, phalanges; r, radius; rm, regenerated muscle; rsc, regenerated spinal cord; ru, radio-ulna; sc, spinal cord; u, ulna; ve, vertebra. Bar = 1 mm.

Fig. 2

Fig. 2

Autotomous lizard tail vertebrae contain fracture planes. Original tails of (A) Anolis carolinensis, (B) Hemidactylus frenatus, (C) Heteronotia binoei, and (D) Hoplodactylus duvaucelii analyzed by micro computed tomography and highlighting the diversity of fracture plane position and structure. Open arrowheads denote intravertebral fracture plane. White-filled arrowheads mark intervertebral pads (ip). Black-filled arrowheads identify Z-joints (z). Bar = 100 μm.

Fig. 3

Fig. 3

Representative lizard tails (A) 0, (B) 3, (C) 6, (D) 9, (E) 12, (F) 15, (G) and 28 days following tail loss highlighting the important structures involved with tail regrowth. ac, apical cap; bl, blastema; ct, cartilage tube; dst, degenerated stump tissue; m, muscle; rm, regenerated muscle; rsc, regenerated spinal cord; sc, spinal cord; we, wound epithelium; ve, vertebra.

Fig. 4

Fig. 4

Regenerated lizard tails are able to re-regenerate following amputation. (A,B) Mature lizard tail regenerates with CTs were amputated in (1) the original tail vertebra (Orig), (2) the proximal regenerated tail (Prox), or (3) the distal regenerated tail (Dist). (A) Morphological and (B) microCT analyses of an intact mature lizard regenerate showing relative position of amputation sites. (B) The skeletons of original, but not regenerated, tail regions. Fracture planes (fp) are present in (C–E) Following 4 weeks of regeneration, tails amputated in the (C) original tail, (D) proximal regenerate, or (E) distal regenerates were analyzed for overall regenerate elongation. fp, fracture plane. Bar = 0.5 cm.

Fig. 5

Fig. 5

Micro computed tomography scans of original lizard tail terminal vertebrae 2, and 6, and 9 days post-autotomy (DPA) analyzed by micro computed tomography. The distal portions of terminal vertebrae are completely degraded by 9 DPA. Bar = 100 μm.

Fig. 6

Fig. 6

(A–C) Analysis of signaling molecules and cell proliferation markers within the regenerating lizard tail. Lizard tail blastemas (9 days following tail loss) were immunostained for IGF-2, FGF-2, Wnt5a, and PCNA. Panels B and C depict higher magnification views of region identified in Panel A. Dashed lines denote amputation planes. (D–F) Effects of FGF-2 and the FGF inhibitor SU5402 on lizard tail regeneration. Beads soaked in (D) vehicle control, (E) 100 μg/ml FGF-2, (F) or 2 mg/ml SU5402 were implanted in lizard tail blastemas. Following 7 days of growth, the tails were collected and analyzed by collagen type II immunohistochemistry. Insets of each panel depict gross tail morphology. Stars denote bead implantation sites. (D) Control tails exhibit normal ependymal tube extension. (E) Tails treated with FGF-2-soaked beads exhibit ependymal tube branches that invade toward implantation sites. (F) Tails treated with SU5402-soaked beads exhibit stunted ependymal tube invasion. ac, apical cap; bl, blastema; et, ependymal tube; ct, cartilage tube. Bar = 2 mm.

Fig. 7

Fig. 7

Close-up of extreme proximal cartilage tube highlighting its resemblance to a fracture callus. ct, cartilage tube; hc, hypertrophic chondrocytes; oc, ossification center; po, periosteum; ve, vertebra. Bar = 100 μm.

Fig. 8

Fig. 8

Comparison of cartilage tube perichondrium calcification between two species of lizards. Cross-sections of mature regenerated tails of (A) _Anolis carolinensi_s and (B) the gecko Dactylocnemis pacificus analyzed by histology (von Kossa / Safranin O). Cartilage stains red, and calcified tissues stain black. The perichondrium of the Anolis cartilage tube calcifies, while the gecko cartilage tube resists calcification. ct, cartilage tube; pc, perichondrium; rsc, regenerated spinal cord. Bar = 50 μm.

Fig. 9

Fig. 9

Lizard tail muscle, spinal cord, peripheral nerve, and blood vessel regeneration. (A) Lizard tail 21 days post amputation (DPA) immunostained for muscle marker myosin heavy chain (MHC). Regenerated muscles begin as distinct myomeres. (B) Close-up of a regenerated muscle myomere. (C) Original and (D) regenerated tail spinal cords analyzed immunostained for neural marker β-III-tubulin and glial cell marker glial fibrillary acidic protein (GFAP). (E, F) Lizard tail 9 DPA immunostained for (E) β-III-tubulin and (F) the blood vessel marker CD31. (E) Peripheral nerves regenerate from dorsal root ganglia in tail stumps into tail blastemas. (F) Blood vessels form at the distal lizard tail blastema tip (G) Blood vessels also form at the distal salamander tail blastema tip. Black arrowhead marks prominent vascular bed. Inset depicts gross morphology of entire salamander tail blastema. Dashed lines denote amputation planes, and solid lines trace tail outlines. bl, blastema; drg, dorsal root ganglion; pn, peripheral nerve; sc, spinal cord. Bar = 25 μm.

Fig. 10

Fig. 10

The lizard spinal cord is necessary and sufficient for inducing regenerated tails in lizards. (A, B) Morphological comparison of lizard tails (A) with and (B) without intact spinal cords two weeks after tail loss. (A) Lizard tails with intact spinal cords regenerate new tails, but (B) tails with disrupted spinal cords fail to regenerate. Dashed line marks amputation plane. (C, D) Morphologies of lizard tails (C) with or (D) without spinal cord implants. After two weeks, (C) tails treated with exogenous spinal cord implants develop ectopic tails at implantation sites, while (D) control tails that did not receive exogenous spinal cord implants did not exhibit any growth. ect, ectopic tail. Bar = 1 mm.

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References

    1. Lozito TP, Tuan RS. Lizard tail regeneration: regulation of two distinct cartilage regions by Indian hedgehog. Developmental Biology. 2015;399(2):249–62. - PubMed
    1. Delorme SL, Lungu IM, Vickaryous MK. Scar-free wound healing and regeneration following tail loss in the leopard gecko, Eublepharis macularius. Anatomical record. 2012;295(10):1575–95. - PubMed
    1. Bellairs AD, Bryant SV. Autotomy and Regeneration in Reptiles. In: Billet CGaF., editor. The Biology Of The Reptilia. Vol. 15. New York: John Wiley & Sons, Inc; 1985. pp. 303–410.
    1. Alibardi L. In: Morphological and Cellular Aspects of Tail and Limb Regeneration in Lizards: A Model System With Implications for Tissue Regeneration in Mammals. Korf H-W, editor. Springer; 2010. - PubMed
    1. Chablais F, Jazwinska A. IGF signaling between blastema and wound epidermis is required for fin regeneration. Development. 2010;137(6):871–9. - PubMed

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