Review: Biological and Molecular Differences between Tail Regeneration and Limb Scarring in Lizard: An Inspiring Model Addressing Limb Regeneration in Amniotes

Abstract

Tissue regeneration in lizards represents a unique model of regeneration and scarring in amniotes. The tail and limb contain putative stem cells but also dedifferentiating cells contribute to regeneration. Following tail amputation, inflammation is low and cell proliferation high, leading to regeneration while the intense inflammation in the limb leads to low proliferation and scarring. FGFs stimulate tail and limb regeneration and are present in the wound epidermis and blastema while they disappear in the limb wound epidermis 2-3 weeks postamputation in the scarring outgrowth. FGFs localize in the tail blastema and the apical epidermal peg (AEP), an epidermal microregion that allows tail growth but is absent in the limb. Inflammatory cells invade the limb blastema and wound epidermis, impeding the formation of an AEP. An embryonic program of growth is activated in the tail, dominated by Wnt-positive and -negative regulators of cell proliferation and noncoding RNAs, that represent the key regenerative genes. The balanced actions of these regulators likely impede the formation of a tumor in the tail tip. Genes for FACIT and fibrillar collagens, protease inhibitors, and embryonic keratins are upregulated in the regenerating tail blastema. A strong downregulation of genes for both B and T-lymphocyte activation suggests the regenerating tail blastema is a temporal immune-tolerated organ, whereas a scarring program is activated in the limb. Wnt inhibitors, pro-inflammatory genes, negative regulators of cell proliferation, downregulation of myogenic genes, proteases, and oxidases favoring scarring are upregulated. The evolution of an efficient immune system may be the main limiting barrier for organ regeneration in amniotes, and the poor regeneration of mammals and birds is associated with the efficiency of their mature immune system. This does not tolerate embryonic antigens formed in reprogrammed embryonic cells (as for neoplastic cells) that are consequently eliminated impeding the regeneration of lost organs.

Perspective: Appendage regeneration in amphibians and some reptiles derived from specific evolutionary histories

“…Embryos have an absent to weak adaptive immune system, their tissues develop and mature before the adaptive immune system, and a perfect wound healing or regeneration can only occur in embryonic‐like stages (Adzick & Longaker, ; Deuchar, ; Nodder & Martin, ). The production of high levels of hyaluronate and high tissue hydration together the activation of embryonic signaling pathways, innervation and vascularization, stimulate regeneration or tumor growth (Alibardi, , ; Boilly, Faulkner, Jobling, & Hondemarck, ; Csoka & Stern, ; Nambiar et al, ; Ross & Gordon, ; Kiricuta & Simplaceanu, ). Regenerating limbs and tails of adult amphibians show that they possess a soft consistency similar to those of the embryos (Figure a–e).…”

Ultrastructural immunolocalization of hyaluronate in regenerating tail of lizards and amphibians supports an immune‐suppressive role to favor regeneration

“…I, therefore, hypothesize that as long as high levels of hyaluronate remains localized around mesenchymal and epidermal cells of the blastema, the circulating lymphocytes and macrophages cannot assess their cell surface and no immune reaction is elicited. Previous studies indicated that the levels of hyaluronate decrease from the apical blastema in the proximal regions as in the latter cells differentiate into new tissues so that only the apical, mesenchymal blastema remains temporary unaffected from the immune system until regeneration is completed (Alibardi, ; Alibardi & Sala, ).…”

“…In conclusion, it is clear that the blastema in regenerative‐competent vertebrates has numerous characteristics of neoplasm outgrowths, including the high production of hyaluronate (Alibardi, ; Csoka & Stern, ). Different from tumors, the blastema has the capacity to regulate its multiplication and growth.…”

“…This particular property of hyaluronate may in part explain why the immune system of fish and amphibians (anamniotes) and lizards (amniotes) apparently does not tag the cells forming the regenerative blastema. In this embryonic organ, some antigens present on the cell membrane of blastema cells might not be recognized as self (Alibardi, ; Vitulo, Dalla Valle, Skobo, Valle, & Alibardi, ). One mechanism of immune‐evasion may involve the formation of a hyaluronate coat around the cells of the blastema (Alibardi, ).…”

Vitamin A administration in lizards during tail regeneration determines epithelial mucogenesis and delays muscle and cartilage differentiation

“…The new tail appears to be an uncompleted copy of the original one and its functionality, in terms of bending and curling, is very limited, except in some geckos (Alibardi & Meyer‐Rochow, ). Past and present evidence have indicated that two tissues of epithelial type are essential for maintaining proliferation of the mesoderm tissues: The apical wound epidermis and the ependymal tube derived from the original spinal cord (Alibardi et al, ; Alibardi, ; Alibardi, ; Lozito & Tuan, ; Simpson, ).…”