Appendage Regeneration in Vertebrates: What Makes This Possible?

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2021 Jan 30

PMID 33513779

Citations 17

Authors

Valentina Daponte

Przemko Tylzanowski

Antonella Forlino

Affiliations

Soon will be listed here.

Abstract

The ability to regenerate amputated or injured tissues and organs is a fascinating property shared by several invertebrates and, interestingly, some vertebrates. The mechanism of evolutionary loss of regeneration in mammals is not understood, yet from the biomedical and clinical point of view, it would be very beneficial to be able, at least partially, to restore that capability. The current availability of new experimental tools, facilitating the comparative study of models with high regenerative ability, provides a powerful instrument to unveil what is needed for a successful regeneration. The present review provides an updated overview of multiple aspects of appendage regeneration in three vertebrates: lizard, salamander, and zebrafish. The deep investigation of this process points to common mechanisms, including the relevance of Wnt/β-catenin and FGF signaling for the restoration of a functional appendage. We discuss the formation and cellular origin of the blastema and the identification of epigenetic and cellular changes and molecular pathways shared by vertebrates capable of regeneration. Understanding the similarities, being aware of the differences of the processes, during lizard, salamander, and zebrafish regeneration can provide a useful guide for supporting effective regenerative strategies in mammals.

Citing Articles

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References

McCusker C, Bryant S, Gardiner D . The axolotl limb blastema: cellular and molecular mechanisms driving blastema formation and limb regeneration in tetrapods. Regeneration (Oxf). 2016; 2(2):54-71. PMC: 4895312. DOI: 10.1002/reg2.32. View

Li J, Barreda D, Zhang Y, Boshra H, Gelman A, LaPatra S . B lymphocytes from early vertebrates have potent phagocytic and microbicidal abilities. Nat Immunol. 2006; 7(10):1116-24. DOI: 10.1038/ni1389. View

Alibardi L, Lovicu F . Immunolocalization of FGF1 and FGF2 in the regenerating tail of the lizard Lampropholis guichenoti: implications for FGFs as trophic factors in lizard tail regeneration. Acta Histochem. 2009; 112(5):459-73. DOI: 10.1016/j.acthis.2009.05.006. View

Poss K, Shen J, Nechiporuk A, McMahon G, Thisse B, Thisse C . Roles for Fgf signaling during zebrafish fin regeneration. Dev Biol. 2000; 222(2):347-58. DOI: 10.1006/dbio.2000.9722. View

Hirose K, Shimoda N, Kikuchi Y . Transient reduction of 5-methylcytosine and 5-hydroxymethylcytosine is associated with active DNA demethylation during regeneration of zebrafish fin. Epigenetics. 2013; 8(9):899-906. PMC: 3883767. DOI: 10.4161/epi.25653. View

Takayama K, Shimoda N, Takanaga S, Hozumi S, Kikuchi Y . Expression patterns of dnmt3aa, dnmt3ab, and dnmt4 during development and fin regeneration in zebrafish. Gene Expr Patterns. 2014; 14(2):105-10. DOI: 10.1016/j.gep.2014.01.005. View

Wehner D, Cizelsky W, Vasudevaro M, Ozhan G, Haase C, Kagermeier-Schenk B . Wnt/β-catenin signaling defines organizing centers that orchestrate growth and differentiation of the regenerating zebrafish caudal fin. Cell Rep. 2014; 6(3):467-81. DOI: 10.1016/j.celrep.2013.12.036. View

Wolpert L . Positional information and pattern formation. Curr Top Dev Biol. 1971; 6(6):183-224. DOI: 10.1016/s0070-2153(08)60641-9. View

Kragl M, Knapp D, Nacu E, Khattak S, Maden M, Epperlein H . Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature. 2009; 460(7251):60-5. DOI: 10.1038/nature08152. View

10.

Lozito T, Tuan R . Lizard tail regeneration as an instructive model of enhanced healing capabilities in an adult amniote. Connect Tissue Res. 2016; 58(2):145-154. PMC: 5484412. DOI: 10.1080/03008207.2016.1215444. View

11.

Nachtrab G, Czerwinski M, Poss K . Sexually dimorphic fin regeneration in zebrafish controlled by androgen/GSK3 signaling. Curr Biol. 2011; 21(22):1912-7. PMC: 3236601. DOI: 10.1016/j.cub.2011.09.050. View

12.

Simoes M, Bensimon-Brito A, Fonseca M, Farinho A, Valerio F, Sousa S . Denervation impairs regeneration of amputated zebrafish fins. BMC Dev Biol. 2015; 14:49. PMC: 4333893. DOI: 10.1186/s12861-014-0049-2. View

13.

Smith A, Avaron F, Guay D, Padhi B, Akimenko M . Inhibition of BMP signaling during zebrafish fin regeneration disrupts fin growth and scleroblasts differentiation and function. Dev Biol. 2006; 299(2):438-54. DOI: 10.1016/j.ydbio.2006.08.016. View

14.

Alibardi L . Hyaluronic acid in the tail and limb of amphibians and lizards recreates permissive embryonic conditions for regeneration due to its hygroscopic and immunosuppressive properties. J Exp Zool B Mol Dev Evol. 2017; 328(8):760-771. DOI: 10.1002/jez.b.22771. View

15.

Knopf F, Hammond C, Chekuru A, Kurth T, Hans S, Weber C . Bone regenerates via dedifferentiation of osteoblasts in the zebrafish fin. Dev Cell. 2011; 20(5):713-24. DOI: 10.1016/j.devcel.2011.04.014. View

16.

Godwin J, Rosenthal N . Scar-free wound healing and regeneration in amphibians: immunological influences on regenerative success. Differentiation. 2014; 87(1-2):66-75. DOI: 10.1016/j.diff.2014.02.002. View

17.

Radugina E, Grigoryan E . Heat shock response and shape regulation during newt tail regeneration. J Therm Biol. 2018; 71:171-179. DOI: 10.1016/j.jtherbio.2017.11.009. View

18.

Lam S, Chua H, Gong Z, Lam T, Sin Y . Development and maturation of the immune system in zebrafish, Danio rerio: a gene expression profiling, in situ hybridization and immunological study. Dev Comp Immunol. 2003; 28(1):9-28. DOI: 10.1016/s0145-305x(03)00103-4. View

19.

Wagner I, Wang H, Weissert P, Straube W, Shevchenko A, Gentzel M . Serum Proteases Potentiate BMP-Induced Cell Cycle Re-entry of Dedifferentiating Muscle Cells during Newt Limb Regeneration. Dev Cell. 2017; 40(6):608-617.e6. DOI: 10.1016/j.devcel.2017.03.002. View

20.

Quint E, Smith A, Avaron F, Laforest L, Miles J, Gaffield W . Bone patterning is altered in the regenerating zebrafish caudal fin after ectopic expression of sonic hedgehog and bmp2b or exposure to cyclopamine. Proc Natl Acad Sci U S A. 2002; 99(13):8713-8. PMC: 124364. DOI: 10.1073/pnas.122571799. View