Abstract
This review explores the historical and current state of our knowledge about urodele limb regeneration. Topics discussed are (1) blastema formation by the proteolytic histolysis of limb tissues to release resident stem cells and mononucleate cells that undergo dedifferentiation, cell cycle entry and accumulation under the apical epidermal cap. (2) The origin, phenotypic memory, and positional memory of blastema cells. (3) The role played by macrophages in the early events of regeneration. (4) The role of neural and AEC factors and interaction between blastema cells in mitosis and distalization. (5) Models of pattern formation based on the results of axial reversal experiments, experiments on the regeneration of half and double half limbs, and experiments using retinoic acid to alter positional identity of blastema cells. (6) Possible mechanisms of distalization during normal and intercalary regeneration. (7) Is pattern formation is a self‐organizing property of the blastema or dictated by chemical signals from adjacent tissues? (8) What is the future for regenerating a human limb?
Highlights
Evidence from the fossil record indicates that urodeles of the Permian period were capable of limb regeneration (Fröbisch, Bickelmann, & Witzmann, 2014)
Triploid-labeled cartilage gave rise to few chondrocytes in the regenerate when grafted to the diploid axolotl limb (Muneoka, Fox et al, 1986a; Steen, 1968) and chondrocytes were not observed to contribute to the blastema at all in another set of experiments where green fluorescent protein (GFP)-labeled cartilage was injured in evoking the formation of a supernumerary blastema and limb (McCusker, Diaz-Castillo, FIGURE 3 Positional memory is encoded in the cell surface. (A) Blastemas derived from the same level (W/W, UA/UA) fuse in a straight line when juxtaposed in culture, but when derived from different levels (W/UA), the more proximal blastema engulfs the distal one
Depletion after a blastema enters the growth phase only delays regeneration. These results suggest a central role for macrophages in limb regeneration by resolving inflammation by shifting cytokine ratios in favor of the anti-inflammatory subset, and by extracellular matrix (ECM) degradation, including the basement membrane
Summary
Evidence from the fossil record indicates that urodeles (salamanders and newts) of the Permian period (the last period of the Paleozoic era, ∼300 million years ago) were capable of limb regeneration (Fröbisch, Bickelmann, & Witzmann, 2014). Adult mice and humans can regenerate the distal tip of the terminal phalanges, their limbs do not regenerate after amputation at more proximal levels. Progenitor cells, and tissue interactions in regenerating salamander limbs are similar to those of regenerating mouse digit tips (for reviews see Simkin et al, 2015; Zielens, Ransom, Leavitt, & Longaker, 2016). These similarities have encouraged the idea that mammals have retained a latent ancestral genetic circuitry for appendage regeneration that might be activated by appropriate interventions and applied to the goal of regenerating a human limb. This paper is intended as a broad review of what we know—and do not know—about the basic biology of urodele limb regeneration
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