The cellular basis of limb regeneration in urodeles

Formation of a regeneration blastema on the amputated urodele limb involves changes in the gene activity of differentiated cells resulting in their histological dedifferentiation and their return to a proliferative state. This review summarizes studies in limb regeneration and in the related fields of tissue repair and limb development that provide new insights into regulatory mechanisms of likely importance in establishing the blastema. Factors required for epithelialization of the wound are briefly described, followed by what is known regarding the biochemistry of extracellular matrix remodeling in the regenerating limb. Cellular "dedifferentiation" is discussed, emphasizing variations in the process among major cell types that give rise to the blastema: fibroblasts, cells of skeletal tissue, muscle cells, Schwann cells, and vascular endothelial cells. Attention is drawn to evidence that cells of connective tissue have a special role in establishing the prepattern of the new limb in the early phase of blastema formation and that angiogenesis may be controlled differently during epimorphic regeneration than in the process of wound repair. Several possible sources of the mitogens which stimulate cell cycle re-entry during dedifferentiation are described, as well as evidence suggesting the importance in limb regeneration of one such class of mitogens, the fibroblast growth factors. The trophic effect of nerves required for cells of dedifferentiating tissues to progress through the cell cycle is summarized briefly, along with recent work suggesting how this neural influence is exerted. Finally, the critical role of the wound epithelium in the cellular events forming the blastema and factors that may mediate the epithelial effect are discussed.