THE CELLULAR BASIS OF LIMB REGENERATION IN URODELES

Formation of a regeneration blastema on the amputated urodele limb inv olves changes in the gene activity of differentiated cells resulting i n their histological dedifferentiation and their return to a prolifera tive 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 estab lishing the blastema. Factors required for epithelialization of the wo und are briefly described, followed by what is known regarding the bio chemistry of extracellular matrix remodeling in the regenerating limb. Cellular ''dedifferentiation'' is discussed, emphasizing variations i n the process among major cell types that give rise to the blastema: f ibroblasts, 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 prepatte rn of the new limb in the early phase of blastema formation and that a ngiogenesis may be controlled differently during epimorphic regenerati on than in the process of wound repair. Several possible sources of th e mitogens which stimulate cell cycle re-entry during dedifferentiatio n are described, as well as evidence suggesting the importance in limb regeneration of one such class of mitogens, the fibroblast growth fac tors. The trophic effect of nerves required for cells of dedifferentia ting tissues to progress through the cell cycle is summarized briefly, along with recent work suggesting how this neural influence is exerte d. Finally, the critical role of the wound epithelium in the cellular events forming the blastema and factors that may mediate the epithelia l effect are discussed.