Plasticity and reprogramming of differentiated cells in amphibian regeneration

Abstract

Regenerative ability is widespread in metazoan phylogeny, but has been lost in many species for reasons that are not understood. The champions of regeneration among adult verterbrates are the urodele amphibians, such as the newt, which can regenerate their limbs, jaws, lens and large sections of the heart. Urodele regeneration depends on the local plasticity of differentiated cells that remain after injury or tissue removal. This involves re-entry to the cell cycle and loss of differentiated characteristics, so as to generate a local progenitor cell of restricted potentiality. The molecular cell biology of urodele plasticity has been investigated in detail in the skeletal myofibre and myotube. Newt myotubes can re-enter the cell cycle by activating a pathway that leads to phosphorylation of the retinoblastoma protein pRb. This pathway is triggered by a ligand that is generated downstream of thrombin activation to which mammalian myotubes are completely unresponsive. Newt myotubes are converted to mononucleate progeny after implantation into the regenerating limb. Mouse myotubes are also converted to mononucleate cells by expression of the Msx-1 gene, by exposure to a substituted purine known as myoseverin or to extracts of a regenerating newt limb. Our understanding of re-programming during urodele regeneration might lead to a marked enhancement of regenerative ability in mammals.