Abstract
The MRL (Murphy Roths Large) mouse has provided a unique model of adult mammalian regeneration as multiple tissues show this important phenotype. Furthermore, the healing employs a blastema-like structure similar to that seen in amphibian regenerating tissue. Cells from the MRL mouse display DNA damage, cell cycle G2/M arrest, and a reduced level of p21CIP1/WAF. A functional role for p21 was confirmed when tissue injury in an adult p21-/- mouse showed a healing phenotype that matched the MRL mouse, with the replacement of tissues, including cartilage, and with hair follicle formation and a lack of scarring. Since the major canonical function of p21 is part of the p53/p21 axis, we explored the consequences of p53 deletion. A regenerative response was not seen in a p53-/- mouse and the elimination of p53 from the MRL background had no negative effect on the regeneration of the MRL.p53-/- mouse. An exploration of other knockout mice to identify p21-dependent, p53-independent regulatory pathways involved in the regenerative response revealed another significant finding showing that elimination of transforming growth factor-β1 displayed a healing response as well. These results are discussed in terms of their effect on senescence and differentiation.
Highlights
We published a study demonstrating that a deletion of the gene p21CIP/WAF converts a non-regenerating strain of mouse to one capable of epimorphic regeneration and has provided a unique opportunity to uncover some of the unknowns of this process in mammals
Multiple tissues were perfectly replaced, cartilage re-grew, and hair follicles reappeared. This type of perfect multi-tissue healing, known as epimorphic regeneration, occurred with the formation of a blastema-like structure that had been shown to be key to amphibian limb regeneration [3,4,5]
This phenomenon had earlier been seen in rabbit ear holes [6,7,8], and a blastema-derived structure had been described during antler re-growth [9]
Summary
We published a study demonstrating that a deletion of the gene p21CIP/WAF converts a non-regenerating strain of mouse to one capable of epimorphic regeneration and has provided a unique opportunity to uncover some of the unknowns of this process in mammals. In an amphibian in vitro model of skeletal muscle regeneration, retinoblastoma (Rb) protein plays a predominant role in cell cycle reentry through phosphorylation by CDK4/6 [67] This process requires serum to stimulate entry of the quiescent nuclei of multinuclear myotubes into S-phase with a serum-derived thrombin-activated factor being necessary for Rb hyperphosphorylation, resulting in its ‘inactivation’ [48,68]. The major role played by p53 as the ‘guardian’ of the genome is due to its ability to respond to DNA damage and cellular stress by inhibiting cell cycle progression and regulating DNA repair, cell cycle control, apoptosis, differentiation, autophagy induction, and senescence It is not clear which of these functions or lack thereof could be responsible for the enhanced differentiation observed in MRL.p53-/- mice [64,71,74,75,76,77,78,79]. An interesting fact is that TGF-β1 enhances Sma-1 production and myofibroblasts associated with scarring [120] and reduces regenerative healing, whereas the TGF-β isoform TGF-β3 enhances scar-free healing [121]
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