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Tissue regeneration and scarless healing involves the complete replacement and functional restoration of damaged organs and tissues. In this study of the “scarless healing” MRL mouse model, we demonstrate that 2-mm diameter through-and-through holes made in the cartilaginous part of previously injured MRL mouse ears are closed more efficiently, and that the regenerative repair response is significantly accelerated compared with unprimed MRL and control “nonhealer” strains of mice. Accelerated healing was detected both locally and distally from the original site of injury indicating the involvement of systemic components such as circulating cell types or soluble factors. Histologically, we observed early differences during the wound repair process (before Day 4 post injury) with accelerated formation of blastema-like structures, epidermal downgrowths, and enhanced epithelium thickening in wound border zones in primed MRL mice versus unprimed MRL mice. Although the mechanism of tissue regeneration remains unclear, the results from this study justify the use of the MRL model for further experimentation directed toward the identification of proteins and cell types capable of stimulating scarless tissue regeneration. [ABSTRACT FROM AUTHOR]