Toeing the line between regeneration and fibrosis

Cardiac injury in mammals and amphibians typically leads to scarring, with minimal regeneration of heart muscle. Here, we demonstrate histologically that zebrafish fully regenerate hearts within 2 months of 20% ventricular resection. Regeneration occurs through robust proliferation of cardiomyocytes localized at the leading epicardial edge of the new myocardium. The hearts of zebrafish with mutations in the Mps1 mitotic checkpoint kinase, a critical cell cycle regulator, failed to regenerate and formed scars. Thus, injury-induced cardiomyocyte proliferation in zebrafish can overcome scar formation, allowing cardiac muscle regeneration. These findings indicate that zebrafish will be useful for genetically dissecting the molecular mechanisms of cardiac regeneration. Show more

SUMMARY Evolutionary modification has produced a spectrum of animal defense traits to escape predation, including the ability to autotomize body parts to elude capture 1,2 . Following autotomy, the missing part is either replaced through regeneration (e.g. urodeles, lizards, arthropods, crustaceans) or is permanently lost (mammals). While most autotomy involves the loss of appendages (e.g. leg, cheliped, antennae, tail), skin autotomy can occur in certain taxa of scincid and gekkonid lizards 3 . Here we report the first demonstration of skin autotomy in Mammalia (African spiny mice, Acomys). Mechanical testing revealed a propensity for skin to tear under very low tension and the absence of a fracture plane. Following skin loss, rapid wound contraction was followed by hair follicle regeneration in dorsal skin wounds. Surprisingly, we found regenerative capacity in Acomys extended to ear holes where they exhibited complete regeneration of hair follicles, sebaceous glands, dermis, and cartilage. Salamanders capable of limb regeneration form a blastema (a mass of lineage-restricted progenitor cells 4 ) following limb loss, and our findings suggest that ear tissue regeneration in Acomys may proceed through assembly of a similar structure. This study underscores the importance of investigating regenerative phenomena outside of traditional model organisms and suggests that mammals may retain a higher capacity for regeneration than previously believed. As re-emergent interest in regenerative medicine seeks to isolate molecular pathways controlling tissue regeneration in mammals, Acomys may prove useful in identifying mechanisms to promote regeneration in lieu of fibrosis and scarring. Show more

The limb blastemal cells of an adult salamander regenerate the structures distal to the level of amputation, and the surface protein Prod 1 is a critical determinant of their proximodistal identity. The anterior gradient protein family member nAG is a secreted ligand for Prod 1 and a growth factor for cultured newt blastemal cells. nAG is sequentially expressed after amputation in the regenerating nerve and the wound epidermis-the key tissues of the stem cell niche-and its expression in both locations is abrogated by denervation. The local expression of nAG after electroporation is sufficient to rescue a denervated blastema and regenerate the distal structures. Our analysis brings together the positional identity of the blastema and the classical nerve dependence of limb regeneration. Show more