Molecular Mechanisms of Limb and Tail Regeneration in Axolotl - PROJECT SUMMARY Axolotls, a type of salamander, are remarkable in their ability to regenerate, as adults, their limbs and tail upon amputation. My lab studies axolotl limb and tail regeneration with the broad goal of delineating the underlying biological processes in order to enable development of novel strategies for scarless tissue regeneration in humans. In mammals, a wound is quickly covered by an epidermal layer followed by formation of a fibrotic scar (fibrosis). However, in axolotls, a wound does not heal with a scar; rather, a pool of progenitor cells, termed the blastema, forms beneath the wound epidermis, and these cells give rise to all of the cell types required for regrowth of limbs and tails. When I entered the field of axolotl research ~15 years ago, I recognized that modern research tools available for analysis of other organisms such as mice were lacking in axolotl research, hindering research progress. To help fill this gap, I played key roles in developing new technologies, including approaches for generating transgenic axolotls, and using advanced approaches for generating and analyzing large datasets on entire biological systems, to answer fundamental questions on regeneration. Recently, I have been a leader in developing cutting-edge approaches for imaging at a subcellular resolution in axolotls. Using these advanced tools, my laboratory has made significant discoveries on axolotl limb and tail regeneration. For example, I discovered that dedifferentiation of fibroblasts is the key for successful limb regeneration in axolotl. In a subsequent study, our team showed that poor dedifferentiation of fibroblasts in Xenopus frogs is the underlying reason for poor limb regeneration in these frogs. Similarly, the unique regenerative capacity of fibroblasts in axolotls is not observed in mammalian fibroblasts, likely leading to fibrosis in mammals. In a recent study, we discovered a novel population of progenitor cells in the axolotl tail that are capable of regenerating all cell types required for tail regeneration, including fibroblasts, muscles, and vertebrae. Identification of these novel progenitors is the first example of such cells in any organism, and their absence in mammals may help explain mammals’ poor regenerative abilities. Many fundamental questions about regeneration in axolotl remain, including: How are cells activated to acquire the characteristics of a blastema cell? Which cell types are essential for regeneration, and which are dispensable? Over the next five years, I will focus on two broad questions: 1) understanding how fibroblast function in limbs is affected by the activities of other cell types; and 2) determining how the novel progenitor cells in tails give rise to the diverse cell types and activate patterning mechanisms. Comparison of my findings in limb versus tail will identify regeneration pathways that are fundamental to both body parts as well as pathways that may be specific to each cellular context. Together, my results will have potential to lead to design of approaches to successfully promote regeneration of injured or diseased musculoskeletal structures, including limbs, in humans.
