Rebuilding limbs, one cell at a time

The regeneration of salamander limbs has been a special fascination among scientists and keen observers for centuries. Perhaps due to how closely the salamander's limb anatomically mirrors our own, a grand aspiration of regenerative medicine has been to provoke such a process following injury or loss of human limbs. Research in the last century has focused on understanding the blastema, a proliferative cell mass that develops after limb amputation (see Box 1 “A primer on limb regeneration” and reviews for discussion of foundational knowledge1-3). The first micrographs of limb blastemas (examples in Thornton4 and Hay5) brought limb regeneration to a cellular level and ushered in a new era of questions centered around the origin, potency, and processes of regenerative cells that has occupied the field ever since. Within this commentary, we will outline some of these persistent questions underlying limb regeneration, and how new technologies and approaches are paving the way toward a cellular understanding of complex tissue regeneration.