Digit Tip Regeneration: Merging Regeneration Biology with Regenerative Medicine.

Regeneration Biology is the study of organisms with endogenous regenerative abilities, whereas Regenerative Medicine focuses on engineering solutions for human injuries that do not regenerate. While the two fields are fundamentally different in their approach, there is an obvious interface involving mammalian regeneration models. The fingertip is the only part of the human limb that is regeneration-competent and the regenerating mouse digit tip has emerged as a model to study a clinically relevant regenerative response. In this article, we discuss how studies of digit tip regeneration have identified critical components of the regenerative response, and how an understanding of endogenous regeneration can lead to expanding the regenerative capabilities of nonregenerative amputation wounds. Such studies demonstrate that regeneration-incompetent wounds can respond to treatment with individual morphogenetic agents by initiating a multi-tissue response that culminates in structural regeneration. In addition, the healing process of nonregenerative wounds are found to cycle through nonresponsive, responsive and nonresponsive phases, and we call the responsive phase the Regeneration Window. We also find the responsiveness of mature healed amputation wounds can be reactivated by reinjury, thus nonregenerated wounds retain a potential for regeneration. We propose that regeneration-incompetent injuries possess dormant regenerative potential that can be activated by targeted treatment with specific morphogenetic agents. We believe that future Regenerative Medicine-based-therapies should be designed to promote, not replace, regenerative responses. Stem Cells Translational Medicine 2018;7:262-270.