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5. CONCLUSIONS 1. ABSTRACT 4. RESULTS 1. Digit tip regeneration is inhibited by repeated amputation 2. Repeated amputation depletes local osteoprogenitor cells 3. There is an unidentified systemic component to mammalian digit tip regeneration Mice are intrinsically capable of regenerating their distal digit tips after amputation and represent a mammalian model of epimorphic regeneration. The cells that reconstitute the regenerated digit are derived from local tissues associated with the amputation injury and not from circulating cells. However, it is unknown whether the progenitor cell niche is restored or depleted after regeneration. To investigate this, we repeatedly amputated the hindlimb digits of mice every four weeks, longitudinally monitoring regeneration using in vivo micro-computed tomography. We find that digit tip regeneration is inhibited after 5 amputations. While the amount of bone volume regenerated gradually decreases after each amputation, bone length is faithfully restored to the same length as the unamputated digit until the final amputation, suggesting that regenerating bone volume and length are regulated independently. To better understand this result we repeated this experiment, but at the time of the 5th amputation (n = 52 digits) also amputated digits on the same animals (n = 26 digits) that had not previously been amputated and which have an intact progenitor cell niche. Curiously, we find that internal control digits, just like digits amputated 5 times, fail to regenerate. Through additional experiments, we show that internal control digit regenerative failure is not explained when you control for age or the number of regenerating digits at one time but may in fact be caused by a depletion of systemic factor(s) resulting from repeated amputation of other digits. Taken together, these data strongly suggest the local progenitor cells are being depleted by repeated amputations, and that there is a previously unappreciated systemic co, RITM0027067, Mice are intrinsically capable of regenerating their distal digit tips after amputation and represent a mammalian model of epimorphic regeneration. The cells that reconstitute the regenerated digit are derived from local tissues associated with the amputation injury and not from circulating cells. However, it is unknown whether the progenitor cell niche is restored or depleted after regeneration. To investigate this, we repeatedly amputated the hindlimb digits of mice every four weeks, longitudinally monitoring regeneration using in vivo micro-computed tomography. We find that digit tip regeneration is inhibited after 5 amputations. While the amount of bone volume regenerated gradually decreases after each amputation, bone length is faithfully restored to the same length as the unamputated digit until the final amputation, suggesting that regenerating bone volume and length are regulated independently. To better understand this result we repeated this experiment, but at the time of the 5th amputation (n = 52 digits) also amputated digits on the same animals (n = 26 digits) that had not previously been amputated and which have an intact progenitor cell niche. Curiously, we find that internal control digits, just like digits amputated 5 times, fail to regenerate. Through additional experiments, we show that internal control digit regenerative failure is not explained when you control for age or the number of regenerating digits at one time but may in fact be caused by a depletion of systemic factor(s) resulting from repeated amputation of other digits. Taken together, these data strongly suggest the local progenitor cells are being depleted by repeated amputations, and that there is a previously unappreciated systemic component of mouse digit tip regeneration.