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children, however a similar response has been documented in adults [ 4 ]. While
human fi ngertip regeneration is well documented in the clinical literature, the details
of this response have not been well characterized, thus it remains more a curiosity
rather than a model upon which regenerative therapies might evolve.
Like the human fi ngertip, the digit tip of mice possesses a similar ability toregenerate; amputation through the terminal phalanx results in the faithful restora-
tion of the digit tip [ 5 ]. This regenerative response is highly reproducible and occurs
following digit amputation during fetal, neonatal and adult stages. Like the regener-
ating urodele limb, the digit tip regenerative response involves blastema formation
and goes through a series of inter-dependent stages, some of which are known to be
essential for successful regeneration. Regeneration of the mouse digit tip correlates
with amputation distal to the nail matrix making it amputation level specifi c, much
like human fi ngertip regeneration. Thus, the regenerating mouse mammalian digit
functions as an important investigative model for uncovering the details surround-
ing endogenous mammalian regenerative response, and conversely, regenerative
failure. In this chapter we summarize recent advances in our understanding of how
regeneration in mammals is controlled.
5.2 Overview of Digit Regeneration
The adult mouse distal phalanx (P3) is a triangular shaped bone with a relatively
wide base and a comparatively smaller distal apex, encased dorsally and medially
within the nail organ (Fig. 5.1a, b ). Distal amputation of P3 transects multiple tissue
types, including the P3 bone, the surrounding soft connective tissue, nerves, vascu-
lature, the ventral epidermis, the nail and associated nail bed (Fig. 5.1b, c ). Distal
amputation does not remove the nail matrix, damage the ventrally located fat pad,
or transect the highly vascularized marrow cavity (Fig. 5.1c ). While prompt wound
closure is associated with the urodele regeneration response, the wound closure of
the mammalian P3 digit is comparatively slow and shows considerable variability,
taking between 8 and 12 days to complete [ 6 ]. Wound healing is complicated
because the wound epidermis does not close directly over the amputated bone sur-
face. Instead, the epidermis initially retracts and attaches to the periosteal surface at
a location proximal to the original amputation plane (Fig. 5.1d ). During this initial
wound response and prior to wound closure, overt tissue histolysis occurs, exempli-
fi ed by the degradation of the bone stump (Fig. 5.1d ). The bone degradation
response is mediated by osteoclasts that create large pits in the stump bone that
eventually causes a secondary amputation proximal to the original (Fig. 5.1e, f ).
Following this injury-induced secondary amputation , the proximally contracted
epidermis is able to migrate through the region of regressed bone and forms a
wound epidermis that eventually caps the distal digit region. In most cases the deg-
radation of distal bone is incomplete and the completion of wound closure results in
L.A. Dawson et al.