Preamputation and postamputation histology of the neonatal opossum hindlimb: Implications for regeneration experiments

Abstract

Mammalian limbs generally do not regenerate, regardless of added hormonal or nervous stimulation, whether amputation occurs during fetal life or post-partum. The one exception, the newborn opossum, has been reported to regenerate the incompletely developed hindlimb (Mizell, '68). In an attempt to repeat and extend these earlier findings, we have examined the histology of the neonatal opossum hindlimb. After amputation on day 4 post-partum, we correlated the histology of the amputated segment with the histology of the remaining stump after a "regeneration time" of several weeks. Amputations through the middle of the hindlimb on day 4 did not transect the tibia and fibula because the rudiments of these bones are still almost completely inside the body wall. Midlimb amputations transected instead the tarsal rudiments or even phalangeal rudiments. Limb stumps were therefore left with distal skeletal rudiments which subsequently underwent further embryonic development and growth giving the erroneous impression of regeneration. Of 30 amputated hindlimbs, none showed regeneration.

BMP signaling induces digit regeneration in neonatal mice

“…Following the lead of Marcus Singer's studies on the neurotrophic influence in amphibian limb regeneration (Singer, 1952), Mizell reported on induced regeneration of amputated newborn opossum hind limbs by implantation of neural tissues (Mizell, 1968). However, in an effort to replicate these studies, Fleming and Tassava reported that anatomical variability in the timing of skeletal outgrowth of the opossum hindlimb, and not neural tissue grafts, could account for the partial regenerative response reported by Mizell (Fleming and Tassava, 1981;Mizell, 1968). The developing mammalian limb bud possesses an endogenous ability to undergo a partial regenerative response in vitro and in vivo, indicating that regenerative ability is enhanced during development (Chan et al, 1991;Deuchar, 1976;Wanek et al, 1989).…”

Evolution of epimorphosis in mammals

“…When regenerative events are considered the product of cycles of evolutionary loss and gain, it can lead to potential solutions for regenerative failure restricted to specific animal groups and not universal across phylogenetic groups. For example, the approach of identifying key neurotrophic regulators of salamander limb regeneration has resulted in promoting limb regeneration in nonregenerative frog species (Mitogawa, Makanae, & Satoh, 2018; Singer, 1951) but not in mammalian species (Fleming & Tassava, 1981). This suggests that a universal solution to regenerative failure in animals in general, and humans in particular, may not exist and that the solution to regenerative failure.…”