Comparing Regeneration of Fingertips Between Species

As a sidebar to yesterday's post on regeneration in mammals, here is a review paper that just considers fingertip regeneration in various species. This can occur in mammals, and even on rare occasions in adult humans, though it isn't well understood as to why it happens at all given the inability to regenerate most other lost appendages. It is possible that this is a useful point of investigation in order to better understand why mammals do not regenerate like salamanders, and how that state of affairs might be changed for the better.

Mammalian fingertips and toes can partially regrow under certain conditions; however, regeneration is greatly limited compared to urodele amphibians such as newts and salamanders that can completely regrow an amputated limb. The question is why there is such a difference between the regenerative potentials of mammals and amphibians. Embryonic, neonatal, and adult mice can regenerate digit tips if the amputation is midway through the third phalanx; however, if the amputation occurs proximal to the midway point of the third phalanx in mice, regeneration of the digit tip does not typically occur. Similarly, young patients have also been documented to regrow the tips of amputated fingers if treated conservatively. Although adults and even elderly individuals have potentially regenerated amputated digit tips, the regenerative process may not be as efficient as it is in younger patients and usually results in fibrous scars in adults. The regeneration process of the digit following injury may be related to the age of the host, with decreased restoration in adults compared to fetal or neonatal mammals. Injured adult mammalian tissues are usually replaced with fibrotic scar tissue, whereas scarless healing typically occurs in fetal wound healing which results in complete tissue recovery. Stem cell activation and scarless wound healing are considered to be essential requisites for quality tissue regeneration; however, for some regenerative processes a dedifferentiation process, but not stem cell activation, is required.

Many theories have been proposed to explain why successful regeneration occurs in urodele amphibians but not in mammals. First, the immune system has been shown to play a major role in the regeneration process of amputated limbs in newts. In mammals, fetal wounds can regenerate because they have an immature immune system; however, in adults, clearing pathogens appears to be evolutionarily favored compared to retaining the ability to regenerate a limb or digit. Second, amphibians have retained limb regeneration-specific genes not found in mammals, which allow their cells to dedifferentiate. A related theory is that mammals have evolved tumor suppression genes that inhibit regeneration. The Ink4a locus is present in mammals but not amphibians; this region encodes the tumor suppression genes p16ink4a and Alternative Reading Frame (ARF). Inactivation of both tumor suppressors retinoblastoma (Rb) and ARF allows terminally differentiated mammalian muscle cells to dedifferentiate. An extension of this theory is that differentiated mammalian tissues can regenerate if the cells are induced to reenter the cell cycle, which occurs in the Murphy Roths Large (MRL) mouse and the p21-deficient mouse. Third, bioelectric signaling (e.g., membrane voltage polarity, ionic channels) may also play a role in the tissues' regeneration potential. Nonregenerating wounds display a positive polarity throughout the healing process, whereas in regenerating animals the polarity is initially positive but then quickly changes to negative polarity with the peak voltage occurring at the time of maximum cellular proliferation.



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