Wound Healing Vs. Regeneration

Why do some animals have the ability to regenerate body parts and others do not?  Experiments outlined here suggest it is how the wound signals are “decoded” – including by Wnt signaling – to stimulate either “wound healing” or “regeneration” pathways.  Can this be somehow manipulated to introduce regeneration to those animals (e.g., humans) that do not naturally have it?  Abstract:

Despite the identification of numerous regulators of regeneration in different animal models, a fundamental question remains: why do some wounds trigger the full regeneration of lost body parts, whereas others resolve by mere healing? By selectively inhibiting regeneration initiation, but not the formation of a wound epidermis, here we create headless planarians and finless zebrafish. Strikingly, in both missing-tissue contexts, injuries that normally do not trigger regeneration activate complete restoration of heads and fin rays. Our results demonstrate that generic wound signals have regeneration-inducing power. However, they are interpreted as regeneration triggers only in a permissive tissue context: when body parts are missing, or when tissue-resident polarity signals, such as Wnt activity in planarians, are modified. Hence, the ability to decode generic wound-induced signals as regeneration-initiating cues may be the crucial difference that distinguishes animals that regenerate from those that cannot.

The Axoxolotl’s Molecular Toolkit

By LoKiLeCh - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3513307

Here is a study demonstrating the utility of unusual model organisms to investigate important questions in biomedicine, in this case development and regeneration, as well as evolution. Abstract:

Salamanders serve as important tetrapod models for developmental, regeneration and evolutionary studies. An extensive molecular toolkit makes the Mexican axolotl (Ambystoma mexicanum) a key representative salamander for molecular investigations. Here we report the sequencing and assembly of the 32-gigabase-pair axolotl genome using an approach that combined long-read sequencing, optical mapping and development of a new genome assembler (MARVEL). We observed a size expansion of introns and intergenic regions, largely attributable to multiplication of long terminal repeat retroelements. We provide evidence that intron size in developmental genes is under constraint and that species-restricted genes may contribute to limb regeneration. The axolotl genome assembly does not contain the essential developmental gene Pax3. However, mutation of the axolotl Pax3 paralogue Pax7 resulted in an axolotl phenotype that was similar to those seen in Pax3-/- and Pax7-/- mutant mice. The axolotl genome provides a rich biological resource for developmental and evolutionary studies.

Limb Regeneration In Humans

Higher animals such as humans lack the limb regeneration capacity of amphibians, for the reasons outlined in the abstract below. Reversing these limitations – which would require significant advances also outlined below – could potentially allow limb regeneration in humans although it would be a lengthy process: “Pharmacological treatments to direct the regenerating limb into normal growth without risk of inducing abnormal or tumorigenic growth must be monitored during the course of the regeneration process - a medical treatment lasting years to fully regain the size of the lost appendage.”  Abstract:

Appendage regeneration occurs by a sequence of events resembling those that take place during development in the embryo. This requires embryonic conditions such as hydration and hyaluronate content where Wnt and other signaling pathways, together with non- coding RNAs, can be re-expressed. These conditions among vertebrates are fully met only in amputated limbs of amphibians, likely because they are neotenic and maintain larval characteristics, including immaturity of their immune system and permanence of numerous stem cells. Although some key genes orchestrating limb regeneration are also present in amniotes, including humans, these genes are not expressed after injury. In amniotes a key problem for regeneration derives from the efficient immune system, largely deficient in anamniotes. As a consequence, wounds and appendage loss tend to scar instead of regenerating. Efforts of regenerative medicine in the attempt to induce the regrowth of limbs in humans must produce outgrowths with high hydration and hyaluronate content in order to create the immune-suppressed conditions similar to those present during development. The induced blastema must be manipulated for long periods of time in order to maintain the same regions present during limb development, an apical epidermal ridge and a polarizing region that forms gradients of expression of Wnt, Shh, FGF, BMP and Hox-genes. Pharmacological treatments to direct the regenerating limb into normal growth without risk of inducing abnormal or tumorigenic growth must be monitored during the course of the regeneration process - a medical treatment lasting years to fully regain the size of the lost appendage.

Aging And Body Repair

Aging is associated with a decline in the ability of the body to repair itself, including tissue and (at least partial) body part regeneration, with mechanisms that may include: “aging, increased Wnt signaling, NF-κB and tumor suppressor activity, and loss of positional information hampers regeneration.” This will enable, as the authors also state “safely activate endogenous regeneration in the elderly, and to generate a regeneration-permissive environment for cell therapies.”  Abstract:

Aging is associated with a significant decline of tissue repair and regeneration, ultimately resulting in tissue dysfunction, multimorbidity, and death. Salamanders possess remarkable regenerative abilities and have been studied with the prospect of inducing regeneration in humans and counteracting regenerative decline with aging. However, epimorphic regeneration, the full replacement of amputated structures, also occurs in mammals. One of the best studied models is digit tip regeneration, which is described for mice, and occurs in humans in a comparable manner. To accomplish regeneration, the amputated digit tip has to undergo three interdependent, overlapping steps: (i) wound healing without formation of a scar; (ii) formation of a blastema, a highly proliferative cell mass; and (iii) spatiotemporally regulated differentiation to generate a pattern similar to the original structure. Aging likely interferes with each of these steps. In this article, we provide an overview of the critical signaling pathways for regeneration, as revealed by investigating mammalian digit regeneration, the possible impact of aging on these pathways, and approaches to induce regeneration in the elderly. We hypothesize that with aging, increased Wnt signaling, NF-κB and tumor suppressor activity, and loss of positional information hampers regeneration. Knowledge about the impact of aging on regenerative mechanisms will enable us to safely activate endogenous regeneration in the elderly, and to generate a regeneration-permissive environment for cell therapies.