Wnt Signaling and Injury Repair

The Oxford English Dictionary’s definition of repair is to “restore to good or proper condition by replacing or fixing parts.” In contrast, regeneration is the process of complete renewal, characterized by a full restoration of form and function. Why do some organisms regenerate tissues after injury, while others do not? And is it possible to induce regeneration in cases where repair is the norm? In this article we discuss some of the recent discoveries that have been made by investigators seeking to understand these differences, and how they have used this information to develop therapeutic strategies aimed at stimulating a regenerative response to acute injury. The “reproduction of lost parts” has long been a subject of intense curiosity. In the 18th century the Swiss naturalist Abraham Trembley demonstrated that when the Cnidarian polyp Hydra was divided into small fragments, each piece “grew again into perfect hydrae” (Trembley 1744). The Scottish biologist and mathematician D’Arcy Thompson was fascinated by these early observations, and wrote that “the ability of an animal to regenerate lost parts [had] excited the interest of crowned heads…ambassadors, and state-couriers, who carried it through Europe” (Thompson 1884). Some years later the Vice President of the British Medical Association voiced a similar interest and wrote, “In these days of strife and stress, when fire and water play havoc with men’s lives and limbs, limb regeneration…would be of inestimable value.” Despite the fact that 238 years have elapsed since those initial observations, our curiosity about regeneration—and the possibility that we could harness this regenerative potential to aid in the healing of our own tissues—has not waned. Our own regenerative capacities are remarkably limited. Early observers (Dinsmore 1992) who were interested in distinguishing “repair” from “regeneration” recognized that animals did not respond uniformly to an act of injury. In some cases, adult animals mount an injury response that results in the complete regeneration of the damaged tissue or organ; the appendage of the aquatic axolotl or the fins of a zebrafish are excellent examples (see Fig. 1) (Poss et al. 2000; Straube et al. 2004; Kawakami et al. 2006; Stewart et al. 2009; Satoh et al. 2010). In other cases, the same tissue or organ in a different species had a very limited regenerative response; for example, reptiles seem to lack this regenerative response, at least in their limbs (Galis et al. 2003), but most species retain the ability to regenerate their tails (McLean and Vickaryous 2011). In contrast, most mammalian tissues respond to injury by generating scar tissue (Harty et al. 2003), which is composed of granulation and fibrous tissues that are poorly organized and lack functionality. Figure 1. Regenerative capacity across species. The ability to regenerate tissues varies across species. Planarians can regenerate their entire body from a single fragment, fish and salamanders can regenerate their fins and limbs, while mammals have a relatively ... One might interpret these observations to mean that an animal’s regenerative capacity is species specific, but this is an oversimplification; some animals begin life with a robust regenerative response that wanes over time. Tadpoles, for instance, exhibit a regenerative capacity only up to metamorphosis; after this developmental event frogs cannot regenerate an amputated limb (Kawakami et al. 2006; Yokoyama et al. 2011). Avian embryos have some ability to regenerate a damaged retina but this potential is lost by the time they are hatchlings (Fischer and Reh 2000; Fischer and Reh 2001). Mammalian embryos also appear to possess an early regenerative ability that erodes by birth (Rinkevich et al. 2011). Why is there such variation in regenerative ability of animals, and between different stages of postnatal life? Such a question has obvious clinical importance, because if we understood the key features that distinguish human healing from that of our amphibian ancestors, then we could potentially “jump-start” a similar regenerative program (Kragl et al. 2009). The observation that “simple animals” such as sponges and flatworms regenerate, whereas more complex organisms do not (Gurtner et al. 2008), is the basis for some theories that propose there is an association between regenerative capacity and tissue complexity (Sanchez Alvarado 2000). Many examples challenge this theory: the teleost, avian, and mammalian retinas exhibit very similar cellular architecture (Reh and Levine 1998). Yet fish can completely regenerate the neural retina (Cameron et al. 1999; Cameron 2000; Raymond et al. 2006), as can birds up to the hatchling stage (Coulombre and Coulombre 1965, 1970), but rodents and primates retain no such inherent regenerative capacity (Tropepe et al. 2000). Another theory proposes that regenerative abilities wane as the immune system matures (Mescher and Neff 2005, 2006). This theory is largely based on the observation that fetal wounds heal without scar formation, and this developmental period is associated with an immature immune system. A third theory posits that the loss of regenerative ability has evolved to curtail inappropriate cell division and malignant transformation (Gardiner 2005; Levesque et al. 2010). Perhaps most relevant to humans is the observation that across multiple species, regenerative capacity diminishes with age (reviewed in Silva and Conboy 2008; but see Eguchi et al. 2011 for conflicting data). The inference from these observations is that aging depletes a stem cell population from which new body parts arise. But this interpretation has been repeatedly challenged, which leaves open an obvious question: if they are not from a reservoir, where do the cells come from that reform the missing or damaged tissues? New data demonstrate that adult cells at the edges of the wound dedifferentiate to generate the new tissues (Straube et al. 2004; Kragl et al. 2009; Azevedo et al. 2011). This feature is not unique to mammals: The wound blastema of an axolotl is composed of tissue-specific progenitor cells that arise from the partial dedifferentiation of neurons, cartilage, and muscle (Kragl et al. 2009). What factors are responsible for stimulating this dedifferentiation of adult cells to a stemlike state or the recruitment of stem/progenitor cells into the regenerating tissue? Growing evidence implicates the Wnt pathway in this critical event. In the following sections we present a summation of recent data supporting a model whereby the act of injury triggers the endogenous Wnt pathway, and that this pathway activity is essential for subsequent healing. Most data suggest that within a damaged tissue, the endogenous Wnt signal activates tissue-resident stem cells, and these cells contribute to the repair and/or regeneration of the damaged tissue. Augmenting this endogenous Wnt signal appears to enhance the healing response; consequently, a number of approaches are being tested that aim to activate Wnt signaling in a local, transient manner to stimulate tissue regeneration in humans.