Wnt signaling and injury repair

Abstract

Wnt signaling is activated by wounding and participates in every subsequent stage of the healing process from the control of inflammation and programmed cell death, to the mobilization of stem cell reservoirs within the wound site. In this review we summarize recent data elucidating the roles that the Wnt pathway plays in the injury repair process. These data provide a foundation for potential Wnt-based therapeutic strategies aimed at stimulating tissue regeneration.

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 poor repair mechanism resulting in inadequate tissue replacement and scarring. A common goal of doctors and scientists is to develop biologic therapies to increase mammalian regenerative potential.

Figure 2.

Wnt signaling is activated in response to injury. Damage in most tissues up-regulates Wnt signaling transiently at the injury site. While too much Wnt signaling has been shown to be deleterious, a number of studies have shown that the exogenous addition of Wnt signaling stimulates healing in a number of different injuries, including bone fractures, retinal damage, skin wounding, and myocardial infarction. (Wnt response seen here in blue, by X-gal staining of murine Axin^LacZ/+ tissue.) (Heart images are thanks to Professor Joseph Wu.)

Figure 3.

Wnt signaling drives tissue repair. In both repair and regeneration, wound healing is characterized by three main phases. During the inflammatory phase there is an influx of inflammatory cells and local Wnt signaling begins to increase. During the proliferative phase a scab (eschar) is formed and the wound is reepithelialized. This phase includes an increased local Wnt response, extracellular matrix deposition, angiogenesis, and the recruitment and proliferation of multiple cell types including stem cells, keratinocytes, and fibroblasts. The third phase, the maturation and remodeling phase, is characterized by extensive extracellular matrix remodeling. Whereas repair leads to scarring, or functionally inadequate tissue, increased Wnt signaling during regeneration leads to a reduced inflammatory response, increased angiogenesis, increased cellular proliferation and recruitment, as well as differences in matrix composition, leading to the complete reconstruction of the original tissue architecture. (Increase in blue color represents an increase in Wnt signaling.)

Figure 4.

Does chronic injury lead to prolonged Wnt signaling and cancer? Injury results in a local increase in Wnt signaling and chronic injury leads to cancer. Many cancers also have up-regulated Wnt signaling. The Wnt pathway is best known to promote proliferation; an intriguing possibility is that chronic injury may induce a prolonged Wnt response leading to uncontrolled cell proliferation and cancer. In the lungs, cigarette smokers inflict chronic injury to the trachea and lung tissue, which may result in lung cancer. Relating to the skin, prolonged UV exposure leads to chronic inflammation of the dermis, which may result in skin cancer. In the liver, chronic alcohol consumption subjects the tissue to constant damage, which may lead to liver cancer.

Figure 5.

Harnessing Wnt signaling for therapeutic applications in injury repair. There are many biological ways to activate or repress the Wnt signaling pathway; these may be therapeutic options for increasing a healing response or reducing uncontrolled proliferation. The use of small molecules, microRNAs, genetically modified cells, as well as ligands and inhibitors, are all potential future therapeutics for both activating and repressing the Wnt signaling pathway.