TGF-β is involved in a number of processes in wound healing: inflammation, stimulating angiogenesis, fibroblast proliferation, collagen synthesis and deposition and remodelling of the new extracellular matrix. Interestingly chronic, non-healing wounds often show a loss of TGF-β1 signaling.[13]
There are several options for the treatment of cutaneous wounds, which are grouped into three categories:[5]
- Dressings
- Topical gels
- Engineered skin
The process of wound healing has to be well orchestrated and disruption of this process, for instance due to the infection of the healing wound, can lead to a failure of wound healing or excessive scar formation.
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| Figure 1. Source(s): Stem Cell Therapy for Dermal Wound Healing[10] / Food List [11] |
Wound Healing Phases
Wound healing progresses in three phases:
- Inflammation phase
- Monocytes/macrophages start phagocytosis in order to remove debris and secret a large number of potent tissue growth factors, thereby activating keratinocytes, fibroblasts, endothelial cells.
- In monocyte/macrophage-deficient animals, it exhibits delayed angiogenesis and re-epithelialization.[9]
- Angiogenesis phase
- The production of angiogenic growth factors and various cytokines by macrophages promotes the formation of new blood vessels.
- Newly formed vessels not only allow leukocyte migration into the wound, but also provide the nutrients and oxygen required to develop the granulation tissues.
- Tissue remodeling phase
- Wound contraction and extra-cellular matrix reorganization occurs over several months, transiting granulation tissues into mature scar.
Overall, efficient wound healing results from a sufficient supply of growth factors and adequate circulation of oxygenated blood.
Regulatory T-cells (FOXP3+ Tregs)
Regulatory T-cells (Tregs) reside in tissues where they control inflammation and mediate tissue-specific functions. The skin of mice and humans contain a large number of Tregs.
Although previously thought to be a relatively homogenous population, it has become increasingly accepted that Tregs residing in peripheral tissues possess tissue-specific functions.
During wound healing, studies have shown that Tregs exhibit a dual function:
- Damage-limiting
- Tregs rapidly accumulate at sites of injury and keep local immune responses under control so that no excessive immune responses develop that could cause additional damage
- Damage-resolving
- Tregs at the site of injury release growth factors, such as Amphiregulin (AREG), that directly contribute to the differentiation of cells within the injured tissues, in this way contributing to wound healing and the restoration of tissue homeostasis.
However, a number of different findings suggest that, on a molecular level, the two functions might not easily be separable.
Roles of Tregs in Wound Healing
In studies, it shows that Tregs in wounded skin facilitate cutaneous wound healing by:[1-3]
- Inducing expression of the epidermal growth factor receptor (EGFR)
- In wound healing EGFR plays an important role in re-epithelialization and dermal maturation.
- Activation of EGFR leads to a number of biological responses, including migration, proliferation, cytoprotection, cellular differentiation, and apoptosis.
- Topical use of recombinant human EGF has been shown to increase re-epithelialization and enhance wound healing.[6]
- Tregs utilize the EGFR pathway to mediate these effects
- The EGFR pathway plays a major role in skin wound healing through stimulating epidermal and dermal regeneration.[29]
- Releasing EGF-like growth factor Amphiregulin (AREG)
- Scientists have speculated that one critical function of AREG is to locally activate latent TGF-β.[3,4] Thus, via this local release of TGF-β, AREG may contribute to both the local suppression of inflammation as well as to the local differentiation of tissue stem cells, and in this way to the process of wound healing and restoration of tissue homeostasis (see Figure 2).
- Reducing IFNγ production and pro-inflammatory macrophage accumulation (in later healing phase)
- The importance of IFNγ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects.
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| Figure 2. Dual function of regulatory T-cells during wound healing. |
References
- Regulatory T cells Facilitate Cutaneous Wound Healing
- Bodnar RJ. Epidermal Growth Factor and Epidermal Growth Factor Receptor: The Yin and Yang in the Treatment of Cutaneous Wounds and Cancer. Adv Wound Care. 2013;2:24–29.
- Immune- and non-immune-mediated roles of regulatory T-cells during wound healing
- Minutti C, Modak R, Macdonald F, Li F, Smyth D, Dorward D et al. A macrophagepericyte axis directs tissue restoration via Amphiregulin-induced TGFb activation. Immunity 2019; 50:645–54.
- Fan K. Tang J. Escandon J. Kirsner RS. State of the art in topical wound-healing products. Plast Reconstr Surg. 2011;127(Suppl 1):44S.
- Berlanga-Acosta J. Gavilondo-Cowley J. Lopez-Saura P. Gonzalez-Lopez T. Castro-Santana MD. Lopez-Mola E, et al. Epidermal growth factor in clinical practice—a review of its biological actions, clinical indications and safety implications. Int Wound J. 2009;6:331.
- Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341:738–746.
- Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003;83:835–870.
- Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78:71–100.
- Stem Cell Therapy for Dermal Wound Healing
- The Science of How the Body Heals Itself with William Li, M.D.
- Researchers find drug that enables healing without scarring
- The role of the TGF-β family in wound healing, burns and scarring: a review
- Klass BR, Grobbelaar AO, Rolfe KJ. Transforming growth factor beta 1 signalling, wound healing and epiair: a multifunctional cytokine with clinical implications for wound repair, a delicate balance. Postgrad Med J. 2009;85:9–14.
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