New insights into the roles of myofibroblasts and innervation during skin healing and innovative therapies to improve scar innervation.

During the resolution phase of normal skin wound healing, there is a considerable loss of various cell types, including myofibroblasts by apoptosis. Inappropriate delay of apoptosis, and thus increased survival of myofibroblasts, may be a factor leading to pathologies and excessive scarring. Considerable data now clearly suggest that innervation plays a major role in wound healing, including the modulation of fibroblast cellular activity. An abnormal level of neuromediators is implicated not only in the development of chronic wounds but also in excessive scar formation. Understanding interactions between neuromediators and myofibroblasts, allowing normal reinnervation and having adequate levels of neuromediators during the healing process are clearly important to avoid the appearance of pathological healing or fibrosis/scarring. The aim of this review was first to discuss the mechanisms leading to normal or excessive scarring and then to present the roles of innervation during wound healing. Finally, the latest therapeutic strategies to help wound repair and reinnervation after skin damage will be introduced. Advantages and limitations in the use of neuropeptides, growth factors and biomaterials will be discussed as well as the most recent studies on electrostimulation and the potential of targeting resident skin mesenchymal stem cells.

Biotechnological Management of Skin Burn Injuries: Challenges and Perspectives in Wound Healing and Sensory Recovery.

Many wound management protocols have been developed to improve wound healing after burn with the primordial aim to restore the barrier function of the skin and also provide a better esthetic outcome. Autologous skin grafts remain the gold standard in the treatment of skin burn, but this treatment has its limitation especially for patients presenting limited donor sites due to extensive burn areas. Deep burn injuries also alter the integrity of skin-sensitive innervation and have an impact on patient's quality of life by compromising perceptions of touch, temperature, and pain. Thus, patients can suffer from long-term disabilities ranging from cutaneous sensibility loss to chronic pain. The cellular mechanisms involved in skin reinnervation following injury are not elucidated yet. Depending on the depth of the burn, nerve sprouting can occur from the wound bed or the surrounding healthy tissue, but somehow this process fails to provide correct reinnervation of the wound during scarring. In addition, several clinical observations indicate that damage to the peripheral nervous system influences wound healing, resulting in delayed wound healing or chronic wounds, underlining the role of innervation and neuromediators for normal cutaneous tissue repair development. Promising tissue engineering strategies, including the use of biomaterials, skin substitutes, and stem cells, could provide novel alternative treatments in wound healing and help in improving patient's sensory recovery.

Effects of small-fiber neuropathy induced by resiniferatoxin on skin healing and axonal regrowth after burn.

BACKGROUND: Damage to the peripheral nervous system influences wound healing and, after a deep burn, imperfect cutaneous nerve regeneration occurs. A third-degree burn model was developed in rats combined with the use of resiniferatoxin (RTX), known to promote sensory neuropathy. METHODS: Rats were injected intraperitoneally either with RTX or vehicle. A mechanical sensory assay and the hot plate thermal sensory test were performed. The structural integrity of the sciatic nerve was assessed using transmission electron microcopy. After RTX injection, third-degree thermal burns were performed. Wound closure was monitored and samples were collected for histological analysis, immunohistochemistry and immunoblotting for neuronal markers. RESULTS: RTX promoted both mechanical and thermal hypoalgesia. This transient RTX-mediated sensory deficit occurred without damaging the integrity of nerve fibers and induced a significant depletion of neuropeptides in both neuronal bodies and intraepidermal nerve fibers. Although wound closure rates were similar in both groups, the kinetic of granulation tissue remodeling was delayed in the RTX group compared with control group. A significant reduction of the peripherin expression in the RTX group was observed indicating impaired axonal regrowth of small fibers within the wound. CONCLUSION: Our study confirms the important roles of innervation during skin healing and the defect of nerve regeneration after burn.

Skin innervation: important roles during normal and pathological cutaneous repair.

The skin is a highly sensitive organ. It is densely innervated with different types of sensory nerve endings, which discriminate between pain, temperature and touch. Autonomic nerve fibres which completely derive from sympathetic (cholinergic) neurons are also present. During all the phases of skin wound healing (inflammatory, proliferative and remodelling phases), neuromediators are involved. Several clinical observations indicate that damage to the peripheral nervous system influences wound healing, resulting in chronic wounds within the affected area. Patients with cutaneous sensory defects due to lepromatous leprosy, spinal cord injury and diabetic neuropathy develop ulcers that fail to heal. In addition, numerous experimental observations suggest that neurogenic stimuli profoundly affect wound repair after injury and that delayed wound healing is observed in animal models after surgical resection of cutaneous nerves. All these observations clearly suggest that innervation and neuromediators play a major role in wound healing. Interactions between neuromediators and different skin cells are certainly crucial in the healing process and ultimately the restoration of pain, temperature, and touch perceptions is a major challenge to solve in order to improve patients' quality of life.

Fibroblasts and myofibroblasts in wound healing.

(Myo)fibroblasts are key players for maintaining skin homeostasis and for orchestrating physiological tissue repair. (Myo)fibroblasts are embedded in a sophisticated extracellular matrix (ECM) that they secrete, and a complex and interactive dialogue exists between (myo)fibroblasts and their microenvironment. In addition to the secretion of the ECM, (myo)fibroblasts, by secreting matrix metalloproteinases and tissue inhibitors of metalloproteinases, are able to remodel this ECM. (Myo)fibroblasts and their microenvironment form an evolving network during tissue repair, with reciprocal actions leading to cell differentiation, proliferation, quiescence, or apoptosis, and actions on growth factor bioavailability by binding, sequestration, and activation. In addition, the (myo)fibroblast phenotype is regulated by mechanical stresses to which they are subjected and thus by mechanical signaling. In pathological situations (excessive scarring or fibrosis), or during aging, this dialogue between the (myo)fibroblasts and their microenvironment may be altered or disrupted, leading to repair defects or to injuries with damaged and/or cosmetic skin alterations such as wrinkle development. The intimate dialogue between the (myo)fibroblasts and their microenvironment therefore represents a fascinating domain that must be better understood in order not only to characterize new therapeutic targets and drugs able to prevent or treat pathological developments but also to interfere with skin alterations observed during normal aging or premature aging induced by a deleterious environment.