The Role of Serotonin during Skin Healing in Post-Thermal Injury

Abstract

Post-burn trauma significantly raises tissue serotonin concentration at the initial stages of injury, which leads us to investigate its possible role in post burn wound healing. Therefore, we planned this study to examine the role of serotonin in wound healing through in vitro and in vivo models of burn injuries. Results from in vitro analysis revealed that serotonin decreased apoptosis and increased cell survival significantly in human fibroblasts and neonatal keratinocytes. Cellular proliferation also increased significantly in both cell types. Moreover, serotonin stimulation significantly accelerated the cell migration, resulting in narrowing of the scratch zone in human neonatal keratinocytes and fibroblasts cultures. Whereas, fluoxetine (a selective serotonin reuptake inhibitor) and ketanserin (serotonin receptor 2A inhibitor) reversed these effects. Scald burn mice model (20% total body surface area) showed that endogenous serotonin improved wound healing process in control group, whereas fluoxetine and ketanserin treatments (disruptors of endogenous serotonin stimulation), resulted in poor reepithelization, bigger wound size and high alpha smooth muscle actin (α-SMA) count. All of these signs refer a prolonged differentiation state, which ultimately exhibits poor wound healing outcomes. Collectively, data showed that the endogenous serotonin pathway contributes to regulating the skin wound healing process. Hence, the results of this study signify the importance of serotonin as a potential therapeutic candidate for enhancing skin healing in burn patients.

Examining the contribution of surrounding intact skin during cutaneous healing

“…The dome model with perforations, which allowed for interactions with the neighboring skin, showed a larger granulation tissue formation and thicker dermal component, a higher number of myofibroblastic cells, and blood vessel formation. These findings suggest that the healing wound most likely receives signaling cues from the periwound to increase myofibroblastic differentiation, which assists in wound contraction for wound closure Shah & Amini-Nik, 2017;Sadiq et al 2018). Future studies are needed to determine whether this primary contribution of the surrounding skin is through direct myofibroblastic migration from the periwound or through the sprouting of blood vessels into the wound area.…”

“…We have previously described and validated a surgical device, a dome, that is used to prevent skin contraction while allowing the housing of a synthetic skin graft . When using skin substitutes on wounds in humans, cells and other factors from the surrounding intact skin and the wound bed infiltrate the skin substitute for wound closure (Poon et al 2009;Bielefeld et al 2011Bielefeld et al , 2013Sadiq et al 2018). However, the extent of contribution from the neighboring skin to wound healing is not yet clear.…”

Promotion of dermal regeneration using pullulan/gelatin porous skin substitute

“…These advantageous phenotypes in granulation tissue formation, cell infiltration, and degradation between PG2 and Control led us to investigate the cell types and the mechanism behind the enhanced degradation of the PG2 scaffold in the wound area. First, the formation of microvessels was studied, considering that angiogenesis and neovascularization are critical determining factors of the wound‐healing outcomes, especially for deep burn wounds (Jeschke et al, ; J. Li et al, ; Sadiq et al, ). Although no superior on increasing the number and size of newly formed microvessels was found in PG2‐treated wounds, these data still show a signal that PG2 is an ideal home that allows for neovascularization during dermis reconstitution in comparison with Control.…”

Stem cells derived from burned skin - The future of burn care

“…Nevertheless, the final phenotype of cells in granulation tissue milieu is mesenchymal and that suggests mesenchymal stem cell therapy as a promising treatment for the management of deficient or complex wounds. Various comparative preclinical studies using different animal models of skin healing support this notion [ 30 , 32 , [40] , [41] , [42] , [43] , [44] , [45] , [46] ]. However, none of the current stem cell sources (e.g., bone-marrow, adipose and umbilical cord) have yet to be clinically relevant due to inherent limitations such as lack of availability, ethical concerns, need for invasive extraction methods and the risk of immunologic rejection for allogenic sources.…”