Macrophages are necessary for skin regeneration during tissue expansion

Abstract

BackgroundTissue expansion is a procedure that promotes skin regeneration by mechanical stretch. During the stress and relaxation cycle, the skin undergoes a repeated microtrauma which triggers an immune response leading to the recruitment of macrophages to repair the damaged tissue. Macrophages have been found to be necessary for tissue repair and wound healing, but their effects on skin regeneration during mechanical stretch remain unclear.MethodsThe dynamic changes of macrophages in the rat skin tissues undergoing expansion were quantitatively determined by immunohistochemistry staining. The area of the expanded skin, skin thickness, dermal collagen density, cell proliferation and tissue vascularization were examined to determine the effects of macrophages on the expanding skin. The phenotypes of macrophages and the growth factors related to skin regeneration were also examined to evaluate the underlying mechanisms for the involvement of macrophages in skin regeneration. As a comparison, the tissue samples of expanding skin in which the macrophages were depleted by topically utilizing clodronate liposomes were also evaluated.ResultsThe number of skin macrophages in skin maintained in the high level during the skin expansion compared to non-expanded skin. We found that a switch from an M1- to M2-dominant response during tissue expansion. After the macrophages were depleted, the skin regeneration was inhibited, as evidenced by a smaller expansion area, thinner skin layers and decreased cell proliferation rate, collagen synthesis and, skin vascularization. The secretion of epidermal growth factor (EGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) were decreased when macrophages were depleted.ConclusionsOur findings suggest that macrophages are necessary for skin regeneration during tissue expansion. Modulating inflammation may provide a key therapeutic strategy to promote skin growth under mechanical strain.Electronic supplementary materialThe online version of this article (10.1186/s12967-019-1780-z) contains supplementary material, which is available to authorized users.

Transcriptomic analysis reveals dynamic molecular changes in skin induced by mechanical forces secondary to tissue expansion

“…Simultaneously, as we previously reported, from 1 h to 3 days of TE, we observed a gradual increase in keratinocyte proliferation in the stretched skin 27 . Our results are in agreement with studies showing the importance of an immune response in stretch-induced skin regeneration in rats 46 and in stimulating excessive keratinocyte proliferation in psoriasis 47 . Therefore, our results confirm that a controlled, moderate inflammatory response activated by mechanical forces is an important factor in stimulating keratinocyte proliferation and initiation of skin regeneration.…”

Senescent cells and macrophages: key players for regeneration?

“…Moreover, the depletion of macrophages in the early stages of cutaneous wound repair delayed re-epithelialization, leading to reduced scar formation, while depletion in the mid-phase of new tissue formation led to an impaired wound closure. Crucially, depletion in the late stages of repair had no effect on the overall repair response, suggesting that macrophages play different and distinct functions during the phases of skin repair [ 54 , 114 ] ( figure 2 ). Ultimately, studies such as these demonstrate that macrophages exert different and distinct functions at different stages of the repair or regeneration processes; a discovery that is crucial if we are to therapeutically manipulate macrophage function in the future to improve organ regeneration.…”

Celecoxib alleviates pathological cardiac hypertrophy and fibrosis via M1-like macrophage infiltration in neonatal mice

“…Consequently, macrophages enhance collagen deposition and fibrosis to scar formation in non-regenerating mice ( Simoes et al., 2020 ). Macrophages also secrete cytokines (TNF-α, IL-1β, and IL-10), matrix metallopeptidase, chemokines (CCL2, CCR7, CXCL9, and CXCL10), and growth factors (transforming growth factor [TGF-β], vascular endothelial growth factor, epidermal growth factor, and fibroblast growth factor) to promote or inhibit wound healing ( Braga et al., 2015 ; Ding et al., 2019 ; Mantovani et al., 2004 ). Interestingly, COX-2 regulates pro-inflammatory and anti-inflammatory responses to modulate tissue repair ( Kaushik and Das, 2019 ; Li et al., 2018 ).…”