Abstract
Several abnormalities have been reported in the peripheral blood mononuclear cells of keloid-forming patients and particularly in the monocyte cell fraction. The goal of this in vitro study was to determine whether monocytes from keloid-prone patients contribute to the keloid phenotype in early developing keloids, and whether monocyte differentiation is affected by the keloid microenvironment. Therefore, keloid-derived keratinocytes and fibroblasts were used to reconstruct a full thickness, human, in vitro keloid scar model. The reconstructed keloid was co-cultured with monocytes from keloid-forming patients and compared to reconstructed normal skin co-cultured with monocytes from non-keloid-formers. The reconstructed keloid showed increased contraction, dermal thickness (trend) and α-SMA+ staining, but co-culture with monocytes did not further enhance the keloid phenotype. After 2-week culture, all monocytes switched from a CD11chigh/CD14high/CD68low to a CD11chigh/CD14low/CD68high phenotype. However, only monocytes co-cultured with either reconstructed keloid scar or normal skin models skewed towards the more fibrotic M2-macrophage phenotype. There was negligible fibroblast and fibrocyte differentiation in mono- and co-cultured monocytes. These results indicate that monocytes differentiate into M2 macrophages when in the vicinity of early regenerating and repairing tissue, independent of whether the individual is prone to normal or keloid scar formation.
Highlights
Keloid scar formation remains a poorly understood complication of abnormal wound healing [27, 30, 32], and further research into its pathogenesis is severely hampered by the lack of a suitable in vivo-like scar model
We developed an immunocompetent keloid and normal skin model by reconstructing skin models in the presence of monocytes derived from the peripheral blood of individuals with and without a history of keloid scar formation, respectively
Monocytes co-cultured with the reconstructed keloid scar as well as reconstructed normal skin skewed towards the M2 macrophage-like phenotype typically involved in tissue remodelling [8] and associated with fibrosis [24, 25], by becoming CD68+/CD206+ [34]
Summary
Keloid scar formation remains a poorly understood complication of abnormal wound healing [27, 30, 32], and further research into its pathogenesis is severely hampered by the lack of a suitable in vivo-like scar model. The differences we observed between our normal skin and keloid scar models were not of the order of magnitude one would expect from such a decidedly abnormal type of scar such as a keloid. This suggests that the intrinsic abnormalities associated with keloid keratinocytes and keloid fibroblasts are not the only causative agents involved in keloid formation. Given the fact that normal wound healing processes involve many different types of cells and a myriad of secreted wound healing factors, it is very likely that keloid scar formation would require more than abnormal keratinocytes and fibroblasts
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