Targeted apoptosis of myofibroblasts by elesclomol inhibits hypertrophic scar formation

Abstract

Background: Hypertrophic scar (HS) is characterized by the increased proliferation and decreased apoptosis of myofibroblasts. Myofibroblasts, the main effector cells for dermal fibrosis, develop from normal fibroblasts. Thus, the stimulation of myofibroblast apoptosis is a possible treatment for HS. We aimed to explore that whether over-activated myofibroblasts can be targeted for apoptosis by anticancer drug elesclomol. Methods: 4 0 ,6-diamidino-2-phenylindole staining, flow cytometry, western blotting, collagen gel contraction and immunofluorescence assays were applied to demonstrate the proapoptotic effect of elesclomol in scar derived myofibroblasts and TGF-b1 induced myofibroblasts. The therapeutic potential of elesclomol was investigated by establishing rabbit ear hypertrophic scar models. Findings: Both 4 0 ,6-diamidino-2-phenylindole staining and flow cytometry indicated that elesclomol targets myofibroblasts in vitro. Collagen gel contraction assay showed that elesclomol inhibited myofibroblast contractility. Flow cytometry and western blot analysis revealed that elesclomol resulted in excessive intracellular levels of reactive oxygen species(ROS), and caspase-3 and cytochrome c proteins. Moreover, compared with the control group, the elesclomol group had a significantly lower scar elevation index in vivo. Immunofluorescence assays for TUNEL and a-smooth muscle actin indicated that elesclomol treatment increased the number of apoptotic myofibroblasts. Interpretation: The above results indicate that elesclomol exerted a significant inhibitory effect on HS formation via targeted myofibroblast apoptosis associated with increased oxidative stress. Thus, elesclomol is a promising candidate drug for the treatment of myofibroblast-related diseases such as HS.

ABT-263 Reduces Hypertrophic Scars by Targeting Apoptosis of Myofibroblasts

“…The gross appearance of each wound was monitored every week by two scar specialists, and the thickness of the scar was calculated by ultrasound (MyLabOne, Italy). SEI (scar elevation index) provided an accurate parameter to assess scar formation and was calculated as follows: SEI = H/H 0 , where H represents the length between the highest point to the surfaces of cartilage in scar, and H 0 represents the length from the epithelium to the surface of the cartilage in adjacent normal skin ( Zhang et al, 2015 ; Lin et al, 2019 ; Feng et al, 2020 ).…”

Emerging Role of IL-10 in Hypertrophic Scars

“…Myofibroblasts also induce changes to the macrophage phenotype by producing TGF-β, thereby affecting ECM degradation. Ultimately, the survival, apoptosis, and aging of myofibroblasts can directly affect scar formation ( 14 ). Similar to TGF-β, other inflammatory cytokines, such as interleukins (ILs) IL-13, IL-4, and tumor necrosis factor α (TNF-α), can indirectly regulate fibrosis, which involves macrophages as the major inflammatory cells ( 15 ).…”

Histology Scoring System for Murine Cutaneous Wounds

“…The SEI, which is based on the dermal thickness in the wound area compared to uninjured healthy skin is a relatively simple parameter to indicate whether excessive scarring has occurred. This is sufficient as a parameter in an overall histological scoring system and has been reported in the literature [32][33][34][35]. More detailed analysis that include collagen fiber orientation and/or skin elasticity is, however, required for investigations focused specifically on collagenous scarring and its characteristics [36].…”