BACKGROUND: Hypertrophic scar (HS) formation is abnormal wound healing characterized by hyperactivation of fibroblasts and overproduction of extracellular matrix (ECM). To date, there are few satisfactory treatments.1 Mechanical stress has been shown to be a key etiological factor in HS formation while the underlying mechanism is not completely understood.2 Piezo1 was identified as the first mechanoresponsive ion channel in vertebrates,3 which has recently been emphasized on its mechanotransduction function in mechanics-related diseases.4 However, currently no research has focused on the biological function of Piezo1 in HS formation. Here we aim to assess the effect of stretch-induced Piezo1 activation on fibroblasts in vitro and HS formation in vivo.
MATERIALS AND METHODS: Human dermal fibroblasts were isolated and divided into 4 groups: control groups (with or without stretch) and GsMT × 4 (Piezo1 specific inhibitor) treated groups (with or without stretch). Cyclic mechanical stretch (10%, 24 hours, 0.5 Hz) was applied by the FlexcellFX-5000 system. Western blot was performed to assess the expression of myofibroblasts marker α-SMA and ECM components including collagen and fibronectin. Stretch-induced HS model on rat tail was established based on previous work5 and was treated with GsMT × 4 by intralesional injection. The scar hypertrophy evaluation was detected by H&E staining and Masson’s trichrome staining. α-SMA expression was confirmed by immunohistochemical staining.
RESULTS: The in vitro results showed that GsMT × 4-treated fibroblasts exhibited less expression of α-SMA, collagen I and fibronectin compared to nontreated fibroblasts after mechanical stretching. The in vivo results showed that GsMT × 4 treatment attenuated HS formation with reduced cross-sectional size of the scar (4.21 ± 1.08 versus 8.04 ± 1.55 mm2; P < 0.005) and decreased scar elevation index (1.69 ± 0.33 versus 3.08 ± 0.65; P < 0.005) compared with the control group. In addition, GsMT × 4-treated scars exhibited the downregulation of α-SMA expression compared with the control group (25.4% ± 1% versus 30.5% ± 2%; P < 0.005).
CONCLUSION: Mechanosensitive ion channel Piezo1 plays a significant role in fibroblasts activation and hypertrophic scarring under mechanical stretch. Piezo1 might be a novel therapeutic target for HS formation.
REFERENCES:
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