Targeted inhibition of YAP/TAZ alters the biological behaviours of keloid fibroblasts

Abstract

Abnormal activation of fibroblasts plays a crucial role in keloid development. However, the mechanism of fibroblast activation remains to be determined. YAP/TAZ are key molecules in the Hippo signalling pathway that promote cell proliferation and inhibit apoptosis. Here, we show that keloid fibroblasts have higher levels of YAP/TAZ mRNA and proteins on primary culture. Targeted knockdown of endogenous YAP or TAZ significantly inhibited cell proliferation, reduced cell migration, induced cell apoptosis and down‐regulated collagen1a1 production by keloid fibroblasts. Moreover, we demonstrate that verteporfin, an inhibitor of YAP/TAZ, has similar but stronger inhibitory effects on fibroblasts compared to YAP/TAZ knockdown. Our study provides evidence that YAP/TAZ may be involved in the pathogenesis of keloids. Targeted inhibition of YAP/TAZ could change the biological behaviours of fibroblasts and can potentially be used as therapy for keloids.

Biomechanical Regulatory Factors and Therapeutic Targets in Keloid Fibrosis

“…Mechanical transduction of YAP/TAZ is mainly controlled by its subcellular localization because YAP/TAZ activation requires its accumulation in the nucleus ( Panciera et al, 2017 ). Gao et al (2022 ) study showed that increased nuclear YAP/TAZ staining was observed in keloid tissue fibroblasts compared with that in normal skin. Activation of YAP-TAZ in the nucleus leads to the expression of pro-fibrosis genes, increased α-SMA expression, and excessive matrix deposition ( Panciera et al, 2017 ).…”

“…Gao et al have significantly inhibited the proliferation of keloid fibroblasts, reduced cell migration, induced apoptosis, and down-regulated collagen I production by targeting low endogenous YAP or TAZ knockdown. YAP/TAZ inhibitor verteporfin has shown similar but stronger inhibitory effect on fibroblasts ( Gao et al, 2022 ).…”

Mechanotransduction in skin wound healing and scar formation: Potential therapeutic targets for controlling hypertrophic scarring

“…Besides, conditional YAP/TAZ knockout in the dermis or application of interfering RNAs to the wound site leads to delayed wound closure due to decreased cell proliferation, indicating that YAP/TAZ promotes wound healing (79). Gao et al found that human keloid fibroblasts have higher YAP/TAZ mRNA and protein levels than normal skin tissue on primary culture (80). Additionally, knockdown of YAP/TAZ with siRNA interference technique or usage of verteporfin significantly reduced proliferation, migration, survival and collagen production of human keloid fibroblasts (Figure 4C), indicating that YAP/TAZ inhibitor had potential clinical significance for HTS management (80).…”

“…(b) Quantification of wound healing rates at each stage in control versus dKO animals ( 79 ). (C) (a) (Left) Human keloid fibroblasts (HKFs) had increased metabolic activity demonstrated by high RLU value than human normal fibroblasts (HNFs) (n = 3) ( 80 ). (Right) Knockdown of YAP or TAZ and verteporfin treatment decreased cell metabolic activity in both HNFs and HKFs (n = 3) ( 80 ).…”

“…(C) (a) (Left) Human keloid fibroblasts (HKFs) had increased metabolic activity demonstrated by high RLU value than human normal fibroblasts (HNFs) (n = 3) ( 80 ). (Right) Knockdown of YAP or TAZ and verteporfin treatment decreased cell metabolic activity in both HNFs and HKFs (n = 3) ( 80 ). (b) (Left) Quantification of cell migration from 3 separate experiments after knockdown of YAP or TAZ in both HNFs and HKFs ( 80 ).…”