单细胞测序揭示YAP/TAZ敲低协同抑制系统性硬化症皮肤和肺纤维化的机制

Abstract

Systemic sclerosis (SSc) is a heterogeneous disease with skin fibrosis. Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) is associated with fibrotic response. This work attempted to determine the precise mechanism of YAP/TAZ in SSc. Single-cell sequencing (scRNA-seq) was used to analyse the differential gene expression between SSc patients and healthy volunteers, showing that the YAP/TAZ signalling pathway was enriched in the fibroblasts of SSc patients. Subsequently, enzyme-linked immunosorbent assay and immunohistochemical analyses were conducted to examine the levels of YAP and TAZ in mild and severe SSc patients. YAP and TAZ were highly expressed in the serum and skin tissues of mild and severe SSc patients, especially severe SSc patients. Additionally, an SSc mouse model was induced by bleomycin , and the impacts of YAP/TAZ knockdown on the pathological changes in skin and lung tissues were detected by haematoxylin and eosin staining and Masson staining. Knockdown of YAP and TAZ inhibited α-SMA mRNA and protein expression in skin and lung tissues of SSc mice. Inhibition of YAP and TAZ reduced skin inflammation and thickness and repressed lung inflammation and fibrosis in SSc mice. Importantly, knockdown of YAP and TAZ synergistically inhibited inflammation and fibrosis in skin and lung tissues in SSc mice. In conclusion, this work demonstrated that knockdown of YAP and TAZ exerted a synergistic effect on alleviating SSc in mice. Thus, this work suggests that YAP/TAZ is a potential target for SSc treatment.