Systems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis

Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by excessive production and accumulation of extracellular matrix, leading to fibrosis of skin and other internal organs. However, the main cellular participants in SSc skin fibrosis remain incompletely understood. Here using differentiation trajectories at a single cell level, we demonstrate a dual source of extracellular matrix deposition in SSc skin from both myofibroblasts and endothelial-to-mesenchymal-transitioning cells (EndoMT). We further define a central role of Hippo pathway effectors in differentiation and homeostasis of myofibroblast and EndoMT, respectively, and show that myofibroblasts and EndoMTs act as central communication hubs that drive key pro-fibrotic signaling pathways in SSc. Together, our data help characterize myofibroblast differentiation and EndoMT phenotypes in SSc skin, and hint that modulation of the Hippo pathway may contribute in reversing the pro-fibrotic phenotypes in myofibroblasts and EndoMTs. Overall design: Single cell RNA sequencing and spatial sequencing on human scleroderma skin tissues

系统性硬化症（Systemic sclerosis, SSc）是一类极具破坏性的自身免疫性疾病，其特征为细胞外基质过度产生并蓄积，最终导致皮肤及其他内脏器官发生纤维化。然而，目前学界对系统性硬化症皮肤纤维化的核心细胞参与者仍未完全明确。本研究通过单细胞水平的分化轨迹分析，证实系统性硬化症皮肤中的细胞外基质沉积源自肌成纤维细胞（myofibroblasts）与内皮细胞向间充质转化细胞（endothelial-to-mesenchymal-transitioning cells, EndoMT）两大来源。本研究进一步明确了Hippo通路（Hippo pathway）效应分子分别在肌成纤维细胞及内皮细胞向间充质转化细胞的分化与稳态维持中的核心调控作用，并证实两类细胞可作为核心通讯枢纽，驱动系统性硬化症中关键的促纤维化信号通路。综上，本研究数据有助于阐明系统性硬化症皮肤中肌成纤维细胞分化与内皮细胞向间充质转化细胞的表型特征，并提示调控Hippo通路或可逆转两类细胞的促纤维化表型。实验设计概况：对人类硬皮病皮肤组织开展单细胞RNA测序与空间转录组测序。