Single-cell RNA-seq reveals fibroblast heterogeneity and increased mesenchymal fibroblasts in human skin fibrotic diseases (RNA-seq)

Skin fibrotic disease representsa major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix.Fibroblasts are found to be heterogeneous in multiple fibrotic diseases,but the fibroblast heterogeneity of skin fibrotic diseases remains unknown.In this study, we performed single-cell RNA-seq in keloid, a paradigm of skin fibrotic diseases, andnormal scardermis tissues.Our results indicate thatkeloid and normal scar fibroblasts could be divided into 4 subpopulations: secretory-papillary, secretory-reticular, mesenchymal and pro-inflammatory.The percentage of mesenchymal fibroblast subpopulationincreased significantly in keloid compared to normal scar. Interestingly, we also found increasing mesenchymal fibroblast subpopulation in scleroderma, another skin fibrotic disease.Function studies showed that the mesenchymal fibroblasts promoted collagen synthesis of the other fibroblasts in keloid partiallythrough secreting POSTN. These findings will help us understandskin fibroticpathogenesis in depth,and provided potential target cells for fibrotic diseases therapies.

皮肤纤维化疾病是全球重大医疗卫生负担，其特征为成纤维细胞过度增殖与细胞外基质过度蓄积。已有研究证实，多种纤维化疾病中的成纤维细胞存在异质性，但皮肤纤维化疾病相关的成纤维细胞异质性仍有待阐明。本研究针对皮肤纤维化疾病的典型模型——瘢痕疙瘩（keloid）以及正常瘢痕皮肤组织开展了单细胞RNA测序（single-cell RNA-seq）。结果显示，瘢痕疙瘩与正常瘢痕中的成纤维细胞可被分为4个亚群：分泌型乳头样、分泌型网状样、间充质型以及促炎型成纤维细胞。与正常瘢痕组织相比，瘢痕疙瘩中的间充质型成纤维细胞亚群占比显著升高。有趣的是，我们还在另一种皮肤纤维化疾病——硬皮病（scleroderma）中发现了间充质型成纤维细胞亚群占比的升高。功能研究证实，间充质型成纤维细胞可通过分泌骨膜蛋白（POSTN）部分促进瘢痕疙瘩中其他成纤维细胞的胶原合成。上述研究结果有助于我们深入阐明皮肤纤维化疾病的发病机制，并为纤维化疾病的治疗提供了潜在的靶细胞群。