Department of Dermatology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea; Samsung Genomic Institute, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea.
Department of Dermatology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea.
J Invest Dermatol. 2022 Aug;142(8):2128-2139.e11. doi: 10.1016/j.jid.2022.01.017. Epub 2022 Feb 4.
Studies on the etiopathogenesis of keloids mostly have focused on fibroblasts and their dysfunction. In this study, two cutting-edge technologies, single-cell RNA sequencing and spatial transcriptomics, were applied to uncover the underlying pathophysiology of keloids. Keloid tissue samples and normal skin control data were analyzed as well as those of patient-matched keloid and normal mature scar. Single-cell RNA sequencing revealed cellular heterogenicity such as fibroblasts, endothelial cells (ECs), and myofibroblasts within the keloids. Spatial transcriptomics results showed that disease-associated fibroblasts were enriched in the deeper keloid areas, mostly located around the spots with endothelial transcripts. Mesenchymal activation was observed in keloid ECs, characterized by dysregulation of TGF-β/SMAD signaling. Colocalization of mesenchymal and vascular markers through multiplex immunofluorescence suggested mesenchymal activation of keloid ECs. Cell‒cell interaction analysis identified a significant network between keloid fibroblasts and ECs, and this cellular crosstalk was supported by colocalization analysis of spatial transcriptomics. This study depicted the cellular landscape of keloids at a single-cell resolution as well as the integration of single-cell and valuable spatial data of keloids using spatial transcriptomics and multiplex immunofluorescence technologies. Our findings suggested a potential role of fibrovascular communication and mesenchymal activation of ECs that might be involved in the keloid pathogenesis.
瘢痕疙瘩的病因学研究大多集中在成纤维细胞及其功能障碍上。在这项研究中，我们应用了两种前沿技术，单细胞 RNA 测序和空间转录组学，以揭示瘢痕疙瘩的潜在病理生理学。分析了瘢痕疙瘩组织样本和正常皮肤对照数据，以及患者匹配的瘢痕疙瘩和正常成熟瘢痕的数据。单细胞 RNA 测序揭示了瘢痕疙瘩内的细胞异质性，如成纤维细胞、内皮细胞（EC）和肌成纤维细胞。空间转录组学结果表明，与疾病相关的成纤维细胞在更深的瘢痕疙瘩区域富集，主要位于内皮转录本所在的部位。在瘢痕疙瘩 EC 中观察到间充质激活，其特征是 TGF-β/SMAD 信号通路失调。通过多重免疫荧光共定位显示了瘢痕疙瘩 EC 中的间充质激活。细胞间相互作用分析确定了瘢痕疙瘩成纤维细胞和 EC 之间存在显著的网络，这种细胞串扰得到了空间转录组学共定位分析的支持。本研究以单细胞分辨率描绘了瘢痕疙瘩的细胞景观，并通过空间转录组学和多重免疫荧光技术整合了瘢痕疙瘩的单细胞和有价值的空间数据。我们的研究结果表明，EC 的成纤维血管通讯和间充质激活可能在瘢痕疙瘩发病机制中发挥作用。
