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Single-cell RNA-seq reveals lineage-specific regulatory changes of fibroblasts and vascular endothelial cells in keloid
bioRxiv - Pathology Pub Date : 2020-05-15 , DOI: 10.1101/2020.05.14.095323
Xuanyu Liu , Wen Chen , Meng Yuan , Zhujun Li , Tian Meng , Jie Chen , Nanze Yu , Xiao Long , Zhou Zhou

Keloid is a benign dermal fibrotic disorder with some features similar to malignant tumors such as hyper-proliferation, apoptosis resistance and invasion. keloid remains a therapeutic challenge in terms of high recurrence rate and lack of satisfactory medical therapies, which is partially due to the incomplete understanding of keloid pathogenesis. A thorough understanding of the cellular and molecular mechanism of keloid pathogenesis would facilitate the development of novel medical therapies for this disease. Here, we performed single-cell RNA-seq of 28,064 cells from keloid skin tissue and adjacent relatively normal tissue. Unbiased clustering revealed substantial cellular heterogeneity of the keloid tissue, which included 21 cell clusters assigned to 11 cell lineages. Differential proportion analysis revealed significant expansion for fibroblasts and vascular endothelial cells in keloid compared with control, reflecting their strong association with keloid pathogenesis. We then identified five previously unrecognized subpopulations of keloid fibroblasts and four subpopulations of vascular endothelial cells. Comparative analyses were performed to identify the dysregulated pathways, regulators and ligand-receptor interactions for keloid fibroblasts and vascular endothelial cells, the two important cell lineages in keloid pathogenesis and for medical interventions. Our results highlight the roles of transforming growth factor beta and Eph-ephrin signaling pathways in both the aberrant fibrogenesis and angiogenesis of keloid. Critical regulators and signaling receptors implicated in the fibrogenesis of other fibrotic disorders, such as TWIST1, FOXO3, SMAD3 and EPHB2, ranked at the top in the regulatory network of keloid fibroblasts. In addition, tumor-related pathways such as negative regulation of PTEN transcription were found to be activated in keloid fibroblasts and vascular endothelial cells, which may be responsible for the malignant features of keloid. Our study put novel insights into the pathogenesis of keloid, and provided potential targets for medical therapies. Our dataset also constitutes a valuable resource for further investigations of the mechanism of keloid pathogenesis.

中文翻译:

单细胞RNA-seq显示瘢痕loid中成纤维细胞和血管内皮细胞的谱系特异性调节变化

瘢痕loid是一种良性皮肤纤维化疾病,具有类似于恶性肿瘤的某些特征,例如过度增殖,抗凋亡和侵袭。就高复发率和缺乏令人满意的药物疗法而言,瘢痕loid仍然是治疗上的挑战,部分原因是对瘢痕loid发病机理的不完全了解。对瘢痕loid发病机理的细胞和分子机制的透彻了解将促进针对该疾病的新型药物治疗的发展。在这里,我们从瘢痕loid皮肤组织和邻近的相对正常组织中进行了28,064个细胞的单细胞RNA测序。无偏聚簇揭示了瘢痕substantial组织的实质性细胞异质性,其中包括分配给11个细胞谱系的21个细胞簇。差异比例分析显示与对照相比,瘢痕loid中成纤维细胞和血管内皮细胞显着扩增,反映出它们与瘢痕loid发病机理密切相关。然后,我们确定了瘢痕loid成纤维细胞的五个以前无法识别的亚群和血管内皮细胞的四个亚群。进行了比较分析,以确定瘢痕loid成纤维细胞和血管内皮细胞,瘢痕loid发病机理中的两个重要细胞谱系以及医学干预的失调途径,调节剂和配体-受体相互作用。我们的研究结果突显了转化生长因子β和Eph-ephrin信号通路在瘢痕loid异常纤维化和血管生成中的作用。与其他纤维化疾病(例如TWIST1,FOXO3,SMAD3和EPHB2)的纤维发生有关的关键调节剂和信号受体在瘢痕loid成纤维细胞的调节网络中排名最高。此外,发现在瘢痕loid成纤维细胞和血管内皮细胞中激活了与肿瘤相关的途径,例如PTEN转录的负调控,这可能是瘢痕loid的恶性特征。我们的研究为瘢痕loid的发病机理提供了新颖的见解,并为药物治疗提供了潜在的靶标。我们的数据集也构成了进一步研究瘢痕loid发病机理的宝贵资源。发现在瘢痕loid成纤维细胞和血管内皮细胞中激活了与肿瘤相关的途径,例如PTEN转录的负调控,这可能是瘢痕loid的恶性特征。我们的研究为瘢痕loid的发病机理提供了新颖的见解,并为药物治疗提供了潜在的靶标。我们的数据集也构成了进一步研究瘢痕loid发病机理的宝贵资源。发现在瘢痕loid成纤维细胞和血管内皮细胞中激活了与肿瘤相关的途径,例如PTEN转录的负调控,这可能是瘢痕loid的恶性特征。我们的研究为瘢痕loid的发病机理提供了新颖的见解,并为药物治疗提供了潜在的靶标。我们的数据集也构成了进一步研究瘢痕path发病机理的宝贵资源。
更新日期:2020-05-15
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