Schwann cells contribute to keloid formation

Due to limited availability of proper models to study keloid development, the underlying pathomechanisms of this severe skin disease is still poorly understood. Here we performed single-cell sequencing of keloids and identified the occurrence of a so far unrecognized keloidal Schwann cell population, remaining in the scar tissue after wound healing. In contrast to normal skin, keloidal Schwann cells possess a repair-like phenotype and high cellular plasticity. Our data reveal that keloidal Schwann cells directly contribute to the formation of the extracellular matrix and affect M2 polarization of macrophages. Indeed, we show that macrophages in keloids predominantly display a M2 polarization and produce factors inhibiting Schwann cell differentiation. Our data suggest that this cross-talk contribute to the infinite growth of keloids and that targeting Schwann cells might represent a novel treatment option for keloids. Overall design: Single cell RNA-sequencing gene expression comparison of keloid tissue with normal scars and healthy skin. Single-cell suspension from four keloids, one normal skin and three normal scars were prepared using MACS Miltenyi Whole Skin Dissociation Kit (Miltenyi). Libraries were generated using Chromium Next GEM Single Cell 3´GEM, Library & Gel Bead Kit v3.1, Chromium Nexxt GEM Chip G Single Cell Kit and Single Index Kit T Set A (all 19x Genomics, Pleasanton, CA, USA). Data were analysed in combination with healthy skin data from Tabib et al. 2018 (PMID:29080679) as well as neurofibroma data from Brosseau et al. 2021 (PMID: 33413690)

由于缺乏用于研究瘢痕疙瘩（keloid）发生发展的合适模型，这种严重皮肤疾病的潜在病理机制仍未被充分阐明。本研究对瘢痕疙瘩组织开展单细胞测序，鉴定出一类此前未被发现的瘢痕疙瘩源性施万细胞（Schwann cell）亚群，该亚群可在伤口愈合后留存于瘢痕组织中。与正常皮肤相比，瘢痕疙瘩源性施万细胞呈现修复样表型，并具备较高的细胞可塑性。本研究数据显示，瘢痕疙瘩源性施万细胞可直接参与细胞外基质（extracellular matrix）的形成，并影响巨噬细胞的M2极化。进一步研究证实，瘢痕疙瘩内的巨噬细胞主要呈现M2极化表型，并可分泌抑制施万细胞分化的细胞因子。本研究数据表明，这种细胞间串扰可推动瘢痕疙瘩的无限增殖，而靶向施万细胞或可成为治疗瘢痕疙瘩的全新策略。实验设计：对瘢痕疙瘩组织、正常瘢痕及健康皮肤组织进行单细胞RNA测序（single-cell RNA-sequencing）的基因表达对比分析。使用MACS Miltenyi Whole Skin Dissociation Kit（Miltenyi）制备4例瘢痕疙瘩、1例正常皮肤及3例正常瘢痕的单细胞悬液。采用Chromium Nexxt GEM Single Cell 3´GEM, Library & Gel Bead Kit v3.1、Chromium Nexxt GEM Chip G Single Cell Kit以及Single Index Kit T Set A（均购自19x Genomics，美国加利福尼亚州普莱森顿）构建测序文库。本研究结合Tabib等2018年发表的健康皮肤测序数据（PMID:29080679）以及Brosseau等2021年发表的神经纤维瘤（neurofibroma）测序数据（PMID: 33413690）完成全部数据分析。