TEM1/endosialin/CD248 通过其在真皮成纤维细胞中的受体稳定性促进病理性瘢痕形成和 TGF-β 活性。

IF 9 2区 医学 Q1 CELL BIOLOGY Journal of Biomedical Science Pub Date : 2024-01-23 DOI:10.1186/s12929-024-01001-0
Yi-Kai Hong, Yu-Chen Lin, Tsung-Lin Cheng, Chao-Han Lai, Yi-Han Chang, Yu-Lun Huang, Chia-Yi Hung, Chen-Han Wu, Kuo-Shu Hung, Ya-Chu Ku, Yen-Ting Ho, Ming-Jer Tang, Shu-Wha Lin, Guey-Yueh Shi, John A McGrath, Hua-Lin Wu, Chao-Kai Hsu
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引用次数: 0

摘要

背景:病理性疤痕(包括瘢痕疙瘩和增生性疤痕)是一种常见的夸张性皮肤疤痕,难以有效预防或治疗。此外,人们对病理性疤痕的病理生物学仍然知之甚少。我们的目的是研究 TEM1(又称内糖蛋白或 CD248)(一种糖基化的 I 型跨膜蛋白)对病理性疤痕发展的影响:为了研究 TEM1 的表达,我们采用了免疫荧光染色、Western 印迹和单细胞 RNA 序列(scRNA-seq)技术。我们进行了体外细胞培养实验和体内拉伸诱导疤痕小鼠模型,研究 TEM1 参与 TGF-β 介导的病理疤痕反应:结果:与正常皮肤相比,增生性疤痕和瘢痕疙瘩中蛋白质 TEM1 的水平都有所升高。对scRNA-seq数据集的重新分析表明,瘢痕疙瘩和增生性疤痕成纤维细胞的一个主要坏死亚群大量表达TEM1,在成纤维细胞活化过程中表达量增加。TEM1 通过与 TGF-β 受体结合并稳定 TGF-β 受体,增强 TGF-β1 信号传导,从而促进人真皮成纤维细胞的活化、增殖和 ECM 生成。在拉伸诱发病理性瘢痕的小鼠模型中,Tem1 的全面缺失明显减少了瘢痕中 ECM 的合成量和炎症。瘤内注射针对 TEM1 的人源化 IgG 单克隆抗体 Ontuxizumab 能显著减少瘢痕疙瘩的大小和胶原密度:我们的数据表明,TEM1在病理性瘢痕形成中发挥作用,其对TGF-β信号传导的协同作用有助于真皮成纤维细胞的活化。以TEM1为靶点可能是降低病理性疤痕发病率的一种新型治疗方法。
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TEM1/endosialin/CD248 promotes pathologic scarring and TGF-β activity through its receptor stability in dermal fibroblasts.

Background: Pathologic scars, including keloids and hypertrophic scars, represent a common form of exaggerated cutaneous scarring that is difficult to prevent or treat effectively. Additionally, the pathobiology of pathologic scars remains poorly understood. We aim at investigating the impact of TEM1 (also known as endosialin or CD248), which is a glycosylated type I transmembrane protein, on development of pathologic scars.

Methods: To investigate the expression of TEM1, we utilized immunofluorescence staining, Western blotting, and single-cell RNA-sequencing (scRNA-seq) techniques. We conducted in vitro cell culture experiments and an in vivo stretch-induced scar mouse model to study the involvement of TEM1 in TGF-β-mediated responses in pathologic scars.

Results: The levels of the protein TEM1 are elevated in both hypertrophic scars and keloids in comparison to normal skin. A re-analysis of scRNA-seq datasets reveals that a major profibrotic subpopulation of keloid and hypertrophic scar fibroblasts greatly expresses TEM1, with expression increasing during fibroblast activation. TEM1 promotes activation, proliferation, and ECM production in human dermal fibroblasts by enhancing TGF-β1 signaling through binding with and stabilizing TGF-β receptors. Global deletion of Tem1 markedly reduces the amount of ECM synthesis and inflammation in a scar in a mouse model of stretch-induced pathologic scarring. The intralesional administration of ontuxizumab, a humanized IgG monoclonal antibody targeting TEM1, significantly decreased both the size and collagen density of keloids.

Conclusions: Our data indicate that TEM1 plays a role in pathologic scarring, with its synergistic effect on the TGF-β signaling contributing to dermal fibroblast activation. Targeting TEM1 may represent a novel therapeutic approach in reducing the morbidity of pathologic scars.

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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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