- 作者: 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
- 作者服務機構: 1.College of Professional Studies, National Pingtung University of Science Technology, Pingtung, Taiwan 2.Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan 3.Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, Taipei, Taiwan 4.Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 5.Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 6.Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 7.Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan 8.Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan 9.Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 10.Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan 11.International Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan 12.Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 13.Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan 14.St John’s Institute of Dermatology, School of Basic and Medical Biosciences, King’s College London, London, UK 15.The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- 中文摘要:
- 英文摘要:
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. - 中文關鍵字:
- 英文關鍵字: Keloid, Hypertrophic scar, TEM1/endosialin/CD248, TGF-β, Fibroblast activation