Wang Jie-Mei, Li Hainan, Xu Liping, Kim Hyunbae, Qiu Yining, Zhang Kezhong
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave, Detroit, MI 48201, USA.
Center for Molecular Medicine and Genetics, Wayne State University, 540 Canfield Street, Detroit, MI 48201, USA.
PNAS Nexus. 2023 Feb 14;2(3):pgad050. doi: 10.1093/pnasnexus/pgad050. eCollection 2023 Mar.
Patients' suffering from large or deep wounds caused by traumatic and/or thermal injuries have significantly lower chances of recapitulating lost skin function through natural healing. We tested whether enhanced unfolded protein response (UPR) by expression of a UPR transcriptional activator, X-box-binding protein 1 (XBP1) can significantly promote wound repair through stimulating growth factor production and promoting angiogenesis. In mouse models of a second-degree thermal wound, a full-thickness traumatic wound, and a full-thickness diabetic wound, the topical gene transfer of the activated form of XBP1 (spliced XBP1, XBP1s) can significantly enhance re-epithelialization and increase angiogenesis, leading to rapid, nearly complete wound closure with intact regenerated epidermis and dermis. Overexpression of XBP1s stimulated the transcription of growth factors in fibroblasts critical to proliferation and remodeling during wound repair, including platelet-derived growth factor BB, basic fibroblast growth factor, and transforming growth factor beta 3. Meanwhile, the overexpression of XBP1s boosted the migration and tube formation of dermal microvascular endothelial cells in vitro. Our functional and mechanistic investigations of XBP1-mediated regulation of wound healing processes provide novel insights into the previously undermined physiological role of the UPR in skin injuries. The finding opens an avenue to developing potential XBP1-based therapeutic strategies in clinical wound care protocols.
因创伤性和/或热损伤导致大面积或深度伤口的患者，通过自然愈合恢复受损皮肤功能的几率显著降低。我们测试了通过表达未折叠蛋白反应（UPR）转录激活因子X盒结合蛋白1（XBP1）增强UPR是否能通过刺激生长因子产生和促进血管生成来显著促进伤口修复。在二度热损伤、全层创伤性伤口和全层糖尿病伤口的小鼠模型中，XBP1的激活形式（剪接型XBP1，XBP1s）的局部基因转移可显著增强上皮再形成并增加血管生成，从而实现快速、近乎完全的伤口闭合，再生的表皮和真皮完整无损。XBP1s的过表达刺激了成纤维细胞中对伤口修复过程中的增殖和重塑至关重要的生长因子的转录，包括血小板衍生生长因子BB、碱性成纤维细胞生长因子和转化生长因子β3。同时，XBP1s的过表达促进了体外真皮微血管内皮细胞的迁移和管腔形成。我们对XBP1介导的伤口愈合过程调节的功能和机制研究为UPR在皮肤损伤中先前被忽视的生理作用提供了新的见解。这一发现为在临床伤口护理方案中开发基于XBP1的潜在治疗策略开辟了一条途径。
