Hong Xiaosi, Cai Leiqin, Li Lanlan, Zheng Dinghao, Lin Jianghong, Liang Zhuoxian, Fu Wan, Liang Diefei, Zeng Tingting, Sun Kan, Wang Wei, Chen Sifan, Ren Meng, Yan Li
Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Arch Physiol Biochem. 2025 Feb;131(1):11-23. doi: 10.1080/13813455.2024.2358020. Epub 2024 Jun 3.
Keratinocyte and fibroblast dysfunctions contribute to delayed healing of diabetic wounds. Small extracellular vesicles (sEV) are key mediators of intercellular communication and are involved in the pathogenesis of several diseases. Recent findings suggest that sEV derived from high-glucose-treated keratinocyte (HaCaT-HG-sEV) can transport LINC01435 to inhibit tube formation and migration of HUVECs, thereby delaying wound healing. This study aimed to elucidate sEV-related communication mechanisms between keratinocytes and fibroblasts during diabetic wound healing. HaCaT-HG-sEV treatment and LINC01435 overexpression significantly decreased fibroblast collagen level and migration ability but significantly increased fibroblast autophagy. However, treatment with an autophagy inhibitor suppressed LINC01435 overexpression-induced decrease in collagen levels in fibroblasts. In diabetic mice, HaCaT-HG-sEV treatment decreased collagen levels and increased the expression of the autophagy-related proteins Beclin-1 and LC3 at the wound site, thereby delaying wound healing. Conclusively, LINC01435 in keratinocyte-derived sEV activates fibroblast autophagy and reduces fibroblast collagen synthesis, leading to impaired diabetic wound healing.
角质形成细胞和成纤维细胞功能障碍导致糖尿病伤口愈合延迟。小细胞外囊泡（sEV）是细胞间通讯的关键介质，参与多种疾病的发病机制。最近的研究发现，高糖处理的角质形成细胞来源的sEV（HaCaT-HG-sEV）可转运LINC01435，抑制人脐静脉内皮细胞（HUVECs）的管腔形成和迁移，从而延迟伤口愈合。本研究旨在阐明糖尿病伤口愈合过程中角质形成细胞与成纤维细胞之间与sEV相关的通讯机制。HaCaT-HG-sEV处理和LINC01435过表达显著降低了成纤维细胞的胶原蛋白水平和迁移能力，但显著增加了成纤维细胞的自噬。然而，用自噬抑制剂处理可抑制LINC01435过表达诱导的成纤维细胞胶原蛋白水平降低。在糖尿病小鼠中，HaCaT-HG-sEV处理降低了伤口部位的胶原蛋白水平，并增加了自噬相关蛋白Beclin-1和LC3的表达，从而延迟了伤口愈合。总之，角质形成细胞来源的sEV中的LINC01435激活成纤维细胞自噬并减少成纤维细胞胶原蛋白合成，导致糖尿病伤口愈合受损。
