Song Sijia, Xiang Rong, Chen Siyu, Wu Jianbo, Chen Wenxia, Li Xianyu
Department of Operative Dentistry and Endodontology, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China.
Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning, China.
Front Cell Dev Biol. 2025 Jul 23;13:1606716. doi: 10.3389/fcell.2025.1606716. eCollection 2025.
Effective skin repair requires rapid wound closure accompanied by precise extracellular matrix (ECM) remodeling and balanced cellular metabolism. Saliva-derived exosomes (S-Exo) have emerged as promising therapeutic agents due to their rich bioactive components; however, their mechanisms in ECM remodeling and metabolic regulation remain unclear. This study aimed to elucidate how S-Exo modulate ECM turnover through metabolic reprogramming, particularly glycolysis, in human skin fibroblasts (HSFs), and identify critical exosomal molecules mediating these effects.
S-Exo were isolated and characterized. A rat full-thickness skin defect model and assays with human skin fibroblasts and HaCaT keratinocytes were employed to evaluate S-Exo effects on wound closure, ECM remodeling, and cellular metabolism. Transcriptomic profiling of wound tissues, targeted metabolomic analysis of fibroblasts, and proteomic evaluation of S-Exo cargo were performed to explore underlying mechanisms. Metabolic interventions further confirmed the contribution of metabolic modulation to S-Exo-mediated wound healing.
S-Exo significantly accelerated wound healing by enhancing fibroblast viability, migration, and ECM remodeling, characterized by elevated secretion of matrix metalloproteinases (MMP1 and MMP3). Transcriptomic, metabolomic, and proteomic analyses revealed that S-Exo robustly activated key metabolic pathways, particularly glycolysis, reflected by increased expression of glycolytic genes (e.g., GLUT1, HK2, PFKM) and enhanced glycolytic flux in fibroblasts. Remarkably, S-Exo were found to carry nearly all enzymes involved in glycolysis, indicating an underlying enzyme-transfer mechanism for sustained metabolic modulation. Importantly, glycolytic activity positively correlated with MMP secretion, and inhibition of glycolysis significantly reduced MMP production, highlighting glycolysis as a crucial regulator of ECM remodeling.
Saliva-derived exosomes promote wound healing by potentially modulating fibroblast metabolism via exosome-associated glycolytic enzymes, enhancing glycolytic flux, and thereby regulating ECM remodeling via increased MMP secretion. These findings provide novel insights into metabolism-targeted exosome therapies for wound healing.
有效的皮肤修复需要快速闭合伤口，同时伴随着精确的细胞外基质（ECM）重塑和平衡的细胞代谢。唾液来源的外泌体（S-Exo）因其丰富的生物活性成分而成为有前景的治疗剂；然而，它们在ECM重塑和代谢调节中的机制仍不清楚。本研究旨在阐明S-Exo如何通过代谢重编程，特别是糖酵解，调节人皮肤成纤维细胞（HSF）中的ECM周转，并鉴定介导这些作用的关键外泌体分子。
分离并鉴定S-Exo。采用大鼠全层皮肤缺损模型以及人皮肤成纤维细胞和HaCaT角质形成细胞试验，评估S-Exo对伤口闭合、ECM重塑和细胞代谢的影响。对伤口组织进行转录组分析、对成纤维细胞进行靶向代谢组分析以及对S-Exo的货物进行蛋白质组评估，以探索潜在机制。代谢干预进一步证实了代谢调节对S-Exo介导的伤口愈合的贡献。
S-Exo通过增强成纤维细胞活力、迁移和ECM重塑，显著加速伤口愈合，其特征是基质金属蛋白酶（MMP1和MMP3）分泌增加。转录组、代谢组和蛋白质组分析表明，S-Exo有力地激活了关键代谢途径，特别是糖酵解，这表现为成纤维细胞中糖酵解基因（如GLUT1、HK2、PFKM）表达增加以及糖酵解通量增强。值得注意的是，发现S-Exo携带几乎所有参与糖酵解的酶，表明存在持续代谢调节的潜在酶转移机制。重要的是，糖酵解活性与MMP分泌呈正相关，抑制糖酵解显著降低MMP产生，突出了糖酵解作为ECM重塑的关键调节因子。
唾液来源的外泌体可能通过外泌体相关的糖酵解酶调节成纤维细胞代谢，增强糖酵解通量，从而通过增加MMP分泌来调节ECM重塑，进而促进伤口愈合。这些发现为伤口愈合的代谢靶向外泌体疗法提供了新的见解。
