牙周膜干细胞通过恢复与PINK1/Parkin相关线粒体质量控制有关的巨噬细胞线粒体稳态来改善实验性结肠炎
Periodontal ligament stem cells ameliorate experimental colitis by restoring macrophage mitochondrial homeostasis associated with PINK1/Parkin-related mitochondrial quality control.
摘要(中文译文)
炎症性肠病（IBD）以持续性黏膜炎症和巨噬细胞反应失调为特征，其中线粒体功能障碍会加剧炎症激活。牙周膜干细胞（PDLSCs）具有免疫调节潜能，但其是否通过恢复结肠炎中巨噬细胞的线粒体稳态来调控巨噬细胞炎症尚不清楚。本研究将人PDLSCs与脂多糖刺激的THP-1来源巨噬细胞进行间接共培养，并进一步在葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠中考察其治疗效应。PDLSCs抑制了巨噬细胞的促炎激活，同时增强了抗炎介质的表达。RNA测序结合MitoCarta3.0分析显示，PDLSC调控的基因富集于线粒体功能、线粒体自噬、氧化应激、铁死亡和代谢适应等通路。机制上，PDLSCs减轻了线粒体超微结构损伤，恢复了mtTFA表达和线粒体膜电位，增强了呼吸链复合物I/III活性和ATP生成，并减弱了细胞内及线粒体氧化剂敏感信号。PDLSCs还降低了OMA1和Drp-1，恢复了OPA1和Mfn1，并促进了PINK1-Parkin信号，而Mdivi-1减弱了其抗炎效应。活体成像显示炎症结肠中存在PDLSC相关荧光，PDLSC治疗减轻了DSS诱导的体重下降、疾病活动度、结肠缩短、MPO激活、组织学损伤、黏液屏障破坏和胶原沉积。PDLSC治疗还抑制了M1相关巨噬细胞激活，同时促进M2相关巨噬细胞极化，保护了线粒体超微结构，改善了线粒体呼吸功能和ATP生成，并恢复了结肠组织中PINK1和Parkin的表达。总之，PDLSCs通过重塑巨噬细胞炎症反应和恢复线粒体质量控制来改善实验性结肠炎，其中可能涉及PINK1/Parkin相关线粒体自噬。
Abstract
Inflammatory bowel disease (IBD) is characterized by persistent mucosal inflammation and dysregulated macrophage responses, in which mitochondrial dysfunction reinforces inflammatory activation. Periodontal ligament stem cells (PDLSCs) possess immunomodulatory potential, but whether they regulate macrophage inflammation by restoring mitochondrial homeostasis in colitis remains unclear. Here, human PDLSCs were indirectly co-cultured with lipopolysaccharide-stimulated THP-1-derived macrophages, and their therapeutic effects were further examined in dextran sulfate sodium (DSS)-induced colitis mice. PDLSCs suppressed macrophage pro-inflammatory activation while enhancing anti-inflammatory mediator expression. RNA sequencing combined with MitoCarta3.0 analysis revealed that PDLSC-regulated genes were enriched in mitochondrial function, mitophagy, oxidative stress, ferroptosis, and metabolic adaptation pathways. Mechanistically, PDLSCs alleviated mitochondrial ultrastructural injury, restored mtTFA expression and mitochondrial membrane potential, enhanced respiratory chain complex I/III activity and ATP production, and attenuated intracellular and mitochondrial oxidant-sensitive signals. PDLSCs also decreased OMA1 and Drp-1, restored OPA1 and Mfn1, and promoted PINK1-Parkin signaling, whereas Mdivi-1 attenuated their anti-inflammatory effects. In vivo imaging revealed PDLSC-associated fluorescence in the inflamed colon, and PDLSC treatment mitigated DSS-induced weight loss, disease activity, colonic shortening, MPO activation, histological injury, mucus barrier disruption, and collagen deposition. PDLSC treatment also suppressed M1-associated macrophage activation while promoting M2-associated macrophage polarization, preserved mitochondrial ultrastructure, improved mitochondrial respiratory function and ATP generation, and restored the expression of PINK1 and Parkin in colonic tissue. In conclusion, PDLSCs ameliorate experimental colitis by reshaping macrophage inflammatory responses and restoring mitochondrial quality control, with potential involvement of PINK1/Parkin-associated mitophagy.
如何引用
AMA
Zekun Li, Yuhui Sun, Juefei Wu, Jixiao Wang, Jichang Li, Wenting Zhang, et al. Periodontal ligament stem cells ameliorate experimental colitis by restoring macrophage mitochondrial homeostasis associated with PINK1/Parkin-related mitochondrial quality control.. Biochimica et biophysica acta. Molecular basis of disease. 2027; doi:10.1016/j.bbadis.2026.168407.
APA
Zekun Li, Yuhui Sun, Juefei Wu, Jixiao Wang, Jichang Li, Wenting Zhang, et al (2027). Periodontal ligament stem cells ameliorate experimental colitis by restoring macrophage mitochondrial homeostasis associated with PINK1/Parkin-related mitochondrial quality control.. Biochimica et biophysica acta. Molecular basis of disease. https://doi.org/10.1016/j.bbadis.2026.168407
GB/T 7714
Zekun Li, Yuhui Sun, Juefei Wu, Jixiao Wang, Jichang Li, Wenting Zhang, et al. Periodontal ligament stem cells ameliorate experimental colitis by restoring macrophage mitochondrial homeostasis associated with PINK1/Parkin-related mitochondrial quality control.[J]. Biochimica et biophysica acta. Molecular basis of disease, 2027 doi:10.1016/j.bbadis.2026.168407.
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