Xu Xin, Zhang Yue, Li Shuo, Liao Chenlong, Yang Xiaosheng, Zhang Wenchuan
Department of Neurosurgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China.
Cells. 2025 Mar 7;14(6):393. doi: 10.3390/cells14060393.
Diabetic peripheral neuropathy (DPN) is a prevalent and disabling complication of diabetes, with painful diabetic peripheral neuropathy (PDPN) being its most severe subtype due to chronic pain and resistance to treatment. Satellite glial cells (SGCs), critical for maintaining dorsal root ganglion (DRG) homeostasis, undergo significant structural and functional changes under pathological conditions. This study investigated the role of galactosylceramide (GalCer), a key sphingolipid, in SGC dysfunction and neuron-glia interactions during DPN progression. Using a rat model of PDPN, we employed single-cell RNA sequencing (scRNA-seq), targeted mass spectrometry, and immunofluorescence analysis. The PDPN group exhibited transcriptional activation and structural reorganization of SGCs, characterized by increased SGC abundance and glial activation, evidenced by elevated Gfap expression. Functional enrichment analyses revealed disruptions in sphingolipid metabolism, including marked reductions in GalCer levels. Subclustering identified vulnerable SGC subsets, such as Cluster a, with dysregulated lipid metabolism. The depletion of GalCer impaired SGC-neuron communication, destabilizing DRG homeostasis and amplifying neurodegeneration and neuropathic pain. These findings demonstrate that GalCer depletion is a central mediator of SGC dysfunction in PDPN, disrupting neuron-glia interactions and exacerbating neuropathic pain. This study provides novel insights into the molecular mechanisms of DPN progression and identifies GalCer metabolism as a potential therapeutic target.
糖尿病性周围神经病变（DPN）是糖尿病常见且致残的并发症，其中疼痛性糖尿病周围神经病变（PDPN）因其慢性疼痛和治疗抵抗性而成为最严重的亚型。卫星神经胶质细胞（SGCs）对维持背根神经节（DRG）内环境稳定至关重要，在病理条件下会发生显著的结构和功能变化。本研究调查了关键鞘脂半乳糖神经酰胺（GalCer）在DPN进展过程中SGC功能障碍及神经元-神经胶质相互作用中的作用。利用PDPN大鼠模型，我们采用了单细胞RNA测序（scRNA-seq）、靶向质谱分析和免疫荧光分析。PDPN组表现出SGCs的转录激活和结构重组，其特征为SGC丰度增加和神经胶质激活，这通过Gfap表达升高得以证实。功能富集分析显示鞘脂代谢紊乱，包括GalCer水平显著降低。亚聚类确定了易损的SGC亚群，如Cluster a，其脂质代谢失调。GalCer的耗竭损害了SGC与神经元之间的通讯，破坏了DRG内环境稳定，加剧了神经退行性变和神经性疼痛。这些发现表明，GalCer耗竭是PDPN中SGC功能障碍的核心介质，破坏了神经元-神经胶质相互作用并加剧了神经性疼痛。本研究为DPN进展的分子机制提供了新见解，并确定GalCer代谢为潜在治疗靶点。
