Research on Peripheral Nerve Aging and Degeneration: Cellular Changes and Mechanism Exploration from the Perspective of Single-Cell Sequencing

As age increases, there are structural and functional alterations in the Peripheral Nervous System (PNS),significantly affecting movement, sensation, and autonomic function. Understanding the characteristics and mechanisms of PNS aging is crucial for preventing and treating related diseases. This study employed single-cell sequencing technology to analyze the dorsal root ganglia (DRG) and sciatic nerve (SN) of aging rats, in comparison to adult rats. The research investigated the mechanisms underlying peripheral nervous system (PNS) aging and degeneration, revealing the transcriptional profiles of various cell types.Significant differences were observed in the proportion of Schwann cells between the DRG and SN of adult and aged rats. The Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) revealed that pathways related to neurodegeneration were upregulated in Schwann cells. Additionally, lipid metabolism pathways were upregulated in the SN of aged rats, suggesting that certain lipid signaling molecules may influence cell proliferation. Through further re-clustering of myelinating Schwann cells, six distinct subtypes were identified. The anti-aging protein protocadherin 9 (PCDH9) was preliminarily screened and found to be significantly downregulated with age. In vitro experiments confirmed that PCDH9 expression is associated with Schwann cell proliferation and differentiation. By using gene expression analysis and cell type across several age groups, this study offers important insights into the mechanisms of PNS aging and degeneration.随着年龄增长，外周神经系统（Peripheral Nervous System, PNS）会出现结构与功能改变，显著影响运动、感觉及自主神经功能。阐明外周神经系统衰老的特征与机制，对相关疾病的防治至关重要。本研究采用单细胞测序技术，对比成年大鼠与衰老大鼠的背根神经节（dorsal root ganglia, DRG）及坐骨神经（sciatic nerve, SN），探究外周神经系统衰老与退变的潜在机制，揭示了各类细胞类型的转录谱。研究发现，成年与衰老大鼠的背根神经节与坐骨神经中雪旺细胞（Schwann cells）的占比存在显著差异。通过京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）、基因本体论（Gene Ontology, GO）及基因集富集分析（Gene Set Enrichment Analysis, GSEA）分析，结果显示雪旺细胞内与神经退变相关的通路呈现上调表达。此外，衰老大鼠坐骨神经内的脂质代谢通路亦出现上调，提示部分脂质信号分子可能参与调控细胞增殖。进一步对有髓雪旺细胞进行重聚类后，共鉴定出6种不同的细胞亚型。本研究初步筛选出抗衰老蛋白原钙粘蛋白9（protocadherin 9, PCDH9），发现其表达随年龄增长显著下调。体外实验证实，PCDH9的表达与雪旺细胞的增殖及分化密切相关。本研究通过多年龄组的基因表达分析与细胞分型，为外周神经系统衰老与退变的机制研究提供了重要见解。