Jiang Zhipeng, Guo Youwei, Wang Zihan, Ouyang Jinhao, Huang Hailong, Huang Haoxuan, Shen Tianqian, Wang Lei, Yin Wen, Jiang Xingjun, Ren Caiping
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China； Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, 410078, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China； Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, 410078, China; The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan Province, 410078, China.
Neurobiol Dis. 2025 Aug;212:106982. doi: 10.1016/j.nbd.2025.106982. Epub 2025 Jun 2.
Spinal cord injury (SCI) initiates a cascade of complex secondary damage processes, prominently involving programmed cell death (PCD). Although apoptosis and necroptosis have been extensively characterized, the role of oncosis in SCI remains inadequately understood. In this study, we examined the expression dynamics and cellular localization of oncosis-related genes (ORGs) following SCI. We conducted an analysis of bulk RNA-seq data to identify differentially expressed ORGs at five distinct time points post-injury. Six candidate genes (Trp53, Casp3, Jun, Tmem123, Chmp6, Map2) were identified based on their temporal expression patterns. Single-cell RNA sequencing and spatial transcriptomics revealed specific cell-type specificity and lesion-centered spatial enrichment of these genes. Trp53 and Casp3 were found to be rapidly upregulated in neurons and microglia, whereas Tmem123 exhibited a progressive downregulation. Jun emonstrated biphasic activation in astrocytes and oligodendrocytes. In vitro experiments using LPS-treated PC12 cells corroborated key expression trends, with transmission electron microscopy (TEM) confirming the morphological characteristics of oncosis. In vivo, quantitative reverse transcription PCR (qRT-PCR) qRT-PCR and immunofluorescence analyses in a rat SCI model further validated the altered expression of these genes. Significantly, a reduction in Map2 and an elevation in Chmp6 were associated with cytoskeletal collapse and plasma membrane rupture, respectively. Together, our findings provide the first spatiotemporal mapping of oncotic gene regulation following SCI and identify potential targets for therapeutic intervention.
脊髓损伤（SCI）引发一系列复杂的继发性损伤过程，其中程序性细胞死亡（PCD）最为突出。尽管细胞凋亡和坏死性凋亡已得到广泛研究，但胀亡在脊髓损伤中的作用仍未得到充分了解。在本研究中，我们检测了脊髓损伤后胀亡相关基因（ORGs）的表达动态和细胞定位。我们对大量RNA测序数据进行分析，以确定损伤后五个不同时间点差异表达的ORGs。根据其时间表达模式，鉴定出六个候选基因（Trp53、Casp3、Jun、Tmem123、Chmp6、Map2）。单细胞RNA测序和空间转录组学揭示了这些基因特定的细胞类型特异性和以损伤为中心的空间富集。发现Trp53和Casp3在神经元和小胶质细胞中迅速上调，而Tmem123则呈逐渐下调。Jun在星形胶质细胞和少突胶质细胞中表现出双相激活。使用脂多糖处理的PC12细胞进行的体外实验证实了关键表达趋势，透射电子显微镜（TEM）确认了胀亡的形态学特征。在体内，大鼠脊髓损伤模型中的定量逆转录PCR（qRT-PCR）和免疫荧光分析进一步验证了这些基因表达的改变。值得注意的是，Map2的减少和Chmp6的升高分别与细胞骨架塌陷和质膜破裂有关。总之，我们的研究结果首次提供了脊髓损伤后胀亡基因调控的时空图谱，并确定了治疗干预的潜在靶点。
