Zheng Rui-Zhe, Xing Jin, Huang Qiong, Yang Xi-Tao, Zhao Chang-Yi, Li Xin-Yuan
Department of Neurosurgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
Department of Neurosurgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China.
Math Biosci Eng. 2021 Jan 14;18(2):1201-1214. doi: 10.3934/mbe.2021065.
Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide, whose symptoms ranging from mild to severe, even life-threatening. However, specific cell types and key regulators involved in traumatic brain injury have not been well elucidated. In this study, utilizing single-cell RNA-seq (scRNA-seq) data from mice with TBI, we have successfully identified and characterized 13 cell populations including astrocytes, oligodendrocyte, newly formed oligodendrocytes, microglia, two types of endothelial cells, five types of excitatory and two types of inhibitory neurons. Differential expression analysis and gene set enrichment analysis (GSEA) revealed the upregulation of microglia and endothelial markers, along with the downregulation of markers of excitatory neurons in TBI. The cell-cell communication analysis revealed that microglia and endothelial cell might interact through the interaction of Icam1-Il2rg and C1qa-Cd93, and microglia might also communicate with each other via Icam1-Itagm. The autocrine ligand-receptor in microglia might result in activation of TYROBP causal network via Icam1-Itgam. The cell-cell contact between microglia and endothelial cell might activate integrin signaling pathways. Moreover, we also found that genes involved in microglia activation were highly downregulated in Tyrobp/Dap12-deficient microglia, indicating that the upregulation of Tyrobp and TYROBP causal network in microglia might be a candidate therapeutic target in TBI. In contrast, the excitatory neurons were involved in maintaining normal brain function, and their inactivation might cause dysfunction of nervous system in TBI patients. In conclusion, the present study has discerned major cell types such as microglia, endothelial cells and excitatory neurons, and revealed key regulator such as TYROBP, C1QA, and CD93 in TBI, which shall improve our understanding of the pathogenesis of TBI.
创伤性脑损伤（TBI）是全球致残和致死的主要原因之一，其症状从轻度到重度不等，甚至危及生命。然而，参与创伤性脑损伤的特定细胞类型和关键调节因子尚未得到充分阐明。在本研究中，利用创伤性脑损伤小鼠的单细胞RNA测序（scRNA-seq）数据，我们成功鉴定并表征了13种细胞群，包括星形胶质细胞、少突胶质细胞、新形成的少突胶质细胞、小胶质细胞、两种类型的内皮细胞、五种类型的兴奋性神经元和两种类型的抑制性神经元。差异表达分析和基因集富集分析（GSEA）显示，创伤性脑损伤中小胶质细胞和内皮细胞标志物上调，同时兴奋性神经元标志物下调。细胞间通讯分析表明，小胶质细胞和内皮细胞可能通过Icam1-Il2rg和C1qa-Cd93的相互作用相互作用，小胶质细胞也可能通过Icam1-Itagm相互通讯。小胶质细胞中的自分泌配体-受体可能通过Icam1-Itgam导致TYROBP因果网络的激活。小胶质细胞与内皮细胞之间的细胞间接触可能激活整合素信号通路。此外，我们还发现，参与小胶质细胞激活的基因在Tyrobp/Dap12缺陷的小胶质细胞中高度下调，这表明小胶质细胞中Tyrobp和TYROBP因果网络的上调可能是创伤性脑损伤的候选治疗靶点。相比之下，兴奋性神经元参与维持正常脑功能，其失活可能导致创伤性脑损伤患者的神经系统功能障碍。总之，本研究识别出了小胶质细胞、内皮细胞和兴奋性神经元等主要细胞类型，并揭示了创伤性脑损伤中的关键调节因子，如TYROBP、C1QA和CD93，这将增进我们对创伤性脑损伤发病机制的理解。
