SLC45A3 Serves as a Potential Therapeutic Biomarker to Attenuate White Matter Injury After Intracerebral Hemorrhage
SLC45A3 Serves as a Potential Therapeutic Biomarker to Attenuate White Matter Injury After Intracerebral Hemorrhage
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DOI：
10.1007/s12975-023-01145-5
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发表时间：
2023-03
影响因子：
6.9
通讯作者：
Yi Zhang;H. Zeng;Feiyang Lou;Xiaoxiao Tan;Xiaotong Zhang;Gao Chen
中科院分区：
文献类型：
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作者：
Yi Zhang;H. Zeng;Feiyang Lou;Xiaoxiao Tan;Xiaotong Zhang;Gao Chen
脑出血是一种严重的脑血管疾病，即使在及时的临床干预下，患者的白色物质也会受损。近10年的研究表明，ICH所致的白色损伤（white matter injury，ICH）与神经功能缺损密切相关，但其发生机制及相关治疗尚不充分。我们收集了两个数据集（GSE 24265和GSE 125512），并通过加权基因共表达网络分析确定的感兴趣的基因之间的交集，我们确定了两个数据集中差异表达基因后的靶基因。额外的单细胞RNA-seq分析（GSE 167593）有助于在细胞类型中定位该基因。此外，我们还建立了自体血或胶原酶诱导的小鼠脑出血模型。应用基础医学实验和扩散张量成像技术验证靶基因在脑出血后脑水肿中的作用。通过杂交和富集分析，确定SLC 45 A3基因为目的基因，该基因在脑出血后少突胶质细胞分化的调控中起关键作用，参与脂肪酸代谢等过程，单细胞RNA-seq分析也显示其主要定位于少突胶质细胞。进一步的实验证实了SLC 45 A3的过表达改善了ICH后的脑损伤。因此，SLC 45 A3可能作为ICH诱导的脑损伤的候选治疗生物标志物，其过表达可能是减轻损伤的潜在途径。
Intracerebral hemorrhage (ICH) is a severe cerebrovascular disease, which impairs patients’ white matter even after timely clinical interventions. Indicated by studies in the past decade, ICH-induced white matter injury (WMI) is closely related to neurological deficits; however, its underlying mechanism and pertinent treatment are yet insufficient. We gathered two datasets (GSE24265 and GSE125512), and by taking an intersection among interesting genes identified by weighted gene co-expression networks analysis, we determined target genes after differentially expressing genes in two datasets. Additional single-cell RNA-seq analysis (GSE167593) helped locate the gene in cell types. Furthermore, we established ICH mice models induced by autologous blood or collagenase. Basic medical experiments and diffusion tensor imaging were applied to verify the function of target genes in WMI after ICH. Through intersection and enrichment analysis, gene SLC45A3 was identified as the target one, which plays a key role in the regulation of oligodendrocyte differentiation involving in fatty acid metabolic process, etc. after ICH, and single-cell RNA-seq analysis also shows that it mainly locates in oligodendrocytes. Further experiments verified overexpression of SLC45A3 ameliorated brain injury after ICH. Therefore, SLC45A3 might serve as a candidate therapeutic biomarker for ICH-induced WMI, and overexpression of it may be a potential approach for injury attenuation.Graphical Abstract