Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Cell Mol Life Sci. 2022 Aug 11;79(9):480. doi: 10.1007/s00018-022-04495-9.
The etiology of mild traumatic brain injury (mTBI) remains elusive due to the tissue and cellular heterogeneity of the affected brain regions that underlie cognitive impairments and subsequent neurological disorders. This complexity is further exacerbated by disrupted circuits within and between cell populations across brain regions and the periphery, which occur at different timescales and in spatial domains.
We profiled three tissues (hippocampus, frontal cortex, and blood leukocytes) at the acute (24-h) and subacute (7-day) phases of mTBI at single-cell resolution.
We demonstrated that the coordinated gene expression patterns across cell types were disrupted and re-organized by TBI at different timescales with distinct regional and cellular patterns. Gene expression-based network modeling implied astrocytes as a key regulator of the cell-cell coordination following mTBI in both hippocampus and frontal cortex across timepoints, and mt-Rnr2, which encodes the mitochondrial peptide humanin, as a potential target for intervention based on its broad regional and dynamic dysregulation following mTBI. Treatment of a murine mTBI model with humanin reversed cognitive impairment caused by mTBI through the restoration of metabolic pathways within astrocytes.
Our results offer a systems-level understanding of the dynamic and spatial regulation of gene programs by mTBI and pinpoint key target genes, pathways, and cell circuits that are amenable to therapeutics.
由于导致认知障碍和随后神经紊乱的受影响脑区的组织和细胞异质性，轻度创伤性脑损伤 (mTBI) 的病因仍然难以捉摸。这种复杂性因脑区和外周细胞群体内部和之间的电路中断而进一步加剧，这些中断发生在不同的时间尺度和空间域中。
我们在 mTBI 的急性（24 小时）和亚急性（7 天）阶段以单细胞分辨率对三种组织（海马体、额叶皮层和血液白细胞）进行了分析。
我们证明了跨细胞类型的协调基因表达模式在不同的时间尺度上被 TBI 破坏和重新组织，具有不同的区域和细胞模式。基于基因表达的网络建模表明，星形胶质细胞是 mTBI 后海马体和额叶皮层中细胞间协调的关键调节因子，mt-Rnr2 是一种潜在的干预靶点，因为它在 mTBI 后具有广泛的区域和动态失调。用 humanin 治疗小鼠 mTBI 模型通过恢复星形胶质细胞内的代谢途径逆转了 mTBI 引起的认知障碍。
我们的结果提供了对 mTBI 动态和空间调节基因程序的系统理解，并确定了对治疗有反应的关键靶基因、途径和细胞电路。
