Human disease-specific cell signatures in non-lesional tissue in Multiple Sclerosis detected by single-cell and spatial transcriptomics.
Human disease-specific cell signatures in non-lesional tissue in Multiple Sclerosis detected by single-cell and spatial transcriptomics.
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通过单细胞和空间转录组学检测多发性硬化症非病变组织中的人类疾病特异性细胞特征。
DOI：
10.1101/2023.12.20.572491
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Menon,Vilas
中科院分区：
文献类型：
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作者：
Lam,Matti;Lee,Dylan;Kosater,Ivy;Khairallah,Anthony;Taga,Mariko;Zhang,Ya;Fujita,Masashi;Nag,Sukriti;Bennett,DavidA;DeJager,Philip;Menon,Vilas
最近使用单细胞分析方法对多发性硬化症（MS）中细胞类型变化的研究主要集中在活动性病变和病变周围脑组织，并涉及许多外周和中枢神经系统细胞类型。然而，一个重要的问题是多发性硬化症患者所谓的“看起来正常”的非病变组织在一生中积累变化的程度。在这里，我们比较了来自宗教秩序研究或拉什记忆和衰老项目（ROSMAP）队列中病理或临床诊断为多发性硬化症的捐赠者的死后非病变脑组织与年龄和性别匹配的非多发性硬化症患者的大脑（对照组）。我们使用单核RNA-seq分析了15名对照个体、8名MS患者和5名其他有害病理伴脱髓鞘患者的三个脑区：背外侧前额叶皮层（DLPFC）、正常外观白质（NAWM）和丘脑pulvinar (PULV)，共78个样本。与对照供体相比，我们确定了来自诊断为多发性硬化症和/或表现出继发性脱髓鞘和其他神经系统疾病的个体的非病变样本的区域和细胞类型特异性差异。这些差异包括在所有三个脑区表达髓鞘相关基因MOBP、MBP、PLP1的少突胶质细胞比例较低，以及CRYAB+少突胶质细胞比例较高。在小胶质细胞特征中，我们确定了脱髓鞘（TMEM163+/ERC2+）较高的亚组，以及MS供体（HIF1A+/SPP1+）和继发性脱髓鞘供体（SOCS6+/MYO1E+）在白质和灰质中的特异性较高的亚组。为了验证我们的发现，我们对来自13个供体的匹配组织生成了Visium空间转录组学数据，并概述了我们对少突胶质细胞和小胶质细胞基因表达差异的观察结果。最后，我们表明，在NAWM中，对照组和MS供者之间观察到的一些差异与之前报道的对照WM和MS供者的活动性病变之间的差异相同。总的来说，我们的研究进一步揭示了即使在非病变的白质和灰质组织中也存在的细胞类型和疾病特异性差异，强调了可能与下游病理变化相关的广泛的细胞特征。
Recent investigations of cell type changes in Multiple Sclerosis (MS) using single-cell profiling methods have focused on active lesional and peri-lesional brain tissue, and have implicated a number of peripheral and central nervous system cell types. However, an important question is the extent to which so-called “normal-appearing” non-lesional tissue in individuals with MS accumulate changes over the lifespan. Here, we compared post-mortem non-lesional brain tissue from donors with a pathological or clinical diagnosis of MS from the Religious Orders Study or Rush Memory and Aging Project (ROSMAP) cohorts to age- and sex-matched brains from persons without MS (controls). We profiled three brain regions using single-nucleus RNA-seq: dorsolateral prefrontal cortex (DLPFC), normal appearing white matter (NAWM) and the pulvinar in thalamus (PULV), from 15 control individuals, 8 individuals with MS, and 5 individuals with other detrimental pathologies accompanied by demyelination, resulting in a total of 78 samples. We identified region- and cell type-specific differences in non-lesional samples from individuals diagnosed with MS and/or exhibiting secondary demyelination with other neurological conditions, as compared to control donors. These differences included lower proportions of oligodendrocytes with expression of myelination related genes MOBP, MBP, PLP1, as well as higher proportions of CRYAB+ oligodendrocytes in all three brain regions. Among microglial signatures, we identified subgroups that were higher in both demyelination (TMEM163+/ERC2+), as well as those that were specifically higher in MS donors (HIF1A+/SPP1+) and specifically in donors with secondary demyelination (SOCS6+/MYO1E+), in both white and grey matter. To validate our findings, we generated Visium spatial transcriptomics data on matched tissue from 13 donors, and recapitulated our observations of gene expression differences in oligodendrocytes and microglia. Finally, we show that some of the differences observed between control and MS donors in NAWM mirror those previously reported between control WM and active lesions in MS donors. Overall, our investigation sheds additional light on cell type- and disease-specific differences present even in non-lesional white and grey matter tissue, highlighting widespread cellular signatures that may be associated with downstream pathological changes.