Kelley Kevin W, Nakao-Inoue Hiromi, Molofsky Anna V, Oldham Michael C
Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA, USA.
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA, USA.
Nat Neurosci. 2018 Sep;21(9):1171-1184. doi: 10.1038/s41593-018-0216-z. Epub 2018 Aug 28.
It is widely assumed that cells must be physically isolated to study their molecular profiles. However, intact tissue samples naturally exhibit variation in cellular composition, which drives covariation of cell-class-specific molecular features. By analyzing transcriptional covariation in 7,221 intact CNS samples from 840 neurotypical individuals, representing billions of cells, we reveal the core transcriptional identities of major CNS cell classes in humans. By modeling intact CNS transcriptomes as a function of variation in cellular composition, we identify cell-class-specific transcriptional differences in Alzheimer's disease, among brain regions, and between species. Among these, we show that PMP2 is expressed by human but not mouse astrocytes and significantly increases mouse astrocyte size upon ectopic expression in vivo, causing them to more closely resemble their human counterparts. Our work is available as an online resource ( http://oldhamlab.ctec.ucsf.edu/ ) and provides a generalizable strategy for determining the core molecular features of cellular identity in intact biological systems.
人们普遍认为，为了研究细胞的分子特征，必须对细胞进行物理分离。然而，完整的组织样本自然会在细胞组成上表现出差异，这会导致细胞类别特异性分子特征的共变。通过分析来自840名神经典型个体的7221个完整中枢神经系统样本中的转录共变情况（这些样本代表了数十亿个细胞），我们揭示了人类主要中枢神经系统细胞类别的核心转录特征。通过将完整的中枢神经系统转录组建模为细胞组成变化的函数，我们确定了阿尔茨海默病、不同脑区以及不同物种之间细胞类别特异性的转录差异。其中，我们发现PMP2在人类星形胶质细胞中表达，而在小鼠星形胶质细胞中不表达，并且在体内异位表达时会显著增加小鼠星形胶质细胞的大小，使其更接近人类星形胶质细胞。我们的研究成果可作为在线资源获取（http://oldhamlab.ctec.ucsf.edu/ ），并为确定完整生物系统中细胞身份的核心分子特征提供了一种可推广的策略。
