人诱导性多能干细胞(iPSCs)可以分化为神经元,提供活的人类神经元来模拟大脑疾病。然而,目前尚不清楚不同类型的分子如何在健康和疾病状态下共同调节干细胞和神经元生物学。在这项研究中,我们进行了综合蛋白质组学,脂质组学,和具有自信识别的代谢组学分析,精确量化,和可重复测量,以比较人类iPSC和iPSC衍生神经元的分子谱。蛋白质,脂质,和与有丝分裂有关的代谢物,DNA复制,多能性,鞘糖脂,iPSCs中能量代谢高度富集,而突触蛋白,神经递质,多不饱和脂肪酸,心磷脂,和轴突引导通路在神经元中高度富集。GRN基因的突变导致颗粒蛋白前体(PGRN)蛋白的缺乏,与各种神经退行性疾病相关。使用这个多组学平台,我们从全细胞水平评价了PGRN缺乏对iPSCs和神经元的影响.蛋白质组学,脂质组学,和代谢组学分析暗示PGRN在神经炎症中的作用,嘌呤代谢,和神经突生长,揭示与神经元投射相关的常见改变的通路,突触功能障碍,和大脑新陈代谢。多组学数据集也指出了相同的假设,即与iPSCs相比,神经元似乎更容易受到PGRN丢失的影响。与携带遗传GRN突变的患者的神经症状和认知障碍一致。
Human induced pluripotent stem cells (iPSCs) can be differentiated into neurons, providing living human neurons to model brain diseases. However, it is unclear how different types of molecules work together to regulate stem cell and neuron biology in healthy and disease states. In this study, we conducted integrated proteomics, lipidomics, and metabolomics analyses with confident identification, accurate quantification, and reproducible measurements to compare the molecular profiles of human iPSCs and iPSC-derived neurons. Proteins, lipids, and metabolites related to mitosis, DNA replication, pluripotency, glycosphingolipids, and energy metabolism were highly enriched in iPSCs, whereas synaptic proteins, neurotransmitters, polyunsaturated fatty acids, cardiolipins, and axon guidance pathways were highly enriched in neurons. Mutations in the GRN gene lead to the deficiency of the progranulin (PGRN) protein, which has been associated with various neurodegenerative diseases. Using this multiomics platform, we evaluated the impact of PGRN deficiency on iPSCs and neurons at the whole-cell level. Proteomics, lipidomics, and metabolomics analyses implicated PGRN\'s roles in neuroinflammation, purine metabolism, and neurite outgrowth, revealing commonly altered pathways related to neuron projection, synaptic dysfunction, and brain metabolism. Multiomics data sets also pointed toward the same hypothesis that neurons seem to be more susceptible to PGRN loss compared to iPSCs, consistent with the neurological symptoms and cognitive impairment from patients carrying inherited GRN mutations.