本研究系统性地探索了通过结合神经元前体转录因子与形态发生素,从诱导性多能干细胞(iPSCs)中生成多样化人类神经元亚型的方法。研究人员设计了一套高通量筛选策略,利用单细胞RNA测序技术分析了近70万个细胞,覆盖了480种不同的形态发生素组合,从而识别出与人体内神经元相似的多种诱导性神经元(iNs)亚型,这些亚型在形态、功能和转录组上都表现出独特性。文章还深入揭示了形态发生素如何通过激活特定的基因调控网络来引导神经元分化,并通过基因敲除和过表达实验验证了这些调控网络的必要性和充分性。此外,研究比较了在诱导转录因子之前或之后进行模式化的不同方案,发现前者能产生更接近原代人类神经元的均匀细胞群。最后,此研究提出了一种普适性的策略,可用于编程其他多样化的细胞亚型,为理解人类生物学、疾病机制和未来细胞治疗提供了宝贵的数据集和方法论。References: Hsiu-Chuan Lin et al. Human neuron subtype programming via single-cell transcriptome-coupled patterning screens.Science389,eadn6121(2025).DOI:10.1126/science.adn6121
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