Table containing cellular stress gene sets.

Human neural organoids offer an exciting opportunity for studying inaccessible human-specific brain development; however, it remains unclear how precisely organoids recapitulate fetal/primary tissue biology. We characterize field-wide replicability and biological fidelity through a meta-analysis of single-cell RNA-sequencing data for first and second trimester human primary brain (2.95 million cells, 51 data sets) and neural organoids (1.59 million cells, 173 data sets). We quantify the degree primary tissue cell type marker expression and co-expression are recapitulated in organoids across 10 different protocol types. By quantifying gene-level preservation of primary tissue co-expression, we show neural organoids lie on a spectrum ranging from virtually no signal to co-expression indistinguishable from primary tissue, demonstrating a high degree of variability in biological fidelity among organoid systems. Our preserved co-expression framework provides cell type-specific measures of fidelity applicable to diverse neural organoids, offering a powerful tool for uncovering unifying axes of variation across heterogeneous neural organoid experiments.

人类神经类器官（neural organoids）为研究难以获取的人类特异性脑发育过程提供了极具潜力的研究模型，但目前仍尚不明确类器官能够在何种精度下重现胎儿/原代组织的生物学特征。本研究通过对早、中孕阶段人类原代脑组织（295万个细胞，涵盖51个数据集）以及神经类器官（159万个细胞，涵盖173个数据集）的单细胞RNA测序（single-cell RNA-sequencing）数据开展荟萃分析，系统表征了该领域的整体可重复性与生物学保真度。我们针对10种不同培养方案的类器官，量化了其对原代组织细胞类型标志物表达与共表达模式的重现程度。通过量化原代组织共表达模式在基因层面的保留情况，本研究发现神经类器官的共表达特征呈现连续谱系分布，从几乎无信号到与原代组织完全无法区分，这表明不同类器官系统间的生物学保真度存在显著差异。我们构建的共表达保留分析框架可提供适用于各类神经类器官的细胞类型特异性保真度量化指标，为解析异质性神经类器官实验中统一的变异维度提供了强有力的研究工具。