arXiv:2603.25240q-bio.QMcs.AI2026-03被引 5

用生成模型模拟细胞状态,预测基因扰动后的表达变化。

Lingshu-Cell: A generative cellular world model for transcriptome modeling toward virtual cells

  • 基于离散扩散模型直接处理单细胞数据,无需预先筛选基因。
  • 在18000个基因上捕捉复杂表达依赖关系,准确还原细胞亚型比例。
  • 可预测新组合的身份与扰动下的全转录组响应,适合药物筛选研究。

构建细胞状态并预测其对扰动的响应是计算生物学和虚拟细胞开发的核心挑战。现有单细胞转录组基础模型虽能提供强大静态表征,但未显式建模细胞状态分布以支持生成模拟。我们提出Lingshu-Cell,一种掩码离散扩散模型,学习转录组状态分布,并支持条件模拟扰动响应。该模型直接在离散标记空间运行,兼容单细胞转录组数据稀疏非序列特性,在约18,000个基因上捕捉全转录组表达依赖关系,无需依赖高变性或表达水平排序等基因筛选。在多种组织与物种中,Lingshu-Cell准确再现转录组分布、标志基因表达模式及细胞亚型比例,展现对复杂细胞异质性的建模能力。通过联合嵌入细胞类型或供体身份与扰动信息,可预测身份与扰动新组合下的全转录组变化。在虚拟细胞挑战赛H1遗传扰动基准测试及人外周血单核细胞(PBMCs)细胞因子诱导响应预测中表现领先。这些结果确立了Lingshu-Cell作为灵活的细胞世界模型,为细胞状态与扰动响应的体外模拟奠定基础,开启生物发现与扰动筛选新范式。

原文摘要 · Abstract (English)

Modeling cellular states and predicting their responses to perturbations are central challenges in computational biology and the development of virtual cells. Existing foundation models for single-cell transcriptomics provide powerful static representations, but they do not explicitly model the distribution of cellular states for generative simulation. Here, we introduce Lingshu-Cell, a masked discrete diffusion model that learns transcriptomic state distributions and supports conditional simulation under perturbation. By operating directly in a discrete token space that is compatible with the sparse, non-sequential nature of single-cell transcriptomic data, Lingshu-Cell captures complex transcriptome-wide expression dependencies across approximately 18,000 genes without relying on prior gene selection, such as filtering by high variability or ranking by expression level. Across diverse tissues and species, Lingshu-Cell accurately reproduces transcriptomic distributions, marker-gene expression patterns and cell-subtype proportions, demonstrating its ability to capture complex cellular heterogeneity. Moreover, by jointly embedding cell type or donor identity with perturbation, Lingshu-Cell can predict whole-transcriptome expression changes for novel combinations of identity and perturbation. It achieves leading performance on the Virtual Cell Challenge H1 genetic perturbation benchmark and in predicting cytokine-induced responses in human PBMCs. Together, these results establish Lingshu-Cell as a flexible cellular world model for in silico simulation of cell states and perturbation responses, laying the foundation for a new paradigm in biological discovery and perturbation screening.

虚拟细胞生成模型单细胞转录组

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