用组织病理图像生成空间基因表达,保留预训练模型的基因关联性。
Adapting a Pre-trained Single-Cell Foundation Model to Spatial Gene Expression Generation from Histology Images
- 改造预训练单细胞模型,通过轻量调制注入视觉信息。
- 在三个数据集上基因相关性平均相关系数提升,空间表达更准确。
- 适合想低成本生成空间转录组数据的研究者使用。
空间转录组(ST)可实现斑点级原位表达分析,但成本高、通量低,促使人们尝试从HE染色病理图像直接预测基因表达。现有生成方法多忽略基因间依赖关系,影响生物学一致性。单细胞基础模型(sc-FM)在多种细胞类型上预训练,能捕捉关键基因关系,但其缺乏视觉路径,与条件化空间转录组目标不匹配,且混合细胞型监督数据稀缺。为此,我们提出HINGE(HIstology-coNditioned GEneration),通过引入SoftAdaLN轻量调制模块,将层间视觉上下文注入主干网络,并采用表达空间掩码扩散目标和热启动课程策略,确保目标对齐与训练稳定。在三个ST数据集上评估,本方法在平均皮尔逊相关系数上优于现有最优基线,空间标记表达模式更精确,配对共表达一致性更高,为适配预训练sc-FM实现基于病理图像的空间表达生成提供了可行路径。
原文摘要 · Abstract (English)
Spatial transcriptomics (ST) enables spot-level in situ expression profiling, but its high cost and limited throughput motivate predicting expression directly from HE-stained histology. Recent advances explore using score- or flow-based generative models to estimate the conditional distribution of gene expression from histology, offering a flexible alternative to deterministic regression approaches. However, most existing generative approaches omit explicit modeling of gene-gene dependencies, undermining biological coherence. Single-cell foundation models (sc-FMs), pre-trained across diverse cell populations, capture these critical gene relationships that histology alone cannot reveal. Yet, applying expression-only sc-FMs to histology-conditioned expression modeling is nontrivial due to the absence of a visual pathway, a mismatch between their pre-training and conditional ST objectives, and the scarcity of mixed-cell ST supervision. To address these challenges, we propose HINGE (HIstology-coNditioned GEneration), which retrofits a pre-trained sc-FM into a conditional expression generator while mostly preserving its learned gene relationships. We achieve this by introducing SoftAdaLN, a lightweight, identity-initialized modulation that injects layer-wise visual context into the backbone, coupled with an expression-space masked diffusion objective and a warm-start curriculum to ensure objective alignment and training stability. Evaluated on three ST datasets, ours outperforms state-of-the-art baselines on mean Pearson correlation and yields more accurate spatial marker expression patterns and higher pairwise co-expression consistency, establishing a practical route to adapt pre-trained sc-FMs for histology-conditioned spatial expression generation.
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