辛辛那提儿童医院医疗中心H. Leighton Grimes课题组近日取得一项新成果。经过不懈努力，他们开发出统一的多模态单细胞框架揭示了小鼠造血的离散状态模型。2025年10月22日出版的《自然—免疫学》杂志发表了这项成果。

为了解决这个问题，研究团队提出了一个框架，该框架将多模态单细胞分析（RNA，表面蛋白和染色质）与高维流式细胞术相结合，并实现了不同细胞状态的半自动富集和功能表征。他们的方法将转录因子表达与染色质活性结合起来，揭示了驱动这些状态的分层基因调控网络。该课题组圈定并分离了稀有骨髓Lin⁻Sca⁻CD117⁺CD27⁺多谱系细胞状态（“MultiLin”），验证了预测的谱系轨迹和绘制的分化电位。此外，研究人员研究了转录因子在染色质上的活性，以追踪和分离多系祖细胞，并进行多能到寡能的谱系限制。在提出的稳态造血模型中，离散状态支配着发育轨迹。该框架为分离和表征不同生物系统中的新细胞状态提供了可扩展的解决方案。

研究人员表示，大规模、无偏见的单细胞基因组学研究复杂的发育区室，如造血，已经推断出新的细胞状态和轨迹；然而，由于难以分离出与离散基因组状态相对应的细胞，进一步的表征受到了阻碍。

附：英文原文

Title: A unified multimodal single-cell framework reveals a discrete state model of hematopoiesis in mice

Author: Ferchen, Kyle, Zhang, Xuan, Thakkar, Kairavee, Li, Guangyuan, Bernardicius, David, Sen, Sidharth, Rawat, Priyanka, Olsson, Andre, Bennett, Sierra N., Potter, Crystal, Finkelman, Fred D., Croteau, Josh, Morris, Samantha, Singh, Harinder, Salomonis, Nathan, Grimes, H. Leighton

Issue&Volume: 2025-10-22

Abstract: Large-scale, unbiased single-cell genomics studies of complex developmental compartments, such as hematopoiesis, have inferred novel cell states and trajectories; however, further characterization has been hampered by difficulty isolating cells corresponding to discrete genomic states. To address this, we present a framework that integrates multimodal single-cell analyses (RNA, surface protein and chromatin) with high-dimensional flow cytometry and enables semiautomated enrichment and functional characterization of diverse cell states. Our approach combines transcription factor expression with chromatin activity to uncover hierarchical gene regulatory networks driving these states. We delineated and isolated rare bone marrow LinScaCD117+CD27+ multilineage cell states (‘MultiLin’), validated predicted lineage trajectories and mapped differentiation potentials. Additionally, we used transcription factor activity on chromatin to trace and isolate multilineage progenitors undergoing multipotent to oligopotent lineage restriction. In the proposed model of steady-state hematopoiesis, discrete states governed developmental trajectories. This framework provides a scalable solution for isolating and characterizing novel cell states across different biological systems.

DOI: 10.1038/s41590-025-02307-3

Source: https://www.nature.com/articles/s41590-025-02307-3