A time- and single-cell-resolved model of murine bone marrow hematopoiesis.

Cell stem cell Pub Date : 2024-02-01 Epub Date: 2024-01-05 DOI:10.1016/j.stem.2023.12.001
Iwo Kucinski, Joana Campos, Melania Barile, Francesco Severi, Natacha Bohin, Pedro N Moreira, Lewis Allen, Hannah Lawson, Myriam L R Haltalli, Sarah J Kinston, Dónal O'Carroll, Kamil R Kranc, Berthold Göttgens
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Abstract

The paradigmatic hematopoietic tree model is increasingly recognized to be limited, as it is based on heterogeneous populations largely defined by non-homeostatic assays testing cell fate potentials. Here, we combine persistent labeling with time-series single-cell RNA sequencing to build a real-time, quantitative model of in vivo tissue dynamics for murine bone marrow hematopoiesis. We couple cascading single-cell expression patterns with dynamic changes in differentiation and growth speeds. The resulting explicit linkage between molecular states and cellular behavior reveals widely varying self-renewal and differentiation properties across distinct lineages. Transplanted stem cells show strong acceleration of differentiation at specific stages of erythroid and neutrophil production, illustrating how the model can quantify the impact of perturbations. Our reconstruction of dynamic behavior from snapshot measurements is akin to how a kinetoscope allows sequential images to merge into a movie. We posit that this approach is generally applicable to understanding tissue-scale dynamics at high resolution.

Abstract Image

小鼠骨髓造血的时间和单细胞分辨模型
人们越来越认识到,典型的造血树模型是有局限性的,因为它是建立在异质群体的基础上的,而异质群体主要是由测试细胞命运潜能的非同源试验确定的。在这里,我们将持续标记与时间序列单细胞 RNA 测序相结合,为小鼠骨髓造血建立了一个实时、定量的体内组织动态模型。我们将级联单细胞表达模式与分化和生长速度的动态变化结合起来。由此产生的分子状态与细胞行为之间的明确联系,揭示了不同品系之间千差万别的自我更新和分化特性。移植干细胞在红细胞和中性粒细胞生成的特定阶段显示出强烈的分化加速,说明了该模型如何量化扰动的影响。我们从快照测量中重建动态行为的方法,类似于动态显微镜如何将连续图像合并成一部电影。我们认为这种方法普遍适用于以高分辨率理解组织尺度的动态变化。
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