Inference of Differentiation Decision Times from Blood Stem Cell Genealogies

在造血干细胞中，分化可以通过适当的荧光标记蛋白的表达来实验评估。细胞的决定与观测到的荧光信号之间存在一定的延迟。在这个项目中，我们想从造血谱系中的标记开始推断分化的确切时间。在姐妹细胞、表兄弟细胞等之间的标记启动同步允许解开涉及的两个过程：分化决定和标记激活。我们将首先从生成模型中生成谱系，其中我们考虑了两个过程的不同分子机制。与此同时，我们对小鼠血细胞谱系进行后处理和分析（来自Helmholtz zentrummnchen干细胞动力学研究部门的schroeder实验室）。这些树是由单细胞跟踪的延时显微镜数据产生的，标记开始是有注释的或定量确定的。树推理方法的发展和应用将使我们能够指定每个谱系中的决策时间。由此，我们将描述标记激活的分子机制，谱系决定因素的作用，以及可能对细胞分化的空间影响。本项目开发的方法可以转移到分化和异质细胞群体的任何细胞谱系和任意分化证据，如特定条件下的形态变化或凋亡。

In blood stem cells, differentiation can be experimentally assessedvia the expression of an appropriate fluorescent marker protein.Between the cellular decision and the observed fluorescent signal, acertain delay is involved. In this project, we want to infer the exacttime of differentiation from the marker onsets in hematopoieticgenealogies. The synchrony of marker onsets between sister cells,cousin cells, etc. allows disentangling the two processes involved:differentiation decision and marker activation. We will first generategenealogies from a generative model where we consider differentmolecular mechanism for the two processes. In parallel, wepost-process and analyze mouse blood cell genealogies (from theSchroeder lab, Stem Cell Dynamics research unit, Helmholtz ZentrumMünchen). These trees are generated from single-cell tracking oftime-lapse microscopy data and marker onset is either annotated orquantitatively determined. Development and application of treeinference methods will allow us to specify the decision time in eachgenealogy. From this we will delineate molecular mechanisms of markeractivation, the role of lineage determining factors, and possiblespatial effects on cellular differentiation. The methods developed inthis project can be transferred to any cellular genealogies ofdifferentiating and heterogeneous cell populations and arbitrarydifferentiation evidence, like morphological change or apoptosis in aspecific condition.