Inference of Differentiation Decision Times from Blood Stem Cell Genealogies

从血液干细胞谱系推断分化决策时间

• 批准号: 251151982
• 负责人: Dr. Carsten Marr
• 金额: --
• 依托单位: Institute of AI for Health (AIH)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/251151982?language=en
• 关键词: Inference; Differentiation; Decision; Times; Blood

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.

在造血干细胞中，分化可以通过表达适当的荧光标记蛋白来实验性地评估。在细胞决定和观察到的荧光信号之间，存在一定的延迟。在这个项目中，我们希望从造血谱系中的标记起始推断分化的确切时间。姐妹细胞、表亲细胞等之间的标志物起始的同步性允许解开所涉及的两个过程：分化决定和标志物激活。我们将首先从一个生成模型中生成系谱，在这个模型中我们考虑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Schroeder实验室，干细胞动力学研究单位，Helmholtz Zentrum München）。这些树是从单细胞跟踪的延时显微镜数据和标记的起始被注释或定量确定。树推理方法的发展和应用将使我们能够在每个系谱中指定决策时间。从这一点，我们将描绘标记激活的分子机制，谱系决定因子的作用，和细胞分化的可能空间效应。该项目开发的方法可以转移到任何分化和异质细胞群体的细胞谱系和任意分化证据，如特定条件下的形态学变化或凋亡。