Stem Cell Laboratory, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
Nat Cell Biol. 2012 Feb 19;14(3):287-94. doi: 10.1038/ncb2442.
How the molecular programs of differentiated cells develop as cells transit from multipotency through lineage commitment remains unexplored. This reflects the inability to access cells undergoing commitment or located in the immediate vicinity of commitment boundaries. It remains unclear whether commitment constitutes a gradual process, or else represents a discrete transition. Analyses of in vitro self-renewing multipotent systems have revealed cellular heterogeneity with individual cells transiently exhibiting distinct biases for lineage commitment. Such systems can be used to molecularly interrogate early stages of lineage affiliation and infer rules of lineage commitment. In haematopoiesis, population-based studies have indicated that lineage choice is governed by global transcriptional noise, with self-renewing multipotent cells reversibly activating transcriptome-wide lineage-affiliated programs. We examine this hypothesis through functional and molecular analysis of individual blood cells captured from self-renewal cultures, during cytokine-driven differentiation and from primary stem and progenitor bone marrow compartments. We show dissociation between self-renewal potential and transcriptome-wide activation of lineage programs, and instead suggest that multipotent cells experience independent activation of individual regulators resulting in a low probability of transition to the committed state.
分化细胞的分子程序如何在细胞从多能性通过谱系承诺过渡时发展尚不清楚。这反映了无法访问正在承诺或位于承诺边界附近的细胞。目前尚不清楚承诺是否构成一个渐进的过程，还是代表一个离散的转变。对体外自我更新的多能系统的分析揭示了细胞异质性，个别细胞暂时表现出对谱系承诺的不同偏向。这些系统可用于分子研究谱系归属的早期阶段，并推断谱系承诺的规则。在造血中，基于群体的研究表明，谱系选择受全局转录噪声控制，自我更新的多能细胞可逆地激活全转录组谱系相关程序。我们通过从自我更新培养物、细胞因子驱动的分化以及从原代干细胞和祖细胞骨髓隔室中捕获的单个血细胞的功能和分子分析来检验这一假设。我们发现自我更新潜力和全转录组谱系程序的激活之间存在分离，而是表明多能细胞经历单个调节剂的独立激活，导致向承诺状态转变的可能性很低。
