Cytokines and lineage choice in hematopoietic precursors

翻译后摘要：人CD34+造血前体细胞可以很容易地从外周血中获得， 成年人了用各种细胞因子混合物处理这些细胞可以诱导细胞的有效产生 沿着红系、巨核系或髓系分化沿着。我们发现不同的细胞因子鸡尾酒诱导 基因表达的快速和广泛的变化模式对于不同的细胞因子鸡尾酒是不同的。 这些变化的显著性表明它们发生在大部分CD 34+细胞中，并且可能 调节单个细胞的分化模式。最近发展的方法， mRNA表达和单细胞DNA甲基化的整体测量使得研究 细胞因子在谱系促进中的作用在特异性水平上迄今尚不清楚。在本申请中 我们建议使用单细胞基因组规模分析和细胞标记的组合， 确定相同细胞是否可以对不同细胞因子治疗产生不同反应的方法， 研究这些不同的反应是否导致沿着交替谱系的分化。最终 目的是确定对谱系特异性细胞因子的早期转录反应的性质，以及是否 这些对于世系规范是指导性的以及许可性的。

Abstract: Human CD34+ hematopoietic precursor cells can readily be obtained from the peripheral blood of adults. Treatment of these cells with various cytokine cocktails can induce efficient production of cells differentiated along erythroid, megakaryocytic or myeloid lines. We find that different cytokine cocktails induce rapid and extensive patterns of change in gene expression that are different for different cytokine cocktails. The prominence of these changes suggests that they occur in a large fraction of the CD34+ cells and may modulate the patterns of differentiation of individual cells. The recent development of methods that permit global measurements of mRNA expression, and DNA methylation in single cells make it possible to investigate the role of cytokines in lineage promotion at a level of specificity hitherto unavailable. In the present application we propose to use a combination of single cell genomic scale analyses, and cell tagging and labeling approaches to establish if the same cell can respond differently to different cytokine treatments, and to investigate whether these different responses result in differentiation along alternate lineages. The ultimate goal is to determine the nature of early transcriptional responses to lineage specific cytokines and whether these are instructional as well as permissive for lineage specification.