Spatial Control of Myeloid Differentiation

摘要： 越来越多的证据表明，谱系决定由支持分化的当地结构控制 在骨髓的不同区域。我们操纵造血来治疗疾病的能力 由于我们对这些解剖线索缺乏理解而受到阻碍。 我们发现在骨髓中HPC是有区域组织的，祖细胞和未成熟细胞属于 到相同的血统，分离到不同的正弦。我们还发现，有一个地区性组织 CSF1产生和特定的BM血管是CSF1的关键来源，CSF1调节MDP、单核细胞和 树突状细胞，而不是HSC或巨噬细胞。中心假设是正弦波的不同子集 作为装配线或枢纽，通过组织和维护不同的造血血统 产生特定血统的细胞因子。我们想要了解这些蜂窝装配线是如何在 急性髓系白血病(AML)的稳态和扰动后。 我们将在两个目标上检验这一假设。在目标1中，我们将确定这些装配线的生理学 使用克隆命运原位映射；识别每条装配线的组件；并有条件地删除 来自每条装配线关键部件的特定细胞因子。在目标2中，我们将研究AML是如何抑制 通过扰乱支持每条流水线的微环境来实现正常的造血。

Abstract: Mounting evidence indicates that lineage decisions are controlled by local structures that support differentiation in distinct regions of the bone marrow. Our ability to manipulate hematopoiesis to treat disease has been hampered by our lack of understanding of these anatomical cues. We have found that HPC are regionally organized in the BM and that progenitors and immature cells belonging to the same lineage segregate to different sinusoids. We have also found that there is regional organization to CSF1 production and that specific BM vessels are critical sources of CSF1 that regulate MDP, monocytes and dendritic cells but not HSC or macrophages. The central hypothesis is that different subsets of sinusoids function as assembly lines or hubs that organize and maintain different hematopoietic lineages through the production of lineage-specific cytokines. We want to understand how these cellular assembly lines function in the steady-state and after perturbation by acute myeloid leukemia (AML). We will test this hypothesis in two aims. In Aim 1 we will determine the physiology of these assembly lines using clonal fate mapping in situ; identifying the components of each assembly line; and conditionally deleting specific cytokines from key components of each assembly line. In Aim 2 we will investigate how AML inhibits normal hematopoiesis by perturbing the microenvironment that supports each assembly line.