Role of the local vascular microenvironment in the bone marrow response to inflammation

摘要： 骨髓(BM)炎症是造血干细胞和祖细胞(HSPC)老化的驱动因素， 转化，骨髓衰竭，也是先天性免疫反应不可缺少的感染。的作用 炎症反应中的微环境尚不完全清楚。我们发现这种独一无二的 骨髓血管亚群不同地调节中性粒细胞或树突状细胞的产生 发炎。我们想了解微环境的局部结构是如何控制的--以及 HSPC对感染/炎症的反应方式。 我们发现CSF1+血管通过以下途径调节紧急树突状细胞的产生 靶向髓系树突状细胞前体细胞(MDP)，而IL1R1+血管调节多潜能祖细胞 并承诺粒系祖细胞对IL1的反应。我们假设“这座城市的当地建筑 骨髓血管微环境控制HSPC对感染/炎症反应的方式和方式。独一无二 BM血管的子集是细胞天线，可以感知不同的炎性侮辱并控制承诺 以及相邻HSPC作为对这些侮辱的反应的区分。IL1R1+和CSF1+血管是两个 这些蜂窝天线的例子“ 我们将在三个目标上检验这一假设。在目标1中，我们将研究不同的血管如何在空间上 组织造血，并检验这样一种假设，即每条血管的接近程度决定了哪个祖细胞 对感染/炎症做出反应。在AIM2中，我们将研究每种类型的 血管调节HSPSC的功能和分化。在目标3中，我们将确定每种类型的船只如何 感知并对不同类型的感染/炎症作出反应，并检验每条血管都有 进化到能感觉到特定的侮辱。

Abstract: Bone marrow (BM) inflammation is a driver of hematopoietic stem and progenitor cell (HSPC) aging, transformation, and marrow failure but also indispensable for innate immune responses to infection. The role of the microenvironment in the response to inflammation is incompletely understood. We found that unique subsets of marrow vessels differentially regulate neutrophil or dendritic cell production in respond to inflammation. We want to understand how the local architecture of the microenvironment controls which –and how- HSPC respond to infection/inflammation. We have found that CSF1+ vessels regulate emergency dendritic cell production in response to infection by targeting myeloid dendritic cell progenitors (MDP) whereas IL1R1+ vessels regulate multipotent progenitors and committed granulocyte progenitors in response to IL1. We hypothesize “that the local architecture of the BM vascular microenvironment controls which-and how- HSPC respond to infection/inflammation. Unique subsets of BM vessels are cellular antennas that sense different inflammatory insults and control commitment and differentiation of adjacent HSPC in response to these insults. IL1R1+ and CSF1+ vessels are two examples of these cellular antennas” We will test this hypothesis in three aims. In Aim 1 we will investigate how the different vessels spatially organize hematopoiesis and test the hypothesis that proximity to each vessel dictates which progenitor responds to infection/inflammation. In Aim2 we will investigate the mechanisms through which each type of vessel regulates HSPSC function and differentiation. In Aim 3 we will determine how each type of vessel senses and responds to different types of infection/inflammation and test the hypothesis that each vessel has evolved to sense specific insults.