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

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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.