Abstract: Defining how the bone marrow functions under stress is indispensable to understand hematopoiesis during disease. A major limitation in the field is that most studies (including those from our group) have ignored the fact that hematopoiesis takes place in multiple bones. Instead, the field has largely focused on investigating hematopoiesis in long bones – as these are readily accessible and yield large amounts of hematopoietic cells for analyses- and assumed that the rest of the skeleton behaved in a similar manner. We have demonstrated that the bone marrow response to a hematopoietic insult is dramatically different depending on the bone examined. In this proposal we want to understand the cellular mechanisms driving these heterogeneous responses. We have found that -after treatment with G-CSF- the sternum shows reduced numbers of neutrophils and neutrophil progenitors while long bones show expansions in these populations. In response to hemorrhage both the sternum and the tibia increase erythrocyte production, however, the skull fails to increase erythropoiesis. Based on this we hypothesize: a) the bone marrow response to stress is variable across the skeleton; b) some bones have specialized to preferentially respond to specific insults; c) this is non-autonomously regulated by the unique composition -and anatomy- of the microenvironment in each bone. We will test this hypothesis in two aims. In Aim 1 we will determine how bone marrow macrophages control the differential response to G-CSF in sternum vs long-bones. In Aim 2 we will whether competition between erythroid progenitors and trabecular bone controls stress erythropoiesis.