The microenvironment in bone marrow hematopoiesis

Abstract: Blood cell production takes place via stepwise differentiation from hematopoietic stem cells into multipotent progenitors that give rise to unipotent progenitors responsible for producing each of the major blood cell lineages (lymphocytes, monocytes, neutrophils, and red blood cells). This process takes place inside the marrow of the bone where a unique microenvironment provides supportive and regulatory signals that regulate stepwise blood cell differentiation. We and others have shown that the bone marrow microenvironment is spatially and functionally heterogeneous and contains local structures with diverse and unique functions in homeostatic, inflammatory, and regenerative hematopoiesis. Our ability to manipulate hematopoiesis to treat disease has been hampered by our lack of understanding of these anatomical cues. Our long-term research objective is to define the physiology of blood cell production in the bone marrow tissue in homeostasis and stress. My short- and medium-term research program (the focus of this proposal) will test the hypothesis that the bone marrow has a high degree of spatial organization; it contains discrete specialized vascular microenvironments -discovered by us using new imaging approaches- that recruit and regulate myeloid and erythroid progenitors and dictate how the bone marrow functions in homeostasis, inflammation, or regeneration. We will carry out the following complementary 3-part research program in the following areas: (1) Dissect the function of specialized microenvironments that function as niches for each major blood lineage during homeostasis, with a focus on understanding how hematopoietic cells move through different specialized microenvironments as they differentiate. (2) Determine how specialized sinusoids function as “antennas” to sense inflammation and decide which -and how- hematopoietic progenitors respond to inflammation. (3) Discover how hematopoietic stem cells and progenitors engraft in the bone marrow after transplantation and define how two types of specialized microenvironments regulate short-term and long-term hematopoietic recovery after transplantation. Together these studies will provide a new framework for understanding blood differentiation, dissecting hematopoiesis during disease, and designing systems for multilineage blood cell production ex vivo