Characterization of hematopoietic stem cells in the circulation

Abstract

Hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate into multiple cell lineages, giving rise to all blood components and immune cells, during the entire life of an individual. HSCs are localized in the bone marrow inside specialized compartments named “hematopoietic niches”. The niche contains stromal cells of mesenchymal origin, as is the case of adipocytes and osteoblasts as well as endothelial cells and cells of hematopoietic origin such as macrophages or megakaryocytes (1). All of these cells produce and deposit elements in the extracellular matrix but also secrete local hematopoietic cytokines that can induce or inhibit the proliferation and differentiation of progenitor cells. Early studies described that some of these HSCs are found travelling through the circulation of the organism (2). Additionally, the release of HSCs from the BM into peripheral blood follows circadian patterns, i.e. their numbers oscillate between day and night (3). In the present thesis we have analyzed whether HSCs in the circulation (named here circulating HSCs) have any physiological function and the mechanisms through which cHSCs are released into bloodstream. We have found that circulating HSC have a myeloid bias and are important for the repopulation of damaged niches. In addition, we found that multiple clones of these cHSCs enter the bloodstream and contribute to the regeneration of hematopoiesis in remote niches. We have found that the chemokine receptor CXCR2 is expressed in HSCs and is important for their homeostatic egress into the circulation. Genetic deficiency of Cxcr2 prevents the release of HSCs and the repopulation of remote damaged niches and gives rise to hematopoietic defects with age. Correspondingly, we have identified a population of perivascular cells inside the BM that express the chemokine ligand CXCL1 and could be key in the signaling of cHSC egress, and ultimately in preserving hematopoietic health through life.