Physiological recirculation of hematopoietic stem and progenitor cells through blood, lymph and extramedullary tissues

Constitutive egress of bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs) into the blood is a well-established phenomenon, but the ultimate fate and functional relevance of circulating HSPCs is largely unknown. We show that mouse thoracic duct (TD) lymph contains HSPCs that possess short- and long-term multilineage reconstitution capacity. TD-derived HSPCs originate in the BM, enter the blood and traffic to multiple non-lymphoid extramedulary tissues, where they reside for at least 36h until entering draining lymphatics to return to the blood and, eventually, the BM. HSPC egress from extramedullary tissues into lymph depends on sphingosine-1-phosphate (S1P) receptors, particularly S1P 1 . Migratory HSPCs proliferate within extramedullary tissues giving rise to tissue-resident myeloid cells, preferentially dendritic cells. HSPC differentiation is amplified upon exposure to Toll-like receptor agonists. Thus, HSPCs can survey peripheral organs and replenish tissue-resident hematopoietic cells by acting as a source of specialized leukocytes during host defense against pathogens.