The journey of neutropoiesis: how complex landscapes in bone marrow guide continuous neutrophil lineage determination

Neutrophils are the most abundant white blood cell, and they differentiate in homeostasis in the bone marrow from hematopoietic stem cells (HSCs) via multiple intermediate progenitor cells into mature cells that enter the circulation. Recent findings support a continuous model of differentiation in the bone marrow of heterogeneous HSCs and progenitor populations. Cell fate decisions at the levels of proliferation and differentiation are enforced through expression of lineage-determining transcription factors and their interactions, which are influenced by intrinsic (intracellular) and extrinsic (extracellular) mechanisms. Neutrophil homeostasis is subjected to positive-feedback loops, stemming from the gut microbiome, as well as negative-feedback loops resulting from the clearance of apoptotic neutrophils by mature macrophages. Finally, the cellular kinetics regarding the replenishing of the mature neutrophil pool is discussed in light of recent contradictory data.