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

Abstract

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.

Graphical abstract

Figure 1

Neutrophil production in the BM. The recognized stages of stem cell differentiation that contribute to neutropoiesis are indicated by the names of the neutrophil progenitors in color. Bifurcations into nonneutrophil-producing lineages are indicated in gray. Importantly, the differentiation occurs in a gradual manner (priming) rather than as discrete steps associated with division. The dominant lineage-determining transcription factors are indicated in blue. The first bias toward neutropoiesis starts with a slow and gradual commitment of MPP3s toward the myeloid lineage. MPP3s can proliferate or differentiate into GMPs, which can proliferate and/or physically cluster together into loose patchecs (p) of GMP. This clustering facilitates differentiation into compact clusters of (c)GMP that, in turn, differentiate into promyelocytes and myelocytes, thereby forming clusters of these cells in the BM. During these last differentiation steps, the progenitors lose their propensity to proliferate (mediated by the expression of C/EBPε) and continue to mature toward mature neutrophils via metamyelocytes and banded cells (see Figure 2). CDP, common dendritic cell progenitor; cMoP, common monocyte progenitor; EGR1/2, early growth response ½; GATA1/2, GATA binding receptor ½; IRF8, interferon regulatory factor-8; MDP, monocyte/macrophage/DC; NAB-2, NGFI-A binding protein 2; preMono, preMonocyte; SCL, stem cell leukemia.

Figure 2

Neutrophil production in the BM under homeostatic conditions. The neutrophil committed compartment in BM consists of dividing progenitors (mitotic pool: promyelocytes and myelocytes) and maturing nondividing progenitors (postmitotic pool: metamyelocytes, banded cells, mature cells, and hypersegmented neutrophils). The postmitotic transfer time is 5 to 6 days., , The origin of functional neutrophil phenotypes is uncertain, but they might be evoked by tissue instructions or parallel differentiation or transdifferentiation.,