Abstract
Homeostasis of neutrophils—the blood cells that respond first to infection and tissue injury—is critical for the regulation of immune responses and regulated through granulopoiesis, a multi-stage process by which neutrophils differentiate from hematopoietic stem cells. Granulopoiesis is a highly dynamic process and altered in certain clinical conditions, such as pathologic and iatrogenic neutropenia, described as demand-adapted granulopoiesis. The regulation of granulopoiesis under stress is not completely understood because studies of granulopoiesis dynamics have been hampered by technical limitations in defining neutrophil precursors. Here, we define a population of neutrophil precursor cells in the bone marrow with unprecedented purity, characterized by the lineage−CD11b+Ly6GloLy6BintCD115−, which we call NeuPs (Neutrophil Precursors). We demonstrated that NeuPs differentiate into mature and functional neutrophils both in vitro and in vivo. By analyzing the gene expression profiles of NeuPs, we also identified NeuP stage-specific genes and characterized patterns of gene regulation throughout granulopoiesis. Importantly, we found that NeuPs have the potential to proliferate, but the proliferation decreased in multiple different hematopoietic stress settings, indicating that proliferating NeuPs are poised at a critical step to regulate granulopoiesis. Our findings will facilitate understanding how the hematopoietic system maintains homeostasis and copes with the demands of granulopoiesis.
Highlights
Certain clinical conditions lead to neutropenia, which triggers demand-adapted granulopoiesis[16,17]
It has been reported that the levels of granulopoietic cytokines, including granulocyte colony-stimulating factor (G-CSF), are upregulated in human patients suffering from anemia, leukemia, or infections[18,19,20]
Neutrophils expressing Ly6G at high levels in the lineage-negative populations were excluded and the remaining CD11b+ cells were further analyzed based on the expression level of CD115 and Ly6B
Summary
Certain clinical conditions lead to neutropenia, which triggers demand-adapted granulopoiesis[16,17]. Non-infectious settings such as myeloablation due to chemotherapy or ionizing radiation, allergic responses, or autoimmune disorders can cause neutropenia and activate a different type of demand-adapted granulopoiesis called reactive granulopoiesis[17] Exquisite regulation of these processes is critical for resolving the clinical condition. In steady state, signaling via G-CSF and its receptor, G-CSFR, maintains circulating neutrophil numbers by enhancing the proliferation and differentiation of precursors[12,23,24,25,26,27,28,29,30], as well as by increasing the survival[29,31,32] and mobilization of mature neutrophils[25,27,28,33,34,35]. Understanding the mechanisms underlying granulopoiesis is essential for resolving clinical conditions that induce aberrant neutrophil numbers, and requires isolation of precursors with high purity and in-depth genomic analysis of the developmental stage. We found that NeuPs are proliferative precursor cells and the proliferation of NeuPs decreased during demand-adapted granulopoiesis, demarcating the NeuP stage as a critical common regulatory point under hematopoietic stress
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