Granulopoiesis in the Control of Hematopoietic Stem Cell Self-Renewal and Niches

Abstract

The bone marrow (BM) vasculature is a critical component of the hematopoietic stem cell (HSC) niche. While the mechanisms through which the vasculature regulates HSC are intensively studied little is known about how this vascular niche is regulated and its function in supporting other aspects of hematopoiesis. We have recently shown that, after myeloablation, BM neutrophils are both sufficient and necessary for the regeneration of the vascular niche. This crosstalk is dependent of TNFα secretion by the neutrophil and TNFR1/TNFR2 expression in the stroma (Bowers et al., 2018). We now demonstrate that the crosstalk between neutrophils and the vasculature is bidirectional and that bone marrow endothelial cells provide a niche for fast neutrophil production in response to stress. Emergency granulopoiesis (EG) is the process through which the hematopoietic system generates large neutrophil numbers-at the expense of lymphocyte production-in response to inflammation or infection. A key EG driver is IL1. This cytokine can induce a myeloid bias on HSC and this is thought to be the main mechanism for IL1-driven EG. While characterizing the BM response to IL1 treatment we noted a fourfold reduction in erythropoiesis. Since erythroid- and myeloid- lineage cells differentiate from a common myeloid progenitor downstream of the HSC these results indicated that IL1 acted on other cells during EG. Differentiation analyses showed that IL1 blocks B cell differentiation at the common lymphoid progenitor and Pro-B to Pre-B transition stages whereas loss of erythropoiesis is detected at the pre-MegE stage and remains suppressed through terminal reticulocyte differentiation. IL1 signals, exclusively, through the IL1 receptor (IL1R1). Using reciprocal transplants and mixed chimera experiments we demonstrate that IL1R1 expression in hematopoietic cells is completely dispensable for IL1-driven neutrophil production. Instead, IL1 acts on stromal cells to increase neutrophil production and diminish lymphocyte and erythrocyte production. Our analyses revealed that, in the stroma, only LepR+ perivascular cells and endothelial cells express IL1R1. Conditional Il1r1 deletion in LepR+ cells did not abrogate any of the hematopoietic phenotypes. However, conditional Il1r1 deletion in endothelial cells completely abrogated neutrophil production but did not prevent loss of erythroid and lymphoid lineages. Differentiation analyses showed that, after exposure to IL1, endothelial cells force the differentiation of immature, unipotent, neutrophil progenitors into terminally differentiated neutrophils. These studies thus demonstrate that endothelial cells provide a niche that is indispensable for neutrophil production during EG. This endothelial niche also uncouples neutrophil production from suppression of other hematopoietic lineages opening the door to targeting this pathway to selectively regulate neutropoiesis. Finally these data also highlight the bidirectional communication between the vascular niche and bone marrow neutrophils during stress.Bowers E, Slaughter A, Frenette PS, Kuick R, Pello OM, Lucas D. Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow. Nat Med. 2018;24:95-102 DisclosuresNo relevant conflicts of interest to declare.