Bone marrow dendritic cells regulate hematopoietic stem/progenitor cell trafficking
Jingzhu Zhang, … , Kathryn Trinkaus, Daniel C. Link
Jingzhu Zhang, … , Kathryn Trinkaus, Daniel C. Link
Published April 30, 2019
Citation Information: J Clin Invest. 2019;129(7):2920-2931. https://doi.org/10.1172/JCI124829.
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Research Article Hematology

Bone marrow dendritic cells regulate hematopoietic stem/progenitor cell trafficking

Abstract

A resident population of dendritic cells (DCs) has been identified in murine bone marrow, but its contribution to the regulation of hematopoiesis and establishment of the stem cell niche is largely unknown. Here, we show that murine bone marrow DCs are perivascular and have a type 2 conventional DC (cDC2) immunophenotype. RNA expression analysis of sorted bone marrow DCs showed that expression of many chemokines and chemokine receptors is distinct from that observed in splenic cDC2s, suggesting that bone marrow DCs might represent a unique DC population. A similar population of DCs was present in human bone marrow. Ablation of conventional DCs (cDCs) results in hematopoietic stem/progenitor cell (HSPC) mobilization that was greater than that seen with ablation of bone marrow macrophages, and cDC ablation also synergizes with granulocyte–colony stimulating factor to mobilize HSPCs. Ablation of cDCs was associated with an expansion of bone marrow endothelial cells and increased vascular permeability. CXCR2 expression in sinusoidal endothelial cells and the expression of 2 CXCR2 ligands, CXCL1 and CXCL2, in the bone marrow were markedly increased following cDC ablation. Treatment of endothelial cells in vitro with CXCL1 induced increased vascular permeability and HSPC transmigration. Finally, we showed that HSPC mobilization after cDC ablation is attenuated in mice lacking CXCR2 expression. Collectively, these data suggest that bone marrow DCs play an important role in regulating HSPC trafficking, in part, through regulation of sinusoidal CXCR2 signaling and vascular permeability.

Authors

Jingzhu Zhang, Teerawit Supakorndej, Joseph R. Krambs, Mahil Rao, Grazia Abou-Ezzi, Rachel Y. Ye, Sidan Li, Kathryn Trinkaus, Daniel C. Link

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Figure 1

The majority of bone marrow dendritic cells have a cDC2-like phenotype, are enriched in the perivascular region, and have a unique RNA expression profile.

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The majority of bone marrow dendritic cells have a cDC2-like phenotype, ...
(A) Representative flow plots showing the gating strategy used to identify bone marrow monocytes, macrophages, and DCs using Cx3cr1CXgfp/+ mice. (B) The gated monocyte, macrophage, and DC populations were profiled for expression of the indicated lineage markers. FMO, fluorescence minus one control. (C) Representative photomicrographs of femur sections from Cx3cr1gfp/+ mice. Top: CX3CR1-GFP (green) and MCH-II (red). Middle and bottom: CX3CR1-GFP (green), Sca1+ arterioles (red), VE-cadherin+ venous sinusoids and arterioles (white). Yellow arrows indicate DCs. Counterstaining with DAPI highlights nuclei (blue). (D, E) Quantification of the distance from DCs to the nearest venous sinusoid (D) or arteriole (E) (data pooled from n = 3 mice). (F) Representative flow plot showing expression of 2 murine cDC markers, XCR1 for cDC1 and CD11b for cDC2. Data are gated on Gr-1– B220– MHC-IIhi CD11chi DCs. (G) Representative flow plot showing the expression of 2 human cDC markers, CD141 for cDC1 and CD1c for cDC2, on human bone marrow cDCs (n = 3 donors). Data are gated on lineage– CD45+ CD14– CD13+ CD33+ CD11c+ HLA-DR+ DCs. (H) Bone marrow DCs were sorted from Cx3cr1gfp/+ mice as Gr-1– B220– MHC-IIhi CD11chi CX3CR1-GFPhi cells. Heatmap comparing the expression of all chemokines and their receptors expressed in murine BM DCs and spleen (Sp) cDC2s (Gene Expression Omnibus database, accession no. GSE110789) (49). Data are mean ± SEM.