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 2

Bone marrow DC ablation induces a loss of macrophages and HSPC mobilization.

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Bone marrow DC ablation induces a loss of macrophages and HSPC mobilizat...
(A) Expression of GFP in bone marrow monocytes (Gr-1lo B220– CD115+ cells), macrophages (Gr-1lo B220– MHC-II+ F4/80+ cells), and DCs (Gr-1lo B220– MHC-IIhi CD11chi cells) from Zbtb46gfp mice is shown. FMO, fluorescence minus one control. (B) Zbtb46dtr bone marrow chimeras were treated with DT for 1 day (n = 5 mice), 2 days (n = 5 mice), 6 days (n = 12 mice), or with PBS (day 0) (n = 11 mice), and BM DCs and macrophages were quantified. (C, D) Mixed bone marrow chimeras containing WT and Zbtb46dtr cells were treated with PBS or DT for 6 days, and the number of DCs (C) and macrophages (D) in the bone marrow that were derived from WT or Zbtb46dtr (Zbtb46-DTR) cells were quantified (n = 5 mice per cohort). (E–H) Zbtb46dtr, CD169dtr (CD169-DTR), and CD169dtr × Zbtb46dtr (CD169/Zbtb46-DTR) chimeras were treated with PBS or DT for 6 days, and the number of lineage- sca1+ c-kit+ (KSL) cells (E) (n = 11, 15, 18, 16 mice) or CD150+ CD48– KSL (KSL-SLAM) cells in the spleen (F) (n = 8, 10, 14, 13 mice) and the number of colony-forming cells (CFU-C) in spleen (G) (n = 14, 13, 12, 15 mice) or blood (H) (n = 15, 14, 12, 16 mice) were quantified. (I) CD11cdtr chimeras were treated with DT for 1 day (n = 3 mice), 6 days (n = 10 mice), or with PBS (n = 10 mice), and BM DCs and macrophages were quantified by flow cytometry. (J–L) CD11cdtr bone marrow chimeras were treated with saline or diphtheria toxin (DT) for 6 days, and the number of CFU-C in bone marrow (J), spleen (K), and blood (L) was quantified (n = 10 mice per cohort). Data are mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 compared with PBS-treated or day 0 mice. Significance was determined using an ANOVA with Tukey’s Honest Significant Difference post hoc analysis for C, E–H, a 2-way ANOVA for B, I, or an unpaired Student’s t test for J–L.