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 6

CXCR2 signaling contributes to HSPC mobilization following bone marrow DC ablation.

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CXCR2 signaling contributes to HSPC mobilization following bone marrow D...
(A–C) Human umbilical vein endothelial cells (HUVECs) cultured in a transwell to establish a monolayer were treated with PBS or CXCL1. (B) Relative amount of Evans blue dye in the lower chamber after 1 hour of CXCL1; data are normalized to PBS-treated samples (n = 5 or 6 mice). (C) Human bone marrow CD34+ cells were seeded on the HUVEC monolayer and treated with CXCL1 for 24 hours; the lower chamber contained 100 ng/ml CXCL12. Shown is the percentage of CD34+ cells that migrated to the lower chamber (n = 11–12 replicates). (D–L) Bone marrow cells from Zbtb46dtr mice were transplanted into irradiated WT or Cxcr2–/– recipients. Eight weeks after transplantation, mice were treated with PBS or DT for 6 days. Total cellularity of bone marrow (D) and spleen (E), the number of KSL cells in bone marrow (F) and spleen (G), the number of KSL-SLAM cells in bone marrow (H) and spleen (I), and the number of CFU-Cs in bone marrow (J), spleen (K), and blood (L) is shown (n = 6 per cohort). The WT recipient data are the same as shown in Figure 2. Data are mean ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001 compared with the PBS-treated group, unless otherwise specified. Significance was determined using an unpaired Student’s t test for B and C, or ANOVA with Tukey’s Honest Significant Difference post hoc analysis for D–L.