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 4

Bone marrow DC ablation induces vascular endothelium permeability and expansion in the bone marrow.

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Bone marrow DC ablation induces vascular endothelium permeability and ex...
(A, B) Representative photomicrographs of femur sections from Zbtb46dtr bone marrow chimeras treated with PBS (left), 1 day of DT (1D-DT, middle) or 6 days of DT (6D-DT, right). (A) FITC-conjugated bovine serum albumin (BSA) was injected intravenously into mice 15 minutes before sacrifice. Sections were imaged for FITC-BSA (green) and VE-cadherin+/CD31+ endothelial cells (red). (B) Sections were imaged for VE-cadherin+/CD31+ endothelial cells (red) and counterstained with DAPI to highlight nuclei (blue). Original magnification, ×200. (C) The ratio of extravascular FITC-BSA to intravascular FITC-BSA was quantified and normalized to the PBS-treated cohort (n = 9, 8, 7 mice). (D, E) Histomorphometry (D) (n = 9, 8, 7 mice) or flow cytometry (E) (n = 4 or 6 mice) was used to quantify endothelium or endothelial cells in the bone marrow; endothelial cells were identified by flow cytometry as lineage– (CD45, Ter119, Gr-1) CD31+ cells. Data are mean ± SEM. *P < 0.05; **P < 0.01 compared with PBS-treated mice. Significance was determined using an ANOVA with Tukey’s Honest Significant Difference post hoc analysis for C and D, or an unpaired Student’s t test for E.