title: Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche.
abstract: Hematopoietic stem cells (HSCs) reside in specialized bone marrow (BM) niches regulated by the sympathetic nervous system (SNS). Here, we have examined whether mononuclear phagocytes modulate the HSC niche. We defined three populations of BM mononuclear phagocytes that include Gr-1(hi) monocytes (MOs), Gr-1(lo) MOs, and macrophages (MΦ) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MΦ conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced BM CXCL12 levels, the selective down-regulation of HSC retention genes in Nestin(+) niche cells, and egress of HSCs/progenitors to the bloodstream. Furthermore, specific depletion of CD169(+) MΦ, which spares BM MOs, was sufficient to induce HSC/progenitor egress. MΦ depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor. These results highlight two antagonistic, tightly balanced pathways that regulate maintenance of HSCs/progenitors in the niche during homeostasis, in which MΦ cross talk with the Nestin(+) niche cell promotes retention, and in contrast, SNS signals enhance egress. Thus, strategies that target BM MΦ hold the potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly.
authors.affiliation: Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chow
authors.forename: Daniel
authors.initials: D
authors.lastname: Lucas
authors.forename: Andrés
authors.initials: A
authors.lastname: Hidalgo
authors.forename: Simón
authors.initials: S
authors.lastname: Méndez-Ferrer
authors.forename: Daigo
authors.initials: D
authors.lastname: Hashimoto
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheiermann
authors.forename: Michela
authors.initials: M
authors.lastname: Battista
authors.forename: Marylene
authors.initials: M
authors.lastname: Leboeuf
authors.forename: Colette
authors.initials: C
authors.lastname: Prophete
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Masato
authors.initials: M
authors.lastname: Tanaka
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D003114:Colony-Forming Units Assay; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006706:Homeostasis / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000276:immunology; D011971:Receptors, Immunologic / Q000378:metabolism*; D063267:Sialic Acid Binding Ig-like Lectin 1
chemical_list: D054377:Chemokine CXCL12; D017931:DNA Primers; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse; D016753:Interleukin-10