Human Bone Marrow Adipocytes Block Granulopoiesis through Neuropilin-1-induced G-CSF Inhibition

¹ Departments of Cytology & Histology and Pathological Anatomy (Giga-R), University of Liege, CHU-B23, 4000 Liège, Belgium. CNRS UMR 8147; Université Paris V René Descartes, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France.
² CNRS UMR 8147; Université Paris V René Descartes, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France.
³ Departments of Cytology & Histology and Pathological Anatomy (Giga-R), University of Liege, CHU-B23, 4000 Liège, Belgium.
⁴ Service de Biochimie et Hormonologie, Hôpital Tenon, 4 rue de la Chine, 75970 Paris Cedex 20, France.
⁵ Laboratory of Hematobiology and Immunohematology (GIGA-R), University of Liege, Belgium.
⁶ Laboratory of Connective Tissue Biology (GIGA-R), University of Liege, CHU-B23, 4000 Liège, Belgium.
⁷ Laboratory of Hematology EMI 0210; Université Paris V René Descartes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France.
⁸ CNRS UMR 8147; Université Paris V René Descartes, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France. Department of Clinical Hematology, Université Paris V René Descartes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France.

^* To whom correspondence should be addressed. E-mail: hermine{at}necker.fr.

	Abstract

Adipocytes are part of hematopoietic microenvironment, even though up to now in humans, their role in hematopoiesis is still questioned. We have previously shown that accumulation of fat cells in femoral bone marrow (BM) coincides with increased expression of neuropilin-1 (NP-1), while it is weakly expressed in hematopoietic iliac crest BM. Starting from this observation, we postulated that adipocytes might exert a negative effect on hematopoiesis mediated through NP-1. To test this hypothesis, we set up BM adipocytes differentiated into fibroblast-like fat cells (FLFC), which share the major characteristics of primitive unilocular fat cells, as an experimental model. As expected, FLFCs constitutively produced M-CSF and induced CD34+ differentiation into macrophages independently of cell-to-cell contact. By contrast, granulopoiesis was hampered by cell-to-cell contact but could be restored in transwell culture conditions, together with G-CSF production. Both functions were also recovered when FLFCs cultured in contact with CD34+ cells were treated with an antibody neutralizing NP-1, which proved its critical implication in contact inhibition. An inflammatory cytokine, such as IL-1 or dexamethasone modulate FLFCs properties to restore granulopoiesis. Our data provide the first evidence that primary adipocytes exert regulatory functions during hematopoiesis that might be implicated in some pathological processes.