[en] 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 macrophage colony stimulating factor 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 granulocyte colony stimulating factor 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 interleukin-1 beta or dexamethasone modulates FLFC 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. Disclosure of potential conflicts of interest is found at the end of this article.
Belaid-Choucair, Zakia ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie - Cytologie
Lepelletier, Yves
Poncin, Géraldine ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie - Cytologie
Thiry, Albert ; Centre Hospitalier Universitaire de Liège - CHU > Anatomie pathologique
Humblet, Chantal ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie - Cytologie
Maachi, M.
Beaulieu, Aurore ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie - Cytologie
Schneider, Elke
Briquet, Alexandra ; Université de Liège - ULiège > Département des sciences cliniques > Hématologie
Mineur, Pierre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Protéines et glycoprot. de matr.extracell. et membran.basal.
Lambert, Charles ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Protéines et glycoprot. de matr.extracell. et membran.basal.
Mendes-Da-Cruz, Daniella
Ahui, Marie Louise
Asnafi, Vahid
Dy, Michel
Boniver, Jacques ; Centre Hospitalier Universitaire de Liège - CHU > Anatomie pathologique
Nusgens, Betty ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Hermine, Olivier
Defresne, Marie-Paule ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie - Cytologie
Bianco P, Riminucci M, Gronthos S et al. Bone marrow stromal stem cells: Nature, biology, and potential applications. STEM CELLS 2001;19:180-192.
Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood 1993;81:2844-2853.
Heyworth CM, Whetton AD, Nicholls S et al. Stem cell factor directly stimulates the development of enriched granulocyte-macrophage colony-forming cells and promotes the effects of other colony-stimulating factors. Blood 1992;80:2230-2236.
Aglietta M, Pasquino P, Sanavio F et al. Granulocyte-macrophage colony stimulating factor and interleukin 3: Target cells and kinetics of response in vivo. STEM CELLS 1993;11(suppl 2):83-87.
Jacobsen K, Kravitz J, Kincade PW et al. Adhesion receptors on bone marrow stromal cells: In vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and gamma-irradiated mice. Blood 1996;87:73-82.
Metcalf D. The molecular control of proliferation and differentiation in hemopoietic cells. C R Acad Sci III 1993;316:860-870.
Nakamura K, Kosaka M, Mizuguchi T et al. Effect of erythroid differentiation factor on maintenance of human hematopoietic cells in co-cultures with allogenic stromal cells. Biochem Biophys Res Commun 1993;194:1103-1110.
Rafii S, Avecilla S, Shmelkov S et al. Angiogenic factors reconstitute hematopoiesis by recruiting stem cells from bone marrow microenvironment. Ann N Y Acad Sci 2003;996:49-60.
Kume K, Satomura K, Nishisho S et al. Potential role of leptin in endochondral ossification. J Histochem Cytochem 2002;50:159-169.
Hattori H, Ishihara M, Fukuda T et al. Establishment of a novel method for enriching osteoblast progenitors from adipose tissues using a difference in cell adhesive properties. Biochem Biophys Res Commun 2006;343:1118-1123.
Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89:2548-2556.
Gregoire FM. Adipocyte differentiation: From fibroblast to endocrine cell. Exp Biol Med (Maywood) 2001;226:997-1002.
Baratta M. Leptin - From a signal of adiposity to a hormonal mediator in peripheral tissues. Med Sci Monit 2002;8:RA282-RA292.
Fukumura D, Ushiyama A, Duda DG et al. Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis. Circ Res 2003;93:e88-e97.
Hattori K, Sumi T, Yasui T et al. VEGF mRNA in adipocytes increase with rebound weight-gain after diet-restriction. Int J Mol Med 2004;13:395-399.
Frühbeck G, Gomez-Ambrosi J. Modulation of the leptin-induced white adipose tissue lipolysis by nitric oxide. Cell Signal 2001;13:827-833.
Mohamed-Ali V, Goodrick S, Rawesh A et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 1997;82:4196-4200.
Belaid Z, Hubint F, Humblet C et al. Differential expression of vascular endothelial growth factor and its receptors in hematopoietic and fatty bone marrow: Evidence that neuropilin-1 is produced by fat cells. Haematologica 2005;90:400-401.
He Z, Tessier-Lavigne M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 1997;90:739-751.
Soker S, Takashima S, Miao HQ et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998;92:735-745.
Kolodkin AL, Levengood DV, Rowe EG et al. Neuropilin is a semaphorin III receptor. Cell 1997;90:753-762.
Neufeld G, Cohen T, Shraga N et al. The neuropilins: Multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc Med 2002;12:13-19.
Tordjman R, Lepelletier Y, Lemarchandel V et al. A neuronal receptor, neuropilin-1, is essential for the initiation of the primary immune response. Nat Immunol 2002;3:477-482.
Lepelletier Y, Smaniotto S, Hadj-Slimane R et al. Control of human thymocyte migration by Neuropilin-1/Semaphorin-3A-mediated interactions. Proc Natl Acad Sci U S A 2007;104:5545-5550.
Tordjman R, Ortega N, Coulombel L et al. Neuropilin-1 is expressed on bone marrow stromal cells: A novel interaction with hematopoietic cells? Blood 1999;94:2301-2309.
Lieschke GJ, Grail D, Hodgson G et al. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 1994;84:1737-1746.
Liu F, Wu HY, Wesselschmidt R et al. Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. Immunity 1996;5:491-501.
Nicola NA, Metcalf D, Johnson GR et al. Separation of functionally distinct human granulocyte-macrophage colony-stimulating factors. Blood 1979;54:614-627.
Sugihara H, Yonemitsu N, Miyabara S et al. Proliferation of unilocular fat cells in the primary culture. J Lipid Res 1987;28:1038-1045.
Sugihara H, Yonemitsu N, Miyabara S et al. Primary cultures of unilocular fat cells: Characteristics of growth in vitro and changes in differentiation properties. Differentiation 1986;31:42-49.
Hubin F, Humblet C, Belaid Z et al. Murine bone marrow stromal cells sustain in vivo the survival of hematopoietic stem cells and the granulopoietic differentiation of more mature progenitors. STEM CELLS 2005;23:1626-1633.
Oh H, Takagi H, Otani A et al. Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF): A mechanism contributing to VEGF-induced angiogenesis. Proc Natl Acad Sci U S A 2002;99:383-388.
Matthies AM, Low QE, Lingen MW et al. Neuropilin-1 participates in wound angiogenesis. Am J Pathol 2002;160:289-296.
Smas CM, Sul HS. Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation. Cell 1993;73:725-734.
Gimble JM, Robinson CE, Wu X et al. The function of adipocytes in the bone marrow stroma: An update. Bone 1996;19:421-428.
Tavassoli M, Crosby WH. Bone marrow histogenesis: A comparison of fatty and red marrow. Science 1970;169:291-293.
Tavassoli M. Fatty involution of marrow and the role of adipose tissue in hemopoiesis. In: Tavassoli M, ed. Handbook of the Hemopoietic Microenvironment. Clifton, NJ: Humana Press, 1989;157-187.
Cancello R, Henegar C, Viguerie N et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 2005;54:2277-2286.
Kanda H, Tateya S, Tamori Y et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006;116:1494-1505.
Bornstein SR, Abu-Asab M, Glasow A et al. Immunohistochemical and ultrastructural localization of leptin and leptin receptor in human white adipose tissue and differentiating human adipose cells in primary culture. Diabetes 2000;49:532-538.
Urs S, Smith C, Campbell B et al. Gene expression profiling in human preadipocytes and adipocytes by microarray analysis. J Nutr 2004;134:762-770.
Hung SC, Chang CF, Ma HL et al. Gene expression profiles of early adipogenesis in human mesenchymal stem cells. Gene 2004;340:141-150.
Ruge T, Sukonina V, Myrnas T et al. Lipoprotein lipase activity/mass ratio is higher in omental than in subcutaneous adipose tissue. Eur J Clin Invest 2006;36:16-21.
Schilling T, Noth U, Klein-Hitpass L et al. Plasticity in adipogenesis and osteogenesis of human mesenchymal stem cells. Mol Cell Endocrinol 2007;271:1-17.
Spiegelman BM, Hu E, Kim JB et al. PPAR gamma and the control of adipogenesis. Biochimie 1997;79:111-112.
Gurnell M. Peroxisome proliferator-activated receptor gamma and the regulation of adipocyte function: Lessons from human genetic studies. Best Pract Res Clin Endocrinol Metab 2005;19:501-523.
Hummasti S, Tontonoz P. The peroxisome proliferator-activated receptor N-terminal domain controls isotype-selective gene expression and adipogenesis. Mol Endocrinol 2006;20:1261-1275.
MacDougald OA, Lane MD. Transcriptional regulation of gene expression during adipocyte differentiation. Ann Rev Biochem 1995;64:345-373.
Mackay DL, Tesar PJ, Liang LN et al. Characterizing medullary and human mesenchymal stem cell-derived adipocytes. J Cell Physiol 2006;207:722-728.
Ibrahimi A, Abumrad NA. Role of CD36 in membrane transport of long-chain fatty acids. Curr Opin Clin Nutr Metab Care 2002;5:139-145.
Rodrigue-Way A, Demers A, Ong H et al. A growth hormone-releasing peptide promotes mitochondrial biogenesis and a fat burning-like phenotype through scavenger receptor CD36 in white adipocytes. Endocrinology 2007;148:1009-1018.
Sell H, Dietze-Schroeder D, Eckardt K et al. Cytokine secretion by human adipocytes is differentially regulated by adiponectin, AICAR, and troglitazone. Biochem Biophys Res Commun 2006;343:700-706.
Hwang CS, Loftus TM, Mandrup S, et al. Adipocyte differentiation and leptin expression. Annual review of cell and developmental biology. 1997;13:231-259.
Zhang F, Chen Y, Heiman M et al. Leptin: Structure, function and biology. Vitam Horm 2005;71:345-372.
Levine JA, Jensen MD, Eberhardt NL et al. Adipocyte macrophage colony-stimulating factor is a mediator of adipose tissue growth. J Clin Invest 1998;101:1557-1564.
Kim DH, Yoo KH, Choi KS et al. Gene expression profile of cytokine and growth factor during differentiation of bone marrow-derived mesenchymal stem cell. Cytokine 2005;31:119-126.
Bonnier S, Campos L, Froehlich C et al. Modification of in vitro hematopoiesis induced by addition of GM-CSF in long term normal human bone marrow cultures [in French]. Pathol Biol (Paris) 1991;39:271-276.
Lee MY, Fukunaga R, Lee TJ et al. Bone modulation in sustained hematopoietic stimulation in mice. Blood 1991;77:2135-2141.
Aoki S, Toda S, Ando T et al. Bone marrow stromal cells, preadipocytes, and dermal fibroblasts promote epidermal regeneration in their distinctive fashions. Mol Biol Cell 2004;15:4647-4657.
Corre J, Planat-Benard V, Corberand JX et al. Human bone marrow adipocytes support complete myeloid and lymphoid differentiation from human CD34 cells. Br J Haematol 2004;127:344-347.
Corre J, Barreau C, Cousin B et al. Human subcutaneous adipose cells support complete differentiation but not self-renewal of hematopoietic progenitors. J Cell Physiol 2006;208:282-288.
Zhou X, Li D, Yin J et al. CLA differently regulates adipogenesis in stromal vascular cells from porcine subcutaneous adipose and skeletal muscle. J Lipid Res. 2007;48:1701-1709.
Bachelder RE, Crago A, Chung J et al. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res 2001;61:5736-5740.
Bachelder RE, Lipscomb EA, Lin X et al. Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Res 2003;63:5230-5233.
Murga M, Fernandez-Capetillo O, Tosato G. Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelial growth factor receptor-2. Blood 2005;105:1992-1999.