Cell membrane-associated proteoglycans mediate extramedullar myeloid proliferation in granulomatous inflammatory reactions to schistosome eggs.
In chronic murine schistosomiasis, extramedullar myelopoiesis was observed, with proliferation of myeloid cells in liver parenchyma and in periovular granulomas. We have studied the question of whether cells obtained from granulomatous connective tissue may act as myelopoietic stroma, supporting long-term myeloid proliferation. Primary cell lines (GR) were obtained in vitro from periovular granulomas, induced in mouse livers by Schistosoma mansoni infection. These cells were characterized as myofibroblasts, and represent liver connective tissue cells involved in fibro-granulomatous reactions. They were able to sustain survival and proliferation of the multipotent myeloid cell lines FDC-P1 and DA-1 (dependent on interleukin-3 and/or granulocyte-macrophage colony stimulating factor, GM-CSF) without the addition of exogenous growth factors. This stimulation was dependent upon myeloid cell attachment to the GR cell layer; GR cell-conditioned medium had no activity. Primary murine skin fibroblasts could not sustain myelopoiesis. The endogenous growth-factor was identified as GM-CSF by neutralization assays with monoclonal antibodies. The stimulation of myelopoiesis occurred also when GR cells had been fixed with glutardialdehyde. The observed stimulatory activity was dependent upon heparan sulphate proteoglycans (HSPGs) associated with GR cell membranes. It could be dislodged from the cell layer with heparin or a high salt buffer. Our results indicate a molecular interaction between endogenous growth-factor and HSPGs; this interaction may be responsible for the stabilization and presentation of growth factors in myelopoietic stromas, mediating extramedullar proliferation of myeloid cells in periovular granulomas.
Departamento de Bioquímica, Instituto de Química, Universidade Federal de Rio de Janeiro, Brazil.
M
M
Alvarez-Silva
L C
LC
da Silva
R
R
Borojevic
D000818:Animals; D002462:Cell Membrane / Q000737:chemistry*; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry*; D015745:Granuloma, Foreign-Body / Q000209:etiology / Q000473:pathology*; D006497:Heparan Sulfate / Q000737:chemistry; D008099:Liver / Q000469:parasitology / Q000473:pathology; D008264:Macrophages; D051379:Mice; D008809:Mice, Inbred C3H; D009196:Myeloproliferative Disorders / Q000209:etiology / Q000473:pathology*; D010063:Ovum / Q000737:chemistry / Q000276:immunology; D011509:Proteoglycans / Q000737:chemistry*; D012555:Schistosomiasis mansoni / Q000150:complications / Q000469:parasitology / Q000473:pathology*
D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006497:Heparan Sulfate; D011509:Proteoglycans