Compartmentalization of a haematopoietic growth factor (GM-CSF) by glycosaminoglycans in the bone marrow microenvironment

Abstract

Haematopoietic progenitor cells proliferate and mature in semisolid media when stimulated by exogenous haematopoietic cell growth factors (HCGFs) such as granulocyte-macrophage colony-stimulating factor (GM-CSF). They also proliferate in association with marrow-derived stromal cells although biologically active amounts of HCGFs cannot be detected in stromal culture supernatants. It is possible that HCGFs are synthesized in small amounts by stromal cells but remain bound to the stromal cells and/or their extracellular matrix (ECM). This interpretation accords with haematopoietic progenitor cell proliferation in close association with stromal layers in long-term cultures. Glycosaminoglycans (GAGs) are found in the ECM produced by stromal cells. They are prime candidates for selectively retaining HCGFs in the stromal layer; they influence embryonic morphogenesis and cyto-differentiation and they may regulate haematopoiesis. We now report that granulocyte-macrophage colony-stimulating activity can be eluted from cultured stromal layers and that exogenous GM-CSF binds to GAGs from bone marrow stromal ECM. Selective compartmentalization of HCGFs in this manner may be an important function of the marrow microenvironment and may be involved in haematopoietic cell regulation.

Endothelial cell support of hematopoiesis is differentially altered by IL-1 and glucocorticoids

“…Contactdependent parameters may be the optimized presentation of cytokines via their proteoglycan-mediated immobilization at the EC surface. [56][57][58] Alternatively, adhesive interactions between progenitors and EC may promote hematopoietic progenitor proliferation. Adhesive interactions may by themselves promote cell proliferation as has been shown for VLA-4, VLA-5 or VLA-6 when binding to their respective ligands.…”

Murine embryonic stem cells without pig-a gene activity are competent for hematopoiesis with the PNH phenotype but not for clonal expansion.

“…The low number of CFU-GM obtained in progenitor assays from pig-aϪ EBs supports the notion that maturation into granulocytes is impaired. This might be related to the fact that GPI-linked proteins in stromal cells may positively influence granulocytic maturation (38)(39)(40).…”

Cytokines in context.

“…Several forms of fibroblast growth factor (FGF) (Rogelj et al, 1989;Baird and Bohlen, 1990), GM-CSE and IL-3 (Gordon et al, 1987;Roberts et al, 1988) are among the cytokines that are deposited in and function when bound to proteoglycans of extracellular matrix. In contrast, the core protein of the proteoglycan decorin (whose synthesis TGF-~ induces) binds and neutralizes TGF-/3 (Yamaguchi et al, 1990).…”