Hepatocyte Growth Factor Is Constitutively Produced by Human Bone Marrow Stromal Cells and Indirectly Promotes Hematopoiesis

Abstract

Bone marrow (BM) stromal cells are required for normal hematopoiesis. A number of soluble factors secreted by these cells that mediate hematopoiesis have been characterized. However, the mechanism of hematopoiesis cannot be explained solely by these known factors, and the existence of other, still unknown stromal factors has been postulated. We showed that hepatocyte growth factor (HGF ) is one such cytokine produced by human BM stromal cells. BM stromal cells were shown to constitutively produce HGF and also to express the c-MET/HGF receptor. The production of HGF was enhanced by addition of heparin and phorbol ester. Dexamethasone and tumor growth factor-β (TGF-β) inhibited the production of HGF. Interleukin-1α (IL-1α) tumor necrosis factor-α (TNF-α), and N6,2′-o-dibutyryl-adenosine-3′:5′-cyclic monophosphate (dbc-AMP) showed no obvious influence on HGF production. Western blot analysis of HGF derived from BM stromal cells showed two bands at 85 and 28 kD corresponding to native and variant HGF, respectively. Addition of recombinant HGF significantly promoted the formation of burst-forming unit-erythroid (BFU-E) and colony-forming unit-granulocyte erythroid macrophage (CFU-GEM) by BM mononuclear cells in the presence of erythropoietin and granulocyte-macrophage colony-stimulating factor (GM-CSF ), but the formation of CFU-GM was not modified. However, HGF had no effects on colony formation by purified CD34+ cells. Within BM mononuclear cells, c-MET was expressed on a proportion of cells (CD34−, CD33+, CD13+, CD14+, and CD15+), but was not found on CD34+ cells. We conclude that HGF is constitutively produced by BM stromal cells and that it enhances hematopoiesis. In addition, expression of c-MET on the stromal cells suggests the presence of an autocrine mechanism, operating through HGF, among stromal cells.

Functional Expression of HGF and HGF Receptor/c‐met in Adult Human Mesenchymal Stem Cells Suggests a Role in Cell Mobilization, Tissue Repair, and Wound Healing

“…Expression of HGF and c-met was also reported by Takai [19] in a bone marrow stromal cell population, but this population was not further characterized. Bone marrow stromal cells are widely used as feeder layers for long-term cultures of hematopoietic stem cells.…”

“…Studies on HGF and c-met expression in bone marrow cells were reported by Takai et al [19]. These authors demonstrated that bone marrow stromal cells constitutively express HGF and promote hematopoiesis.…”

The role of hepatocyte growth factor and its receptor c‐met in interactions between lymphocytes and stromal cells in secondary human lymphoid organs

“…The present studies con®rm and extend recent reports indicating that this indeed is the case with c-met being expressed by immature B cells, in vitro-activated B cells and B cells within germinal centres (centroblasts strongly, centrocytes weakly) as well as by haematopoietic cell precursors. 4,5,9 Because CD40L and anti-m ligation, used in this work to stimulate B cells, mimics processes of germinal centre reaction, it is likely that c-met is strongly expressed early after stimulation and then its expression declines as B lymphocytes differentiate to centrocytes stage and later to antibody-secreting cells. The disappearance of the receptor may be a result of either shedding or internalization and remains to be established.…”

“…4). 9 When combined with CD40L, TNF-a showed an additive effect while with IL-1b there was some suggestion of synergy in augmentation of HGF secretion (Table 3). On the other hand IL-2, IL-4, IL-6 and IL-10 had no effect on stromal HGF, either when tested alone or in combination with CD40L (data not shown).…”

Interactions between scatter factors and their receptors: hints for therapeutic applications

“…Indeed, HGF promotes remodeling of epithelial cells cultured in 3-dimensional collagen gels (10)(11)(12)(13), and induces the formation of branching tubular structures in mammary gland (14) and metanephric organ cultures (15). More generally, a vast number of studies following its identification demonstrated that HGF functions in virtually every tissue of the body (16): hematopoiesis (17,18), bone formation and resorption (19), chondrogenesis (20), angiogenesis (21,22), and axonal chemoattraction (23,24) are all critically controlled by HGF. Together, these features make HGF a powerful mitogenic and morphogenic molecule endowed with crucial functions during embryonic development and tissue regeneration.…”