HEPATOCYTE GROWTH-FACTOR IS CONSTITUTIVELY PRODUCED BY HUMAN BONE-MARROW STROMAL CELLS AND INDIRECTLY PROMOTES HEMATOPOIESIS

Bone marrow (BM) stromal cells are required for normal hematopoiesis. A number of soluble factors secreted by these cells that mediate hemat opoiesis have been characterized. However, the mechanism of hematopoie sis cannot be explained solely by these known factors, and the existen ce of other, still unknown stromal factors has been postulated. We sho wed that hepatocyte growth factor (HGF) is one such cytokine produced by human BM stromal cells. BM stromal cells were shown to constitutive ly produce HGF and also to express the c-MET/HGF receptor. The product ion of HGF was enhanced by addition of heparin and phorbol ester. Dexa methasone and tumor growth factor-beta (TGF-beta) inhibited the produc tion of HGF. Interleukin-1 alpha (IL-1 alpha) tumor necrosis factor-al pha (TNF-alpha), and N-6,2'-o-dibutyryl-adenosine-3':5'-cyclic monopho sphate (dbc-AMP) showed no obvious influence on HGF production. Wester n 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 b urst-forming unit-erythroid (BFU-E) and colony-forming unit-granulocyt e erythroid macrophage (CFU-GEM) by BM mononuclear cells in the presen ce of erythropoietin and granulocyte-macrophage colony-stimulating fac tor (GM-CSF), but the formation of CFU-GM was not modified. However, H GF had no effects on colony formation by puri fled CD34(+) cells. With in BM mononuclear cells, c-MET was expressed on a proportion of cells (CD34(-), CD33(+), CD13(+), CD14(+), and CD15(+)), but was not found o n CD34(+) cells. We conclude that HGF is constitutively produced by BM stromal cells and that it enhances hematopoiesis. In addition, expres sion of c-MET on the stromal cells suggests the presence of an autocri ne mechanism, operating through HGF, among stromal cells. (C) 1997 by The American Society of Hematology.