Hepatocyte growth factor plays roles in the induction and autocrine maintenance of bone marrow stromal cell IL-11, SDF-1 alpha, and stem cell factor.
OBJECTIVE
Bone marrow (BM) stroma provides the microenvironment required for long-term hematopoiesis, and this is supported by direct interaction between stromal cells and hematopoietic cells, mediated by adhesion molecules, and through cytokine releases from the BM stroma. In a previous study, we demonstrated that hepatocyte growth factor (HGF) is one of the cytokines constitutively produced from BM stromal cells, promoting hematopoiesis mainly in an indirect way. We also showed that stromal cells themselves express HGF receptor c-MET. It was therefore postulated that HGF exerts its effect on hematopoiesis and maintenance of the hematopoietic microenvironment in a paracrine and autocrine manner.


METHODS
The effect of HGF on stromal cells was analyzed by neutralizing intrinsic HGF.


RESULTS
Addition of neutralizing anti-HGF antibody inhibited the ability of BM stromal cells to support colony formation from CD34(+) cells and reduced production of significant cytokines from stromal cells, interleukin-11 (IL-11), stromal cell-derived factor-1 alpha (SDF-1 alpha), and to a lesser extent, stem cell factor (SCF). Furthermore, this neutralizing antibody reduced proliferation of stromal cells and inhibited adhesion of stromal cells to collagen type IV and fibronectin. Inhibition of adhesion to fibronectin was mediated by inhibition of alpha(5)beta(1)-integrin.


CONCLUSIONS
These findings indicate that HGF constitutively produced from BM stromal cells is an autocrine regulator, which is able to maintain the hematopoietic microenvironment through stimulating proliferation and adhesion to the extracellular matrix and promoting hematopoiesis through inducing constitutive production of IL-11, SDF-1 alpha, and SCF by stromal cells themselves.
Matsuda-Hashii
Yoshiko
Y
Department of Developmental Medicine, Osaka University, Graduate School of Medicine, Suita, Osaka 565-0871, Japan. matsuda@ped.med.osaka-u.ac.jp
Takai
Kenji
K
Ohta
Hideaki
H
Fujisaki
Hiroyuki
H
Tokimasa
Sadao
S
Osugi
Yuko
Y
Ozono
Keiichi
K
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Hara
Junichi
J
D019898:Autocrine Communication / Q000502:physiology*; D001854:Bone Marrow Cells; D002448:Cell Adhesion; D049109:Cell Proliferation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D017370:Interleukin-11 / Q000096:biosynthesis; D019089:Stem Cell Factor / Q000096:biosynthesis; D017154:Stromal Cells / Q000378:metabolism*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D017370:Interleukin-11; D019089:Stem Cell Factor; D017228:Hepatocyte Growth Factor