OL-045 Hepatocyte growth factor promotes liver regeneration induced by transfusion of bone marrow mononuclear cells in a murine acute liver failure model

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.

Download Full-text

Transplantation of Human Hepatocytes Cultured with Deleted Variant of Hepatocyte Growth Factor Prolongs the Survival of Mice with Acute Liver Failure

Transplantation Journal ◽

10.1097/01.tp.0000160813.37515.97 ◽

2005 ◽

Vol 79 (10) ◽

pp. 1378-1385 ◽

Cited By ~ 21

Author(s):

Yong Chen ◽

Naoya Kobayashi ◽

Satoshi Suzuki ◽

Alejandro Soto-Gutierrez ◽

Jorge David Rivas-Carrillo ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Liver Failure ◽

Acute Liver Failure ◽

Human Hepatocytes ◽

Hepatocyte Growth

Download Full-text

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

Blood ◽

10.1182/blood.v89.5.1560 ◽

1997 ◽

Vol 89 (5) ◽

pp. 1560-1565 ◽

Cited By ~ 123

Author(s):

Kenji Takai ◽

Junichi Hara ◽

Kunio Matsumoto ◽

Gaku Hosoi ◽

Yuko Osugi ◽

...

Keyword(s):

Bone Marrow ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Stromal Cells ◽

Mononuclear Cells ◽

Gm Csf ◽

Tumor Growth Factor ◽

Cd34 Cells ◽

Factor Α ◽

Hepatocyte Growth

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.

Download Full-text

Liver regeneration in a retrorsine/CCl4 – induced acute liver failure model: do bone marrow-derived cells contribute?

Journal of Hepatology ◽

10.1016/s0168-8278(03)00264-2 ◽

2003 ◽

Vol 39 (3) ◽

pp. 365-373 ◽

Cited By ~ 41

Author(s):

Marc H Dahlke ◽

Felix C Popp ◽

Ferdinand H Bahlmann ◽

Heiko Aselmann ◽

Mark D Jäger ◽

...

Keyword(s):

Bone Marrow ◽

Liver Failure ◽

Acute Liver Failure ◽

Liver Regeneration ◽

Failure Model ◽

Bone Marrow Derived Cells

Download Full-text

High levels of hepatocyte growth factor predict the outcome of acute liver failure in children

Journal of Hepatology ◽

10.1016/s0168-8278(01)81218-6 ◽

2001 ◽

Vol 34 ◽

pp. 97

Author(s):

M. Hussain ◽

M. Kallas ◽

H. Yagita ◽

P. Cheeseman ◽

G. Mieli-Vergani ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Liver Failure ◽

Acute Liver Failure ◽

Hepatocyte Growth

Download Full-text

In a Rat Model of Acute Liver Failure, Icaritin Improved the Therapeutic Effect of Mesenchymal Stem Cells by Activation of the Hepatocyte Growth Factor/c-Met Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/4253846 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13

Author(s):

Lu Wang ◽

Shu Li ◽

Han-Yu Wang ◽

Juan Zeng ◽

Zheng-Zheng Zhang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Survival Rate ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Liver Failure ◽

Acute Liver Failure ◽

Therapeutic Effect ◽

Factor C ◽

Hepatocyte Growth

Acute liver failure (ALF) is a serious life-threatening condition. Mesenchymal stem cells (MSCs) may be an effective treatment for this condition and a good alternative to liver transplantation. Icaritin (ICT) is an active ingredient of the genus Epimedium, a traditional Chinese medicine, with the potential to enhance the proliferation of MSCs. The purpose of this study was to explore whether ICT increased the therapeutic effects of MSCs and explore its underlying mechanisms. For in vivo experiments, a rat ALF model was established by intraperitoneal injection of D(+)-galactosamine/ lipopolysaccharide. MSCs cocultured with ICT were used to treat ALF rats and the protective effects assessed as survival rate, levels of serum AST and ALT, and histological changes in liver tissue. For in vitro experiments, MSCs were treated in serum-free culture for 72 h to simulate the disruption of intrahepatic microcirculation. MSCs apoptosis was examined to determine whether ICT rescued impaired MSCs. The role of the hepatocyte growth factor (HGF)/c-Met pathway in MSCs was assessed by constructing genetically modified MSCs overexpressing c-Met and by using the c-Met receptor inhibitor (crizotinib). The results showed that MSCs increased the survival rate of ALF rats and reduced liver damage. MSCs cocultured with ICT exerted a greater therapeutic effect than MSCs alone. Further, the HGF/c-Met pathway played a key role in the antiapoptotic activity of MSCs, which was associated with the optimized efficacy of ICT. In conclusion, this study demonstrated that ICT enhances the therapeutic effect of MSCs in a model of ALF, improving the antiapoptotic potential of MSCs by upregulation of the HGF/c-Met pathway. The combination of stem cell therapy with traditional herbal extracts may improve MSC-based clinical applications.

Download Full-text

Paracrine Effects of Bone Marrow Mononuclear Cells in Survival and Cytokine Expression after 90% Partial Hepatectomy

Stem Cells International ◽

10.1155/2017/5270527 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Carlos Oscar Kieling ◽

Carolina Uribe-Cruz ◽

Mónica Luján López ◽

Alessandro Bersch Osvaldt ◽

Themis Reverbel da Silveira ◽

...

Keyword(s):

Gene Expression ◽

Bone Marrow ◽

Liver Failure ◽

Acute Liver Failure ◽

Partial Hepatectomy ◽

Mononuclear Cells ◽

Bone Marrow Mononuclear Cells ◽

Remnant Liver ◽

Promising Alternative ◽

Paracrine Effects

Acute liver failure is a complex and fatal disease. Cell-based therapies are a promising alternative therapeutic approach for liver failure due to relatively simple technique and lower cost. The use of semipermeable microcapsules has become an interesting tool for evaluating paracrine effects in vivo. In this study, we aimed to assess the paracrine effects of bone marrow mononuclear cells (BMMC) encapsulated in sodium alginate to treat acute liver failure in an animal model of 90% partial hepatectomy (90% PH). Encapsulated BMMC were able to increase 10-day survival without enhancing liver regeneration markers. Gene expression of Il-6 and Il-10 in the remnant liver was markedly reduced at 6 h after 90% PH in animals receiving encapsulated BMMC compared to controls. This difference, however, was neither reflected by changes in the number of CD68+ cells nor by serum levels of IL6. On the other hand, treated animals presented increased caspase activity and gene expression in the liver. Taken together, these results suggest that BMMC regulate immune response and promote apoptosis in the liver after 90% PH by paracrine factors. These changes ultimately may be related to the higher survival observed in treated animals, suggesting that BMMC may be a promising alternative to treat acute liver failure.

Download Full-text