Human Adipose Derived Stem Cells Exhibit Enhanced Liver Regeneration in Acute Liver Injury by Controlled Releasing Hepatocyte Growth Factor

Background: Transplantation of adipose-derived stem cells (ADSCs) is a potential therapy for a variety of liver diseases. Previous studies have shown that ADSC-based therapy is promising for liver fibrosis treatment. Recently, many publications have suggested that pretreating ADSCs with growth factors before transplantation can elevate the effectiveness of the therapy. Therefore, we hypothesize that human ADSCs (hADSCs) pretreated with platelet-rich plasma (PRP) and hepatocyte growth factor (HGF), compared to ADSCs alone, would accelerate the treatment effects on liver fibrosis in mice. Methods: The hADSCs were cultured solely with conventional media, or with HGF (human recombinant; 20 ng/ml), or with HGF and PRP (from healthy human blood, 10%), concomitantly added to the medium for 7 days before transplantation. Eight-week-old male mice were treated with CCl4 (1 ml/kg) for 11 weeks to induce liver fibrosis. The mice were then subsequently divided into: 1) Placebo group (PBS injection); 2) ADSCs/HGF+PRP (5x105HGF and PRP pre-treated cells/mice); 3) ADSCs/HGF (5x105HGF pre-treated cells/mice) and 4) ADSCs (5x105non-pretreated cells/mice). Results: Seven days post-transplantation, the alanine transaminase (ALT) level in the placebo was notably elevated (143.10±14.96 IU/L), compared to ALT levels of ADSCs-, ADSCs/HGF+PR-, and ADSCs/HGF-transplanted mice, which showed an improvement (67.94±18.57 IU/L, 49.44±7.56 IU/L, and 57.93±5.75 IU/L, respectively). The procollagen-α1 and alpha-smooth muscle actin (α-SMA) mRNA levels were significantly down-regulated in the ADSCs-transplanted group compared to those of the placebo. Importantly, these levels were lower in ADSCs/HGF+PR (procollagen-α1: 75.64±45.89; α-SMA: 36.17±36.09) than those of ADSCs/HGF (procollagen-α1: 212.8±84.35; α-SMA: 52.41±7.93) and ADSCs only (procollagen-α1: 310.50 ± 55.36; α-SMA: 184.70±14.06). Stem cell transplantation also improved histological index, reducing inflammation and collagen/necrotic structure accumulation. However, there were no statistical differences between three ADSCs treatment groups after 14 days after transplantation. Conclusion: Pre-treatment with PRP and HGF for 7 days enhanced the efficacy of ADSCs in alleviating liver fibrosis in vivo.

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Anti-hepatocyte growth factor antibody inhibits the in vivo proliferative response of hepatocytes to acute liver injury

Gastroenterology ◽

10.1016/0016-5085(95)28466-4 ◽

1995 ◽

Vol 108 (4) ◽

pp. A1041

Author(s):

AW Burr ◽

K. Toole ◽

JE Hines ◽

C Chapman ◽

AD Burt

Keyword(s):

Growth Factor ◽

Liver Injury ◽

Hepatocyte Growth Factor ◽

Proliferative Response ◽

Acute Liver Injury ◽

Hepatocyte Growth

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Hepatocyte Growth Factor Secreted from Human Adipose-Derived Stem Cells Inhibits Fibrosis in Hypertrophic Scar Fibroblasts

Current Molecular Medicine ◽

10.2174/1566524020666200106095745 ◽

2020 ◽

Vol 20 (7) ◽

pp. 558-571 ◽

Cited By ~ 6

Author(s):

Ji Ma ◽

Xin Yan ◽

Yue Lin ◽

Qian Tan

Keyword(s):

Stem Cells ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Hypertrophic Scar ◽

Collagen Type ◽

Smooth Muscle Actin ◽

Adipose Derived Stem Cells ◽

Collagen Production ◽

Rabbit Ear ◽

Hepatocyte Growth

Aims: To study the effect of Adipose-derived stem cells (ADSCs) on fibrosis of hypertrophic scar-derived fibroblasts (HSFs) and its concrete mechanism. Background: ADSCs have been reported to reduce collagen production and fibroblast proliferation in co-culture experiments. Conditioned medium from adipose-derived stem cells (ADSCs-CM) has successfully inhibited fibrosis by decreasing the expression of collagen type І (Col1) and α-smooth muscle actin (α-SMA) in rabbit ear scar models. Hepatocyte growth factor (HGF), the primary growth factor in ADSCs-CM, has been shown to reverse fibrosis in various fibrotic diseases. Background: ADSCs have been reported to reduce collagen production and fibroblast proliferation in co-culture experiments. Conditioned medium from adipose-derived stem cells (ADSCs-CM) has successfully inhibited fibrosis by decreasing the expression of collagen type І (Col1) and α-smooth muscle actin (α-SMA) in rabbit ear scar models. Hepatocyte growth factor (HGF), the primary growth factor in ADSCs-CM, has been shown to reverse fibrosis in various fibrotic diseases. Objective: To test the hypothesis that ADSCs inhibit fibrosis of HSFs through the secretion of HGF. Methods: HSFs were treated with DMEM containing 0%, 10%, 50% and 100% concentration of ADSCs-CM. The effect of ADSCs-CM on the viability was determined by cell viability assay, and the collagen production in HSFs was examined by Sirius red staining. Expression and secretion of fibrosis and degradation proteins were detected separately. After measuring the concentration of HGF in ADSCs-CM, the same number of HSFs were treated with 50% ADSCs-CM or HGF. HGF activity in ADSCs-CM was neutralized with a goat anti-human HGF antibody. Results: The results demonstrated that ADSCs-CM dose-dependently decreased cell viability, expression of fibrosis molecules, and tissue inhibitor of metalloproteinases-1 (TIMP-1), and significantly increased matrix metalloproteinase-1 (MMP-1) expression in HSFs. Collagen production and the ratio of collagen type І and type III (Col1/Col3) were also suppressed by ADSCs-CM in a dose-dependent manner. When HSFs were cultured with either 50% ADSCs-CM or HGF (1 ng/ml), a similar trend was observed in gene expression and protein secretion. Adding an HGF antibody to both groups returned protein expression and secretion to basal levels but did not significantly affect the fibrosis factors in the control group. Conclusion: Our findings revealed that adipose-derived stem cell-secreted HGF effectively inhibits fibrosis-related factors and regulates extracellular matrix (ECM) remodeling in hypertrophic scar fibroblasts.

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Suppression of Hepatocyte Growth Factor Production Impairs the Ability of Adipose-Derived Stem Cells to Promote Ischemic Tissue Revascularization

Stem Cells ◽

10.1634/stemcells.2007-0388 ◽

2007 ◽

Vol 25 (12) ◽

pp. 3234-3243 ◽

Cited By ~ 144

Author(s):

Liying Cai ◽

Brian H. Johnstone ◽

Todd G. Cook ◽

Zhong Liang ◽

Dmitry Traktuev ◽

...

Keyword(s):

Stem Cells ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Adipose Derived Stem Cells ◽

Factor Production ◽

Ischemic Tissue ◽

Growth Factor Production ◽

Hepatocyte Growth

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Suppression of acute hepatic injury by a synthetic prostacyclin agonist through hepatocyte growth factor expression

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00216.2011 ◽

2012 ◽

Vol 302 (4) ◽

pp. G420-G429 ◽

Cited By ~ 10

Author(s):

Qing Xu ◽

Mizuho Nakayama ◽

Yoshinori Suzuki ◽

Katsuya Sakai ◽

Takahiro Nakamura ◽

...

Keyword(s):

Growth Factor ◽

Liver Injury ◽

Hepatocyte Growth Factor ◽

Hepatic Injury ◽

Acute Liver Injury ◽

Protective Action ◽

Liver Cells ◽

Cyclooxygenase 2 ◽

Peroral Administration ◽

Hepatocyte Growth

Previous studies have demonstrated that mice disrupted with the cyclooxygenase-2 gene showed much more severe liver damage compared with wild-type mice after liver injury, and prostaglandins (PGs) such as PGE1/2 and PGI2 have decreased hepatic injury, but the mechanisms by which prostaglandins exhibit protective action on the liver have yet to be addressed. In the present study, we investigated the mechanism of the protective action of PGI2 using the synthetic IP receptor agonist ONO-1301. In primary cultures of hepatocytes and nonparenchymal liver cells, ONO-1301 did not show protective action directly on hepatocytes, whereas it stimulated expression of hepatocyte growth factor (HGF) in nonparenchymal liver cells. In mice, peroral administration of ONO-1301 increased hepatic gene expression and protein levels of HGF. Injections of CCl4 induced acute liver injury in mice, but the onset of acute liver injury was strongly suppressed by administration of ONO-1301. The increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by CCl4 were suppressed by 10 mg/kg ONO-1301 to 39.4 and 33.6%, respectively. When neutralizing antibody against HGF was administered with ONO-1301 and CCl4, the decreases by ONO-1301 in serum ALT and AST, apoptotic liver cells, and expansion of necrotic areas in liver tissue were strongly reversed by neutralization of endogenous HGF. These results indicate that ONO-1301 increases expression of HGF and that hepatoprotective action of ONO-1301 in CCl4-induced liver injury may be attributable to its activity to induce expression of HGF, at least in part. The potential for involvement of HGF-Met-mediated signaling in the hepatotrophic action of endogenous prostaglandins generated by injury-dependent cyclooxygenase-2 induction is considerable.

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