Increased Engraftment of Hepatic Progenitors After Activation of the Hepatocyte Growth Factor Signaling Pathway by Protein Transduction

2009 ◽  
Vol 234 (9) ◽  
pp. 1102-1108 ◽  
Author(s):  
Guillaume Kellermann ◽  
Lyes Boudechiche ◽  
Anne Weber ◽  
Michelle Hadchouel
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Signaling Pathway ◽  
Cell Types ◽  
Cell Surface Receptor ◽  
Migration And Invasion ◽  
Protein Transduction ◽  
Growth Factor Signaling ◽  
Hepatocyte Growth

Cell transplantation has become a major focus in biomedical research. However, efficient engraftment in solid tissues remains a challenge. Hepatocyte growth factor (HGF) signaling increases survival, proliferation, migration, and invasion of many cell types through Met, its cell surface receptor. Therefore, activation of this signaling pathway may improve the ability of many cells to be transplanted. We constructed a constitutively activated form of Met (Tpr-Met) fused to the protein transduction domain of HIV-TAT to activate the HGF/Met pathway for a few hours following cell injection. Matrix-assisted refolding was used to renature TAT-Tpr-Met protein, which was efficiently delivered into cells and recapitulated several biological functions of Met in vitro. Furthermore, treatment of hepatic progenitors with this molecule for one hour before transplantation significantly improved engraftment efficiency (31% untreated cells, 58% treated cells). These findings suggest that the transient transfer of Tpr-Met may provide a new approach to increase the proportion of successfully engrafted cells.

scholarly journals Hepatocyte growth factor modulates in vitro survival and proliferation of germ cells during postnatal testis development

2006 ◽  
Vol 189 (1) ◽  
pp. 137-146 ◽  
Author(s):  
A Catizone ◽  
G Ricci ◽  
J Del Bravo ◽  
M Galdieri
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Germ Cell ◽  
Germ Cells ◽  
Cell Types ◽  
Tyrosine Kinase Receptor ◽  
Testis Development ◽  
Pachytene Spermatocytes ◽  
Hepatocyte Growth

The hepatocyte growth factor (HGF) is a pleiotropic cytokine that influences mitogenesis, motility and differentiation of many different cell types by its tyrosine kinase receptor c-Met. We previously demonstrated that the c-Met/HGF system is present and functionally active during postnatal testis development. We found also that spermatozoa express c-Met and that HGF has a positive effect on the maintenance of sperm motility. In the present paper, we extend our study on the germ cells at different stages of differentiation during the postnatal development of the testis. We demonstrate that c-met is present in rat spermatogonia, pachytene spermatocytes and round spermatids and that HGF significantly increases spermatogonial proliferation in 8- to 10-day-old pre-pubertal rats. At this age HGF does not affect Sertoli cells and peritubular myoid cells proliferation. In addition, we studied the effect of the factor on germ cell apoptosis and we show that HGF prevents the germ cell apoptotic process. We also studied the effect of HGF on 18- to 20-day-old and 28- to 30-day-old rat testes. At these ages also the factor significantly increases germ cell duplication and decreases the number of apoptotic cells. However, the effect on programmed cell death is higher in the 8- to 10-day-old rats and declines in the older animals. In conclusion, we report that rat germ cells (spermatogonia, pachytene spermatocytes and round spermatids) express c-met and that HGF modulates germ cell proliferating activity and apoptosis in vitro. These data indicate that the c-Met/HGF system is involved in male germ cell homeostasis and, consequently, has a role in male fertility.

scholarly journals Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development.

1993 ◽  
Vol 123 (1) ◽  
pp. 223-235 ◽  
Author(s):  
E Sonnenberg ◽  
D Meyer ◽  
K M Weidner ◽  
C Birchmeier
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Hepatocyte Growth Factor ◽  
Tyrosine Kinase ◽  
Cell Surface Receptor ◽  
Mouse Development ◽  
Scatter Factor ◽  
Rnase Protection ◽  
Hepatocyte Growth

Scatter factor/hepatocyte growth factor (SF/HGF) has potent motogenic, mitogenic, and morphogenetic activities on epithelial cells in vitro. The cell surface receptor for this factor was recently identified: it is the product of the c-met protooncogene, a receptor-type tyrosine kinase. We report here the novel and distinct expression patterns of SF/HGF and its receptor during mouse development, which was determined by a combination of in situ hybridization and RNase protection experiments. Predominantly, we detect transcripts of c-met in epithelial cells of various developing organs, whereas the ligand is expressed in distinct mesenchymal cells in close vicinity. In addition, transient SF/HGF and c-met expression is found at certain sites of muscle formation; transient expression of the c-met gene is also detected in developing motoneurons. SF/HGF and the c-met receptor might thus play multiple developmental roles, most notably, mediate a signal given by mesenchyme and received by epithelial. Mesenchymal signals are known to govern differentiation and morphogenesis of many epithelia, but the molecular nature of the signals has remained poorly understood. Therefore, the known biological activities of SF/HGF in vitro and the embryonal expression pattern reported here indicate that this mesenchymal factor can transmit morphogenetic signals in epithelial development and suggest a molecular mechanism for mesenchymal epithelial interactions.

scholarly journals An overview of the c-MET signaling pathway

2011 ◽  
Vol 3 (1_suppl) ◽  
pp. S7-S19 ◽  
Author(s):  
Shawna Leslie Organ ◽  
Ming-Sound Tsao
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Signaling Pathway ◽  
Receptor Tyrosine Kinase ◽  
Tissue Homeostasis ◽  
Migration And Invasion ◽  
Protein Overexpression ◽  
Physiological Conditions ◽  
Wide Range ◽  
Hepatocyte Growth

c-MET is a receptor tyrosine kinase that, after binding with its ligand, hepatocyte growth factor, activates a wide range of different cellular signaling pathways, including those involved in proliferation, motility, migration and invasion. Although c-MET is important in the control of tissue homeostasis under normal physiological conditions, it has also been found to be aberrantly activated in human cancers via mutation, amplification or protein overexpression. This paper provides an overview of the c-MET signaling pathway, including its role in the development of cancers, and provides a rationale for targeting the pathway as a possible treatment option.

Targeting the hepatocyte growth factor/Met pathway in cancer

2017 ◽  
Vol 45 (4) ◽  
pp. 855-870 ◽  
Author(s):  
Dinuka M. De Silva ◽  
Arpita Roy ◽  
Takashi Kato ◽  
Fabiola Cecchi ◽  
Young H. Lee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cancer Treatment ◽  
Target Cell ◽  
Wide Spectrum ◽  
Cell Types ◽  
Receptor Activation ◽  
Model Systems ◽  
Cell Surface Receptor ◽  
Hepatocyte Growth

Hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase, drives mitogenesis, motogenesis and morphogenesis in a wide spectrum of target cell types and embryologic, developmental and homeostatic contexts. Typical paracrine HGF/Met signaling is regulated by HGF activation at target cell surfaces, HGF binding-induced receptor activation, internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis, tumor angiogenesis and invasiveness, and tumor metastasis in many types of cancer, leading to the rapid growth of pathway-targeted anticancer drug development programs. We review here HGF and Met structure and function, basic properties of HGF/Met pathway antagonists now in clinical development, and recent clinical trial results. Presently, the main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment include optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of effective therapy combinations. The wealth of basic information, analytical reagents and model systems available regarding normal and oncogenic HGF/Met signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective cancer treatment.

scholarly journals Targeting hepatocyte growth factor in epithelial–stromal interactions in an in vitro experimental model of human periodontitis

Odontology ◽  
2021 ◽  
Author(s):  
Yoko Yamaguchi ◽  
Akira Saito ◽  
Masafumi Horie ◽  
Akira Aoki ◽  
Patrick Micke ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Experimental Studies ◽  
Three Dimensional ◽  
Collagen Gel ◽  
Neutralizing Antibody ◽  
Chronic Inflammatory Disease ◽  
Collagen Degradation ◽  
Hepatocyte Growth

AbstractPeriodontitis is a chronic inflammatory disease leading to progressive connective tissue degradation and loss of the tooth-supporting bone. Clinical and experimental studies suggest that hepatocyte growth factor (HGF) is involved in the dysregulated fibroblast–epithelial cell interactions in periodontitis. The aim of this study was to explore effects of HGF to impact fibroblast-induced collagen degradation. A patient-derived experimental cell culture model of periodontitis was applied. Primary human epithelial cells and fibroblasts isolated from periodontitis-affected gingiva were co-cultured in a three-dimensional collagen gel. The effects of HGF neutralizing antibody on collagen gel degradation were tested and transcriptome analyses were performed. HGF neutralizing antibody attenuated collagen degradation and elicited expression changes of genes related to extracellular matrix (ECM) and cell adhesion, indicating that HGF signaling inhibition leads to extensive impact on cell–cell and cell–ECM interactions. Our study highlights a potential role of HGF in periodontitis. Antagonizing HGF signaling by a neutralizing antibody may represent a novel approach for periodontitis treatment.

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