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Coordinated Induction of VEGF Receptors in Mesenchymal Cell Types During Rat Hepatic Wound Healing

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Coordinated Induction of VEGF Receptors in Mesenchymal Cell Types During Rat Hepatic Wound Healing Oncogene (1998) 17, 115 ± 121 ã 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Coordinated induction of VEGF receptors in mesenchymal cell types during rat hepatic wound healing V Ankoma-Sey1,3, M Matli1, KB Chang1, A Lalazar1, DB Donner2, L Wong1, RS Warren1 and SL Friedman1 1UCSF Liver Center & Departments of Medicine & Surgery, University of California, San Francisco, California; 2Department of Physiology and Biophysics and the Walther Oncology Center, University of Indiana, Indiapolis, Indiana, USA Homology PCR has been used to identify receptor transition which is similar regardless of the type of tyrosine kinases (RTKs) expressed during activation of liver injury, and which re¯ects a cascade of gene rat hepatic stellate cells, the key ®brogenic mesenchymal induction comprising both regulatory and structural element in the liver. Partial cDNAs encoding several components (Friedman, 1996). RTKs were cloned from stellate cells activated in vivo, An important role in stellate cell activation has including those of Flt-1, Flk-1, c-met, PDGFR, and emerged for receptor tyrosine kinases (RTKs), signal- Tyro10/DDR2. RNAse protection from cells activated in ing molecules which underlie cell growth and differ- vivo demonstrated biphasic induction of ¯t-1 and ¯k-1 entiation in all tissues. Many of the phenotypic features mRNAs, receptors for vascular endothelial growth factor of stellate cell activation are mediated by signaling (VEGF). Culture-activation of stellate cells was asso- through RTKs. For example, stellate cell proliferation ciated with increased [125I]VEGF binding and Flt-1 and in culture and in vivo is preceded by rapid induction of Flk-1 receptor protein. Induction of VEGF binding sites the b subunit of platelet derived growth factor receptor correlated with an 2.5-fold increase in DNA synthesis in (PDGFR) (Wong et al., 1994). Similarly, basic response to VEGF, but only if cells were activated by ®broblast growth factor (bFGF), another RTK growth on collagen I, whereas cells maintained in a ligand, is produced by and stimulates proliferation of quiescent state on a basement membrane-like substratum stellate cells (Hioki et al., 1996; Rosenbaum et al., (EHS matrix) were nonproliferative. In both stellate and 1995). FGF receptors have been identi®ed on stellate endothelial cells VEGF-induced mitogenesis was aug- cells, and bFGF also mediates the mitogenic eect of mented by co-incubation with basic ®broblast growth transforming growth factor b1 (TGFb1) in activated factor (bFGF), a cytokine with known synergy with human stellate cells (Rosenbaum et al., 1995). In vivo, VEGF. These ®ndings suggest that the cellular targets of FGF may stimulate extracellular matrix production VEGF in liver may not be con®ned to sinusoidal and vascularization following liver injury by both endothelial cells, and that VEGF responses re¯ect autorcrine and paracrine mechanisms (Hioki et al., combined eects on both hepatic stellate cells and 1996). sinusoidal endothelium. The general organization of RTKs is well estab- lished. All RTKs are composed of three major Keywords: hepatic stellate cells; sinusoidal endothelium; domains: a highly conserved cytoplasmic tyrosine hepatic ®brosis; receptor tyrosine kinases kinase domain, comprising about 200 ± 300 amino acids (Hanks et al., 1988), a single transmembrane spanning domain and a highly diverse extracellular region (reviewed in Fantl et al., 1993). Binding by Introduction ligands elicits a diverse range of cellular responses depending on the cell-type and the speci®c RTK A central event in the pathogenesis of tissue ®brosis is (Schlessinger, 1993). Responsiveness of cells to RTK the activation of resident perivascular mesenchymal ligands may also be regulated by extracellular matrix cells which proliferate and produce extracellular matrix (ECM), which can modulate RTK abundance or in response to injury. In the liver, the hepatic stellate function (Xu and Clark, 1996). Because changes in cell ful®ls this role (Friedman, 1993b). These perisinu- ECM composition are a major component of liver soidal vitamin A-storing cells are widely distributed injury, it is possible that one consequence of ®brosis throughout the normal liver, and transform during may be altered RTK expression and/or signaling. injury into a ®brogenic cell (Friedman et al., 1985; Given the importance of RTKs to wound healing in Gressner, 1995) which is proliferative (Geerts et al., liver, in this study we exploited the technique of 1991) and contractile (Kawada et al., 1992; Rockey et homology PCR to clone RTKs expressed during al., 1993). Stellate cell activation is a phenotypic stellate cell activation in order to de®ne their role in liver injury, and as a model for how RTKs might contribute to tissue repair in other organs. Because this Correspondence: SL Friedman, Box 1123, Division of Liver Diseases, approach yielded the unexpected ®nding of receptors Mount Sinai School of Medicine, 1425 Madison Ave, Room 11-70F, for vascular endothelial growth factor (VEGF) in New York, NY 10029, USA stellate cells, we have speci®cally explored the 3Current address: Division of Gastroenterology, University of Texas potential role of VEGF signaling in mediating features at Houston Medical School, 6431 Fannin, MSB 4.23, Houston, Texas of stellate cell activation, and have compared their 77030, USA Received 7 October 1997; revised 17 February 1998; accepted 18 response to sinusoidal endothelial cells, the other February 1998 mesenchymal cell type of the hepatic sinusoid. Tyrosine kinases in rat hepatic wound healing V Ankoma-Sey et al 116 lial cells, which are known to express receptors for Results VEGF (Yamane et al., 1994). Speci®c binding of [125I]VEGF to freshly isolated stellate cells and SECs Homology PCR cloning of RTKs in activated stellate increased with ligand concentration and was saturable. cells The Scatchard plots (Figure 2) demonstrated two To identify cDNAs expressed during activation of classes of high anity binding sites/receptors on each stellate cells, homology cloning was performed accord- cell type (Table 2). ing to the strategy of Raz et al. (1991). The template was a rat stellate cell activation-induced cDNA library VEGF activity and eect of extracellular matrix in derived by subtraction cloning from stellate cells cultured stellate cells isolated 3 h after a single dose of intragastric CCL4 (Lalazar et al., 1997). The PCR cloning strategy We and others (Friedman et al., 1989; Davis, 1988) yielded 64 clones representing six dierent RTK have previously demonstrated that the composition of genes, all containing the expected *200 bp insert (see the extracellular matrix determines whether stellate Table 1). These included receptors for vascular cells will activate in primary culture. Modulation of endothelial growth factor, hepatocyte growth factor, VEGF binding during stellate cell activation was platelet derived growth factor, and an orphan receptor explored by allowing the cells to activate through (Tie-1). Tie-1 is expressed on human hematopoietic growth on type I collagen, an established model of progenitor cells, endothelial cells and megakaryocytes culture activation (Friedman et al., 1989). [125I]VEGF (Batard et al., 1996; Rodewald and Sato, 1996) and binding sites/cell were determined in stellate cells and plays an important role in vasculogenesis (Dumont et SECs after 1 and 10 days in cultlure on collagen I. al., 1993; Sato et al., 1995). In addition to these known Maximal VEGF binding by stellate cells occurred RTKs. a novel RTK, clone `RTK40' (Genbank following 10 days in culture associated with expression Accession no. AF016247), was recovered whose of Flt-1 and Flk-1 by Western blot (Figure 3); the tyrosine kinase sequence assigns it to a new subfamily which have a lectin-like domain in their extracellular regions (other members include Tyro 10/DDR2) (Johnson et al., 1993; Lai and Lemke, 1994). a Characterization of 125I VEGF binding sites in stellate cells The cloning of VEGF receptor cDNAs from stellate cells was surprising given its presumed restriction to endothelial cells. To con®rm expression of ¯k-1 and ¯t- 1 mRNA by stellate cells we analysed their expression in pure cell isolates after activation in vivo by administration of CCl4. There was biphasic expression of the two VEGF receptors in stellate cells during injury: ¯t-1 mRNA was modestly induced beginning 3 h after CCl4 (Figure 1) whereas ¯k-1 mRNA was down-regulated initially. However, both transcripts were markedly induced in vivo beginning 96 h after a single dose of CCl4. This time course of induction diers from that of the b-PDGF receptor which is induced within 1 h under identical conditions (Wong et al., 1994 ). b To further characterize VEGF binding sites on stellate cells, saturation binding studies were per- formed and compared to those of sinusoidal endothe- Table 1 Receptor tyrosine kinase cDNAs identi®ed in activated hepatic stellate cells by homology PCR Clone % nt homology name Homologies to (Genbank #) Ligand RTK 17 Flt-1,4 95 to mouse (L07297) VEGF RTK 19 Tie-1 95 to mouse (X73960) Unknown RTK 40 Tyro 10/DDR2 91 to mouse (X76505) Collagens RTK 47 c-met 89 to mouse (S52036) HGF Figure 1 Flt-1 and Flk-1 mRNA in hepatic stellate cells after RTK 48 PDGF-R 85 to mouse (X04367) PDGF CCl4-induced liver injury. (a) ¯t-1 and ¯k-1 mRNA expression RTK 61 Flk-1 89 to mouse (X59397) VEGF were analysed by RNAse protection assay in 10 mg total RNA Six distinct 200 bp cDNAs were represented among 64 clones from puri®ed rat hepatic stellate cells at intervals after a single analysed. GenBank accession numbers listed refer to closest dose of CCl4. S14, a ribosomal protein mRNA, is shown as an nucleotide homologies based on FASTA sequence search. The clone internal control. (b) Normalized relative expression of ¯t-1 and RTK40 sequence has been entered into GenBank, accession number ¯k-1 mRNAs from a, expressed as fold increase compared to cells AF016247 from normal animals Tyrosine kinases in rat hepatic wound healing V Ankoma-Sey et al 117 larger increase in Flk-1 vs Flt-1 further suggests that remain quiescent (Friedman et al., 1989).
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