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Taina Pihlajaniemi - One of the best experts on this subject based on the ideXlab platform.
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Basement Membrane Zone Collagens XV and XVIII/ Proteoglycans Mediate Leukocyte Influx in Renal Ischemia/Reperfusion
2016Co-Authors: Azadeh Zaferani, Ditmer T Talsma, Johanna W A M Celie, Saleh Yazdani, Mari Aikio, Taina Pihlajaniemi, Ritva Heljasvaara, Gerjan Navis, Jacob Van Den BornAbstract:Collagen Type XV and XVIII are proteoglycans found in the basement membrane zones of endothelial and epithelial cells, and known for their cryptic anti-angiogenic domains named restin and endostatin, respectively. Mutations or deletions of these Collagens are associated with eye, muscle and microvessel phenoTypes. We now describe a novel role for these Collagens, namely a supportive role in leukocyte recruitment. We subjected mice deficient in Collagen XV or Collagen XVIII, and their compound mutant, as well as the wild-Type control mice to bilateral renal ischemia/reperfusion, and evaluated renal function, tubular injury, and neutrophil and macrophage influx at different time points after ischemia/reperfusion. Five days after ischemia/reperfusion, the Collagen XV, Collagen XVIII and the compound mutant mice showed diminished serum urea levels compared to wild-Type mice (all p,0.05). Histology showed reduced tubular damage, and decreased inflammatory cell influx in all mutant mice, which were more pronounced in the compound mutant despite increased expression of MCP-1 and TNF-a in double mutant mice compared to wildType mice. Both Type XV and Type XVIII Collagen bear glycosaminoglycan side chains and an in vitro approach with recombinant Collagen XVIII fragments with variable glycanation indicated a role for these side chains in leukocyte migration. Thus, basement membrane zone Collagen/ proteoglycan hybrids facilitate leukocyte influx and tubular damage after renal ischemia/reperfusion and might be potentia
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basement membrane zone Collagens xv and XVIII proteoglycans mediate leukocyte influx in renal ischemia reperfusion
PLOS ONE, 2014Co-Authors: Azadeh Zaferani, Ditmer T Talsma, Johanna W A M Celie, Saleh Yazdani, Mari Aikio, Taina Pihlajaniemi, Ritva Heljasvaara, Gerjan Navis, Jacob Van Den BornAbstract:Collagen Type XV and XVIII are proteoglycans found in the basement membrane zones of endothelial and epithelial cells, and known for their cryptic anti-angiogenic domains named restin and endostatin, respectively. Mutations or deletions of these Collagens are associated with eye, muscle and microvessel phenoTypes. We now describe a novel role for these Collagens, namely a supportive role in leukocyte recruitment. We subjected mice deficient in Collagen XV or Collagen XVIII, and their compound mutant, as well as the wild-Type control mice to bilateral renal ischemia/reperfusion, and evaluated renal function, tubular injury, and neutrophil and macrophage influx at different time points after ischemia/reperfusion. Five days after ischemia/reperfusion, the Collagen XV, Collagen XVIII and the compound mutant mice showed diminished serum urea levels compared to wild-Type mice (all p<0.05). Histology showed reduced tubular damage, and decreased inflammatory cell influx in all mutant mice, which were more pronounced in the compound mutant despite increased expression of MCP-1 and TNF-α in double mutant mice compared to wildType mice. Both Type XV and Type XVIII Collagen bear glycosaminoglycan side chains and an in vitro approach with recombinant Collagen XVIII fragments with variable glycanation indicated a role for these side chains in leukocyte migration. Thus, basement membrane zone Collagen/proteoglycan hybrids facilitate leukocyte influx and tubular damage after renal ischemia/reperfusion and might be potential intervention targets for the reduction of inflammation in this condition.
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The FASEB Journal express article 10.1096/fj.02-1001fje. Published online October 2, 2003. Lack of Type XVIII Collagen results in anterior ocular defects
2013Co-Authors: Lauri Eklund, Raija Sormunen, Antti I. Kontiola, Aino Utriainen, Marko Määttä, Naomi Fukai, Bjorn R. Olsen, Taina PihlajaniemiAbstract:Mice lacking Type XVIII Collagen have defects in the posterior part of the eye, including delayed regression of the hyaloid vasculature and poor outgrowth of the retinal vessels. We report here that these mice also have a fragile iris and develop atrophy of the ciliary body. The irises of Col18a1 −/ − mice can be seen to adhere to the lens and cornea. After the pupils begin to function, the double layer of epithelial cells separates at the apical cell contacts, leading to defoliation of its posterior pigment epithelial cell layer, and extracellular material begins to accumulate in the basement membrane zones of the iris. In contrast to the iris epithelia, where no clear signs of cellular atrophy were detected, the lack of Type XVIII Collagen resulted in atrophy of the pigmented epithelial cells of the ciliary body, and there were also ultrastructural abnormalities in the basement membrane zones. These changes did not lead to chronically elevated intraocular pressures, however. Our results indicate that Type XVIII Collagen is needed for the integrity of the epithelial basement membranes of the iris and the ciliary body and that its gene should therefore be taken into account as a new potential cause of anterior segment disorders in the eye. Key words: anterior eye segment defects • basement membranes • iris • ciliary bod
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The NC1/Endostatin Domain of Caenorhabditis elegans Type XVIII Collagen Affects Cell Migration and Axon Guidance
2013Co-Authors: Brian D. Ackley, Taina Pihlajaniemi, Jennifer R. Crew, Harri Elamaa, Calvin J. Kuo, James M. KramerAbstract:Abstract. Type XVIII Collagen is a homotrimeric basement membrane molecule of unknown function, whose COOH-terminal NC1 domain contains endostatin (ES), a potent antiangiogenic agent. The Caenorhabditis elegans Collagen XVIII homologue, cle-1, encodes three developmentally regulated protein isoforms expressed predominantly in neurons. The CLE-1 protein is found in low amounts in all basement membranes but accumulates at high levels in the nervous system. Deletion of the cle-1 NC1 domain results in viable fertile animals that display multiple cell migration and axon guidance defects. Particular defects can be rescued by ectopic expression of the NC1 domain, which is shown to be capable of forming trimers. In contrast, expression of monomeric ES does not rescue but dominantly causes cell and axon migration defects that phenocopy the NC1 deletion, suggesting that ES inhibits the promigratory activity of the NC1 domain. These results indicate that the cle-1 NC1/ES domain regulates cell and axon migrations in C. elegans. Key words: cell migration • neurogenesis • endostatin • Collagen • Caenorhabditis elegan
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Type XVIII Collagen degradation products in acute lung injury
Critical care (London England), 2009Co-Authors: Gavin D Perkins, Taina Pihlajaniemi, Ritva Heljasvaara, Nazim Nathani, Murali Shyamsundar, Mav Manji, William Tunnicliffe, Alex Richter, Daniel Park, Daniel F. McauleyAbstract:Introduction In acute lung injury, repair of the damaged alveolar-capillary barrier is an essential part of recovery. Endostatin is a 20 to 28 kDa proteolytic fragment of the basement membrane Collagen XVIII, which has been shown to inhibit angiogenesis via action on endothelial cells. We hypothesised that endostatin may have a role in inhibiting lung repair in patients with lung injury. The aims of the study were to determine if endostatin is elevated in the plasma/bronchoalveolar lavage fluid of patients with acute lung injury and ascertain whether the levels reflect the severity of injury and alveolar inflammation, and to assess if endostatin changes occur early after the injurious lung stimuli of one lung ventilation and lipopolysaccharide (LPS) challenge.
Ritva Heljasvaara - One of the best experts on this subject based on the ideXlab platform.
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Basement Membrane Zone Collagens XV and XVIII/ Proteoglycans Mediate Leukocyte Influx in Renal Ischemia/Reperfusion
2016Co-Authors: Azadeh Zaferani, Ditmer T Talsma, Johanna W A M Celie, Saleh Yazdani, Mari Aikio, Taina Pihlajaniemi, Ritva Heljasvaara, Gerjan Navis, Jacob Van Den BornAbstract:Collagen Type XV and XVIII are proteoglycans found in the basement membrane zones of endothelial and epithelial cells, and known for their cryptic anti-angiogenic domains named restin and endostatin, respectively. Mutations or deletions of these Collagens are associated with eye, muscle and microvessel phenoTypes. We now describe a novel role for these Collagens, namely a supportive role in leukocyte recruitment. We subjected mice deficient in Collagen XV or Collagen XVIII, and their compound mutant, as well as the wild-Type control mice to bilateral renal ischemia/reperfusion, and evaluated renal function, tubular injury, and neutrophil and macrophage influx at different time points after ischemia/reperfusion. Five days after ischemia/reperfusion, the Collagen XV, Collagen XVIII and the compound mutant mice showed diminished serum urea levels compared to wild-Type mice (all p,0.05). Histology showed reduced tubular damage, and decreased inflammatory cell influx in all mutant mice, which were more pronounced in the compound mutant despite increased expression of MCP-1 and TNF-a in double mutant mice compared to wildType mice. Both Type XV and Type XVIII Collagen bear glycosaminoglycan side chains and an in vitro approach with recombinant Collagen XVIII fragments with variable glycanation indicated a role for these side chains in leukocyte migration. Thus, basement membrane zone Collagen/ proteoglycan hybrids facilitate leukocyte influx and tubular damage after renal ischemia/reperfusion and might be potentia
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basement membrane zone Collagens xv and XVIII proteoglycans mediate leukocyte influx in renal ischemia reperfusion
PLOS ONE, 2014Co-Authors: Azadeh Zaferani, Ditmer T Talsma, Johanna W A M Celie, Saleh Yazdani, Mari Aikio, Taina Pihlajaniemi, Ritva Heljasvaara, Gerjan Navis, Jacob Van Den BornAbstract:Collagen Type XV and XVIII are proteoglycans found in the basement membrane zones of endothelial and epithelial cells, and known for their cryptic anti-angiogenic domains named restin and endostatin, respectively. Mutations or deletions of these Collagens are associated with eye, muscle and microvessel phenoTypes. We now describe a novel role for these Collagens, namely a supportive role in leukocyte recruitment. We subjected mice deficient in Collagen XV or Collagen XVIII, and their compound mutant, as well as the wild-Type control mice to bilateral renal ischemia/reperfusion, and evaluated renal function, tubular injury, and neutrophil and macrophage influx at different time points after ischemia/reperfusion. Five days after ischemia/reperfusion, the Collagen XV, Collagen XVIII and the compound mutant mice showed diminished serum urea levels compared to wild-Type mice (all p<0.05). Histology showed reduced tubular damage, and decreased inflammatory cell influx in all mutant mice, which were more pronounced in the compound mutant despite increased expression of MCP-1 and TNF-α in double mutant mice compared to wildType mice. Both Type XV and Type XVIII Collagen bear glycosaminoglycan side chains and an in vitro approach with recombinant Collagen XVIII fragments with variable glycanation indicated a role for these side chains in leukocyte migration. Thus, basement membrane zone Collagen/proteoglycan hybrids facilitate leukocyte influx and tubular damage after renal ischemia/reperfusion and might be potential intervention targets for the reduction of inflammation in this condition.
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© 2009 Molecular Vision Novel pathogenic mutations and skin biopsy analysis in Knobloch syndrome
2013Co-Authors: Oscar Suzuki, Ritva Heljasvaara, Erika Kague, Kelly Bagatini, P.h.c. Godoi, Gisele De ,oliveira, Lorenza Carvalhaes, Ra Gava, Glaucius OlivaAbstract:Purpose: To facilitate future diagnosis of Knobloch syndrome (KS) and better understand its etiology, we sought to identify not yet described COL18A1 mutations in KS patients. In addition, we tested whether mutations in this gene lead to absence of the COL18A1 gene product and attempted to better characterize the functional effect of a previously reported missense mutation. Methods: Direct sequencing of COL18A1 exons was performed in KS patients from four unrelated pedigrees. We used immunofluorescent histochemistry in skin biopsies to evaluate the presence of Type XVIII Collagen in four KS patients carrying two already described mutations: c.3277C>T, a nonsense mutation, and c.3601G>A, a missense mutation. Furthermore, we determined the binding properties of the mutated endostatin domain p.A1381T (c.3601G>A) to extracellular matrix proteins using ELISA and surface plasmon resonance assays. Results: We identified four novel mutations in COL18A1, including a large deletion involving exon 41. Skin biopsies from KS patients revealed lack of Type XVIII Collagen in epithelial basement membranes and blood vessels. We also found a reduced affinity of p.A1381T endostatin to some extracellular matrix components. Conclusions: COL18A1 mutations involved in Knobloch syndrome have a distribution bias toward the coding exons o
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Novel pathogenic mutations and skin biopsy analysis in Knobloch syndrome.
Molecular vision, 2009Co-Authors: Oscar T. Suzuki, Ritva Heljasvaara, Lorenza Machado De Souza Carvalhaes, Erika Kague, Kelly Bagatini, Elisandra Gava, Gisele Pena De Oliveira, P.h.c. Godoi, Glaucius OlivaAbstract:Purpose: To facilitate future diagnosis of Knobloch syndrome (KS) and better understand its etiology, we sought to identify not yet described COL18A1 mutations in KS patients. In addition, we tested whether mutations in this gene lead to absence of the COL18A1 gene product and attempted to better characterize the functional effect of a previously reported missense mutation. Methods: Direct sequencing of COL18A1 exons was performed in KS patients from four unrelated pedigrees. We used immunofluorescent histochemistry in skin biopsies to evaluate the presence of Type XVIII Collagen in four KS patients carrying two already described mutations: c.3277C>T, a nonsense mutation, and c.3601G>A, a missense mutation. Furthermore, we determined the binding properties of the mutated endostatin domain p.A1381T (c.3601G>A) to extracellular matrix proteins using ELISA and surface plasmon resonance assays. Results: We identified four novel mutations in COL18A1, including a large deletion involving exon 41. Skin biopsies from KS patients revealed lack of Type XVIII Collagen in epithelial basement membranes and blood vessels. We also found a reduced affinity of p.A1381T endostatin to some extracellular matrix components. Conclusions: COL18A1 mutations involved in Knobloch syndrome have a distribution bias toward the coding exons of the C-terminal end. Large deletions must also be considered when point mutations are not identified in patients with characteristic KS phenoType. We report, for the first time, lack of Type XVIII Collagen in KS patients by immunofluorescent histochemistry in skin biopsy samples. As a final point, we suggest the employment of this technique as a preliminary and complementary test for diagnosis of KS in cases when mutation screening either does not detect mutations or reveals mutations of uncertain effect, such as the p.A1381T change.
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Type XVIII Collagen degradation products in acute lung injury
Critical care (London England), 2009Co-Authors: Gavin D Perkins, Taina Pihlajaniemi, Ritva Heljasvaara, Nazim Nathani, Murali Shyamsundar, Mav Manji, William Tunnicliffe, Alex Richter, Daniel Park, Daniel F. McauleyAbstract:Introduction In acute lung injury, repair of the damaged alveolar-capillary barrier is an essential part of recovery. Endostatin is a 20 to 28 kDa proteolytic fragment of the basement membrane Collagen XVIII, which has been shown to inhibit angiogenesis via action on endothelial cells. We hypothesised that endostatin may have a role in inhibiting lung repair in patients with lung injury. The aims of the study were to determine if endostatin is elevated in the plasma/bronchoalveolar lavage fluid of patients with acute lung injury and ascertain whether the levels reflect the severity of injury and alveolar inflammation, and to assess if endostatin changes occur early after the injurious lung stimuli of one lung ventilation and lipopolysaccharide (LPS) challenge.
Marko Rehn - One of the best experts on this subject based on the ideXlab platform.
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Generation of biologically active endostatin fragments from human Collagen XVIII by distinct matrix metalloproteases
Experimental cell research, 2005Co-Authors: Ritva Heljasvaara, Marko Rehn, Pia Nyberg, Jani Luostarinen, Mataleena Parikka, Pia Heikkilä, Timo Sorsa, Tuula Salo, Taina PihlajaniemiAbstract:Abstract Endostatin, a potent inhibitor of endothelial cell proliferation, migration, angiogenesis and tumor growth, is proteolytically cleaved from the C-terminal nonCollagenous NC1 domain of Type XVIII Collagen. We investigated the endostatin formation from human Collagen XVIII by several MMPs in vitro. The generation of endostatin fragments differing in molecular size (24–30 kDa) and in N-terminal sequences was identified in the cases of MMP-3, -7, -9, -13 and -20. The cleavage sites were located in the protease-sensitive hinge region between the trimerization and endostatin domains of NC1. MMP-1, -2, -8 and -12 did not show any significant activity against the C-terminus of Collagen XVIII. The anti-proliferative effect of the 20-kDa endostatin, three longer endostatin-containing fragments generated in vitro by distinct MMPs and the entire NC1 domain, on bFGF-stimulated human umbilical vein endothelial cells was established. The anti-migratory potential of some of these fragments was also studied. In addition, production of endostatin fragments between 24–30 kDa by human hepatoblastoma cells was shown to be due to MMP action on Type XVIII Collagen. Our results indicate that certain, especially cancer-related, MMP family members can generate biologically active endostatin-containing polypeptides from Collagen XVIII and thus, by releasing endostatin fragments, may participate in the inhibition of endothelial cell proliferation, migration and angiogenesis.
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Endostatin Overexpression Specifically in the Lens and Skin Leads to Cataract and Ultrastructural Alterations in Basement Membranes
The American journal of pathology, 2005Co-Authors: Harri Elamaa, Marko Rehn, Raija Sormunen, Raija Soininen, Taina PihlajaniemiAbstract:Endostatin, a proteolytic fragment of Type XVIII Collagen, has been shown to inhibit angiogenesis, tumor growth, and endothelial cell proliferation and migration. We analyzed its functions in vivo by generating transgenic mice in which it was overexpressed in the skin and lens capsule under the keratin K14 promoter. Opacity of the lens occurred at 4 months of age in the mouse line J4, with the highest level of endostatin expression. The lens epithelial cells appeared to lose contact with the capsule and began to vacuolize. In 1-year-old mice the lens epithelial cell layer had entirely degenerated, and instead, large plaques of spindle-shaped cells had formed in the anterior region of the lens. Moreover, a widening of the epidermal basement membrane (BM) zone of the skin was observed in electron microscopy. The epidermal BM was conspicuously altered in the J4 mice with high transgene expression, including clear broadening and occurrence of pearl-like protrusions in some areas, whereas the BM was more even in appearance but consistently broadened in the mouse line G20 with moderate transgene expression. In both lines the BM was continuous. Measurements indicated that the lamina densa was 78.54 ± 53.10 nm in line J4, the large variation reflecting the protrusions of the lamina densa, and 44.24 ± 11.52 nm in line G20, compared with 33.74 ± 9.96 nm in wild-Type adult mice. Immunoelectron microscopy of wild-Type mouse skin Type XVIII Collagen showed a polarized orientation in the BMs, with the C-terminal endostatin region localized in the lamina densa and the N terminus in average ∼40 nm more on the dermal side. Type XVIII Collagen was dispersed in the transgenic skin, suggesting that the transgene-derived endostatin fragment displaces the full-length Collagen XVIII. This may impair the anchoring of the lamina densa to the dermis and thereby lead to loosening of the BMs, resembling the previously observed situation in Collagen XVIII-null mice.
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Characterization of the human Type XVIII Collagen gene and proteolytic processing and tissue location of the variant containing a frizzled motif.
Matrix biology : journal of the International Society for Matrix Biology, 2003Co-Authors: Harri Elamaa, Marko Rehn, Helena Autio-harmainen, Anne Snellman, Taina PihlajaniemiAbstract:Abstract Human Type XVIII Collagen was found to be expressed as three variants, termed NC1-303, NC1-493 and NC1-728, differing in their N-terminal non-Collagenous domains (NC1). The corresponding gene was found to be ∼105 kb in size and contain 43 exons. The short variant is derived from utilization of an upstream promoter associated with the first two exons of the gene. The two other variants are derived from a downstream promoter and alternative splicing of exon 3, resulting in 192 residues of shared sequences characterized by a putative ∼30 residue conserved coiled–coil motif and 235 residues of sequences specific to NC1-728. The NC1-728 variant has a conserved cysteine-rich domain homologous with the ligand-binding part of the frizzled proteins. A polyclonal antibody specific to the NC1-728 variant was generated, and immunostaining of fetal tissues revealed staining in lung and skeletal muscle. Human serum contained 173- and 144-kDa α1(XVIII) chains corresponding to the NC1-728 and NC1-493 variants, respectively. A 200-kDa polypeptide was detected in cells transfected with a cDNA construct corresponding to the full-length NC1-728 variant, and EBNA-293 cells endogenously synthesizing low amounts of Type XVIII Collagen had a 45-kDa fragment in their culture medium that corresponded to most of the NC1 domain of the NC1-728 variant, suggesting processing of the N-terminal frizzled-containing domain.
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Induced repatterning of Type XVIII Collagen expression in ureter bud from kidney to lung Type: association with sonic hedgehog and ectopic surfactant protein C.
Development (Cambridge England), 2001Co-Authors: Yanfeng Lin, Taina Pihlajaniemi, Ritva Heljasvaara, Marko Rehn, Shaobing Zhang, Petri Itäranta, Juha Tuukkanen, Hellevi Peltoketo, Seppo VainioAbstract:Epithelial-mesenchymal tissue interactions regulate the formation of signaling centers that play a role in the coordination of organogenesis, but it is not clear how their activity leads to differences in organogenesis. We report that Type XVIII Collagen, which contains both a frizzled and an endostatin domain, is expressed throughout the respective epithelial bud at the initiation of lung and kidney organogenesis. It becomes localized to the epithelial tips in the lung during the early stages of epithelial branching, while its expression in the kidney is confined to the epithelial stalk region and is lost from the nearly formed ureter tips, thus displaying the reverse pattern to that in the lung. In recombinants, between ureter bud and lung mesenchyme, Type XVIII Collagen expression pattern in the ureter bud shifts from the kidney to the lung Type, accompanied by a shift in sonic hedgehog expression in the epithelium. The lung mesenchyme is also sufficient to induce ectopic lung surfactant protein C expression in the ureter bud. Moreover, the shift in Type XVIII Collagen expression is associated with changes in ureter development, thus resembling aspects of early lung Type epigenesis in the recombinants. Respecification of Collagen is necessary for the repatterning process, as Type XVIII Collagen antibody blocking had no effect on ureter development in the intact kidney, whereas it reduced the number of epithelial tips in the lung and completely blocked ureter development with lung mesenchyme. Type XVIII Collagen antibody blocking also led to a notable reduction in the expression of Wnt2, which is expressed in the lung mesenchyme but not in that of the kidney, suggesting a regulatory interaction between this Collagen and Wnt2. Respecification also occurred in a chimeric organ containing the ureter bud and both kidney and lung mesenchymes, indicating that the epithelial tips can integrate the morphogenetic signals independently. A glial cell line-derived neurotrophic factor signal induces loss of Type XVIII Collagen from the ureter tips and renders the ureter bud competent for repatterning by lung mesenchyme-derived signals. Our data suggest that differential organ morphogenesis is regulated by an intra-organ patterning process that involves coordination between inductive signals and matrix molecules, such as Type XVIII Collagen.
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Collagen XVIII is localized in sinusoids and basement membrane zones and expressed by hepatocytes and activated stellate cells in fibrotic human liver
Hepatology, 1998Co-Authors: Orlando Musso, Nathalie Théret, Elina Hintikka, Dominique Lotrian, Jean-pierre Campion, Janna Saarela, Jocelyne Liétard, Taina Pihlajaniemi, Marko Rehn, Bruno ClementAbstract:Type XVIII Collagen is a recently discovered nonfibrillar Collagen associated with basement membranes in mice and expressed at high levels in human liver. We studied the origin, distribution, and RNA levels of Type XVIII Collagen in normal and fibrotic human livers by in situ hybridization, immunohistochemistry, and Northern and dot blots and compared proCollagen α1(XVIII) RNA levels with those of proCollagen α1(IV) and laminin γ1, the two major components of liver basement membranes. In normal liver, Type XVIII Collagen was heavily deposited in perisinusoidal spaces and basement membrane zones. The major source of Type XVIII Collagen was hepatocytes and, to a lesser extent, endothelial, biliary epithelial, and vascular smooth muscle cells and peripheral nerves. In cirrhosis, Type XVIII Collagen formed a thick deposit along capillarized sinusoids. Grain counts after in situ hybridization showed myofibroblasts to increase their expression 13-fold in active and twofold in quiescent fibrosis, whereas hepatocytes increased their expression only twofold in both active and quiescent fibrosis. Activated stellate cells in vitro expressed Type XVIII Collagen at high levels. These data indicate that Type XVIII Collagen is a component of the perisinusoidal space and is associated with basement membrane remodeling. Hepatocytes and activated stellate cells are important sources of Type XVIII Collagen in normal and fibrotic liver respectively, which suggests tissue-specific regulation of its expression.
Raghu Kalluri - One of the best experts on this subject based on the ideXlab platform.
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Type XVIII Collagen is essential for survival during acute liver injury in mice.
Disease models & mechanisms, 2013Co-Authors: Michael Duncan, Changqing Yang, Harikrishna Tanjore, Patrick M. Boyle, Doruk Keskin, Hikaru Sugimoto, Michael Zeisberg, Björn Olsen, Raghu KalluriAbstract:SUMMARY The regenerative response to drug- and toxin-induced liver injury induces changes to the hepatic stroma, including the extracellular matrix. Although the extracellular matrix is known to undergo changes during the injury response, its impact on maintaining hepatocyte function and viability in this process remains largely unknown. We demonstrate that recovery from toxin-mediated injury is impaired in mice deficient in a key liver extracellular matrix molecule, Type XVIII Collagen, and results in rapid death. The Type-XVIII-Collagen-dependent response to liver injury is mediated by survival signals induced by α1β1 integrin, integrin linked kinase and the Akt pathway, and mice deficient in either α1β1 integrin or hepatocyte integrin linked kinase also succumb to toxic liver injury. These findings demonstrate that Type XVIII Collagen is an important functional component of the
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Type XVIII Collagen is essential for survival during acute liver injury in mice
The Company of Biologists, 2013Co-Authors: Michael B. Duncan, Changqing Yang, Harikrishna Tanjore, Patrick M. Boyle, Doruk Keskin, Hikaru Sugimoto, Michael Zeisberg, Bjorn R. Olsen, Raghu KalluriAbstract:SUMMARY The regenerative response to drug- and toxin-induced liver injury induces changes to the hepatic stroma, including the extracellular matrix. Although the extracellular matrix is known to undergo changes during the injury response, its impact on maintaining hepatocyte function and viability in this process remains largely unknown. We demonstrate that recovery from toxin-mediated injury is impaired in mice deficient in a key liver extracellular matrix molecule, Type XVIII Collagen, and results in rapid death. The Type-XVIII-Collagen-dependent response to liver injury is mediated by survival signals induced by α1β1 integrin, integrin linked kinase and the Akt pathway, and mice deficient in either α1β1 integrin or hepatocyte integrin linked kinase also succumb to toxic liver injury. These findings demonstrate that Type XVIII Collagen is an important functional component of the liver matrix microenvironment and is crucial for hepatocyte survival during injury and stress
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Basement Membrane Derived Inhibitors of Angiogenesis
Angiogenesis, 2008Co-Authors: Michael Duncan, Raghu KalluriAbstract:Blood vessel growth during development and disease is likely governed by the balance between proand antiangiogenic factors. Numerous reports have focused on the important role of various growth factors during angiogenesis. Peptide fragments derived from basement membranes constitute a relatively new and expanding class of antiangiogenic factors with a potential for clinical relevance. These factors have been studied in a variety of disease models, and genetic evidence for their role in controlling angiogenesis is beginning to be realized. This chapter highlights several of these factors and their mechanism of action as we understand them to date. Gaining additional insight into the full compliment of these antiangiogenic fragments from basement membranes, how they are derived, and their full mechanism of action represents an important challenge in vascular biology today. The vascular basement membrane (VBM) is a complex structure composed of a variety of functionally diverse glycoproteins and proteoglycans (Fig. 11.1) [1]. The primary molecules detected in the VBM are the heparan sulfate proteoglycans (such as perlecan and Type XVIII Collagen), laminin, niodogen, entactin, fibulin, as well as Type IV Collagen. While providing structural support to the vessel, these molecules also serve important functional roles in endothelial cell (EC) signaling and adhesion. Therefore, these basement membrane molecules play a critical role in EC proliferation, migration, morphogenesis, survival, and vessel stability [2]. Much of the interactions and subsequent biological activity of VBM macromolecules are due to their ability to engage endothelial cell surface receptors, namely the integrins [3]. In some instances, evidence suggests that the antiangiogenic functionality of basement membrane molecules is elicited only when cryptic fragments of these molecules are revealed through proteolytic processing [4]. These findings highlight an essential role for (1) understanding the structural organization of the VBM in normal and disease states, (2) identifying the full complement of antiangiogenic entities derived from the VBM and other basement membranes, and (3) defining the mechanisms by which changes in the vascular microenvironment, and subsequent changes in the balance of angiogenic mediators, occur. This chapter highlights the origin and biological activity of some recently discovered basement membrane derived antiangiogenic molecules.
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Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression.
Cancer research, 2004Co-Authors: Yuki Hamano, Hikaru Sugimoto, Björn Olsen, Akulapalli Sudhakar, Mary A. Soubasakos, Mark W. Kieran, Jack Lawler, Raghu KalluriAbstract:Low-dose cyclophosphamide (LDC) induces selective apoptosis of endothelial cells within the vascular bed of tumors. Here, we investigated a hypothesis that the effect of LDC is mediated by the pro-apoptotic action of endogenous inhibitors of angiogenesis. Tumors treated with LDC demonstrate similar expression of matrix metalloproteinases and also basement membrane-derived angiogenesis inhibitors when compared with wild-Type tumors, whereas the expression of thrombospondin-1 (TSP-1) is significantly elevated in LDC-treated tumors. We used mice with an absence of Type XVIII Collagen (endostatin) or Type IV Collagen alpha3 chain (tumstatin) or TSP-1 to assess the contribution of these endogenous inhibitors of angiogenesis on LDC-mediated tumor suppression. Lack of TSP-1 in the host in addition to tumor cells leads to diminished capacity of LDC to suppress tumor growth, whereas the absence of endostatin and tumstatin did not alter the effect of LDC. LDC treatment predominantly induces selective expression of TSP-1 in tumor cells and peri-vascular cells and facilitates apoptosis of proliferating endothelial cells, with minimal direct effect on tumor cells and peri-vascular cells. These studies indicate that TSP-1 contributes to tumor growth suppression induced by LDC and suggest that tumors that express high basal level of TSP-1 may be more susceptible to tumor suppression by such a regimen. This study also makes a strong case for TSP-1 expression levels as a potential predictive marker for the successful use of LDC in cancer patients.
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Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by αvβ3 and α5β1 integrins
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Akulapalli Sudhakar, Changqing Yang, Hikaru Sugimoto, Michael Zeisberg, Julie C. Lively, Raghu KalluriAbstract:Tumstatin and endostatin are two inhibitors of angiogenesis derived from precursor human Collagen molecules known as α3 chain of Type IV Collagen and α1 chain of Type XVIII Collagen, respectively. Although both these inhibitors are nonCollagenous (NC1) domain fragments of Collagens, they only share a 14% amino acid homology. In the present study we evaluated the functional receptors, mechanism of action, and intracellular signaling induced by these two Collagen-derived inhibitors. Human tumstatin prevents angiogenesis via inhibition of endothelial cell proliferation and promotion of apoptosis with no effect on migration, whereas human endostatin prevents endothelial cell migration with no effect on proliferation. We demonstrate that human tumstatin binds to αvβ3 integrin in a vitronectin/fibronectin/RGD cyclic peptide independent manner, whereas human endostatin competes with fibronectin/RGD cyclic peptide to bind α5β1 integrin. The activity of human tumstatin is mediated by αvβ3 integrin, whereas the activity of human endostatin is mediated by α5β1 integrin. Additionally, although human tumstatin binding to αvβ3 integrin leads to the inhibition of Cap-dependent translation (protein synthesis) mediated by focal adhesion kinase/phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 pathway, human endostatin binding to α5β1 integrin leads to the inhibition of focal adhesion kinase/c-Raf/MEK1/2/p38/ERK1 mitogen-activated protein kinase pathway, with no effect on phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 and Cap-dependent translation. Collectively, such distinct properties of human tumstatin and human endostatin provide the first insight into their diverse antiangiogenic actions and argue for combining them for targeting tumor angiogenesis.
Seppo Vainio - One of the best experts on this subject based on the ideXlab platform.
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Induced repatterning of Type XVIII Collagen associates with ectopic Sonic hedgehog and lung surfactant C gene expression and changes in epithelial epigenesis in the ureteric bud.
Journal of the American Society of Nephrology : JASN, 2003Co-Authors: Seppo Vainio, Yanfeng Lin, Taina PihlajaniemiAbstract:How cell and tissue interactions lead to complex organ structures and differentiated cell Types during organogenesis is one of the most fundamental questions in developmental biology. The embryonic lung and kidney of the mouse are useful models for studying the molecular mechanisms of morphogenesis, and in both of these organs, the epithelial bud undergoes a characteristic branching process. This review discusses the potential role of an extracellular matrix molecule, Type XVIII Collagen, in the generation of the branching patterns in the lung and kidney and how its experimental respecification in tissue recombinants between the ureteric bud and lung mesenchyme correlates with changes in expression of signaling molecules such as sonic hedgehog and changes in cell fate as judged by ectopic expression of the lung surfactant C gene.
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Induced repatterning of Type XVIII Collagen expression in ureter bud from kidney to lung Type: association with sonic hedgehog and ectopic surfactant protein C.
Development (Cambridge England), 2001Co-Authors: Yanfeng Lin, Taina Pihlajaniemi, Ritva Heljasvaara, Marko Rehn, Shaobing Zhang, Petri Itäranta, Juha Tuukkanen, Hellevi Peltoketo, Seppo VainioAbstract:Epithelial-mesenchymal tissue interactions regulate the formation of signaling centers that play a role in the coordination of organogenesis, but it is not clear how their activity leads to differences in organogenesis. We report that Type XVIII Collagen, which contains both a frizzled and an endostatin domain, is expressed throughout the respective epithelial bud at the initiation of lung and kidney organogenesis. It becomes localized to the epithelial tips in the lung during the early stages of epithelial branching, while its expression in the kidney is confined to the epithelial stalk region and is lost from the nearly formed ureter tips, thus displaying the reverse pattern to that in the lung. In recombinants, between ureter bud and lung mesenchyme, Type XVIII Collagen expression pattern in the ureter bud shifts from the kidney to the lung Type, accompanied by a shift in sonic hedgehog expression in the epithelium. The lung mesenchyme is also sufficient to induce ectopic lung surfactant protein C expression in the ureter bud. Moreover, the shift in Type XVIII Collagen expression is associated with changes in ureter development, thus resembling aspects of early lung Type epigenesis in the recombinants. Respecification of Collagen is necessary for the repatterning process, as Type XVIII Collagen antibody blocking had no effect on ureter development in the intact kidney, whereas it reduced the number of epithelial tips in the lung and completely blocked ureter development with lung mesenchyme. Type XVIII Collagen antibody blocking also led to a notable reduction in the expression of Wnt2, which is expressed in the lung mesenchyme but not in that of the kidney, suggesting a regulatory interaction between this Collagen and Wnt2. Respecification also occurred in a chimeric organ containing the ureter bud and both kidney and lung mesenchymes, indicating that the epithelial tips can integrate the morphogenetic signals independently. A glial cell line-derived neurotrophic factor signal induces loss of Type XVIII Collagen from the ureter tips and renders the ureter bud competent for repatterning by lung mesenchyme-derived signals. Our data suggest that differential organ morphogenesis is regulated by an intra-organ patterning process that involves coordination between inductive signals and matrix molecules, such as Type XVIII Collagen.
