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Toshio Suda

Publications and source records attributed to Toshio Suda.

At least 37 records · Page 2Linked to original sources
PubMed2005

The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis.

PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePten(flox/+) mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85alpha and p110gamma. In vitro, Tie2CrePten(flox/+) endothelial cells showed enhanced proliferation/migration. Tie2CrePten(flox/flox) mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110gamma rather than on p85alpha and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.

Animals↗
PubMed2005

DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells.

Osteoclasts are bone-resorbing cells that play a pivotal role in bone remodeling. Osteoclasts form large multinuclear giant cells by fusion of mononuclear osteoclasts. How cell fusion is mediated, however, is unclear. We identify the dendritic cell-specific transmembrane protein (DC-STAMP), a putative seven-transmembrane protein, by a DNA subtraction screen between multinuclear osteoclasts and mononuclear macrophages. DC-STAMP is highly expressed in osteoclasts but not in macrophages. DC-STAMP-deficient mice were generated, and osteoclast cell fusion was completely abrogated in homozygotes despite normal expression of osteoclast markers and cytoskeletal structure. As osteoclast multinucleation was restored by retroviral introduction of DC-STAMP, loss of cell fusion was directly attributable to a lack of DC-STAMP. Defects in osteoclast multinucleation reduce bone-resorbing activity, leading to osteopetrosis. Similar to osteoclasts, foreign body giant cell formation by macrophage cell fusion was also completely abrogated in DC-STAMP-deficient mice. We have thus identified an essential regulator of osteoclast and macrophage cell fusion, DC-STAMP, and an essential role of osteoclast multinucleation in bone homeostasis.

Animals↗
PubMed2005

Oncogenic transcription factor Evi1 regulates hematopoietic stem cell proliferation through GATA-2 expression.

The ecotropic viral integration site-1 (Evi1) is an oncogenic transcription factor in murine and human myeloid leukemia. We herein show that Evi1 is predominantly expressed in hematopoietic stem cells (HSCs) in embryos and adult bone marrows, suggesting a physiological role of Evi1 in HSCs. We therefore investigate the role and authentic target genes of Evi1 in hematopoiesis using Evi1-/- mice, which die at embryonic day 10.5. HSCs in Evi1-/- embryos are markedly decreased in numbers in vivo with defective self-renewing proliferation and repopulating capacity. Notably, expression rate of GATA-2 mRNA, which is essential for proliferation of definitive HSCs, is profoundly reduced in HSCs of Evi1-/- embryos. Restoration of the Evi1 or GATA-2 expression in Evi1-/- HSCs could prevent the failure of in vitro maintenance and proliferation of HSC through upregulation of GATA-2 expression. An analysis of the GATA-2 promoter region revealed that Evi1 directly binds to GATA-2 promoter as an enhancer. Our results reveal that GATA-2 is presumably one of critical targets for Evi1 and that transcription factors regulate the HSC pool hierarchically.

Angiopoietin-1↗
PubMed2005

Isolation and expression patterns of genes for three angiopoietin-like proteins, Angptl1, 2 and 6 in zebrafish.

Angiopoietin-like proteins (Angptls) are known to possess biological activities not only in the vascular system, but in the other mammalian tissues; however, their expression patterns and function in embryogenesis have not been extensively characterized. Here, we identify three zebrafish genes (Zangptl1, Zangptl2 and Zangptl6) highly homologous to mammalian Angptl1/ARP1, Angptl2/ARP2 and Angptl6/AGF, and describe their adult and embryonic temporal and spatial expression patterns. Zangptl1 is expressed faintly in the somites, while Zangptl2 is first detected in the yolk sac extension, spinal cord and branchial arches and is later expressed in the liver primordium and pectoral fin buds. Zangptl6 is expressed in the notochord. In addition to its embryonic expression, Zangptl2 is induced in adult fish during fin regeneration.

Angiopoietin-Like Protein 1↗
PubMed2005

Increase of smooth muscle cell migration and of intimal hyperplasia in mice lacking the alpha/beta hydrolase domain containing 2 gene.

Multiple steps, including the migration of vascular smooth muscle cells (SMCs), are involved in the pathogenesis of atherosclerosis. To discover genes which are involved in these steps, we screened mutant mouse lines established by the exchangeable gene trap method utilizing X-gal staining during their embryonic development. One of these lines showed strong reporter gene expression in the vitelline vessels of yolk sacs at embryonic day (E) 12.5. The trap vector was inserted into the fifth intron of alpha/beta hydrolase domain containing 2 (Abhd2) gene which was shown to be expressed in vascular and non-vascular SMCs of adult mice. Although homozygous mutant mice were apparently normal, enhanced SMC migration in the explants SMCs culture and marked intimal hyperplasia after cuff placement were observed in homozygous mice in comparison with wild-type mice. Our results show that Abhd2 is involved in SMC migration and neointimal thickening on vascular SMCs.

Animals↗
PubMed2005

Angiopoietin-related growth factor antagonizes obesity and insulin resistance.

Angiopoietin-related growth factor (AGF), a member of the angiopoietin-like protein (Angptl) family, is secreted predominantly from the liver into the systemic circulation. Here, we show that most (>80%) of the AGF-deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. In parallel, mice with targeted activation of AGF show leanness and increased insulin sensitivity resulting from increased energy expenditure. They are also protected from high-fat diet-induced obesity, insulin resistance and nonadipose tissue steatosis. Hepatic overexpression of AGF by adenoviral transduction, which leads to an approximately 2.5-fold increase in serum AGF concentrations, results in a significant (P < 0.01) body weight loss and increases insulin sensitivity in mice fed a high-fat diet. This study establishes AGF as a new hepatocyte-derived circulating factor that counteracts obesity and related insulin resistance.

Angiopoietin-Like Protein 6↗
PubMed2005

Angiopoietin-1 promotes lymphatic sprouting and hyperplasia.

Angiopoietin 1 (Ang1), a ligand for the receptor tyrosine kinase Tie2, regulates the formation and stabilization of the blood vessel network during embryogenesis. In adults, Ang1 is associated with blood vessel stabilization and recruitment of perivascular cells, whereas Ang2 acts to counter these actions. Recent results from gene-targeted mice have shown that Ang2 is also essential for the proper patterning of lymphatic vessels and that Ang1 can be substituted for this function. In order to characterize the effects of the angiopoietins on lymphatic vessels, we employed viral vectors for overexpression of Ang1 in adult mouse tissues. We found that Ang1 activated lymphatic vessel endothelial proliferation, vessel enlargement, and generation of long endothelial cell filopodia that eventually fused, leading to new sprouts and vessel development. Cutaneous lymphatic hyperplasia was also detected in transgenic mice expressing Ang1 in the basal epidermal cells. Tie2 was expressed in the lymphatic endothelial cells and Ang1 stimulation of these cells resulted in up-regulation of vascular endothelial growth factor receptor 3 (VEGFR-3). Furthermore, a soluble form of VEGFR-3 inhibited the observed lymphatic sprouting. Our results reinforce the concept that Ang1 therapy may be useful in settings of tissue edema.

Adenoviridae↗
PubMed2005

Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation.

Angiopoietin (Ang) signaling plays a role in angiogenesis and remodeling of blood vessels through the receptor tyrosine kinase Tie2, which is expressed on blood vessel endothelial cells (BECs). Recently it has been shown that Ang-2 is crucial for the formation of lymphatic vasculature and that defects in lymphangiogenesis seen in Ang-2 mutant mice are rescued by Ang-1. These findings suggest important roles for Ang signaling in the lymphatic vessel system; however, Ang function in lymphangiogenesis has not been characterized. In this study, we reveal that lymphatic vascular endothelial hyaluronan receptor 1-positive (LYVE-1(+)) lymphatic endothelial cells (LECs) express Tie2 in both embryonic and adult settings, indicating that Ang signaling occurs in lymphatic vessels. Therefore, we examined whether Ang-1 acts on in vivo lymphatic angiogenesis and in vitro growth of LECs. A chimeric form of Ang-1, cartilage oligomeric matrix protein (COMP)-Ang-1, promotes in vivo lymphatic angiogenesis in mouse cornea. Moreover, we found that COMP-Ang-1 stimulates in vitro colony formation of LECs. These Ang-1-induced in vivo and in vitro effects on LECs were suppressed by soluble Tie2-Fc fusion protein, which acts as an inhibitor by sequestering Ang-1. On the basis of these observations, we propose that Ang signaling regulates lymphatic vessel formation through Tie2.

Angiopoietin-1↗
PubMed2005

Hematopoietic stem cells and their niche.

Recent evidence indicates that osteoblasts are crucial components of the particular microenvironments, or niches, for hematopoietic stem cells (HSCs) in adult bone marrow (BM). Stem cells persist in an immature state within the BM. The quiescence of HSCs is controlled dynamically by the signaling of receptors-ligands and cell-adhesion molecules. In this review, the characteristics of HSCs in the niche are discussed. The understanding of the relationship between normal and cancer stem cells and their niches should lead to the development of new strategies directed toward regeneration medicine and cancer therapeutics.

Animals↗
PubMed2005

Regulation of hematopoietic stem cells by the niche.

The quiescent state in the cell cycle is thought to be indispensable for the maintenance of hematopoietic stem cells (HSCs). Interaction of HSCs with their particular microenvironments, known as niches, is critical for maintaining the stem cell properties of HSCs, including cell adhesion, survival, and cell division. Hematopoietic stem cells balance quiescence and cell division in the stem cell niche and also maintain the potential for long-term hematopoiesis. We have recently reported that HSCs expressing the receptor tyrosine kinase Tie2 are in the G0 phase and anti-apoptotic, and comprise a side-population (SP) of HSCs, which contacts osteoblasts (OBs), the source of the angiopoietin-1 (Ang-1) ligand for Tie2 in the bone marrow (BM) niche. Tie2/Ang-1 signaling occurs in interactions between HSCs and niche cells. The interaction of Tie2 with Ang-1 in vitro induces tight adhesion of HSCs to stromal cells and is sufficient to maintain the long-term blood-repopulating (LTR) activity of HSCs in vivo by preventing cell division. In addition, Ang-1 enhances the ability of HSCs to become quiescent and induces their adhesion to the bone surface in vivo, resulting in protection of the HSC compartment from stresses suppressing hematopoiesis. These data suggest that the Tie2/Ang-1 signaling pathway plays a critical role in the maintenance of HSCs in the adult BM niche. Ang-1 produced by OBs activates Tie2 on HSCs and promotes tight adhesion of HSCs to the niche, resulting in quiescence and enhanced survival of HSCs.

Angiopoietin-1↗
PubMed2005

Regulation of stem cells in the niche.

Stem cells have a self-renewal capacity as well as the capacity to differentiate into single or multiple lineages. In this review, we discuss the mechanism of maintenance of "stemness" in hematopoietic systems and refer to our studies of corneal epithelial stem cells. The quiescent state is believed to be indispensable for the maintenance of hematopoietic stem cells (HSC). Interaction of HSC with their particular microenvironments, known as stem cell niches, is critical for the cell cycle regulation of HSC. Monitoring of the quiescence of HSC by a side population (SP) revealed that the cell cycle status of HSC is dynamically controlled by microenvironments. We recently discovered a molecular mechanism by which the cell cycle of HSC is regulated by the niche. HSC expressing tyrosine kinase Tie2 receptors adhere to osteoblasts in the bone marrow (BM) niche. The interaction of Tie2 and its ligand angiopoietin-1 (Ang-1) leads to tight adhesion of HSC to stromal cells, resulting in the maintenance of long-term repopulating activity of HSC. Thus, the Tie2/Ang-1 signaling pathway plays a critical role in maintaining HSC in the quiescent state in the BM niche. Understanding of the relationships of stem cells to their niches should lead to development of new strategies directed toward regeneration.

Cell Cycle↗
PubMed2005

Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor.

PURPOSE: To investigate the anti-inflammatory and anti-angiogenic effects of telmisartan, an angiotensin II type 1 receptor (AT1-R) antagonist, on ischemia-induced retinal neovascularization. METHODS: C57BL/6 neonatal mice were reared in an 80% concentration of oxygen from postnatal day (P)7 to P12, followed by room-air breathing until P17, to induce ischemia-initiated retinal neovascularization (i.e., a murine model of ischemic retinopathy). Tissue localization of AT1-R was examined by immunohistochemistry for murine retinal wholemounts and human fibrovascular tissues excised at vitrectomy for proliferative diabetic retinopathy. Animals received intraperitoneal injection of telmisartan or vehicle. A concanavalin A lectin perfusion-labeling technique was used to evaluate the areas of physiological and pathologic retinal new vessels and the number of leukocytes adhering to the vasculature. Retinal mRNA and protein levels of intercellular adhesion molecule (ICAM)-1, vascular endothelial growth factor receptor (VEGFR)-1, and VEGFR-2 were examined by RT-PCR and ELISA. RESULTS: Vessels in human fibrovascular tissues and the murine retinas were positive for AT1-R. Pathologic (P < 0.01), but not physiologic (P > 0.05), retinal neovascularization was significantly suppressed in telmisartan-treated mice compared with vehicle-treated animals. The number of adherent leukocytes (P < 0.01) was also significantly reduced, together with retinal ICAM-1 levels (P < 0.01) in the telmisartan-treated group compared with the control group. No significant difference was detected in retinal VEGFR-2 levels between the two groups, whereas retinal VEGFR-1 levels in the telmisartan-treated group were significantly (P < 0.05) lower than in the vehicle-treated group. CONCLUSIONS: The present findings suggest that the AT1-R signaling blockade leads to the selective suppression of pathologic, but not physiological, retinal neovascularization through the inhibition of the inflammatory processes related to pathologic neovascularization.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Suppression of ocular inflammation in endotoxin-induced uveitis by blocking the angiotensin II type 1 receptor.

PURPOSE: To examine whether the angiotensin II type 1 receptor (AT1-R) signaling plays a role in ocular inflammation in endotoxin-induced uveitis (EIU). METHODS: EIU was induced in C57BL/6 mice by a single intraperitoneal injection of 150 mug lipopolysaccharide (LPS). Tissue localization, mRNA expression, and protein levels of AT1-R in murine retinas were examined by immunohistochemistry, RT-PCR, and Western blot analyses, respectively. Telmisartan, an AT1-R antagonist widely used as an antihypertensive agent, was administered intraperitoneally at a dose of 10 mg/kg daily for 5 days until the injection of LPS. Twenty-four hours after administration, leukocyte adhesion to the retinal vasculature was evaluated with a concanavalin A lectin perfusion-labeling technique. Retinal mRNA and protein levels of intercellular adhesion molecule (ICAM)-1 were examined by RT-PCR and ELISA, respectively. Protein concentration and inflammatory cells in the aqueous humor were also measured. RESULTS: Retinal vessels were positive for AT1-R. In mice with EIU, retinal AT1-R mRNA and protein levels were significantly increased when compared to the normal control. EIU animals also showed significant increases in the number of inflammatory cells infiltrating the anterior chamber and adhering to the retinal vessels and in retinal ICAM-1 levels. Administration of telmisartan to EIU mice resulted in significant suppression of retinal ICAM-1 expression and leukocyte adhesion and infiltration compared with vehicle treatment. Protein concentration in the aqueous humor of telmisartan-treated EIU mice tended to be lower than that of vehicle-treated EIU mice, but the difference was not statistically significant. CONCLUSIONS: AT1-R signaling blockade inhibited retinal ICAM-1 upregulation and leukocyte adhesion and infiltration in the EIU model. These results suggest the potential use of an AT1-R antagonist as a therapeutic agent to reduce ocular inflammation.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Regulation of hematopoiesis and its interaction with stem cell niches.

Hematopoietic stem cells (HSCs) are responsible for blood cell production throughout the lifetime of an individual. Interaction of HSCs with their particular microenvironments, known as stem cell niches, is critical for maintaining stem cell properties, including self-renewal capability and ability for differentiation into single and multiple lineages. In the niche, the niche cells produce signaling molecules, extracellular matrix, and cell adhesion molecules and regulate stem cell fates. Long-term bone marrow (BM)-repopulating HSCs recently have been found frequently to exist in the BM trabecular bone surface, and it has been clarified that osteoblasts (OBs) are a critical component for sustaining HSCs. HSCs keep a balance between quiescence and cell division/proliferation in the osteoblastic niche. The specific properties of HSCs are controlled dynamically by signaling of receptor/ligand and cell adhesion molecules produced by OBs.

Animals↗
PubMed2005

[Differentiation and function of monocyte/macrophage lineage cells and osteoblasts].

Macrophages, osteoclasts and dendritic cells are derived from hematopoietic stem cells through monocyte/macrophage lineage common precursor cells. Macrophages are induced in the presence of M-CSF alone whereas osteoclasts are induced by M-CSF and RANKL. The cooperation of transcription factors, c-Fos and NFATc1 is essential for osteoclast differentiation. GM-CSF is an inducer of dendritic cells, and in contrast to osteoclast differentiation, M-CSF and c-Fos are inhibitors of dendritic cell differentiation. On the other hand, mesenchymal stem cells(MSCs) give rise to osteoblasts. In embryonic stage, MSCs in perichondrium are marked by ALCAM. Recently, osteoblasts are reported to provide 'Niche' for hematopoietic stem cells in bone marrow. Here we review the differentiation and functions of monocyte/macrophage lineage cells and osteoblasts.

Animals↗
PubMed2004

Regulation of cell cycle in hematopoietic stem cells by the niche.

The quiescent state is thought to be an indispensable property for the maintenance of hematopoietic stem cells (HSCs). Interaction of HSCs with their particular microenvironments, known as the stem cell niches, is critical for cell cycle regulation of HSCs. Monitoring of the quiescence of HSCs using by a new stem cell marker, Side Population (SP), revealed that the cell cycle status of HSCs is dynamically controlled by the microenvironments. We have recently revealed a molecular mechanism in which cell cycle of HSCs is regulated by the niche. HSCs expressing the receptor tyrosine kinase Tie2 are adhere to osteoblasts (OBs) in the BM niche. The interaction of Tie2 and its ligand Angiopoietin-1 (Ang-1) leads to tight adhesion of HSCs to stromal cells, resulting in maintainance of long-term repopulating activity of HSCs. Thus, Tie2/Ang-1 signaling pathway plays a critical role in the maintenance of HSCs in a quiescent state in the BM niche. The understanding of cell cycle control in stem cells leads to development of new strategy for progress in regenerative medicine.

Angiopoietin-1↗
PubMed2004

Dimer formation of receptor activator of nuclear factor kappaB induces incomplete osteoclast formation.

Receptor activator of nuclear factor kappaB-ligand (RANKL) transduces a differentiation signal appropriate to osteoclasts likely through induction a receptor homotrimer; however, biological importance of RANK-trimerizarion is unknown. To address the signaling mechanism of the RANK receptor, we analyzed the effect of two different types of homodimer inducers RANK-TM-FKBP36v and hEpoR-RANK-TM on osteoclastogenesis. Dimerizing component FKBP36v or extracellular portion of human erythropoietin receptor (hEpoR) was fused to RANK lacking the extracellular domain, and the dimerization of this fusion protein was induced by addition of the chemical inducer of dimerization AP20187 or erythropoietin, respectively. Such treatment resulted in induction of TRAP-activity, a marker of osteoclast in a dose dependent manner, with an efficiency equivalent to that of induction by RANKL. However, dimerized-RANK-induced osteoclasts showed relatively low levels of multinucleation, pit forming activity, and expression of calcitonin receptor and cathepsin K, compared with osteoclasts which were induced in the presence of RANKL. As expression of nuclear factor of activated T cells 1 (NFATc1) was also reduced in dimerized-RANK-induced osteoclasts, RANK oligomerization by RANKL is a critical event to generate fully matured osteoclasts through upregulation of NFATc1.

Animals↗