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Biomedical subjects

G Serini

Publications and source records attributed to G Serini.

13 recordsLinked to original sources
PubMed2006

Role of repulsive factors in vascularization dynamics.

Capillary networks are essential in vertebrates to supply tissues with nutrients. Experiments of in vitro capillary formation show that endothelial cells randomly spread on a gel matrix autonomously organize to form vascular networks with a characteristic length independent of the initial cell density. A mathematical model based on free cell migration and on cell cross-talk mediated by soluble chemical factors has been recently proposed and explains the main dynamical and geometrical properties of the networks. We extend this model introducing the action of repulsive factors and we show that their activity results in a larger degree of reorganization of cellular matter and in more robust control over the size of the growing vascular network.

Animals↗
PubMed2004

Cell directional persistence [corrected] and chemotaxis in vascular morphogenesis.

In vertebrates, supply of oxygen and nutrients to tissues is carried out by the blood vascular system through capillary networks. Capillary patterns are closely mimicked by endothelial cells cultured on Matrigel, a preparation of basement membrane proteins. On the Matrigel surface, single randomly dispersed endothelial cells self-organize into vascular networks. The network is characterized by a typical length scale, which is independent of the initial mean density of deposed cells n over a wide range of values of n. We give here a detailed description of a mathematical model of the process which is able to reproduce several qualitative and quantitative features of in vitro vascularization experiments. Cell matter is basically modelled as an elastic fluid subjected to a specific force field depending on the concentration of a chemoattractant factor. Starting from sparse initial data, mimicking the initial conditions realized in laboratory experiments, numerical solutions reproduce characteristic network structures, similar to observed ones, whose average size is theoretically related to the finite range of chemoattractant diffusion. A possible area of application of the model is the design of properly vascularized artificial tissues.

Blood Vessels↗
PubMed2003

Percolation, morphogenesis, and burgers dynamics in blood vessels formation.

Experiments of in vitro formation of blood vessels show that cells randomly spread on a gel matrix autonomously organize to form a connected vascular network. We propose a simple model which reproduces many features of the biological system. We show that both the model and the real system exhibit a fractal behavior at small scales, due to the process of migration and dynamical aggregation, followed at large scale by a random percolation behavior due to the coalescence of aggregates. The results are in good agreement with the analysis performed on the experimental data.

Computer Simulation↗
PubMed2001

Interactions between endothelial cells and HIV-1.

Endothelial cells (EC) participate in inflammatory and immune reactions by producing and responding to soluble mediators. Human immunodeficiency virus (HIV)-1 profoundly alters the features of EC. In some anatomical districts, they are infected by the virus and may represent a relevant reservoir. During lymphomononuclear cell diapedesis, EC activate virus replication in crossing cells. Direct or indirect damage of EC is particularly relevant in central nervous system, where blood-brain barrier perturbation is pivotal in neuronal degeneration. The observed alterations of EC adhesive properties contribute in altered leukocyte traffic from blood to lymphoid organs and tissues and play a role in the onset of immune surveillance alteration. These alterations of EC functions are relevant for the general vasculopathy, which marks the acquired immunodeficiency syndrome, and in particular are instrumental in the pathogenesis of Kaposi's sarcoma. Here we discuss the biological and molecular activation of EC in HIV-1 infection that represents the basis to understand the pathogenesis of HIV-1 associated vascular diseases.

Endothelium, Vascular↗
PubMed2001

Dynamic modules and heterogeneity of function: a lesson from tyrosine kinase receptors in endothelial cells.

An important unresolved issue related to tyrosine kinase receptor signaling pathways is the lack of specificity of the molecular effectors involved. The specificity of the biological responses that are nevertheless elicited may be explained by differences in activation thresholds, as well as by temporal (transient versus sustained) and topographical aspects of receptor activation. On the basis of recent lessons from endothelial cells, we argue that an additional strategy can be adopted to generate specificity, i.e. tyrosine kinase receptors may form distinct signaling modules with other transmembrane proteins, such as adhesive receptors, to elicit different biological programs in stimulated cells.

Animals↗
PubMed1998

Growth factor-dependent activation of alphavbeta3 integrin in normal epithelial cells: implications for tumor invasion.

Integrin activation is a multifaceted phenomenon leading to increased affinity and avidity for matrix ligands. To investigate whether cytokines produced during stromal infiltration of carcinoma cells activate nonfunctional epithelial integrins, a cellular system of human thyroid clones derived from normal glands (HTU-5) and papillary carcinomas (HTU-34) was employed. In HTU-5 cells, alphavbeta3 integrin was diffused all over the membrane, disconnected from the cytoskeleton, and unable to mediate adhesion. Conversely, in HTU-34 cells, alphavbeta3 was clustered at focal contacts (FCs) and mediated firm attachment and spreading. alphavbeta3 recruitment at FCs and ligand-binding activity, essentially identical to those of HTU-34, occurred in HTU-5 cells upon treatment with hepatocyte growth factor/scatter factor (HGF/SF). The HTU-34 clone secreted HGF/SF and its receptor was constitutively tyrosine phosphorylated suggesting an autocrine loop responsible for alphavbeta3 activated state. Antibody-mediated inhibition of HGF/SF function in HTU-34 cells disrupted alphavbeta3 enrichment at FCs and impaired adhesion. Accordingly, activation of alphavbeta3 in normal cells was produced by HTU-34 conditioned medium on the basis of its content of HGF/SF. These results provide the first example of a growth factor-driven integrin activation mechanism in normal epithelial cells and uncover the importance of cytokine-based autocrine loops for the physiological control of integrin activation.

Antigens, CD↗
PubMed1998

The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1.

Transforming growth factor-beta1 (TGFbeta1), a major promoter of myofibroblast differentiation, induces alpha-smooth muscle (sn) actin, modulates the expression of adhesive receptors, and enhances the synthesis of extracellular matrix (ECM) molecules including ED-A fibronectin (FN), an isoform de novo expressed during wound healing and fibrotic changes. We report here that ED-A FN deposition precedes alpha-SM actin expression by fibroblasts during granulation tissue evolution in vivo and after TGFbeta1 stimulation in vitro. Moreover, there is a correlation between in vitro expression of alpha-SM actin and ED-A FN in different fibroblastic populations. Seeding fibroblasts on ED-A FN does not elicit per se alpha-SM actin expression; however, incubation of fibroblasts with the anti-ED-A monoclonal antibody IST-9 specifically blocks the TGFbeta1-triggered enhancement of alpha-SM actin and collagen type I, but not that of plasminogen activator inhibitor-1 mRNA. Interestingly, the same inhibiting action is exerted by the soluble recombinant domain ED-A, but neither of these inhibitory agents alter FN matrix assembly. Our findings indicate that ED-A-containing polymerized FN is necessary for the induction of the myofibroblastic phenotype by TGFbeta1 and identify a hitherto unknown mechanism of cytokine-determined gene stimulation based on the generation of an ECM-derived permissive outside in signaling, under the control of the cytokine itself.

Actins↗
PubMed1996

Changes in integrin and E-cadherin expression in neoplastic versus normal thyroid tissue.

UNLABELLED: BACK: The functional organization of polarized epithelia depends mostly on adhesion molecules belonging to the integrin and cadherin families. These molecules either recognize basement membrane components, such as laminins, or form intercellular junctions via homotypic interactions. Such tissue organization is often disrupted upon neoplastic transformation, and the resulting loss of functional polarization and cell cohesion might be a prerequisite for the invasive and metastatic behavior of carcinomas. PURPOSE: We studied modifications on thyroid adhesive mechanisms at various stages of neoplastic progression in terms of adhesion molecule expression, topography, and functional regulation by tyrosine kinases. Starting from this working hypothesis, we sought to identify one or more biological markers that would be suggestive of malignant transformation and poorer prognosis and that could be developed as a reliable indicator(s) in early diagnostic steps. METHODS: The study was carried out on both surgical samples and the corresponding fine-needle aspiration biopsy smears (numbers of specimens collected: 19 adenomas, seven follicular carcinomas, 13 papilary carcinomas, and 39 normal tissues). Immunohistochemistry of tissue sections and smears and immuno-precipitation and western blot analysis of protein extracts were done with a battery of monoclonal and polyclonal antibodies. Northern blotting was performed on RNA extracts from frozen tissue samples and use of an integrin subunit beta4 complementary DNA probe. RESULTS: Our findings can be summarized as follows: 1) In normal thyroid cells, the cooperative role of integrin alpha6beta4 and laminin 5/kalinin in hemidesmosome-mediated adhesion adhesion is missing, and recognition of the basal lamina occurs via integrin alpha3beta1 and laminin 1 and/or 2 (this pattern being maintained in adenomas but altered in carcinomas regardless of their histotype or differentiation grade); 2) only in carcinomas with clinical and/or histologic aggressiveness do neoexpression of integrin subunit beta4 and loss of laminin 2/merosin occur, indicating de novo assembly of integrin alpha6beta4; 3) pericellular redistribution and cytoskeletal disconnection of the E-cadherin-catenin complex occur; and 4) basal E-cadherin tyrosine phosphorylation decreases in carcinomas as compared with that in normal and adenomatous tissue. CONCLUSION: The malignant progression of thyroid tumors involves marked rearrangement of cell-basement membrane and cell-cell adhesion molecules and changes in their cytoskeleton linkage. These rearrangements are also easily and reproducibly detected on fine-needle aspiration biopsy smears. IMPLICATIONS: Immunodetection of adhesion molecules in sections and/or fine-needle smears may complement the toolbox of thyroid surgical pathologists; it may expand the possibilities of achieving a correct early diagnosis of thyroid tumors and of gaining some prognostic information on thyroid tumors.

Adenocarcinoma, Follicular↗
PubMedDate not supplied

Modulation of alpha-smooth muscle actin expression in fibroblasts by transforming growth factor-beta isoforms: an in vivo and in vitro study.

Myofibroblasts are granulation tissue fibroblasts bearing ultrastructural and biochemical features of smooth muscle cells, such as cytoplasmic microfilaments and alpha-smooth muscle actin expression. They appear transiently during wound healing and more permanently during several pathologic situations such as fibrotic diseases. Transforming growth factor-beta1 has been suggested to be an important promoter of the myofibroblastic phenotype. Here we show that (1) transforming growth factor-beta2, like transforming growth factor-beta1, induces myofibroblast formation in vivo and in vitro; (2) transforming growth factor-beta3 acts as a negative regulator of the myofibroblastic phenotype in vivo but not in vitro; and (3) in vitro, the three different transforming growth factor-beta isoforms are equally able to induce alpha-smooth muscle actin messenger RNA and protein expression in growing and quiescent cultured human and rat subcutaneous tissue fibroblasts. These data confirm that in vitro the behavior of the three different transforming growth factor-beta isoforms is similar, whereas in vivo transforming growth factor-beta isoforms possibly play different but complementary roles in myofibroblast modulation during wound repair.

Journal Article↗
PubMedDate not supplied

Differential integrin expression in thyroid and laryngeal carcinomas.

Several laryngeal and thyroid carcinomas were studied immunohistochemically to evaluate whether the expression and distribution of integrins and basal lamina components can represent reproducible markers for correct early diagnosis and prognosis. In laryngeal cancers, the depolarization and pericellular redistribution of alpha 3 beta 1 and alpha 6 beta 4, and focal or massive fragmentation of the basal lamina, according to tumor prognosis, occurred. In thyroid carcinomas, loss of polar topography of alpha 3 beta 1 and neo-expression of alpha 6 beta 4 in histopathologically or clinically aggressive cancers were observed. Therefore, the addition of a panel of adhesion molecules to the toolbox of surgical pathologists may improve diagnostic and prognostic procedures.

Adult↗