Biomedical subjects

Penelope C Georges

Publications and source records attributed to Penelope C Georges.

5 recordsLinked to original sources

PubMed2006

Negative normal stress in semiflexible biopolymer gels.

When subject to stress or external loads, most materials resist deformation. Any stable material, for instance, resists compression-even liquids. Solids also resist simple shear deformations that conserve volume. Under shear, however, most materials also have a tendency to expand in the direction perpendicular to the applied shear stress, a response that is known as positive normal stress. For example, wet sand tends to dilate when sheared, and therefore dries around our feet when we walk on the beach. In the case of simple solids, elastic rods or wires tend to elongate when subject to torsion. Here, we show that networks of semiflexible biopolymers such as those that make up both the cytoskeleton of cells and the extracellular matrix exhibit the opposite tendency: when sheared between two plates, they tend to pull the plates together. We show that these negative normal stresses can be as large as the shear stress and that this property is directly related to the nonlinear strain-stiffening behaviour of biopolymer gels.

Biopolymers↗

PubMed2006

Matrices with compliance comparable to that of brain tissue select neuronal over glial growth in mixed cortical cultures.

Cortical neurons and astrocytes respond strongly to changes in matrix rigidity when cultured on flexible substrates. In this study, existing polyacrylamide gel polymerization methods were modified into a novel method for making substrates capable of engaging specific cell-adhesion receptors. Embryonic cortical dissociations were cultured on polyacrylamide or fibrin gel scaffolds of varying compliance. On soft gels, astrocytes do not spread and have disorganized F-actin compared to the cytoskeletons of astrocytes on hard surfaces. Neurons, however, extend long neurites and polymerize actin filaments on both soft and hard gels. Compared to tissue culture plastic or stiff gel substrates coated with laminin, on which astrocytes overgrow neurons in mixed cultures, laminin-coated soft gels encourage attachment and growth of neurons while suppressing astrocyte growth. The number of astrocytes on soft gels is lower than on hard even in the absence of mitotic inhibitors normally used to temper the astrocyte population. Dissociated embryonic rat cortices grown on flexible fibrin gels, a biomaterial with potential use as an implant material, display a similar mechano-dependent difference in cell population. The stiffness of materials required for optimal neuronal growth, characterized by an elastic modulus of several hundred Pa, is in the range measured for intact rat brain. Together, these data emphasize the potential importance of material substrate stiffness as a design feature in the next generation of biomaterials intended to promote neuronal regeneration across a lesion in the central nervous system while simultaneously minimizing the ingrowth of astrocytes into the lesion area.

Acrylic Resins↗

PubMed2005

Inactivation of endotoxin by human plasma gelsolin.

Septic shock from bacterial endotoxin, triggered by the release of lipopolysaccharide (LPS) molecules from the outer wall of Gram-negative bacteria, is a major cause of human death for which there is no effective treatment once the complex inflammatory pathways stimulated by these small amphipathic molecules are activated. Here we report that plasma gelsolin, a highly conserved human protein, binds LPS from various bacteria with high affinity. Solid-phase binding assays, fluorescence measurements, and functional assays of actin depolymerizing effects show that gelsolin binds more tightly to LPS than it does to its other known lipid ligands, phosphatidylinositol 4,5-bisphosphate and lysophosphatidic acid. Gelsolin also competes with LPS-binding protein (LBP), a high-affinity carrier for LPS. One result of gelsolin-LPS binding is inhibition of the actin binding activity of gelsolin as well as the actin depolymerizing activity of blood serum. Simultaneously, effects of LPS on cellular functions, including cytoskeletal actin remodeling, and collagen-induced platelet activation by pathways independent of toll-like receptors (TLRs) are neutralized by gelsolin and by a peptide based on gelsolin residues 160-169 (GSN160-169) which comprise part of gelsolin's phosphoinositide binding site. Additionally, TLR-dependent NF-kappaB translocation in astrocytes appears to be blocked by gelsolin. These results show a strong effect of LPS on plasma gelsolin function and suggest that some effects of endotoxin in vivo may be mediated or inhibited by plasma gelsolin.

Actin Cytoskeleton↗

PubMed2005

Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion.

The morphology and cytoskeletal structure of fibroblasts, endothelial cells, and neutrophils are documented for cells cultured on surfaces with stiffness ranging from 2 to 55,000 Pa that have been laminated with fibronectin or collagen as adhesive ligand. When grown in sparse culture with no cell-cell contacts, fibroblasts and endothelial cells show an abrupt change in spread area that occurs at a stiffness range around 3,000 Pa. No actin stress fibers are seen in fibroblasts on soft surfaces, and the appearance of stress fibers is abrupt and complete at a stiffness range coincident with that at which they spread. Upregulation of alpha5 integrin also occurs in the same stiffness range, but exogenous expression of alpha5 integrin is not sufficient to cause cell spreading on soft surfaces. Neutrophils, in contrast, show no dependence of either resting shape or ability to spread after activation when cultured on surfaces as soft as 2 Pa compared to glass. The shape and cytoskeletal differences evident in single cells on soft compared to hard substrates are eliminated when fibroblasts or endothelial cells make cell-cell contact. These results support the hypothesis that mechanical factors impact different cell types in fundamentally different ways, and can trigger specific changes similar to those stimulated by soluble ligands.

Actins↗

PubMed2005

Cell type-specific response to growth on soft materials.

Many cell types respond to forces as acutely as they do to chemical stimuli, but the mechanisms by which cells sense mechanical stimuli and how these factors alter cellular structure and function in vivo are far less explored than those triggered by chemical ligands. Forces arise both from effects outside the cell and from mechanochemical reactions within the cell that generate stresses on the surface to which the cells adhere. Several recent reviews have summarized how externally applied forces may trigger a cellular response (Silver FH and Siperko LM. Crit Rev Biomed Eng 31: 255-331, 2003; Estes BT, Gimble JM, and Guilak F. Curr Top Dev Biol 60: 91-126, 2004; Janmey PA and Weitz DA. Trends Biochem Sci 29: 364-370, 2004). The purpose of this review is to examine the information available in the current literature describing the relationship between a cell and the rigidity of the matrix on which it resides. We will review recent studies and techniques that focus on substrate compliance as a major variable in cell culture studies. We will discuss the specificity of cell response to stiffness and discuss how this may be important in particular tissue systems. We will attempt to link the mechanoresponse to real pathological states and speculate on the possible biological significance of mechanosensing.

Animals↗