Tissue Engineering of Articular Cartilage
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi in Articular Cartilage, 2017
A seemingly simple act, such as compressing cartilage, can result in complex changes, including matrix and cell deformation, hydrostatic pressure gradients, fluid flow, osmotic pressure changes, and fluctuations in ion concentration and fixed charge density (Urban et al. 1993). Any one of these factors can elicit a biological response from cells, most likely through mechanosensitive ion channels (Martinac 2004) or integrins (Ingber 1991) at the cellular membrane. In the former, mechanical stimulation causes an influx of ions (e.g., calcium) that activate intracellular signaling pathways. Hyperpolarization of the membrane can occur through activation of slow-conductance Ca2+-sensitive K+ channels (Wright et al. 1996). Alternatively, stretch-activated ion channels can allow an influx of Ca2+ to levels that trigger calcium-dependent signaling pathways (Pingguan-Murphy et al. 2005). Membrane-associated integrins also act as intermediaries to external mechanical forces. The integrin receptor has an extracellular domain that binds matrix molecules surrounding the cell and an intracellular region that interacts with cytoplasmic molecules and the cytoskeleton, forming a bridge across the cell membrane. This allows for the transduction of mechanical forces directly to intracellular biochemical responses (Hynes 1992; Martinac 2004; Ramage et al. 2009). See Section 1.2.3 for more detailed discussions of the signaling pathways related to mechanotransduction.
Mechanotransduction Mechanisms of Hypertrophy and Performance with Resistance Exercise
Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse in The Routledge Handbook on Biochemistry of Exercise, 2020
The family of integrin proteins, 24 in all, are heterodimeric consisting of 18 α and 8 β subunits (13). As transmembrane proteins, the integrin physically connects the extracellular matrix to the intracellular space. Within the cell, the integrin indirectly connects to the actin cytoskeleton through scaffolding proteins positioned at the integrin's cytoplasmic tail such as talin, kindlin, and paxillin. Thus, through its transmembrane nature, the integrin allows communication in a bidirectional manner—both in an inside-out and outside-in fashion (96). Interestingly, research has shed light upon the extended physical continuity from the cytoskeleton into the nucleus, made possible by the linker of the nucleoskeleton and cytoskeleton (LINC) complex (109). This continuous physical link from the extracellular space, through the integrin to the cytoskeleton, and into the nucleus via the LINC complex, directly influences gene expression in a matter of seconds upon mechanical activity, such as muscle tension produced with exercise.
Cell Structure and Functions
Malgorzata Lekka in Cellular Analysis by Atomic Force Microscopy, 2017
There are at least 18 well-recognized α-type and 9 β-type integrin subunits [1, 2]. Their extracellular domains participate in bivalent metal ion-dependent interactions with various extracellular matrix proteins and other receptors of neighboring cells belonging predominantly to the immunoglobulin superfamily. It is worth to mention that metal ions play a critical role in the ligand binding function of all integrin heterodimers. It has been shown that the presence of arginine-aspartate-glycine (RDG) amino acid sequence has been ascertained for the interaction with ECM proteins such as fibronectin, vitronectin or collagen I. Upon binding to their ligands, integrins activate members of intracellular signaling pathway cascades, transducing in and out signals that can stimulate or regulate motility and invasiveness, cell growth, and survival. The expression of integrins depends on the tissue of origin and the degree of differentiation. Cancer cells very often switch the types of expressed integrins, favoring those that transmit growth signals [1, 14].
Comparison of Surgically Excised Premacular Membranes in Eyes with Macular Pucker and Proliferative Vitreoretinopathy
Published in Current Eye Research, 2019
Stefanie R. Guenther, Ricarda G. Schumann, Felix Hagenau, Armin Wolf, Siegfried G. Priglinger, Denise Vogt
In our study, anti-integrin αv as well as anti-galectin were seen strongly positive. Described as a marker for myofibroblast-like transdifferentiation, integrin αv is a heterodimeric transmembrane cell adhesion protein consisting of non-covalently linked α and β subunits. The integrin-mediated adhesion can affect signal cascades that determine cellular motility, proliferation and differentiation. The integrins αV, in particular the subforms αVβ3, αVβ5 and αVβ6, are attributed to an important function in the transdifferentiation from fibroblasts into myofibroblasts.6 In eyes with iMP, integrins have a profibrotic influence, especially indirectly via activation of latent TGF-β1.4,6 In detail, accumulated TGF-β1 is activated by integrin-mediated contractile cellular forces leading to neo-expression of α-SMA in fibroblasts.4,6,16–19 Galectins are a profibrotic protein group that bind to β-galactosides. They occur in the cell nucleus, cytoplasm, on the cell surface and in the extracellular matrix and are primarily involved in cell–cell and cell–matrix interactions.20,21 It has been shown that galectin-3 seems to be important for activation, migration and proliferation of myofibroblasts.20,22 In addition to its regulatory function on TGF-β receptors, galectin-3 also plays an important role in integrin-mediated signaling pathways. Galectin-1 is also involved in the regulation of cellular migration, proliferation and differentiation and supports the migration of retinal pigment epithelial cells into laminin and fibronectin-containing matrices.12
Roles of membrane lipids in the organization of epithelial cells: Old and new problems
Published in Tissue Barriers, 2018
Finally, in this section, I introduce the findings about the roles of lipids in the formation of cell membrane structures involved in cell adhesion. In the basolatelral membrane domains, epithelial cells form membrane structures involved in the cell-cell or cell-matrix adhesion. Among cell adhesion structures, the roles of membrane lipids have been more intensively studied in the cell-matrix adhesion. The cell adhesion receptor responsible for the cell-matrix adhesion is integrin. First, cholesterol-rich membrane domain was reported to be involved in the clustering of integrins, which regfulates their activation.24 Cholesterol depletion significantly affected the formation of integrin-mediated cell adhesion.25 In parallel, activated integrins preferentially localize to cholesterol-rich membrane domains.26 Interestingly, cell detachment triggered internalization of plasma membrane cholesterol and lipid raft markers such as GPI anchored protein.27,28 Adhesion of cells to the matrix via integrins also facilitates the transport of cholesterol-enriched vesicles to the plasma membrane.28 Thus, integrin mediated cell-adhesion reciprocally alters the composition of the plasma membrane.
Emerging drugs for the treatment of diabetic retinopathy
Published in Expert Opinion on Emerging Drugs, 2020
Elio Striglia, Andrea Caccioppo, Niccolò Castellino, Michele Reibaldi, Massimo Porta
ALG-1001 (Luminate®, Allegro Ophthalmics) is an integrin receptor antagonist. Integrins play a key role in the proliferation of new vessels. There are about 27 known integrin receptors. This drug targets four different integrin receptor sites and acts with two different mechanism: anti-angiogenesis and vitreolysis. ALG-1001 can be administered monthly intravitreally in monotherapy or with bevacizumab [61]. In 2014 Allegro Ophthalmics reported that ALG-1001 inhibits growth and leakage of new vessels and then started a phase 2 clinical trial (NCT 02348918) to compare safety and efficacy of Luminate vs bevacizumab in the treatment of DME. The trial showed that BCVA increased by 7.1 letters in the group treated with Luminate and bevacizumab compared to + 6.1 letters in the control group with bevacizumab alone. Although a small improvement, the authors suggested that Luminate may be an interesting option to treat patients, particularly those who don’t respond to anti-VEGF.
Related Knowledge Centers
- Cadherin
- Coagulation
- Cytoskeleton
- Signal Transduction
- Platelet
- Extracellular Matrix
- Cell Surface Receptor
- Cell Cycle
- Integrin-Like Receptors
- Immunoglobulin Superfamily