Cell Surface Access Is Modulated by Tethered Bottlebrush Proteoglycans

Chang, Patrick; McLane, Louis T.; Fogg, Ruth; Scrimgeour, Jan; Temenoff, Johnna S.; Granqvist, Anna; Curtis, Jennifer E.

doi:10.1016/j.bpj.2016.05.027

Cited by 23 publications

(32 citation statements)

References 71 publications

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“…However, these glycocalyx constituents are highly variable because of dynamically changing glycosylation states and decoration with side chains. The stiffness of bottlebrush mucins or proteindecorated HA chains likely depends strongly on the side chain density, size, composition, and charge (6,10). Although bottlebrush polymer theory provides relations between the polymer persistence length and the side chain properties (50), detailed experimental measurements of the decoration-dependent stiffness would be useful to develop a quantitative understanding of the glycocalyx and its functions on the cell membrane.…”

Section: Discussionmentioning

confidence: 99%

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Equilibrium Modeling of the Mechanics and Structure of the Cancer Glycocalyx

Gandhi

Koch

Paszek

2019

Biophysical Journal

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The glycocalyx is a thick coat of proteins and carbohydrates on the outer surface of all eukaryotic cells. Overproduction of large, flexible or rod-like biopolymers, including hyaluronic acid and mucins, in the glycocalyx strongly correlates with the aggression of many cancer types. However, theoretical frameworks to predict the effects of these changes on cancer cell adhesion and other biophysical processes remain limited. Here, we propose a detailed modeling framework for the glycocalyx incorporating important physical effects of biopolymer flexibility, excluded volume, counterion mobility, and coupled membrane deformations. Because mucin and hyaluronic biopolymers are proposed to extend and rigidify depending on the extent of their decoration with side chains, we propose and consider two limiting cases for the structural elements of the glycocalyx: stiff beams and flexible chains. Simulations predict the mechanical response of the glycocalyx to compressive loads, which are imposed on cells residing in the highly confined spaces of the solid tumor or invaded tissues. Notably, the shape of the mechanical response transitions from hyperbolic to sigmoidal for more rod-like glycocalyx elements. These mechanical responses, along with the corresponding equilibrium protein organizations and membrane topographies, are summarized to aid in hypothesis generation and the evaluation of future experimental measurements. Overall, the modeling framework developed provides a theoretical basis for understanding the physical biology of the glycocalyx in human health.

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Section: Discussionmentioning

confidence: 99%

“…In particular, hyaluronic acid (HA), a polysaccharide composed of repeating disaccharide units, strongly correlates with diverse cancer types (7)(8)(9). HA molecules typically resemble flexible chains, although decoration with proteoglycans, such as aggrecans and versicans, can rigidify and extend the chains (10).…”

Section: Introductionmentioning

confidence: 99%

Equilibrium Modeling of the Mechanics and Structure of the Cancer Glycocalyx

Gandhi

Koch

Paszek

2019

Biophysical Journal

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“…In chondrocytes, their thickness reaches several micrometers and their mechanical properties are essential to cartilage function (e.g. Clarris and Fraser, 1968;Cohen et al, 2003;Evanko et al, 2007;McLane et al, 2013;Chang et al, 2016). PCMs consist of hyaluronan, collagens, proteoglycans, such as aggrecan or versican, and glycoproteins, like fibronectin (Evanko et al, 2007;Müller et al, 2014).…”

Section: Adhesion Mediated By Pericellular Matrix Interactionsmentioning

confidence: 99%

Dynamic cell–cell adhesion mediated by pericellular matrix interaction – a hypothesis

Winklbauer

2019

Journal of Cell Science

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Cell-cell adhesion strength, measured as tissue surface tension, spans an enormous 1000-fold range when different cell types are compared. However, the examination of basic mechanical principles of cell adhesion indicates that cadherin-based and related mechanisms are not able to promote the high-strength adhesion experimentally observed in many late embryonic or malignant tissues. Therefore, the hypothesis is explored that the interaction of the pericellular matrices of cells generates strong adhesion by a mechanism akin to the self-adhesion/self-healing of dynamically cross-linked hydrogels. Quantitative data from biofilm matrices support this model. The mechanism links tissue surface tension to pericellular matrix stiffness. Moreover, it explains the wide, matrixfilled spaces around cells in liquid-like, yet highly cohesive, tissues, and it rehabilitates aspects of the original interpretation of classical cell sorting experiments, as expressed in Steinberg's differential adhesion hypothesis: that quantitative differences in adhesion energies between cells are sufficient to drive sorting.

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“…Prior work has established that the number of aggrecans bound to HA depends on aggrecan solution concentration (28). To ensure that our experiments took place in a regime where the HA chain was saturated with bound aggrecans, we used an aggrecan concentration of 2 mg/mL, reportedly close to the overlap concentration (29).…”

Section: Methodsmentioning

confidence: 99%

Single-Molecule Mechanical Measurements of the Hyaluronan-Aggrecan Bottlebrush

Innes-Gold

Berezney

Saleh

2020

Biophysical Journal

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Large bottlebrush complexes formed from the polysaccharide hyaluronan (HA) and the proteoglycan aggrecan contribute to cartilage compression resistance and are necessary for healthy joint function. A variety of mechanical forces act on these complexes in the cartilage extracellular matrix, motivating the need for a quantitative description of their structure and mechanical response. Studies using electron microscopy have imaged the HA-aggrecan brush but require adsorption to a surface, dramatically altering the complex from its native conformation. We use magnetic tweezers force spectroscopy to measure changes in extension and mechanical response of an HA chain as aggrecan monomers bind and form a bottlebrush. This technique directly measures changes undergone by a single complex with time and under varying solution conditions. Upon addition of aggrecan, we find a large swelling effect manifests when the HA chain is under little to no tension (stretching forces less than 1 pN). Theory of polymer brushes and models of side-chain-induced internal tension show our data are consistent with a polydisperse aggrecan population, attributable to varying degrees of glycosylation. Our results provide a mechanistic picture of how flexibility and size of HA and aggrecan lead to the brush architecture and mechanical properties of this important component of cartilage.

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Cell Surface Access Is Modulated by Tethered Bottlebrush Proteoglycans

Cited by 23 publications

References 71 publications

Equilibrium Modeling of the Mechanics and Structure of the Cancer Glycocalyx

Equilibrium Modeling of the Mechanics and Structure of the Cancer Glycocalyx

Dynamic cell–cell adhesion mediated by pericellular matrix interaction – a hypothesis

Single-Molecule Mechanical Measurements of the Hyaluronan-Aggrecan Bottlebrush

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