Changes in Fibroblast Mechanostat Set Point and Mechanosensitivity: An Adaptive Response to Mechanical Stress in Floppy Eyelid Syndrome

Ezra, Daniel G.; Ellis, J. S.; Beaconsfield, Michele; Collin, Richard; Bailly, Maryse

doi:10.1167/iovs.09-4724

Cited by 42 publications

(71 citation statements)

References 54 publications

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“…The ability of GO fibroblasts to differentiate into adipocytes has been widely described [3], [5], [6], [10], [34], but little is known about their fibrotic potential. Using our well-characterised 3D model of collagen contraction, we have previously shown that fibroblasts derived from fibrotic ocular tissues display an increased contractile phenotype as compared to controls, and these fibroblasts retain, in vitro , both altered biomechanical properties and a specific molecular signature that might underlie their behaviour in disease [17]. Here we have uncovered a similar feature for orbital fibroblasts from patients with active Graves’ orbitopathy, suggesting that these cells have acquired an intrinsic fibro-proliferative phenotype and increased sensitivity to inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Independent Adipogenic and Contractile Properties of Fibroblasts in Graves’ Orbitopathy: An In Vitro Model for the Evaluation of Treatments

Li¹,

Fitchett²,

Kozdon³

et al. 2014

PLoS ONE

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Graves’ orbitopathy (GO) is a disfiguring and sometimes blinding disease, characterised by inflammation and swelling of orbital tissues, with fibrosis and adipogenesis being predominant features. Little is known about the disease aetiology and the molecular mechanisms driving the phenotypic changes in orbital fibroblasts are unknown. Using fibroblasts isolated from the orbital fat of undiseased individuals or GO patients, we have established a novel in vitro model to evaluate the dual profile of GO cells in a three-dimensional collagen matrix; this pseudo-physiological 3D environment allows measurement of their contractile and adipogenic properties. GO cells contracted collagen matrices more efficiently than control cells following serum or TGFβ1 stimulation, and showed a slightly increased ability to proliferate in the 3D matrix, in accordance with a fibro-proliferative phenotype. GO cells, unlike controls, also spontaneously differentiated into adipocytes in 3D cultures - confirming an intrinsic adipogenic profile. However, both control and GO cells underwent adipogenesis when cultured under pathological pressure levels. We further demonstrate that a Thy-1-low population of GO cells underlies the adipogenic - but not the contractile - phenotype and, using inhibitors, confirm that the contractile and adipogenic phenotypes are regulated by separate pathways. In view of the current lack of suitable treatment for GO, we propose that this new model testing the duality of the GO phenotype could be useful as a preclinical evaluation for the efficacy of potential treatments.

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Section: Discussionmentioning

confidence: 99%

Independent Adipogenic and Contractile Properties of Fibroblasts in Graves’ Orbitopathy: An In Vitro Model for the Evaluation of Treatments

Li¹,

Fitchett²,

Kozdon³

et al. 2014

PLoS ONE

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“…In a particularly important early study, uniaxial collagen gels fixed at both ends were observed to develop within a few hours an internal stress to a certain (apparently homeostatic) plateau level when seeded with fibroblasts. If this homeostatic state was perturbed by suddenly stretching or relaxing the gel, an immediate elastic change of stress in the gel was followed by a slow, exponential return back toward the homeostatic level [26, 27]. It is important to distinguish this behavior from passive viscoelastic stress relaxation common in many biological soft tissues [28].…”

Section: Experimental and Clinical Observationsmentioning

confidence: 99%

Growth and remodeling of load-bearing biological soft tissues

2016

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The past two decades reveal a growing role of continuum biomechanics in understanding homeostasis, adaptation, and disease progression in soft tissues. In this paper, we briefly review the two primary theoretical approaches for describing mechano-regulated soft tissue growth and remodeling on the continuum level as well as hybrid approaches that attempt to combine the advantages of these two approaches while avoiding their disadvantages. We also discuss emerging concepts, including that of mechanobiological stability. Moreover, to motivate and put into context the different theoretical approaches, we briefly review findings from mechanobiology that show the importance of mass turnover and the prestressing of both extant and new extracellular matrix in most cases of growth and remodeling. For illustrative purposes, these concepts and findings are discussed, in large part, within the context of two load-bearing, collagen dominated soft tissues – tendons/ligaments and blood vessels. We conclude by emphasizing further examples, needs, and opportunities in this exciting field of modeling soft tissues.

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“…ECM adaptation is supported by a corresponding adaptational change in the contractile properties of tarsal plate fibroblasts 37 . Intrinsic cellular contractility is altered in FES allowing tarsal fibroblasts to maintain a dynamic range of contraction against a background of higher mechanical stress.…”

Section: Discussionmentioning

confidence: 99%

“…36 ECM adaptation is supported by a corresponding adaptational change in the contractile properties of tarsal plate fibroblasts. 37 Intrinsic cellular contractility is altered in FES allowing tarsal fibroblasts to maintain a dynamic range of contraction against a background of higher mechanical stress. The adaptation of the tarsal plate to pathological loading may therefore be taking place at multiple hierarchical levels including both cellular and ECM changes.…”

Section: Discussionmentioning

confidence: 99%

Changes in tarsal plate fibrillar collagens and elastic fibre phenotype in floppy eyelid syndrome

Ezra

Ellis²,

Gaughan³

et al. 2011

Clinical &Amp; Experimental Ophthalmology

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Changes in Fibroblast Mechanostat Set Point and Mechanosensitivity: An Adaptive Response to Mechanical Stress in Floppy Eyelid Syndrome

Cited by 42 publications

References 54 publications

Independent Adipogenic and Contractile Properties of Fibroblasts in Graves’ Orbitopathy: An In Vitro Model for the Evaluation of Treatments

Independent Adipogenic and Contractile Properties of Fibroblasts in Graves’ Orbitopathy: An In Vitro Model for the Evaluation of Treatments

Growth and remodeling of load-bearing biological soft tissues

Changes in tarsal plate fibrillar collagens and elastic fibre phenotype in floppy eyelid syndrome

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