Bailly Lab: Tissue contraction, scarring and mechanoregulation
A given tensional homeostasis level is an intrinsic property of cells, and deregulation of tensional homeostasis in stromal cells is at the basis of stress-induced pathological remodelling such as fibrosis and scarring. Indeed, we and others have shown that cells from fibrotic tissue display altered mechanoproperties compared to their normal counterparts. Yet, little is known about how stromal cells determine and maintain tensional homeostasis, and how this is altered in fibrosis.
Our interests are centred round the identification of the molecular mechanisms that underlie tissue contraction and fibrosis, with a specific focus on the role of mechanoregulation and how cells use the remodelling of their actin cytoskeleton to interact with their environment. We use a range of cellular models to study tissue contraction in normal and fibrotic cells, as well as their responses to mechanical stress. The lab’s interests broadly fall under three areas:
1) Mechanisms of fibroblast-mediated contraction during wound healing:
Scarring is essentially a consequence of an exacerbation of the fibroblast-mediated tissue contraction that is part of the normal wound healing process.Primary ocular fibroblasts can be cultured in vitro where they display an elaborate cytosleleton of actin with multiple substrate attachment. They also retain the property of contracting collagen gels when stimulated with growth factors in a manner similar to what happens during the scarring process in vivo, and this process is thought to be dependant on the remodelling of their cytoskeleton. We have developed a range of in vitro and ex-vivo models of conjunctiva contraction, using cells in soft 3D collagen matrices, engineered collagen tissues,or intact conjunctiva fragments. Using these models, we have shown that tissue contraction is determined by both the level of individual cell protrusive activity and the remodelling of the matrix by matrix metalloproteinases (MMPs), and have recently identified the small GTPaseRac1 as a major regulator of both these aspects of tissue contraction. We are currently investigating how Rac1 controls tissue contraction and evaluating its potential as a new target for anti-scarring
2) Molecular mechanisms underlying fibrotic diseases in the eye:
Through a collaboration with Dr Daniel Ezra (Ocular Plastic surgeon, Moorfields Eye Hospital) and Dr Matthew Burton (Ophthalmologist, London School of Tropical Hygiene and Medicine), we have started to use our contraction models to identify the molecular mechanisms underlying fibrosis in specific eye diseases with a major fibrotic component such as Floppy Eyelid Syndrome (FES), Thyroid Eye Disease (TED) and recurrent trachomatoustrichiasis (TT), where the disease mechanisms are unknown and no good treatment is available. The studies have so far identified a specific molecular signature underlying the disease phenotype for each disease, and demonstrated that the fibrotic diseased cells display specific alterations in their mechanical properties that underlie they ability to contract tissues and promote scarring.
3) Tensional homeostasis, mechanical stress and modulation of the activity of the SRF transcription factor and its co-activator MRTF-A:
Mechanical sensing through cell attachment to the surrounding matrix is a fundamental process that regulates essential cellular features such as shape, motility, proliferation or differentiation. Deregulation of the tissue tensional homeostasis in stromal cells is at the basis of most stress-induced pathological remodelling, such as cardiac hypertrophy, fibrosis and scarring. We have recently identified myocardin-related transcription factor A (MRTF-A), the co-activator of Serum Response Factor (SRF, a major transcription factor linked to development, tissue homeostasis and fibrosis), as biosensor for tensional homeostasis in cells. The nuclear traffic of MRTF-A is down-regulated at tensional homeostasis, and we have shown that cofilin, a major regulator of actin dynamics, is a key regulator of the process. In addition, there is mounting evidence that the MTRF-A/SRF pathway is involved in mechanoregulation and fibrosis. Our goal is now to use our various models of tissue contraction and fibrosis to identify a)the mechanisms by which cells measure their internal tension, b)what actually determines the intrinsic tensional homeostasis level in individual cells, c) what is therole of the MRTF-A/SRF pathway in the processand, d) how it is altered in fibrotic disease.
Jenny (Zanetta) Kechagia
Full publication list:
- AnandagodaN, EzraDG, CheemaU ,BaillyM and BrownRA (2012). HyaluronanHydration Generates 3D Meso-Scale Structure In Engineered Collagen Tissues. In press Journal of the Royal Society Interface.
- EzraDG, KrellJ, Rose GE, BaillyM, Stebbing J, CastellanoL (2012).Transcriptome level microarray expression profiling implicates IGF-1 and Wnt signalling dysregulation in the pathogenesis of thyroid-associated orbitopathy. J. Clin. Pathol 65, 608-13.
- Tovell, VE, KhawPT and BaillyM (2012).Rac1 inhibition prevents tissue contraction and remodeling in the conjunctiva. Invest Ophthalmol Vis Sci . 53, 4682-4691.
- Nola, S.,Daigaku, R., Smolarczyk, K., Carstens, M., Martin-Martin, B., Longmore, G., Bailly, M.& Braga, V.M.M. (2011) Ajuba is required for Rac activation and maintenance of E-cadherin adhesion. J. Cell Biology 195, 855-871.
- McGeeKM, VartiainenMK, KhawPT, TreismanR and BaillyM. (2011) Nuclear transport of the serum response factor coactivator MRTF-A is downregulated at tensional homeostasis. EMBO Reports 12, 963-970.
- Ezra, DG, Ellis, JS, Gaughan, C, Beaconsfield, M, Collin, R, Bunce C, Bailly M and Luthert P. (2011) Changes in tarsal plate fibrillar collagens and elastic fibre phenotype in Floppy Eyelid Syndrome. Clinical Experimental Ophthalmology 39, 564-571.
- Tovell V, Dahlmann-Noor AH, Khaw PT, Bailly M. (2011) Advancing the Treatment of Conjunctival Scarring: A Novel Ex Vivo Model. Archives of Ophtalmology 129, 619-627.
- Martin-Martin B, Tovell V, Dahlmann-Noor AH, Khaw PT, Bailly M. (2011) The effect of the MMP inhibitor GM6001 on early fibroblast-mediated collagen matrix contraction is correlated to a decrease in cell protrusive activity. Eur J Cell Biol . 90, 26-36.
- Brooks, SP, Coccia, M, Tang, HR, Kanuga, N, Machesky, LM, Bailly, M , Cheetham ME and Hardcastle AJ (2010). The Nance-Horan Syndrome protein encodes a functional WAVE Homology Domain (WHD) and is important for co-ordinating actin remodelling and maintaining cell morphology. Human Molecular Genetics 19, 2421-2432.
- Ezra, DG, Ellis, JS, Beaconsfield, M, Collin, R, Bailly, M (2010). Changes in fibroblast mechanostat set point and mechano-sensitivity suggest an adaptive response to mechanical stress in Floppy Eyelid Syndrome. Invest Ophthalmol Vis Sci . 51, 3853-63.
- Dahlmann-Noor AH, Cosgrave E, Lowe S, Bailly M, Vivian AJ. (2009). Brimonidine and apraclonidine as vasoconstrictors in adjustable strabismus surgery. J AAPOS. 13(2):123-6.
This page last modified
1 March, 2013
by David Daniel