Tissue contraction, scarring and mechanoregulation
Tissue contraction, scarring and fibrosis are a major cause of morbidity in the human body, from pulmonary fibrosis to cardiovascular disease. In particular, in the eye, these processes play a part in the pathogenesis or failure of treatment of virtually every major blinding disease. Yet there are no specific treatments available for scarring and fibrosis, and in the eye, the anti-scarring agents currently used are primarily anti-cancer drugs, which carry significant side effects that can lead to blindness. There is thus a strong need to better understand the biology of tissue contraction and scarring and identify suitable targets and delivery mode for therapy. A fundamental property of vertebrate tissues is their ability to sense mechanical stress, and respond to it, by altering the functional properties of cells to maintain homeostasis. 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 GTPase Rac1 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 treatments.
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 trachomatous trichiasis (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.
Actin cytoskeleton (red) and vinculin (green) at substrate attachment points in primary human corneal fibroblasts (Left). 3-D reconstruction of a GFP-labelled corneal fibroblast (green) embedded in a matrix of collagen 1 for contraction studies (Right).
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 the role of the MRTF-A/SRF pathway in the process and, d) how it is altered in fibrotic disease.
MRTF-A (green) nuclear localisation in NIH3T3 fibroblasts contracting a collagen matrix following serum stimulation (Left). MRTF-A nuclear accumulation is prevented when the cells are allowed to reach tensional homeostasis in the gel (Right). Red shows the F-actin cytoskeleton.
Consultant Ophthalmologist and clinical trials lead for Adnexal / UCL Honorary Lecturer
Moorfields Eye Hospital Email: firstname.lastname@example.org
Jenny (Zanetta) Kechagia
PhD student Email: email@example.com
NIHR BRC/Francis CRICK clinical fellow
- He Li, Roos J.C.P., Rose, G.E., Bailly M. and Ezra D.G. (2015) Skin fibroblasts isolated from the upper eyelid and sternum differ in their matrix contraction potential and responses to inflammatory cytokines. PRS Global Open, in press.
- Li H., Fitchett C., Kozdon K., Jayaram H., Rose G.E, Bailly M. and Ezra D.G.
(2014) Independent adipogenic and contractile properties of fibroblasts in
Graves’ orbitopathy: an in vitro model for the evaluation of treatments. PLoSONE 9(4):e95586.doi:10.1371/journal.pone.0095586.
- Li H., Ezra D.G., Burton M.J. and Bailly M. (2013) Doxycycline prevents matrix remodeling and contraction by trichiasis-derived conjunctival fibroblasts. Invest Ophthalmol Vis Sci. 54, 4675-4682.
- Anandagoda N, Ezra DG, Cheema U , Bailly M and Brown RA (2012). Hyaluronan Hydration Generates 3D Meso-Scale Structure In Engineered Collagen Tissues. In press Journal of the Royal Society Interface.
- Terry SJ, Elbediwy A, Zihni C, Harris AR, Bailly M, Charras GT, Balda MS, Matter K. (2012) Stimulation of Cortical Myosin Phosphorylation by p114RhoGEF Drives Cell Migration and Tumor Cell Invasion. PLoS One.7(11):e50188.
- Ezra DG, Krell J, Rose GE, Bailly M, Stebbing J, Castellano L (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, Khaw PT and Bailly M (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.
- McGee KM, Vartiainen MK, Khaw PT, Treisman R and Bailly M. (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.