Trosolwg
Between 10-15% of the world population has Chronic Kidney Disease, characterized by progressive scarring of the kidney. My research addresses the mechanisms underlying the injury and progression of this scarring. Our focus is on understanding the cell- cell and cell-extracellular matrix interactions that control scarring and fibrosis. These interactions are similar to those involved in normal wound healing and by contrasting wound healing and fibrotic responses we have identified several novel potential therapeutic targets.
I am Outreach and Dissemination Lead of Wales Kidney Research Unit, a Biomedical Research Unit funded by Health and Care Research Wales to deliver an All-Wales strategy for the study, diagnosis, prevention, treatment and social context of kidney disease. See: http://kidneyresearchunit.wales/en/
Grant review
I peer-review grant applications for:
MRC
Kidney Research UK
The Wellcome Trust
University committees
2005-present. Cardiff Institute of tissue Engineering and Repair (CITER) Learning and Teaching Committee Member
2005-present. CITER MSc in Tissue Engineering Programme Committee. Vice-Chair
2007 - 2016. School of Medicine Research Degrees Committee. Member
2007 - 2016. School of Medicine, Postgraduate Course in Biomedical Research Techniques Advisory Group. Chair
Bywgraffiad
Education/Qualifications
1989, PhD; University of Wales, Cardiff.
1986, MSc; University of Birmingham, Birmingham
1978, BSc; University of Wales, Aberystwyth
Career overview
1993-1997 Lecturer in Cell Biology, Institute of Nephrology, University of Wales College of Medicine, Royal Infirmary, Cardiff, UK
1992-1993 Postdoctoral Research Fellow, Institute of Nephrology, University of Wales College of Medicine, Royal Infirmary, Cardiff, UK
1990-1992 Visiting Senior Fullbright Scholar, Department of Cell Biology and Anatomy, University of Alabama at Birmingham, Alabama, USA.
Aelodaethau proffesiynol
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Biochemical Society
The Renal Association
British Society for Matrix Biology
Tissue and Cell Engineering Society
Society for Endocrinology
Member of the Cardiff Institute of Tissue Engineering and Repair.
Pwyllgorau ac adolygu
2005-present. Cardiff Institute of tissue Engineering and Repair (CITER) Learning and Teaching Committee Member
2005-present. CITER MSc in Tissue Engineering Programme Committee. Vice-Chair
2007-2016. School of Medicine Research Degrees Committee. Member
2004-2016. School of Medicine, Postgraduate Course in Biomedical Research Techniques. Director
2009-2016. School of Medicine, Master of Research in Biomedical Research. Director
2014-2016. School of Medicine, MSc in Medical Research and Innovation. Director
Cyhoeddiadau
2023
- Grigorieva, I., Woods, E. L., Steadman, R., Bowen, T. and Meran, S. 2023. Hyaluronan in kidney fibrosis. In: Passi, A. ed. Hyaluronan: Structure, Biology and Biotechnology., Vol. 14. Biology of Extracellular Matrix Springer, pp. 77-97., (10.1007/978-3-031-30300-5_5)
2022
- Hamilton, K. D. et al. 2022. Anti-fibrotic potential of Tomentosenol A, a constituent of cerumen from the Australian native stingless bee, Tetragonula carbonaria. Antioxidants 11(8), article number: e1604. (10.3390/antiox11081604)
2021
- Woods, E. L. et al. 2021. CD147 mediates the CD44s-dependent differentiation of myofibroblasts driven by transforming growth factor-β1. Journal of Biological Chemistry 297(3), article number: 100987. (10.1016/j.jbc.2021.100987)
- Tai, Y., Woods, E. L., Dally, J., Kong, D., Steadman, R., Moseley, R. and Midgley, A. C. 2021. Myofibroblasts: function, formation, and scope of molecular therapies for skin fibrosis. Biomolecules 11(8), article number: 1095. (10.3390/biom11081095)
2020
- Moses, R. L. et al. 2020. Novel epoxy-tiglianes stimulate skin keratinocyte wound healing responses and re-epithelialization via protein kinase C activation. Biochemical Pharmacology 178, article number: 114048. (10.1016/j.bcp.2020.114048)
- Midgley, A. C. et al. 2020. Hyaluronidase-2 regulates RhoA signalling, myofibroblast contractility and other key pro-fibrotic myofibroblast functions. American Journal of Pathology 190(6), pp. 1236-1255. (10.1016/j.ajpath.2020.02.012)
2019
- Wilson, N. et al. 2019. Role of hyaluronan in human adipogenesis: Evidence from in-vitro and in-vivo studies. International Journal of Molecular Sciences 20(11), article number: 2675. (10.3390/ijms20112675)
2017
- Midgley, A. C., Oltean, S., Hascall, V., Woods, E. L., Steadman, R., Phillips, A. O. and Meran, S. 2017. Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype. Science Signaling 10(506), article number: eaao1822. (10.1126/scisignal.aao1822)
- Dally, J. et al. 2017. Hepatocyte growth factor mediates enhanced wound healing responses and resistance to transforming growth factor-β1-driven myofibroblast differentiation in oral mucosal fibroblasts. International Journal of Molecular Sciences 18, article number: 1843. (10.3390/ijms18091843)
2016
- Midgley, A. C., Morris, G., Phillips, A. O. and Steadman, R. 2016. 17β‐estradiol ameliorates age‐associated loss of fibroblast function by attenuating IFN‐γ/STAT1‐dependent miR‐7 upregulation. Aging Cell 15(3), pp. 531-541. (10.1111/acel.12462)
- Martin, J., Midgley, A., Meran, S., Woods, E., Bowen, T., Phillips, A. O. and Steadman, R. 2016. Tumour necrosis factor-stimulated gene (TSG)-6-mediated interactions with the inter-alpha-inhibitor heavy chain 5 facilitate TGF beta1-dependent fibroblast to myofibroblast differentiation.. Journal of Biological Chemistry 291, pp. 13789-13801. (10.1074/jbc.M115.670521)
2015
- Midgley, A. C., Druggal, L., Jenkins, R., Hascall, V., Steadman, R., Phillips, A. O. and Meran, S. 2015. Hyaluronan regulates bone morphogenetic protein-7-dependent prevention and reversal of myofibroblast phenotype. Journal of Biological Chemistry 290(18), pp. 11218-11234. (10.1074/jbc.M114.625939)
- Webber, J. P. et al. 2015. Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene 34(3), pp. 290-302. (10.1038/onc.2013.560)
2014
- Midgley, A. C., Bowen, T., Phillips, A. O. and Steadman, R. 2014. MicroRNA-7 inhibition rescues age-associated loss of epidermal growth factor receptor and hyaluronan-dependent differentiation in fibroblasts. Aging Cell 13(2), pp. 235-244. (10.1111/acel.12167)
2013
- Meran, S., Martin, J., Luo, D. D., Steadman, R. and Phillips, A. O. 2013. Interleukin-1β induces hyaluronan and CD44-dependent cell protrusions that facilitate fibroblast-monocyte binding. American Journal of Pathology 182(6), pp. 2223-2240. (10.1016/j.ajpath.2013.02.038)
- Midgley, A. C., Rogers, M. J., Hallett, M. B., Clayton, A., Bowen, T., Phillips, A. O. and Steadman, R. 2013. Transforming growth factor-β1 (TGF-β1)-stimulated fibroblast to myofibroblast differentiation Is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts. Journal of Biological Chemistry 288(21), pp. 14824-14838. (10.1074/jbc.M113.451336)
2011
- Bommayya, G., Meran, S., Krupa, A., Phillips, A. O. and Steadman, R. 2011. Tumour necrosis factor-stimulated gene (TSG)-6 controls epithelial–mesenchymal transition of proximal tubular epithelial cells. International Journal of Biochemistry & Cell Biology 43(12), pp. 1739-1746. (10.1016/j.biocel.2011.08.009)
- Meran, S., Luo, D. D., Simpson, R. M. L., Martin, J., Wells, A., Steadman, R. and Phillips, A. O. 2011. Hyaluronan facilitates transforming growth factor-β1-dependent proliferation via CD44 and epidermal growth factor receptor interaction. Journal of Biological Chemistry 286(20), pp. 17618-17630. (10.1074/jbc.M111.226563)
- Meran, S. and Steadman, R. 2011. Fibroblasts and myofibroblasts in renal fibrosis. International Journal of Experimental Pathology 92(3), pp. 158-167. (10.1111/j.1365-2613.2011.00764.x)
- Khammas, H., Bowen, T., Williams, J. D., Phillips, A. O., Steadman, R. and Martin, J. 2011. Characterisation of the human ADAM15 promoter. Nephron Experimental Nephrology 118(2), pp. e27-e38. (10.1159/000320698)
2010
- Webber, J. P., Steadman, R., Mason, M. D., Tabi, Z. and Clayton, A. 2010. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Research 70(23), pp. 9621-9630. (10.1158/0008-5472.CAN-10-1722)
- Simpson, R. M. L., Wells, A., Thomas, D. W., Stephens, P., Steadman, R. and Phillips, A. O. 2010. Aging fibroblasts resist phenotypic maturation because of impaired hyaluronan-dependent CD44/epidermal growth factor receptor signaling. American Journal of Pathology 176(3), pp. 1215-1228. (10.2353/ajpath.2010.090802)
2009
- Simpson, R. M. L., Meran, S., Thomas, D. W., Stephens, P., Bowen, T., Steadman, R. and Phillips, A. O. 2009. Age-related changes in pericellular hyaluronan organization leads to impaired dermal fibroblast to myofibroblast differentiation. American Journal of Pathology 175(5), pp. 1915-1928. (10.2353/ajpath.2009.090045)
- Zhang, L. et al. 2009. Thyrotropin receptor activation increases hyaluronan production in preadipocyte fibroblasts: Contributory role in hyaluronan accumulation in thyroid dysfunction. Journal of Biological Chemistry 284(39), pp. 26447-26455. (10.1074/jbc.M109.003616)
- Webber, J. P., Jenkins, R. H., Meran, S., Phillips, A. O. and Steadman, R. 2009. Modulation of TGFβ1-dependent myofibroblast differentiation by hyaluronan. American Journal of Pathology 175(1), pp. 148-160. (10.2353/ajpath.2009.080837)
- Webber, J. P., Meran, S., Steadman, R. and Phillips, A. O. 2009. Hyaluronan orchestrates transforming growth factor-β1-dependent maintenance of myofibroblast phenotype. Journal of Biological Chemistry 284(14), pp. 9083-9092. (10.1074/jbc.M806989200)
- Simpson, R. M., Stephens, P., Thomas, D., Webber, J. P., Meran, S., Steadman, R. and Phillips, A. O. 2009. Age related changes in pericellular hyaluronan leads to impaired dermal fibroblast to myofibroblast differentiation. International Journal of Experimental Pathology 90(2), pp. A128-A129.
2008
- Meran, S., Thomas, D. W., Stephens, P., Enoch, S., Martin, J., Steadman, R. and Phillips, A. O. 2008. Hyaluronan facilitates transforming growth factor-β1-mediated fibroblast proliferation. Journal of Biological Chemistry 283(10), pp. 6530-6545. (10.1074/jbc.M704819200)
- Lewis, A. G., Steadman, R., Manley, P., Craig, K. J., de la Motte, C., Hascall, V. and Phillips, A. O. 2008. Diabetic nephropathy, inflammation, hyaluronan and interstitial fibrosis. Histology and Histopathology 23(6), pp. 731-739.
- Meran, S., Steadman, R., Phillips, A. O., Thomas, D. W. and Stephens, P. 2008. Hyaluronan facilitates TGF beta 1 mediated myofibroblastic differentiation [Abstract]. Wound Repair and Regeneration 16(2), pp. A12. (10.1111/j.1524-475X.2008.00371.x)
2007
- Kastner, S., Thomas, G. J., Jenkins, R. H., Davies, M. and Steadman, R. 2007. Hyaluronan induces the selective accumulation of matrix- and cell-associated proteoglycans by mesangial cells. American Journal of Pathology 171, pp. 1811-1821. (10.2353/ajpath.2007.070085)
- Meran, S., Thomas, D. W., Stephens, P., Martin, J., Bowen, T., Phillips, A. O. and Steadman, R. 2007. Involvement of hyaluronan in regulation of fibroblast phenotype. The Journal of Biological Chemistry 282(35), pp. 25687-25697. (10.1074/jbc.M700773200)
2006
- Martin, J., Bowen, T. and Steadman, R. 2006. The pluripotent cytokine pleiotrophin is induced by wounding in human mesangial cells. Kidney International 70(9), pp. 1616-1622. (10.1038/sj.ki.5001800)
- Khera, T., Martin, J., Riley, S. G., Steadman, R. and Phillips, A. O. 2006. Glucose enhances mesangial cell apoptosis. Laboratory Investigation 86(6), pp. 566-577. (10.1038/labinvest.3700418)
2004
- Jenkins, R. H., Thomas, G. J., Williams, J. D. and Steadman, R. 2004. Myofibroblastic differentiation leads to hyaluronan accumulation through reduced hyaluronan turnover. The Journal of Biological Chemistry 279(40), pp. 41453-41460. (10.1074/jbc.M401678200)
- Clayton, A., Turkes, A., Dewitt, S., Steadman, R., Mason, M. D. and Hallett, M. B. 2004. Adhesion and signaling by B cell-derived exosomes: the role of integrins. The FASEB Journal 18, pp. 977-979. (10.1096/fj.03-1094fje)
2003
- Thomas, G. J., Clayton, A., Thomas, J., Davies, M. and Steadman, R. 2003. Structural and functional changes in heparan sulfate proteoglycan expression associated with the myofibroblastic phenotype. America Journal of Pathology 162(3), pp. 977-989.
- Blaber, R., Stylianou, E., Clayton, A. and Steadman, R. 2003. Selective regulation of ICAM-1 and RANTES gene expression after ICAM-1 ligation on human renal fibroblasts. Journal of the American Society of Nephrology 14(1), pp. 116-127. (10.1097/01.ASN.0000040595.35207.62)
2002
- Martin, J., Eynstone, L. V., Davies, M., Williams, J. D. and Steadman, R. 2002. The role of ADAM 15 in glomerular mesangial cell migration. The Journal of Biological Chemistry 277(37), pp. 33683-33689. (10.1074/jbc.M200988200)
2001
- Clayton, A., Thomas, J., Thomas, G. J., Davies, M. and Steadman, R. 2001. Cell surface heparan sulfate proteoglycans control the response of renal interstitial fibroblasts to fibroblast growth factor-2. Kidney International 59(6), pp. 2084-2094. (10.1046/j.1523-1755.2001.00723.x)
- Martin, J., Eynstone, L. V., Davies, M. and Steadman, R. 2001. Induction of metalloproteinases by glomerular mesangial cells stimulated by proteins of the extracellular matrix. Journal of the American Society of Nephrology 12(1), pp. 88-96.
1999
- Clayton, A. and Steadman, R. 1999. ICAM-1 interactions in the renal interstitium: a novel activator of fibroblasts during nephritis. Histology and Histopathology 14(3), pp. 861-870.
- Clayton, A., Thomas, J., Thomas, G., Davies, M. and Steadman, R. 1999. Fibroblasts from the cortical interstitium express cell surface heparan sulphate proteoglycans [Abstract]. Kidney International 55(6), pp. 2588-2588. (10.1046/j.1523-1755.2002.t01-1-00456.x)
- Evans, R. E., Clayton, A., Martin, J., Williams, J. D., Davies, M. and Steadman, R. 1999. Neutrophil binding stimulates the synthesis, release and activation of MMP 3 and MMP 2 from endothelial cells in vitro [Abstract]. Kidney International 55(5), pp. 2105-2105. (10.1046/j.1523-1755.1999.00404.x)
1998
- Clayton, A., Evans, R. A., Pettit, E., Hallett, M., Williams, J. D. and Steadman, R. 1998. Cellular activation through the ligation of intercellular adhesion molecule-1. Journal of Cell Science 111(4), pp. 443-453.
1997
- Evans, R. A., Clayton, A., Martin, J., Williams, J. D., Davies, M. and Steadman, R. 1997. Neutrophil binding stimulates the synthesis, release and activation of MMP 2 from endothelial cells in vitro. Journal of the American Society of Nephrology 8, pp. A2390-A2390.
- Clayton, A., Williams, J. D. and Steadman, R. 1997. The ligation of ICAM-1 on renal cortical fibroblasts initiates the de novo expression of ICAM-1 and VCAM-1. Journal of the American Society of Nephrology 8, pp. A2385-A2385.
- Clayton, A., Williams, J. D. and Steadman, R. 1997. Ligation of ICAM-1 on the surface of renal cortical fibroblasts stimulates de novo expression of ICAM-1 and VCAM-1 [Abstract]. Kidney International 52(1), pp. 262-263. (10.1038/ki.1997.329)
- Clayton, A., Steadman, R. and Williams, J. D. 1997. Cells isolated from the human cortical interstitium resemble myofibroblasts and bind neutrophils in an ICAM-1--dependent manner. Journal of the American Society of Nephrology 8(4), pp. 604-615.
1996
- Steadman, R., Clayton, A., Pettit, J., Hallett, B. and Williams, J. D. 1996. Leukocytes trigger an influx of calcium in renal interstitial fibroblasts through ligation ICAM-1. Journal of the American Society of Nephrology 7(9), pp. A2594-A2594.
1995
- Clayton, A., Steadman, R. and Williams, J. D. 1995. Human renal cortical fibroblasts (RCF) bind leukocytes in-vitro through a CD18-dependent and VLA(4)-dependent interaction. Journal of the American Society of Nephrology 6(3), pp. 894-894.
1988
- Steadman, R., Topley, N., Jenner, D. E., Davies, M. and Williams, J. D. 1988. Type-1 fimbriate escherichia-coli stimulates a unique pattern of de-granulation by human polymorphonuclear leukocytes. Infection and Immunity 56(4), pp. 815-822.
- Steadman, R., Topley, N., MacKenzie, R. K., Davies, M. and Williams, J. D. 1988. Scarring potential, fimbrial type-alpha-hemolysin production and human neutrophil (pmn) activation by uropathogenic strains of escherichia-coli [Abstract]. Kidney International 33(1), pp. 325-325.
The research of my group focuses on understanding the common mechanisms controlling the processes of wound healing, scarring and fibrosis. These all centre on the induction and function of the myofibroblast. This cell is not present in normal tissue but differentiates either from endogenous cells, such as fibroblasts or epithelial cells or from circulating fibrocytes that are targeted to sites of tissue remodelling. This differentiation is under the influence of growth factors such as transforming growth factor (TGF)b1 and this is central to the pathological process.
Fibroblasts are cells that populate the connective tissue of most organs of the body. When they take up a myofibroblast phenotype they lose their spindle-shaped morphology and become large contractile cells. They develop intracellular actin stress fibres that incorporate a-smooth muscle actin (a-sma) and allow the cell to contract, closing the wound or pulling scar-tissue together. This process is essential to healing skin wounds but pathological when it happens in a solid organ such as the kidney, lungs or liver.
Our current focus on the glycosaminoglycan hyaluronan began with the observation that hyaluronan was incorporated into large pericellular matrices when a fibroblast differentiated into a myofibroblast (Jenkins et al JBC, 2004). Delineating the mechanisms regulating this and assigning a role to this matrix has revealed that there is a causal relationship between hyaluronan assembly and cell phenotype . We are now at the point where we’re beginning to understand some of the factors that are involved in controlling the hyaluronan-dependent regulation of cell phenotype and have begun to fill the mechanistic gaps in our understanding.