Cells in animal tissues are in contact with organized complexes of structural molecules called extracellular matrix (ECM). The ECM induces a variety of signals that regulate cellular behavior and fundamental physiological processes. Aberrations in signal transduction from the ECM cause chronic degenerative and fibrotic disorders. Our overall long-term objective is to advance understanding of the molecular mechanisms underlying tissue-specific constitution induced by cell-ECM interactions during development, tissue repair, and carcinogenesis. We use transgenic mice as an in vivo model system. We focus on the interdependence of the ECM glycoprotein fibronectin and the profibrogenic cytokine TGF-β to fibrogenic response to tissue damage. We have found that fibronectin-deficiency shows elevated local TGF-β bioavailability, mediated predominantly by β6-integrins, and we have identified TGF-β-signaling and type V-collagen as essential elements in the initial fibrogenic response to liver injury. We also focus on how mechanical forces are converted into biochemical signals and are pursuing studies on tendon biology and tissue engineering. We have demonstrated that, although TGF-β induces and maintains the expression of basic helix-loop-helix transcription factor Scleraxis in tendon cells in vitro, the excessive amount of active TGF-β released immediately after tendon transection injury leads to massive tendon cell death. Thus, our study directly links an excess of active TGF-β released from the ECM to adult tendon pathology. We utilize extensive mouse genetic approaches, including conditional-knockout technology, as well as a wide range of biochemical, cellular, and molecular biological techniques to address these clinically relevant topics.
Cells in animal tissues are in contact with organized complexes of structural molecules called the extracellular matrix (ECM). The ECM induces a variety of signals that regulate cellular behavior and fundamental physiological processes. Aberrations in signal transduction from the ECM cause chronic degenerative and fibrotic disorders. Our laboratory intends to explore the molecular mechanisms underlying adult tissue repair following injury using unique transgenic mouse models. Identifying the key regulatory players in this process will provide the basis for a future direction to generate novel therapeutic strategies for the millions of patients.
Thomas Egelhoff, Ph.D., Department of Cell Biology, The Cleveland Clinic,
Cleveland , OH
Harihara Baskaran, Ph.D., Department of Chemical Engineering, Case Western
Reserve University, Cleveland, OH
Ronen Schweitzer, Ph.D., Shriners Hospital for Children, Research Division,
Portland , OR.
Tsujimoto I, Moriya K, Sakai K, Dickneite G, Sakai T. Critical role of factor XIII in the initial stages of carbon tetrachloride-induced adult liver remodeling. Am J Pathol 2011. In Press.
Maeda T, Sakabe T, Sunaga A, Sakai K, Rivera AL, Keene DR, Stavnezer E, Iannotti J, Schweitzer R, Ilic D, Baskaran H, Sakai T. Conversion of mechanical force into TGF-β-mediated biochemical signals. Curr Biol 2011;21:933-941 [Epub 2011 May 19].
Moriya K, Bae E, Honda K, Sakai K, Sakaguchi T, Tsujimoto I, Kamisoyama H, Keene DR, Sasaki T, Sakai T. A fibronectin-independent mechanism of collagen fibrillogenesis in adult liver remodeling. Gastroenterology 2011;140:1653-1663 [Epub 2011 Feb 12].
Honda K, Sakaguchi T, Sakai K, Schmedt C, Ramirez A, Jorcano JL, Tarakhovsky A, Kamisoyama H, Sakai T. Epidermal hyperplasia and papillomatosis in mice with a keratinocyte-restrictive deletion of csk. Carcinogenesis 2007;28:2074-2081.
Lerner Research Institute
Mail Code NB21
9500 Euclid Avenue
Cleveland, Ohio 44195