Livingston Van De Water
University of Rochester
Myofibroblasts are prominent and persistent components within the tumor microenvironment where they support carcinoma progression. During fibrosis, a pathological form of healing, myofibroblasts deposit functionally inappropriate amounts of scar in organs such as skin, lung, liver and kidney. This contrasts with the process of normal wound healing, in which myofibroblasts assemble a scar that has minimal impact on tissue function. In normal wounds these myofibroblasts undergo apoptosis or revert to a fibroblast, thereby limiting their duration; in diseases like cancer and fibrosis, myofibroblasts seem to persist contributing to these pathologies. What intracellular mechanisms determine these distinct myofibroblast fates?
Our lab seeks to understand the cellular and molecular mechanisms that control the differentiation of fibroblasts to myofibroblasts and that regulate myofibroblast persistence in pathogenic settings. To do so, we are testing how growth factors, extracellular matrix proteins, such as fibronectin, integrins and focal adhesion proteins work coordinately to regulate myofibroblast differentiation, persistence and function. In addition, we are studying, in collaboration with Dr. Mike DiPersio in our Center, whether and to what extent keratinocytes secrete factors that regulate myofibroblasts. Our overall goal is to develop a basis for novel therapeutics that will modulate myofibroblast generation, function and persistence in pathogenic tissue repair and tumor stroma.
- Shinde, A., Kelsh, R.M., Peters, J.H., Sekiguchi, K., Van De Water, L., and McKeown-Longo, P.J.: The alpha4/beta1 integrin and the EDA domain of fibronectin regulate a profibrotic phenotype in dermal fibroblasts. Matrix Biol. pii:S)945-053A(14)00216-9. doi: 10.1016/j.matbio.2014.11.004 [Epub ahead of print].
- Van De Water, L., Varney, S., and Tomasek, J.J. Mechanoregulation of the myofibroblast in wound contraction, scarring, and fibrosis: Opportunities for new therapeutic intervention. Adv. Wound Care 2:122-141, 2013.
- Wang X, Betts C, Van De Water L, Zhou J: Transforming growth factor-beta1-induced transcript 1 protein (Hic-5), a novel marker for smooth muscle contractile phenotype, is regulated by serum response factor/myocardin. J Biol Chem 286: 41589-99, 2011.
- Singh, P., Chen, C., Stepp, M.A., Sheppard, D., Van De Water, L.: Loss of integrin alpha9/beta1 results in defects in proliferation, causing poor re-epithelialization during cutaneous wound healing. J. Invest. Dermatol. 129:217-228, 2009.
- Dabiri, G., Tumbarello, D.A., Turnder, C.E., and Van De Water, L.: Hic-5 promotes the hypertrophic scar myofibroblast phenotype by regulating the TGF-beta1 autocrine loop. J. Invest. Dermatol. 128(10):2518-2525, 20080.
- Shinde, A.V., Bystroff, C., Wang, C., Vogelzang, M.G., Vincent, P.A., Hynes, R.O., and Van De Water, L.: Identification of the peptide sequences within the EIIIA (ED-A) segment of fibronectin that mediate integrin alpha9/beta1-dependent cellular activities. J. Biol. Chem. 283(5):2858-2870, 2008.