Inhibition of MMP-2 Increases the Biomechanics of Fibroblast Tissue Rings

Wu, Yanying

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Year:: 2022
Contributor:: Wu, Yanying (creator); Morgan, Jeffrey (Advisor); Schell, Jacquelyn (Reader); Achilli, Toni-Marie (Reader); Brown University. Biology and Medicine: Pathobiology (sponsor)
Genre:: theses
Subject:: Tissues--Mechanical properties; 3D Cell Culture; Matrix Metalloproteinases (MMPs)
Extent:: 7, 50 p.

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Abstract:: Synthesis and degradation of the extracellular matrix (ECM) are important for tissue development, morphogenesis, repair, and remodeling. Multiple proteinases are involved in the degradation of ECM, but matrix metalloproteinases (MMPs) are the most important ones, especially with regards to collagen which is resistant to proteolytic digestion. Inhibitors of MMPs have been proposed as emerging targets in the treatment of cancer, fibrosis, and cardiovascular diseases. Dermal fibroblasts produce MMP-2 and incyclinide, an inhibitor of MMP-2, has been extensively investigated and even evaluated in several clinical trials, but with disappointing results. To aid in the development of new drugs that can influence the ECM, there is a need for new in vitro models that can replicate the 3D architecture of the human ECM and its biomechanics. In this research, a 3D in vitro fibroblast microtissue ring model was tested. This model creates a highly aligned human ECM environment that mimics the histological and mechanical properties of ligamentous tissues. Different doses of incyclinide were tested on the fibroblast rings to test its effects on MMP-2. By measuring the morphological change, the ultimate tensile strength (UTS), and the maximum tangent modulus (MTM) of the rings, we found that the biomechanics of tissue rings treated with 5 μM incyclinide increased significantly. This indicated that inhibition of MMP-2 influenced the collagen and proteins in the ECM in a way that increased biomechanics. Besides the inhibitory effect of MMP-2, incyclinide also showed toxic effects at the highest dose, including the inhibition of cell growth and proliferation, as well as the apoptosis of cells. These results provide valuable insights into a new 3D model for testing new treatments that target the complex proteins of the extracellular matrix.
Notes:: Thesis (Sc. M.)--Brown University, 2022

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Citation

Wu, Yanying, "Inhibition of MMP-2 Increases the Biomechanics of Fibroblast Tissue Rings" (2022). Pathobiology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:phpy39pg/

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Pathobiology Theses and Dissertations

Theses and Dissertations for the Pathobiology department.
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