Focus

Extracellular matrix regulation of cell functions

Research

The extracellular matrix (ECM) is a fibrous, branched network that is assembled by cells from secreted glycoproteins and proteoglycans and provides specific environmental signals to control cell morphology, migration, differentiation, and proliferation. The ECM is required to organize cells into tissues. Deficiencies in matrix composition and architecture correspond with the onset and progression of developmental defects and major diseases including cancer, fibrosis, and skeletal dysplasias. The goal of our research is to uncover novel mechanisms governing the assembly of the ECM protein fibronectin and its role in directing assembly of other ECM proteins to form a definitive matrix. Understanding these mechanisms will help us to determine how tissue-specific variations in matrix structure and organization regulate and modulate cell activities and contribute to developmental and disease processes.

Fibronectin is a ubiquitous adhesive glycoprotein and a major component of the ECM. As a multi-domain protein, fibronectin interacts with integrin receptors to transmit signals into cells while simultaneously interacting with ECM components such as collagens, proteoglycans, and other fibronectins. The latter interactions are essential for assembly of fibronectin into a multimeric fibrillar matrix. Using cell culture-based systems, we have determined the key steps in the assembly of fibronectin fibrils and our work has implicated fibronectin matrix assembly in a variety of biological processes including cell cycle progression, stem cell self-renewal and differentiation, and collagen fibrillogenesis.

The critical final step in fibronectin matrix assembly is the irreversible conversion of nascent fibronectin fibrils into an insoluble network that then supports the ECM incorporation of collagens, matricellular proteins, and growth factors to build a definitive matrix. Our results suggest a combination of fibronectin conformational changes and clustering of fibronectins near the cell surface is involved in the assembly process. Ongoing research is targeted at understanding the specific molecular interactions required for fibril insolubility with a focus on the role of heparan sulfate proteoglycans.

Our recent discovery of a mutation in human FN1 in an individual with clinical skeletal dysplasia provides us with a new model to study the role of fibronectin in the skeleton. The identification of this mutation opens entirely new and exciting avenues for research into the effects of fibronectin matrix perturbations on morphogenesis and differentiation. Defects in matrix assembly also lead to fibrosis, a common complication in a metabolic disease such as diabetic nephropathy. Elevated glucose levels activate intracellular pathways, change gene expression patterns, and cause the accumulation of disorganized ECM. We are investigating the results of RNA-seq experiments showing that ECM-related genes are significantly up-regulated by glucose and highlighting pathways not previously linked to ECM that may be contributing to the fibrotic response.

Since assembly of an appropriate ECM is essential for tissue repair, we are developing novel biomaterials using cell growth on chemically-patterned synthetic polymeric materials to direct the organization of the ECM. These biomaterials are designed for potential use as tissue mimetics in regenerative medicine. Our work thus far is providing new ideas about how to direct nerve regeneration using a composite ECM-synthetic polymer material as an implant for spinal cord and peripheral nerve repair.

Biography

Jean E. Schwarzbauer, Ph.D., is the Eugene Higgins Professor of Molecular Biology at Princeton University. She is also a member of the New Jersey Center for Biomaterials, a core faculty member of the Center’s NIH Tissue Engineering training program, and an Associate member of the Rutgers Cancer Institute of New Jersey. Her research focuses on extracellular matrix assembly and cell-matrix interactions in normal and pathogenic situations including cartilage development, kidney fibrosis, tumor formation, and tissue repair and regeneration. She has published more than 125 papers and holds several patents related to her work. She received her B.S. in Chemistry from the University of Wisconsin – Milwaukee and studied protein-RNA interactions in the bacterial ribosome for her Ph.D. in Molecular Biology from the University of Wisconsin – Madison. After a post-doctoral fellowship at MIT studying the extracellular matrix protein fibronectin, she joined Princeton University as an Assistant Professor in 1986. Professor Schwarzbauer teaches cell biology at the undergraduate and graduate levels and, prior to becoming Associate Chair of the department, she served as the Director of Graduate Studies for the Molecular Biology Program from 2008 - 2013. In addition to her service to the department and the university, Professor Schwarzbauer also contributes to the scientific community with service on numerous boards and panels. She recently completed terms as President of the American Society for Matrix Biology, Secretary of the American Society for Cell Biology, and on the Gordon Research Conferences Board of Trustees. Currently, she is an editor for Molecular Biology of the Cell, associate editor for Matrix Biology, and on the editorial board of the Journal of Cell Biology. Her record of service also includes multiple NIH study sections (including chair of Pathobiochemistry and of Intercellular Interactions), review panels for the Wellcome Trust, ACS, DOD Breast Cancer Program, Deutsche Forschungsgemeinschaft, among others, and advisory boards for programs at U. Penn, Cornell University, NSF, and others. She has organized national and international conferences in matrix biology, cell biology, biomaterials, and bioengineering. She is the first recipient of the Peggy Wheelock Award for Excellence in Research, Mentoring, and Promotion of Women in Science at the Univ. of Nebraska Medical Center.