People

Research Interests

Mechanotransduction via the extracellular matrix; fibronectin; engineered cell culture platforms for regulating cell behavior in vitro.

Current Research

The form and function of cells and tissues is regulated by various properties of their local microenvironment such as rigidity and cell shape. In vivo, these properties are defined by the extracellular matrix (ECM) and adjacent cells. During dynamic processes such as development, these properties regulate ECM turnover and remodeling in addition to cell movement, proliferation, and contractility. This newly remodeled matrix and altered tissue shape then redefines the local microenvironment, thus further enjoining the cell response in an iterative, closed loop which leads to the coordinated self assembly of higher order structures. The ECM is more than a passive mechanical element in this process since it presents an array of binding sites for cells and cell signaling molecules. Furthermore, cell contractile forces stretch some components of the ECM, for example fibrillar structures composed of the protein fibronectin (Fn), into non-equilibrium conformations that have altered signaling properties. This can occur through protein unfolding, thus exposing amino acids with cell signaling functions that are normally buried in the equilibrium fold of the protein. Understanding how these microenvironmental properties regulate cell fate should increase the clinical efficacy of tissue engineering scaffolds that depend upon both biochemical and physical cues. Alternatively, engineered cell culture platforms might permit long-term maintenance of cell phenotype in vitro, thus permitting diagnostic research on the laboratory bench that might otherwise require animal experimentation. However, much remains to be learned about how these properties converge to direct cell fate in vivo. Predictions derived from reductionist systems often break down in more complicated environments. Broadly speaking, my lab focuses on quantifying the relationship between environmental cues and ECM production, elucidating the mechanisms by which Fn tension and unfolding alters its cell signaling capacity, and finally engineering culture environments to control the form and function of the ECM. These goals are accomplished using an interdisciplinary toolbox including a spectroscopic approach for quantifying strain within Fn matrix fibrils and microfabricated cell culture environments.

Selected Recent Publications

Little W, Smith ML, Ebneter U, Vogel V “Assay to Mechanically Tune and Optically Probe Fibrillar Fibronectin Conformations From Fully Relaxed to Breakage” Matrix Biology 27: 451-461 (2008)

 

Smith ML, Gourdon D, Little W, Kubow KE, Andresen Eguiluz R, Morris S, Vogel V “Force-Induced Unfolding of Fibronectin in the Extracellular Matrix of Living Cells” PLoS Biology 5(10): e268 (2007)

Ochsner M, Dusseiller MR, Grandin HM, Morris S, Textor M, Vogel V, Smith ML “Micro-Well Arrays for 3D Shape Control and High Resolution Analysis of Single Cells” Lab on a Chip 7(8): 1074-1077 (2007)

Smith ML, Sperandio M, Galkina EV, Ley K “Autoperfused Flow Chamber Reveals Synergistic Neutrophil Accumulation Through P-selectin and E-selectin” Journal of Leukocyte Biology 76(5): 985-993 (2004)

 

Smith ML, Olson TS, Ley K “CXCR2- and E-selectin-induced Neutrophil Arrest During Inflammation in vivo” Journal of Experimental Medicine 200(7): 935-939 (2004)

Smith ML, Long DS, Damiano ER, Ley K “Near-Wall Micro-PIV Reveals the Presence of a Hemodynamically Relevant Endothelial Surface Layer in Venules in vivo” Biophysical Journal 85: 637-645 (2003)