Lab website: Tissue Mechanobiology Lab

Ph.D. in Biology from Dartmouth College, Hanover, New Hampshire.

Research Areas:

Epithelial tissue biology, cell biology of embryonic stem cells, mechanobiology of cells and tissues, biomaging sciences, computational biology

Research Interests:
The Matsudaira lab research has been in two broad areas, the biochemistry, structure, and mechanics of the actin cytoskeleton and technology development.

Structure and Mechanobiology of the Actin Cytoskeleton

The main thrust of research in the last decade has been on the cellular engines that generate force. This focus evolved from structural studies on actin bundles in the acrosome (30,45,90) and dynamic studies of cell adhesion (93,115) where imaging captured the structure and short-lived dynamics of podosomes. A 2000 review (103) described a class of poorly understood cellular engines that works on the principle of a biological spring. Interestingly, biological springs power the fastest and largest cell movements. In the case of the acrosomal process, a twist of actin filaments in a crystalline bundle (122) causes the extension of a 60 um-long bundle (140). By applying imaging and biophysical force-measurement methods, we studied the mechanics of actin bundles and networks which has resulted in a complete phase diagram of stiffness in which networks exhibit strain-stiffening properties (118). In vitro studies of actin bundle mechanics complement the development of technically difficult measurements of the mechanics of force-production by the acrosome (114,117,140). Similar concepts apply in the retraction of the Vorticella spasmoneme (144), a centrin-based cytoskeleton.

With the ability to measure the mechanics of complex biophysical movements, the research has turned to computation and imaging to describe the mechanics of cell migration. In current research, the lab is studying two main problems: epithelial cell migration on 2D surfaces and mesenchymal/amoeboid cell migration in 3D matrices. We are studying how epithelial cells move in cell culture and in vivo and are characterizing the mechanical factors that control movement and the type of motility. One project is developing a non-computational method for imaging the sites and magnitude of force transduction with a fluorescent force sensor (139). Measurements of force from these and other studies feed into a force-based computational model that simulates single cell migration in 3D matrices (130,133). This computational model is one of a very few that is capable of capturing the mechanics and sterics of complex migration processes. The new directions of research in the lab is devoted to imaging cell migration ex vivo as well as studying embryonic stem cells as a model for basic mechanobiology of cells.

Microanalytical Methods

Basic research in mechanobiology requires tools and approaches for studying molecular and cell-based processes. Consequently, technology development in the lab has consistently been in the area of microanalytical techniques with the development of the SDS minigel format (1) and a highly-cited micromethod for sequencing pmol quantities of proteins from minigel blots (13). The latter method enabled the cloning of genes from small stretches of protein sequence. At that time gene cloning required laborious and inefficient protein purification methods. More recent interests have moved to microfluidic devices in a long-term partnership with Dr. Dan Ehrlich. The bioMEMS research has led to the development of a commercial genome sequencing system, the Shimadzhu DeNova (DeNova) based on microchannel electrophoresis in large plates (128) for DNA sequencing. The same core technology is at the heart of small devices (126) for DNA genotyping/forensics and further refined by the lab and spun-out commercially to Network Biosystems (Network) a company founded by members of the lab. The most recent microdevice is a sensor, a wireless CMOS chip for the detection of fluorescent DNA in microarray formats (150). Potentially a breakthrough technology because its commercial applications will be as a core sensor for in vivo measurement of biologically relevant molecules.

BioImaging Sciences

Our interests in imaging arose from studies on the dynamics of actin bundles and cell adhesions (115). From its origin in the WI Keck Microscopy Facility and the WI-MIT BioImaging Center at MIT, the scale and scope of bioimaging has grown and moved to the NUS Centre for BioImaging Sciences. The Center is devoted to development and application of imaging hardware and computation to problems in cell and systems biology. Recent research in the group include: development of quantitative imaging methods (141), fluorescent force biosensors (139), high content imaging concepts (138), and 3D optical traps for quorum sensing (135, 137). The imaging group has extensive collaborations with commercial microscope and image processing/analysis software companies.

Selected publications (from 150):

1. 1. Schmid, M.F., Sherman, M.B., Matsudaira, P., Chiu, W. Structure of the acrosomal bundle. Nature. 431:104-107 (2004).

2. Gardel, M.L., Shin, J.H., MacKintosh, F.C., Mahadevan, L., Matsudaira, P., Weitz, D.A. Scaling of F-actin networks to probe single filament elasticity and Dyamics. Phys. Rev. Let. 93(18):188102 (2004).

3. Goedecke, N., McKenna, B., El-Difrawy S., Carey, L., Matsudaira, P., Ehrlich, D., A high-performance multilane microdevice system designed for the DNA forensics laboratory. Electrophoresis 25:1678-1686 (2004).

4. Zaman, M.H., Kamm, R., Matsudaira, P., Lauffenburger, D.A., Computational model for cell migration in three-dimensional matrices. Biophys J. 89:1389-97 (2005).

5. Zaman, M.H., Trapani, L.M., Siemeski, A., Wells, A., Lauffenburger, D.A., Matsudaira, P. Cell migration in three-dimensional matrices Is inversely-dependent on cell-matrix adhesiveness and matrix stiffness. Proc. Natl. Acad. Sci. 103:10889-10894 (2006).

6. Shin, J.H., Tam, B.K., Brau, R.R., Lang, M.J., Mahadevan, L., Matsudaira, P. Force of an actin spring. Biophysical Journal 92:1-5 (2007).

7. Tarsa P.B., Brau R.R., Barch M., Ferrer J.M., Freyzon Y., Matsudaira P., Lang M.J. Detecting force-induced molecular transitions with fluorescence resonant energy transfer. Angew Chem Int Ed Engl. 119: 2045-2047 (2007).

8. Evans, J.G., Matsudaira, P. Linking microscopy and high content screening in large-scale biomedical research. Methods Mol. Biol. 356:33-8 (2007).

9. Zeskind, B.J., Jordan, C.D., Timp, W., Trapani, L., Waller, G., Horodincu, V., Ehrlich, D.J., Matsudaira, P. Nucleic acid and protein mass mapping by live-cell deep-ultraviolet microscopy. Nature Methods 4:567-9 (2007).

10. Lodish, Berk, Kaiser, Krieger, Scott, Bretscher, Ploegh, and Matsudaira. Molecular Biology of the Cell, 6th edition, W.H. Freeman (2008).

11. Anwar, M, P. Matsudaira 2009 Appl. Physics Lett. (in press)
    

full list of publications (pdf)