Mechanobiology

Professor G.V. Shivashankar is the Deputy Director of the Mechanobiology Institute (MBI), National University of Singapore and holds the IFOM-NUS Chair Professorship. Following his post-doctoral research at the NEC Research Institute, Princeton USA, Prof. Shivashankar moved to the National Center for Biological Sciences in Bangalore, India. In 2010, Prof. Shivashankar relocated to NUS and established his research group at the Mechanobiology Institute. Recipient of several scientific awards, Prof. Shivashankar also heads the Joint Research Laboratory, which was established at the MBI in collaboration with the FIRC Institute of Molecular Oncology (IFOM), Italy. Prof. Shivashankar’s lab focuses on studying the role of cell geometry on nuclear mechanics and genome regulation.

Professor Michael Sheetz is the Director of the Mechanobiology Institute, National University of Singapore (NUS), a Distinguished Professor at NUS and an Emeritus professor at Columbia University. Prof. Sheetz has over 40 years of experience in cell biology and biomechanics and his seminal work in studying cellular motor functions led to the discovery of a novel class of motor proteins called kinesins. A recipient of several prestigious awards given in recognition of his contributions to biomedical sciences, Prof. Sheetz is a pioneer in the emerging field of mechanobiology. Prof. Sheetz’ lab focuses on studying the molecular mechanisms of force sensing and transmission during cell motility.

Professor Paul Matsudaira is the Head of Department of Biological Sciences, National University of Singapore (NUS) and is also the Director of NUS Centre for Bioimaging Sciences and Co-Director of Mechanobiology Institute, NUS. After receiving his PhD in Biology from Dartmouth College, New Hampshire, Prof. Matsudaira served as a Professor of Biology and Bioengineering at the Massachusetts Institute of Technology for more than two decades, until he relocated to Singapore in 2009. Prof. Matsudaira’s lab is interested in studying the mechanics of epithelial cell migration and using state-of-the-art imaging techniques to visualize nanoscale structure and dynamics of cellular machinery in living systems.

Molecular machines composed of nm-scale proteins and nucleic acids organize into micrometer-size cells that assemble into tissues and eventually organisms. The emerging discipline in biology, mechanobiology, seeks a quantitative understanding of the physico-chemical designs that regulate the patterns of self-organization during development of cells and organisms. Advances in technology, combining microfabrication with high-speed super-resolution imaging allows us to detect and measure force and how molecular machines sense and respond to physical forces across the scales of structure and function. The new experimental tools combined with theoretical modeling have begun to provide testable predictions to enhance our understanding of the physico-chemical parameters governing molecular, cell, and tissue dynamics.

Biological cells sense their local physical microenvironment to regulate their behavior in tissues. Such sensing requires elaborate mechanosignaling mechanisms both at the level of cellular interactions with the extra-cellular matrix as well as cell–cell junctions. In response to such signals, a number of mechanotransduction pathways are activated both in prokaryotes and eukaryotes that regulate the cytoskeletal organization as well as the genomes. At the molecular scale, we get an insight into the force dependent regulation of unfolding and folding of nucleic acids and small proteins (Yan et al. DOI: 10.1039/C5IB00038F) and an analysis of the molecular interactions between integrins, filamins and talins, the fundamental units of force sensing, by Mofrad et al. (DOI: 10.1039/C5IB00133A). Using state of-the art imaging techniques, Ha, Wang et al. (DOI: 10.1039/C5IB00080G) provide important insights into the measurement of forces across single integrins that enable the cell to spread on a substrate. Strömblad, Lock et al. (DOI: 10.1039/C4IB00291A) analyze how the heterogeneity in talin expression levels could result in diverse cellular responses. An accurate sensing of contractile forces is necessary for various cellular functions and thus these sensing elements could be targets for small molecule screens. Krishnan et al. (DOI: 10.1039/C5IB00054H) provide technological innovation to identify small molecule modulators of contractile forces with high-throughput screening methods.

Multi-component signaling systems are a major strategy by which cells respond to environmental stresses. Kenney, Heilemann et al. (DOI: 10.1039/C5IB00077G) use super-resolution microscopy to provide direct visualization of the two-component regulatory system with respect to chromosomes in bacterial systems. Maier et al. (DOI: 10.1039/C5IB00018A) describe how oxygen-sensitive forces between pili organize bacteria into a micro-colony.

Another major advancement in technology in recent years has been the generation of patterned substrates. These methods enable us to dissociate the complex properties of the substrate, such as traction force, geometry, confinement of the cell, into quantifiable parameters, which allows one to segregate and understand the cellular responses to each of them. One major response by the cell is regulation of the cytoskeleton. Shivashankar et al. (DOI: 10.1039/C5IB00027K) report that cell–matrix constraints differentially regulate the dynamics of cytoskeleton interactions with chromatin linking proteins that are important in nuclear mechanotransduction. Iskratsch, Kam et al. (DOI: 10.1039/C5IB00032G) present how environmental cues activate different receptors such as LFA-1 or TCR within the same cell, and have different effects on remodeling of the cytoskeleton.

Cells performing functions in either a 2D or 3D tissue environment constantly monitor and respond to the microenvironment stiffness, thereby modulating cellular functions including differentiation and motility. Lutolf et al. (DOI: 10.1039/C4IB00176A) show that substrate elasticity regulates response of stem cells to the environmental cues, aiding differentiation of these cells. In the case of T-cells, Arkhipov et al. (DOI: 10.1039/C4IB00300D) provide new insights into microtubule appendages that have a role for cell motility and its polarization. Following the theme of migration, Matsudaira, Chiam et al. (DOI: 10.1039/C4IB00245H) present a detailed traction stress analysis of amoeboidal migration of cells in confined spaces which requires the integrity of membrane–cortex interactions. Ravichandran et al. (DOI: 10.1039/C5IB00013K) describe imaging strategies to quantify cell-induced matrix deformation that would be essential to understand how cells feedback on the matrix. Weihs et al. (DOI: 10.1039/C5IB00056D) provide compelling evidence to demonstrate that the ratio of total traction forces to cell area is preserved during differentiation.

Cells must balance cell–cell versus cell–matrix interactions to maintain tissue homeostasis. This has opened a new arena to investigate the role of extra-cellular traction force sensed by cell–matrix and cell–cell junctions and its role in diseases such as cancer progression. Ladoux, Ravasio et al. (DOI: 10.1039/C5IB00196J) demonstrate how the epithelial cells polarize in response to cell–matrix interactions. Mège et al. (DOI: 10.1039/C5IB00070J) discuss our current understanding of cellular response and adaptation at cell–cell junctions. One important consequence of imbalances in these forces is reflected in the invasive properties of cancer cells. Weaver et al. (DOI: 10.1039/C5IB00040H) show that tumor cell invasion and its aggression in human breast cancer correlates with matrix properties.

In order to gain further insight, theoretical modeling and predictions have helped drive the field forward. Kamm, Zaman et al. (DOI: 10.1039/C5IB00043B) review computational modeling approaches that provide an integration of molecular processes to multiscale systems. Models of epithelial sheets during wound closure are presented by Neufeld et al. (DOI: 10.1039/C5IB00053J) while computational approaches to analyze neuronal deformation by underlying matrix gratings are described by Sergi et al. (DOI: 10.1039/C5IB00045A). Finally, cellular growth and expansion in wound healing, invasion and other biological processes are susceptible to curvature-induced instabilities. Gov et al. (DOI: 10.1039/C5IB00092K) present physical insights into such instabilities and show that they could be precursors to leader cell formation driving cell migration.

Taken together, experimental and theoretical approaches are beginning to provide a more comprehensive picture of the regulation of cell states and gene functions across various length and time scales. We hope you will enjoy reading these articles in this Mechanobiology themed issue.

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