Showing papers by "Ovijit Chaudhuri published in 2020"

Effects of extracellular matrix viscoelasticity on cellular behaviour.

Abstract: Substantial research over the past two decades has established that extracellular matrix (ECM) elasticity, or stiffness, affects fundamental cellular processes, including spreading, growth, proliferation, migration, differentiation and organoid formation. Linearly elastic polyacrylamide hydrogels and polydimethylsiloxane (PDMS) elastomers coated with ECM proteins are widely used to assess the role of stiffness, and results from such experiments are often assumed to reproduce the effect of the mechanical environment experienced by cells in vivo. However, tissues and ECMs are not linearly elastic materials-they exhibit far more complex mechanical behaviours, including viscoelasticity (a time-dependent response to loading or deformation), as well as mechanical plasticity and nonlinear elasticity. Here we review the complex mechanical behaviours of tissues and ECMs, discuss the effect of ECM viscoelasticity on cells, and describe the potential use of viscoelastic biomaterials in regenerative medicine. Recent work has revealed that matrix viscoelasticity regulates these same fundamental cell processes, and can promote behaviours that are not observed with elastic hydrogels in both two- and three-dimensional culture microenvironments. These findings have provided insights into cell-matrix interactions and how these interactions differentially modulate mechano-sensitive molecular pathways in cells. Moreover, these results suggest design guidelines for the next generation of biomaterials, with the goal of matching tissue and ECM mechanics for in vitro tissue models and applications in regenerative medicine.

Nonlinear Elastic and Inelastic Properties of Cells.

Abstract: Mechanical forces play an important role in various physiological processes, such as morphogenesis, cytokinesis, and migration. Thus, in order to illuminate mechanisms underlying these physiological processes, it is crucial to understand how cells deform and respond to external mechanical stimuli. During recent decades, the mechanical properties of cells have been studied extensively using diverse measurement techniques. A number of experimental studies have shown that cells are far from linear elastic materials. Cells exhibit a wide variety of nonlinear elastic and inelastic properties. Such complicated properties of cells are known to emerge from unique mechanical characteristics of cellular components. In this review, we introduce major cellular components that largely govern cell mechanical properties and provide brief explanations of several experimental techniques used for rheological measurements of cell mechanics. Then, we discuss the representative nonlinear elastic and inelastic properties of cells. Finally, continuum and discrete computational models of cell mechanics, which model both nonlinear elastic and inelastic properties of cells, will be described.

Recursive Feedback between Matrix Dissipation and Chemo-Mechanical Signaling Drives Oscillatory Growth of Cancer Cell Invadopodia

Abstract: As cells migrate through the extracellular matrix (ECM), they can sense the mechanical properties of their environment and remodel the matrix. Most ECMs are known to be dissipative, exhibiting viscoelastic and often plastic behaviors. However, the influence of dissipation on cell motility, in particular the plasticity in 3D confining microenvironments that endows matrix with intrinsic long-term mechanical memory, is not clear. In this study, we develop a chemo-mechanical model to predict the impact of matrix plasticity on the dynamics of invadopodia, the protrusive structures that cancer cells use to facilitate invasion and motility. By considering myosin dynamics, actin polymerization, adhesion formation, and biochemical signaling, we demonstrate that matrix dissipation facilitates invadopodia oscillations by softening the ECM over repeated cycles, during which plastic deformation gradually accumulates via cyclic ratcheting. Our model reveals that distinct patterns of protrusion behavior, oscillatory or monotonic, emerge from the interplay between timescales of extension-associated viscosity and signaling-associated myosin recruitment; oscillations are only observed when these timescales are comparable. Further, we predict and experimentally validate the influence of pharmacological treatments that target myosin activity, adhesions and Rho and Rho kinase (ROCK) pathways on invadopodia dynamics. More importantly, our model provides a quantitative framework to understand how the matrix can serve as a memory storage mechanism for protrusions that is “written on” or “read” by cells.

Multi-scale cellular engineering: From molecules to organ-on-a-chip.

Abstract: Recent technological advances in cellular and molecular engineering have provided new insights into biology and enabled the design, manufacturing, and manipulation of complex living systems. Here, we summarize the state of advances at the molecular, cellular, and multi-cellular levels using experimental and computational tools. The areas of focus include intrinsically disordered proteins, synthetic proteins, spatiotemporally dynamic extracellular matrices, organ-on-a-chip approaches, and computational modeling, which all have tremendous potential for advancing fundamental and translational science. Perspectives on the current limitations and future directions are also described, with the goal of stimulating interest to overcome these hurdles using multi-disciplinary approaches.

Roles of Interactions Between Cells and Extracellular Matrices for Cell Migration and Matrix Remodeling

Abstract: Cells can sense mechanical properties of surrounding environments and also structurally remodel the environments. Interactions between cells and extracellular matrix (ECM) play a crucial role in diverse cellular behaviors, including migration, growth, and differentiation. Advances in experimental and computational methods enabled us to better understand the molecular bases and underlying mechanisms of the cell-ECM interactions. This chapter provides a comprehensive review regarding how cells sense and remodel ECMs and why such capabilities are of great importance for cell migration. First, the molecular structure, dynamics, and functions of focal adhesions (FAs) formed between cells and ECM are discussed, followed by a brief review about the significance of interactions between FAs and the actin cytoskeleton occurring in the intracellular space. Then, it is discussed how cells remodel surrounding ECMs mechanically and biochemically. Additionally, various experimental and computational methods designed for studying cell migration facilitated by cell-ECM interactions and ECM remodeling are summarized, and findings obtained using these methods are discussed.

The nature of mitotic forces in epithelial monolayers

Abstract: Epithelial cells undergo striking morphological changes during mitosis to ensure proper segregation of genetic and cytoplasmic materials. These morphological changes occur despite dividing cells being mechanically restricted by neighboring cells, indicating the need for extracellular force generation. While forces generated during mitotic rounding are well understood, forces generated after rounding remain unknown. Here, we identify two distinct stages of mitotic force generation that follow rounding: (1) protrusive forces along the mitotic axis that drive mitotic elongation, and (2) outward forces that facilitate post-mitotic re-spreading. Cytokinetic ring contraction of the mitotic cell, but not activity of neighboring cells, generates extracellular forces that propel mitotic elongation and also contribute to chromosome separation. Forces from mitotic elongation are observed in epithelia across many model organisms. Thus, forces from mitotic elongation represent a universal mechanism that powers mitosis in confining epithelia.

Introduction to Editorial Board Member: Professor David J. Mooney

Abstract: In this issue of Bioengineering and Translational Medicine, we are pleased to introduce our Editorial Board Member, Professor David J. Mooney (Figure 1). Professor Mooney is the Robert P. Pinkas Family Professor of Bioengineering at the John A. Paulson School of Engineering and Applied Sciences at Harvard University. He is a founding member of the Wyss Institute for Biologically Inspired Engineering at Harvard University, in which he serves as a core faculty member. He is a member of both the National Academy of Engineering and the National Academy of Medicine, and he is a fellow of the National Academy of Inventors. Professor Mooney is widely recognized for his influential work in biomaterials, drug delivery, tissue engineering and regenerative medicine, mechanotransduction, and immunotherapy. His publications have been cited over 90,000 times and include 13 papers with over 1,000 citations, his h-index is 150, and he has given over 400 invited lectures. In 2019, Nature Biotechnology named him one of the top 10 translational researchers in biotechnology. Professor Mooney earned his BS in Chemical Engineering at the University of Wisconsin, Madison. He then went on to conduct his PhD work in Chemical Engineering at the Massachusetts Institute of Technology, under the mentorship of Professor Robert Langer. After finishing his PhD, he worked as a postdoctoral fellow at Harvard University under the guidance of Dr Joseph Vacanti and Professor Donald Ingber. He started his career as a professor at the University of Michigan in 1994 and then moved to Harvard University in 2004. In his early work, Professor Mooney made major advances in the use of biomaterials for regenerative medicine and tissue engineering. At the time, the paradigm in regenerative medicine had been the bolus delivery of single growth factors, which had limited efficacy. To address these limitations, Professor Mooney and others developed approaches to use biomaterial carriers for localized and sustained delivery of growth factors and other bioactive agents. His group demonstrated that modified, porous poly(lactide-co-glycolide) (PLG) scaffolds could deliver multiple growth factors with distinct kinetics to drive angiogenesis and bone formation, as well as deliver DNA-encoding growth factors intracellularly to promote angiogenesis in vivo. They also developed a number of in vitro applications using these materials, including tissue-engineered bone and models of tumors. Professor Mooney's early efforts also pioneered the use of alginate hydrogels for various biomedical applications. Alginate is a polysaccharide derived fromalgae, which forms a three-dimensional (3D) nanoporous hydrogel when crosslinked with calcium that has similar structural characteristics to extracellular matrix. Alginate hydrogels are biocompatible, gel under mild conditions, and are injectable. Professor Mooney recognized and exploited these useful properties both in vivo and in vitro. His group showed how tuning various parameters, such as degradation and crosslinking, or applying mechanical perturbation can be used to control the spatiotemporal release of single or multiple bioactive molecules. They utilized alginate gels to deliver a wide variety of bioactive molecules, including vascular endothelial growth factor and other heparin-binding growth factors that naturally bind to alginate, as well as other bioactive molecules that must first be packaged or tethered to control their release. These approaches were used to promote angiogenesis, bone formation, and smoothmuscle tissue formation in vivo. In parallel, they demonstrated that coupling the RGD (Arginine-Glycine-Aspartate) cell adhesion peptide sequence to the alginate allows cells to adhere to the otherwise inert gels. This enabled in vivo regenerative medicine applications involving infiltration of host cells into gels or delivery of exogenous cells, as well as twodimensional (2D) and 3D culture of adherent cells in vitro. Professor Mooney's group continues to work on applying alginate toward therapeutic angiogenesis and regeneration of musculoskeletal tissues. Furthermore, they have continued to innovate with alginate, introducing various ways to modify the gels chemically and physically and expanding their use to new applications. Recent developments include alginate-based tough gels and tough adhesives. Professor Mooney is also a leader in the field of mechanotransduction, the process by which cells sense and respond to mechanical cues. Professor Mooney's group has extensively characterized the mechanical properties of alginate gels and elucidated their underlying mechanisms; based on this knowledge, they have devised various approaches to modulate the mechanical properties of alginate-based materials. In their early studies, they discovered that the stiffness of RGD-coupled alginate hydrogels impacts cell proliferation, apoptosis, and differentiation in 2D culture, and they identified integrin clustering as a key mediator of mechanotransduction. They went on to show that hydrogel stiffness regulates the differentiation of mesenchymal stem cells in 3D culture and applied this finding to design a material that optimally promotes bone regeneration in vivo. Professor Mooney also recognized that tissues and extracellular matrices are typically not elastic but viscoelastic. His group developed alginate hydrogels with tunable viscoelasticity and showed that Received: 22 April 2020 Accepted: 22 April 2020