The effects of internal forces and membrane heterogeneity on three-dimensional cell shapes.

The shape of cells and the control thereof plays a central role in a variety of cellular processes, including endo- and exocytosis, cell division and cell movement. Intra- and extracellular forces control the shapes, and while the shape changes in some processes such as exocytosis are intracellularly-controlled and localized in the cell, movement requires force transmission to the environment, and the feedback from it can affect the cell shape and mode of movement used. The shape of a cell is determined by its cytoskeleton (CSK), and thus shape changes involved in various processes involve controlled remodeling of the CSK. While much is known about individual components involved in these processes, an integrated understanding of how intra- and extracellular signals are coupled to the control of the mechanical changes involved is not at hand for any of them. As a first step toward understanding the interaction between intracellular forces imposed on the membrane and cell shape, we investigate the role of distributed surrogates for cortical forces in producing the observed three-dimensional shapes. We show how different balances of applied forces lead to such shapes, that there are different routes to the same end state, and that state transitions between axisymmetric shapes need not all be axisymmetric. Examples of the force distributions that lead to protrusions are given, and the shape changes induced by adhesion of a cell to a surface are studied. The results provide a reference framework for developing detailed models of intracellular force distributions observed experimentally, and provide a basis for studying how movement of a cell in a tissue or fluid is influenced by its shape.

A Random Walk Approach to Transport in Tissues and Complex Media: From Microscale Descriptions to Macroscale Models.

The biological processes necessary for the development and continued survival of any organism are often strongly influenced by the transport properties of various biologically active species. The transport phenomena involved vary over multiple temporal and spatial scales, from organism-level behaviors such as the search for food, to systemic processes such as the transport of oxygen from the lungs to distant organs, down to microscopic phenomena such as the stochastic movement of proteins in a cell. Each of these processes is influenced by many interrelated factors. Identifying which factors are the most important, and how they interact to determine the overall result is a problem of great importance and interest. Experimental observations are often fit to relatively simple models, but in reality the observations are the output of complicated functions of the physicochemical, topological, and geometrical properties of a given system. Herein we use multistate continuous-time random walks and generalized master equations to model transport processes involving spatial jumps, immobilization at defined sites, and stochastic internal state changes. The underlying spatial models, which are framed as graphs, may have different classes of nodes, and walkers may have internal states that are governed by a Markov process. A general form of the solutions, using Fourier-Laplace transforms and asymptotic analysis, is developed for several spatially infinite regular lattices in one and two spatial dimensions, and the theory is developed for the analysis of transport and internal state changes on general graphs. The goal in each case is to shed light on how experimentally observable macroscale transport coefficients can be explained in terms of microscale properties of the underlying processes. This work is motivated by problems arising in transport in biological tissues, but the results are applicable to a broad class of problems that arise in other applications.

Growth control in the Drosophila wing disk.

The regulation of size and shape is a fundamental requirement of biological development and has been a subject of scientific study for centuries, but we still lack an understanding of how organisms know when to stop growing. Imaginal wing disks of the fruit fly Drosophila melanogaster, which are precursors of the adult wings, are an archetypal tissue for studying growth control. The growth of the disks is dependent on many inter- and intra-organ factors such as morphogens, mechanical forces, nutrient levels, and hormones that influence gene expression and cell growth. Extracellular signals are transduced into gene-control signals via complex signal transduction networks, and since cells typically receive many different signals, a mechanism for integrating the signals is needed. Our understanding of the effect of morphogens on tissue-level growth regulation via individual pathways has increased significantly in the last half century, but our understanding of how multiple biochemical and mechanical signals are integrated to determine whether or not a cell decides to divide is still rudimentary. Numerous fundamental questions are involved in understanding the decision-making process, and here we review the major biochemical and mechanical pathways involved in disk development with a view toward providing a basis for beginning to understand how multiple signals can be integrated at the cell level, and how this translates into growth control at the level of the imaginal disk. This article is categorized under: Analytical and Computational Methods > Computational Methods Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Cellular Models.