Spatio-temporal Models of Lymphangiogenesis in Wound Healing

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total

Modeling Cell Gradient Sensing and Migration in Competing Chemoattractant Fields

Directed cell migration mediates physiological and pathological processes. In particular, immune cell trafficking in tissues is crucial for inducing immune responses and is coordinated by multiple environmental cues such as chemoattractant gradients. Although the chemotaxis mechanism has been extensively studied, how cells integrate multiple chemotactic signals for effective trafficking and positioning in tissues is not clearly defined. Results from previous neutrophil chemotaxis experiments and modeling studies suggested that ligand-induced homologous receptor desensitization may provide an important mechanism for cell migration in competing chemoattractant gradients. However, the previous mathematical model is oversimplified to cell gradient sensing in one-dimensional (1-D) environment. To better understand the receptor desensitization mechanism for chemotactic navigation, we further developed the model to test the role of homologous receptor desensitization in regulating both cell gradient sensing and migration in different configurations of chemoattractant fields in two-dimension (2-D). Our results show that cells expressing normal desensitizable receptors preferentially orient and migrate toward the distant gradient in the presence of a second local competing gradient, which are consistent with the experimentally observed preferential migration of cells toward the distant attractant source and confirm the requirement of receptor desensitization for such migratory behaviors. Furthermore, our results are in qualitative agreement with the experimentally observed cell migration patterns in different configurations of competing chemoattractant fields

Translational Systems Biology of Inflammation

Inflammation is a complex, multi-scale biologic response to stress that is also required for repair and regeneration after injury. Despite the repository of detailed data about the cellular and molecular processes involved in inflammation, including some understanding of its pathophysiology, little progress has been made in treating the severe inflammatory syndrome of sepsis. To address the gap between basic science knowledge and therapy for sepsis, a community of biologists and physicians is using systems biology approaches in hopes of yielding basic insights into the biology of inflammation. “Systems biology” is a discipline that combines experimental discovery with mathematical modeling to aid in the understanding of the dynamic global organization and function of a biologic system (cell to organ to organism). We propose the term translational systems biology for the application of similar tools and engineering principles to biologic systems with the primary goal of optimizing clinical practice. We describe the efforts to use translational systems biology to develop an integrated framework to gain insight into the problem of acute inflammation. Progress in understanding inflammation using translational systems biology tools highlights the promise of this multidisciplinary field. Future advances in understanding complex medical problems are highly dependent on methodological advances and integration of the computational systems biology community with biologists and clinicians

Three-Dimensional Cell and Tissue Patterning in a Strained Fibrin Gel System

Techniques developed for the in vitro reproduction of three-dimensional (3D) biomimetic tissue will be valuable for investigating changes in cell function in tissues and for fabricating cell/matrix composites for applications in tissue engineering techniques. In this study, we show that the simple application of a continuous strain to a fibrin gel facilitates the development of fibril alignment and bundle-like structures in the fibrin gel in the direction of the applied strain. Myoblasts cultured in this gel also exhibited well-aligned cell patterning in a direction parallel to the direction of the strain. Interestingly, the direction of cell proliferation was identical to that of cell alignment. Finally, the oriented cells formed linear groups that were aligned parallel to the direction of the strain and replicated the native skeletal muscle cell patterning. In addition, vein endothelial cells formed a linear, aligned vessel-like structure in this system. Thus, the system enables the in vitro reproduction of 3D aligned cell sets replicating biological tissue patterns

Combinatorial Guidance by CCR7 Ligands for T Lymphocytes Migration in Co-Existing Chemokine Fields

Chemokines mediate the trafficking and positioning of lymphocytes in lymphoid tissues that is crucial for immune surveillance and immune responses. In particular, a CCR7 ligand, CCL21, plays important roles in recruiting T cells to secondary lymphoid tissues (SLT). Furthermore, CCL21 together with another CCR7 ligand, CCL19, direct the navigation and compartmentation of T cells within SLT. However, the distinct roles of these two chemokines for regulating cell trafficking and positioning are not clear. In this study, we explore the effect of co-existing CCL19 and CCL21 concentration fields on guiding T cell migration. Using microfluidic devices that can configure single and superimposed chemokine fields we show that under physiological gradient conditions, human peripheral blood T cells chemotax to CCL21 but not CCL19. Furthermore, T cells migrate away from the CCL19 gradient in a uniform background of CCL21. This repulsive migratory response is predicted by mathematical modeling based on the competition of CCL19 and CCL21 for CCR7 signaling and the differential ability of the two chemokines for desensitizing CCR7. These results suggest a new combinatorial guiding mechanism by CCL19 and CCL21 for the migration and trafficking of CCR7 expressing leukocytes

Topography of Extracellular Matrix Mediates Vascular Morphogenesis and Migration Speeds in Angiogenesis

The extracellular matrix plays a critical role in orchestrating the events necessary for wound healing, muscle repair, morphogenesis, new blood vessel growth, and cancer invasion. In this study, we investigate the influence of extracellular matrix topography on the coordination of multi-cellular interactions in the context of angiogenesis. To do this, we validate our spatio-temporal mathematical model of angiogenesis against empirical data, and within this framework, we vary the density of the matrix fibers to simulate different tissue environments and to explore the possibility of manipulating the extracellular matrix to achieve pro- and anti-angiogenic effects. The model predicts specific ranges of matrix fiber densities that maximize sprout extension speed, induce branching, or interrupt normal angiogenesis, which are independently confirmed by experiment. We then explore matrix fiber alignment as a key factor contributing to peak sprout velocities and in mediating cell shape and orientation. We also quantify the effects of proteolytic matrix degradation by the tip cell on sprout velocity and demonstrate that degradation promotes sprout growth at high matrix densities, but has an inhibitory effect at lower densities. Our results are discussed in the context of ECM targeted pro- and anti-angiogenic therapies that can be tested empirically

Mechanics rules cell biology

Cells in the musculoskeletal system are subjected to various mechanical forces in vivo. Years of research have shown that these mechanical forces, including tension and compression, greatly influence various cellular functions such as gene expression, cell proliferation and differentiation, and secretion of matrix proteins. Cells also use mechanotransduction mechanisms to convert mechanical signals into a cascade of cellular and molecular events. This mini-review provides an overview of cell mechanobiology to highlight the notion that mechanics, mainly in the form of mechanical forces, dictates cell behaviors in terms of both cellular mechanobiological responses and mechanotransduction