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Advanced Drug Delivery Reviews (v.59, #13)
Natural and artificial cellular microenvironments for soft tissue repair
by Richard A.F. Clark Theme Editor (pp. 1291-1292).
Three-dimensional microenvironments modulate fibroblast signaling responses by J. Angelo Green; Kenneth M. Yamada (pp. 1293-1298).
Modes of signaling in fibroblasts can differ substantially depending on whether these cells are in their natural three-dimensional environment compared to artificial two-dimensional culture conditions. Although studying cell behavior in two-dimensional environments has been valuable for understanding biological processes, questions can be raised about their in vivo physiological relevance. This review focuses on some of our research involving fibroblast behavior in cell-derived three-dimensional matrices. Specifically, we examine how these matrices affect cell morphology, adhesion, proliferation, and signaling compared to two-dimensional substrates. We stress the importance of controls for three-dimensional matrix studies and discuss cancer as an example in which altered three-dimensional matrices can influence fibroblast signaling. Studying cells in three-dimensional microenvironments can lead to the design of more physiologically relevant conditions for assaying drug responses and deciphering biological mechanisms.
Keywords: Abbreviations; ECM; extracellular matrix; FN; fibronectin; 3D; three-dimensional; 2D; two-dimensional; FAK; focal adhesion kinase; MAP kinase; mitogen-activated protein kinase; ERK1/2; extracellular signal-regulated kinase1/2; PI3K; phosphatidylinositol 3′-kinase; PIP; 3; phosphatidylinositol-3,4,5-trisphosphate.Fibroblast; Fibronectin; Three-dimensional matrix; Integrin signaling; Rho GTPases
Fibroblast mechanics in 3D collagen matrices by Sangmyung Rhee; Frederick Grinnell (pp. 1299-1305).
Connective tissues provide mechanical support and frameworks for the other tissues of the body. Type 1 collagen is the major protein component of ordinary connective tissue, and fibroblasts are the cell type primarily responsible for its biosynthesis and remodeling. Research on fibroblasts interacting with collagen matrices explores all four quadrants of cell mechanics: pro-migratory vs. pro-contractile growth factor environments on one axis; high tension vs. low tension cell–matrix interactions on the other. The dendritic fibroblast — probably equivalent to the resting tissue fibroblast — can be observed only in the low tension quadrant and generally has not been appreciated from research on cells incubated with planar culture surfaces. Fibroblasts in the low tension quadrant require microtubules for formation of dendritic extensions, whereas fibroblasts in the high tension quadrant require microtubules for polarization but not for spreading. Ruffling of dendritic extensions rather than their overall protrusion or retraction provides the mechanism for remodeling of floating collagen matrices, and floating matrix remodeling likely reflects a model of tissue mechanical homeostasis.
Keywords: Adhesion; Migration; Contraction; Extracellular matrix; Wound repair; Tissue engineering; Tensegrity; Platelet-derived growth factor; Lysophosphatidic acid
Micromechanical control of cell and tissue development: Implications for tissue engineering by Kaustabh Ghosh; Donald E. Ingber (pp. 1306-1318).
Tissue engineering approaches for repair of diseased or lost organs will require the development of new biomaterials that guide cell behavior and seamlessly integrate with living tissues. Previous approaches to engineer artificial tissues have focused largely on optimization of scaffold polymer chemistry and selection of appropriate biochemical additives ( e.g., growth factors, adhesive ligands) to provide effective developmental control. However, recent work has shown that micromechanical forces and local variations of extracellular matrix (ECM) elasticity at the microscale regulate cell and tissue development both in vitro and in vivo. The micromechanical properties of the host tissue microenvironment also play a critical role in control of stem cell lineage switching. Here we discuss how new understanding of the fundamental role that mechanical forces play in tissue development might be leveraged to facilitate the development of new types of biomimetic materials for regenerative medicine, with a focus on the design of injectable materials that can target to injury sites, recruit stem cells and direct cellular self-assembly to regenerate functional tissues and organs in situ.
Keywords: Tissue engineering; Cell–ECM interface; Tissue development; Scaffold
Cellular and multicellular form and function by Wendy F. Liu; Christopher S. Chen (pp. 1319-1328).
Engineering artificial tissue constructs requires the appropriate spatial arrangement of cells within scaffolds. The introduction of microengineering tools to the biological community has provided a valuable set of techniques to manipulate the cellular environment, and to examine how cell structure affects cellular function. Using micropatterning techniques, investigators have found that the geometric presentation of cell–matrix adhesions are important regulators of various cell behaviors including cell growth, proliferation, differentiation, polarity and migration. Furthermore, the presence of neighboring cells in multicellular aggregates has a significant impact on the proliferative and differentiated state of cells. Using microengineering tools, it will now be possible to manipulate the various environmental factors for practical applications such as engineering tissue constructs with greater control over the physical structure and spatial arrangement of cells within their surrounding microenvironment.
Keywords: Microengineering; Adherens junction; Cell–matrix adhesion; Photolithography
Cell responses to the mechanochemical microenvironment—Implications for regenerative medicine and drug delivery by Florian Rehfeldt; Adam J. Engler; Adam Eckhardt; Fariyal Ahmed; Dennis E. Discher (pp. 1329-1339).
Soft-tissue cells are surprisingly sensitive to the elasticity of their microenvironment, suggesting that traditional culture plastic and glass are less relevant to tissue regeneration and chemotherapeutics than might be achieved. Cells grown on gels that mimic the elasticity of tissue reveal a significant influence of matrix elasticity on adhesion, cytoskeletal organization, and even the differentiation of human adult derived stem cells. Cellular forces and feedback are keys to how cells feel their mechanical microenvironment, but detailed molecular mechanisms are still being elucidated. This review summarizes our initial findings for multipotent stem cells and also the elasticity-coupled effects of drugs on cancer cells and smooth muscle cells. The drugs include the contractility inhibitor blebbistatin, the proliferation inhibitor mitomycin C, an apoptotis-inducing antibody against CD47, and the translation inhibitor cycloheximide. The differential effects not only lend insight into mechano-sensing of the substrate by cells, but also have important implications for regeneration and molecular therapies.
Keywords: Cells; Tissue regeneration; Drug delivery; Matrix elasticity; Extracellular matrix; Atomic force microscopy (AFM); Mesenchymal stem cell (MSC)
Spatiotemporal control over growth factor signaling for therapeutic neovascularization by Lan Cao; David J. Mooney (pp. 1340-1350).
Many of the qualitative roles of growth factors involved in neovascularization have been delineated, but it is unclear yet from an engineering perspective how to use these factors as therapies. We propose that an approach that integrates quantitative spatiotemporal measurements of growth factor signaling using 3-D in vitro and in vivo models, mathematic modeling of factor tissue distribution, and new delivery technologies may provide an opportunity to engineer neovascularization on demand.
Keywords: Therapeutic neovascularization; Angiogenesis; Growth factor; Temporal and spatial; Quantitative; Delivery system
Hyaluronan-dependent pericellular matrix by Stephen P. Evanko; Markku I. Tammi; Raija H. Tammi; Thomas N. Wight (pp. 1351-1365).
Hyaluronan is a multifunctional glycosaminoglycan that forms the structural basis of the pericellular matrix. Hyaluronan is extruded directly through the plasma membrane by one of three hyaluronan synthases and anchored to the cell surface by the synthase or cell surface receptors such as CD44 or RHAMM. Aggregating proteoglycans and other hyaluronan-binding proteins, contribute to the material and biological properties of the matrix and regulate cell and tissue function. The pericellular matrix plays multiple complex roles in cell adhesion/de-adhesion, and cell shape changes associated with proliferation and locomotion. Time-lapse studies show that pericellular matrix formation facilitates cell detachment and mitotic cell rounding. Hyaluronan crosslinking occurs through various proteins, such as tenascin, TSG-6, inter-alpha-trypsin inhibitor, pentraxin and TSP-1. This creates higher order levels of structured hyaluronan that may regulate inflammation and other biological processes. Microvillous or filopodial membrane protrusions are created by active hyaluronan synthesis, and form the scaffold of hyaluronan coats in certain cells. The importance of the pericellular matrix in cellular mechanotransduction and the response to mechanical strain are also discussed.
Keywords: Proteoglycan; Hyaluronan; Versican; Aggrecan; CD44; RHAMM; Mechanotransduction; Cell adhesion; Cell traction
Growth factor binding to the pericellular matrix and its importance in tissue engineering by Lauren Macri; David Silverstein; Richard A.F. Clark (pp. 1366-1381).
In addition to its typical role as a scaffold, molecular filter, and cell modulator, the pericellular matrix can bind bioactive molecules and serve as a repository, while regulating their activation, synthesis, and degradation. This review focuses on interactions between bioactives, specifically growth factors and cytokines, with various components of the pericellular matrix. For example, biglycan and betaglycan, proteoglycans of the pericellular matrix, and decorin, a proteoglycan of the interstitial extracellular matrix, bind and regulate the activity and availability of transforming growth factor-beta. From evidence presented in this paper, it is obvious that the presence of growth factors in the pericellular matrix is integral to the spatiotemporal coordination of cellular activities to ensure proper tissue/organ formation during wound healing. It is believed by many researchers that the delivery of the right growth factors at the right time is instrumental to the orchestration of tissue regeneration. Thus, the interplay between the pericellular environment and bioactive molecules provides an underutilized knowledge base in the design and creation of tissue engineered constructs.
Keywords: Pericellular matrix; Extracellular matrix; Tissue engineering; Growth factor; Cytokine; Growth factor binding