As the crucial non-cellular component of tissues, the extracellular matrix (ECM) provides both physical support and signaling regulation to cells. Some ECM molecules provide a fibrillar environment ...around cells, while others provide a sheet-like basement membrane scaffold beneath epithelial cells. In this Review, we focus on recent studies investigating the mechanical, biophysical and signaling cues provided to developing tissues by different types of ECM in a variety of developing organisms. In addition, we discuss how the ECM helps to regulate tissue morphology during embryonic development by governing key elements of cell shape, adhesion, migration and differentiation.
Three-dimensional (3D) in vitro models span the gap between two-dimensional cell cultures and whole-animal systems. By mimicking features of the in vivo environment and taking advantage of the same ...tools used to study cells in traditional cell culture, 3D models provide unique perspectives on the behavior of stem cells, developing tissues and organs, and tumors. These models may help to accelerate translational research in cancer biology and tissue engineering.
Cells migrating on flat two-dimensional (2D) surfaces use actin polymerization to extend the leading edge of the plasma membrane during lamellipodia-based migration. This mode of migration is not ...universal; it represents only one of several mechanisms of cell motility in three-dimensional (3D) environments. The distinct modes of 3D migration are strongly dependent on the physical properties of the extracellular matrix, and they can be distinguished by the structure of the leading edge and the degree of matrix adhesion. How are these distinct modes of cell motility in 3D environments related to each other and regulated? Recent studies show that the same type of cell migrating in 3D extracellular matrix can switch between different leading edge structures. This mode-switching behavior, or plasticity, by a single cell suggests that the apparent diversity of motility mechanisms is integrated by a common intracellular signaling pathway that governs the mode of cell migration. In this Commentary, we propose that the mode of 3D cell migration is governed by a signaling axis involving cell-matrix adhesions, RhoA signaling and actomyosin contractility, and that this might represent a universal mechanism that controls 3D cell migration.
Cell adhesions mediate important bidirectional interactions between cells and the extracellular matrix. They provide an interactive interface between the extracellular chemical and physical ...environment and the cellular scaffolding and signaling machinery. This dynamic, reciprocal regulation of intracellular processes and the matrix is mediated by membrane receptors such as the integrins, as well as many other components that comprise the adhesome. Adhesome constituents assemble themselves into different types of cell adhesion structures that vary in molecular complexity and change over time. These cell adhesions play crucial roles in cell migration, proliferation, and determination of cell fate.
Cells use actomyosin contractility to move through three-dimensional (3D) extracellular matrices. Contractility affects the type of protrusions cells use to migrate in 3D, but the mechanisms are ...unclear. In this work, we found that contractility generated high-pressure lobopodial protrusions in human cells migrating in a 3D matrix. In these cells, the nucleus physically divided the cytoplasm into forward and rear compartments. Actomyosin contractility with the nucleoskeleton-intermediate filament linker protein nesprin-3 pulled the nucleus forward and pressurized the front of the cell. Reducing expression of nesprin-3 decreased and equalized the intracellular pressure. Thus, the nucleus can act as a piston that physically compartmentalizes the cytoplasm and increases the hydrostatic pressure between the nucleus and the leading edge of the cell to drive lamellipodia-independent 3D cell migration.
Tissues consist of cells and their surrounding extracellular matrix (ECM). Cell–ECM interactions play crucial roles in embryonic development, differentiation, tissue remodeling, and diseases ...including fibrosis and cancer. Recent research advances in characterizing cell–matrix interactions include detailed descriptions of hundreds of ECM and associated molecules, their complex intermolecular interactions in development and disease, identification of distinctive modes of cell migration in different 3D ECMs, and new insights into mechanisms of organ formation. Exploring the roles of the physical features of different ECM microenvironments and the bidirectional regulation of cell signaling and matrix organization emphasize the dynamic nature of these interactions, which can include feedback loops that exacerbate disease. Understanding mechanisms of cell–matrix interactions can potentially lead to targeted therapeutic interventions.
The diversity of hundreds of extracellular matrix (ECM) molecules in different tissues and their interactions are now being documented in ‘matrisome’ databases.Physical properties of the 3D ECM, including viscoelasticity and microarchitecture, can govern cell adhesion, mechanotransduction, and multiple modes of cell migration.New advances in ECM biology are identifying mechanisms of cancer progression and fibrosis, as well as potential therapeutic targets.Characterizations of cell–ECM feedback loops and computational modeling are providing new insights and potential opportunities for intervention in diseases and disorders.
Metalloenzymes are essential proteins with vital activity that promote high-efficiency enzymatic reactions. To ensure catalytic activity, stability, and reusability for safe, nontoxic, sustainable ...chemistry, and green organic synthesis, it is important to develop metalloenzyme-inspired polymer-supported metal catalysts. Here, we present a highly active, reusable, self-assembled catalyst of poly(imidazole-acrylamide) and palladium species inspired by metalloenzymes and apply our convolution methodology to the preparation of polymeric metal catalysts. Thus, a metalloenzyme-inspired polymeric imidazole Pd catalyst (MEPI-Pd) was readily prepared by the coordinative convolution of (NH(4))(2)PdCl(4) and poly(N-vinylimidazole)-co-(N-isopropylacrylamide)(5) in a methanol-water solution at 80 °C for 30 min. SEM observation revealed that MEPI-Pd has a globular-aggregated, self-assembled structure. TEM observation and XPS and EDX analyses indicated that PdCl(2) and Pd(0) nanoparticles were uniformly dispersed in MEPI-Pd. MEPI-Pd was utilized for the allylic arylation/alkenylation/vinylation of allylic esters and carbonates with aryl/alkenylboronic acids, vinylboronic acid esters, and tetraaryl borates. Even 0.8-40 mol ppm Pd of MEPI-Pd efficiently promoted allylic arylation/alkenylation/vinylation in alcohol and/or water with a catalytic turnover number (TON) of 20,000-1,250,000. Furthermore, MEPI-Pd efficiently promoted the Suzuki-Miyaura reaction of a variety of inactivated aryl chlorides as well as aryl bromides and iodides in water with a TON of up to 3,570,000. MEPI-Pd was reused for the allylic arylation and Suzuki-Miyaura reaction of an aryl chloride without loss of catalytic activity.
Cells migrate through 3D environments using a surprisingly wide variety of molecular mechanisms. These distinct modes of migration often rely on the same intracellular components, which are used in ...different ways to achieve cell motility. Recent work reveals that how a cell moves can be dictated by the relative amounts of cell-matrix adhesion and actomyosin contractility. A current concept is that the level of difficulty in squeezing the nucleus through a confining 3D environment determines the amounts of adhesion and contractility required for cell motility. Ultimately, determining how the nucleus controls the mode of cell migration will be essential for understanding both physiological and pathological processes dependent on cell migration in the body.
Self-assembly of copper sulfate and a poly(imidazole-acrylamide) amphiphile provided a highly active, reusable, globular, solid-phase catalyst for click chemistry. The self-assembled polymeric Cu ...catalyst was readily prepared from poly(N-isopropylacrylamide-co-N-vinylimidazole) and CuSO(4) via coordinative convolution. The surface of the catalyst was covered with globular particles tens of nanometers in diameter, and those sheetlike composites were layered to build an aggregated structure. Moreover, the imidazole units in the polymeric ligand coordinate to CuSO(4) to give a self-assembled, layered, polymeric copper complex. The insoluble amphiphilic polymeric imidazole Cu catalyst with even 4.5-45 mol ppm drove the Huisgen 1,3-dipolar cycloaddition of a variety of alkynes and organic azides, including the three-component cyclization of a variety of alkynes, organic halides, and sodium azide. The catalytic turnover number and frequency were up to 209000 and 6740 h(-1), respectively. The catalyst was readily reused without loss of catalytic activity to give the corresponding triazoles quantitatively.
The physical properties of two-dimensional (2D) extracellular matrices (ECMs) modulate cell adhesion dynamics and motility, but little is known about the roles of local microenvironmental differences ...in three-dimensional (3D) ECMs. Here we generate 3D collagen gels of varying matrix microarchitectures to characterize their regulation of 3D adhesion dynamics and cell migration. ECMs containing bundled fibrils demonstrate enhanced local adhesion-scale stiffness and increased adhesion stability through balanced ECM/adhesion coupling, whereas highly pliable reticular matrices promote adhesion retraction. 3D adhesion dynamics are locally regulated by ECM rigidity together with integrin/ECM association and myosin II contractility. Unlike 2D migration, abrogating contractility stalls 3D migration regardless of ECM pore size. We find force is not required for clustering of activated integrins on 3D native collagen fibrils. We propose that efficient 3D migration requires local balancing of contractility with ECM stiffness to stabilize adhesions, which facilitates the detachment of activated integrins from ECM fibrils.
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