The emergence of ECM mechanics and cytoskeletal tension as important regulators of cell function.
ABSTRACT The ability to harvest and maintain viable cells from mammalian tissues represented a critical advance in biomedical research, enabling individual cells to be cultured and studied in molecular detail. However, in these traditional cultures, cells are grown on rigid glass or polystyrene substrates, the mechanical properties of which often do not match those of the in vivo tissue from which the cells were originally derived. This mechanical mismatch likely contributes to abrupt changes in cellular phenotype. In fact, it has been proposed that mechanical changes in the cellular microenvironment may alone be responsible for driving specific cellular behaviors. Recent multidisciplinary efforts from basic scientists and engineers have begun to address this hypothesis more explicitly by probing the effects of ECM mechanics on cell and tissue function. Understanding the consequences of such mechanical changes is physiologically relevant in the context of a number of tissues in which altered mechanics may either correlate with or play an important role in the onset of pathology. Examples include changes in the compliance of blood vessels associated with atherosclerosis and intimal hyperplasia, as well as changes in the mechanical properties of developing tumors. Compelling evidence from 2-D in vitro model systems has shown that substrate mechanical properties induce changes in cell shape, migration, proliferation, and differentiation, but it remains to be seen whether or not these same effects translate to 3-D systems or in vivo. Furthermore, the molecular "mechanotransduction" mechanisms by which cells respond to changes in ECM mechanics remain unclear. Here, we provide some historical context for this emerging area of research, and discuss recent evidence that regulation of cytoskeletal tension by changes in ECM mechanics (either directly or indirectly) may provide a critical switch that controls cell function.
SourceAvailable from: Jed Johnson[Show abstract] [Hide abstract]
ABSTRACT: Hydrogels, electrospun fiber mats (EFMs), and their composites have been extensively studied for tissue engineering because of their physical and chemical similarity to native biological systems. However, while chemically similar, hydrogels and electrospun fiber mats display very different topographical features. Here, we examine the influence of surface topography and composition of hydrogels, EFMs, and hydrogel-EFM composites on cell behavior. Materials studied were composed of synthetic poly(ethylene glycol) (PEG) and poly(ethylene glycol)-poly(ε-caprolactone) (PEGPCL) hydrogels and electrospun poly(caprolactone) (PCL) and core/shell PCL/PEGPCL constituent materials. The number of adherent cells and cell circularity were most strongly influenced by the fibrous nature of materials (e.g., topography), whereas cell spreading was more strongly influenced by material composition (e.g., chemistry). These results suggest that cell attachment and proliferation to hydrogel-EFM composites can be tuned by varying these properties to provide important insights for the future design of such composite materials.12/2012; 3(3):497-513. DOI:10.3390/jfb3030497
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ABSTRACT: Endometriosis is a chronic disease in which epithelial and stromal cells that resemble the eutopic endometrium are found in ectopic lesions. In order to examine how microenvironmental factors such as extracellular matrix (ECM) and macrophages influence disease progression, 12Z (an immortalized ectopic epithelial cell line) were cultured on tissue culture plastic or in gels of recombinant basement membrane (rBM) or collagen I. Unlike cells in other conditions, cells in rBM formed multi-cellular structures in a 67 kDa non-integrin laminin receptor (67LR)-dependent manner. To examine the impact of macrophage-secreted factors on cell behavior, 12Z cells on all three substrates were treated with conditioned media from differentiated THP-1 (an immortalized monocytic cell line). Significant proliferation and invasion was observed only with cells cultured in rBM, indicating that ECM cues help dictate cell response to soluble signals. Cells cultured on rBM were then treated with individual cytokines detected in the conditioned media, with increased proliferation observed following exposure to interleukin-8 (CXCL8/IL-8) and both increased proliferation and invasion following treatment with heparin-binding EGF-like growth factor (HB-EGF). This study suggests that rBM gels can be used to induce in vitro lesion formation in order to identify soluble factors that influence proliferation and invasion.Cellular and Molecular Bioengineering 09/2014; 7(3):409-420. DOI:10.1007/s12195-014-0339-6 · 1.23 Impact Factor
Article: The importance of being a lumen[Show abstract] [Hide abstract]
ABSTRACT: Advances in tissue engineering and microtechnology have enabled researchers to more easily generate in vitro tissue models that mimic the tissue geometry and spatial organization found in vivo (e.g., vessel or mammary duct models with tubular structures). However, the widespread adoption of these models for biological studies has been slow, in part due to the lack of direct comparisons between existing 2-dimensional and 3-dimensional cell culture models and new organotypic models that better replicate tissue structure. Using previously developed vessel and mammary duct models with 3-dimensional lumen structures, we have begun to explore this question. In a direct comparison between these next generation organotypic models and more traditional methods, we observed differences in the levels of several secreted growth factors and cytokines. In addition, endothelial vessel geometry profoundly affects the phenotypic behavior of carcinoma cells, suggesting that more traditional in vitro assays may not capture in vivo events. Here, we seek to review and add to the increasing evidence supporting the hypothesis that using cell culture models with more relevant tissue structure influences cell fate and behavior, potentially increasing the relevance of biological findings.-Bischel, L. L., Sung, K. E., Jiménez-Torres, J. A., Mader, B., Keely, P. J., Beebe, D. J. The importance of being a lumen.The FASEB Journal 07/2014; 28(11). DOI:10.1096/fj.13-243733 · 5.48 Impact Factor