The TNFSF12/TWEAK Modulates Colonic Inflammatory Fibroblast Differentiation and Promotes Fibroblast-Monocyte Interactions.

Fibroblasts acquire a proinflammatory phenotype in inflammatory bowel disease, but the factors driving this process and how fibroblasts contribute to mucosal immune responses are incompletely understood. TNF superfamily member 12 (TNFSF12, or TNF-like weak inducer of apoptosis [TWEAK]) has gained interest as a mediator of chronic inflammation. In this study, we explore its role as a driver of inflammatory responses in fibroblasts and its contribution to fibroblast-monocyte interaction using human primary colonic fibroblasts, THP-1 and primary monocytes.

Retinoic acid receptor β modulates mechanosensing and invasion in pancreatic cancer cells via myosin light chain 2.

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, characterised by stromal remodelling, elevated matrix stiffness and high metastatic rate. Retinoids, compounds derived from vitamin A, have a history of clinical use in cancer for their anti-proliferative and differentiation effects, and more recently have been explored as anti-stromal therapies in PDAC for their ability to induce mechanical quiescence in cancer associated fibroblasts. Here, we demonstrate that retinoic acid receptor β (RAR-β) transcriptionally represses myosin light chain 2 (MLC-2) expression in pancreatic cancer cells.

Mesenchymal Stem Cells Sense the Toughness of Nanomaterials and Interfaces.

Stem cells are known to sense and respond to the mechanical properties of biomaterials. In turn, cells exert forces on their environment that can lead to striking changes in shape, size and contraction of associated tissues, and may result in mechanical disruption and functional failure. However, no study has so far correlated stem cell phenotype and biomaterials toughness.

Impact of the multiscale viscoelasticity of quasi-2D self-assembled protein networks on stem cell expansion at liquid interfaces.

Although not typically thought to sustain cell adhesion and expansion, liquid substrates have recently been shown to support such phenotypes, providing protein nanosheets could be assembled at corresponding liquid-liquid interfaces. However, the precise mechanical properties required from such quasi-2D nanoassemblies and how these correlate with molecular structure and nanoscale architecture has remained unclear. In this report, we screen a broad range of surfactants, proteins, oils and cell types and correlate interfacial mechanical properties with stem cell expansion.

Substrate Stiffness-Driven Membrane Tension Modulates Vesicular Trafficking Caveolin-1.

Liver fibrosis, a condition characterized by extensive deposition and cross-linking of extracellular matrix (ECM) proteins, is idiosyncratic in cases of chronic liver injury. The dysregulation of ECM remodeling by hepatic stellate cells (HSCs), the main mediators of fibrosis, results in an elevated ECM stiffness that drives the development of chronic liver disease such as cirrhosis and hepatocellular carcinoma. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is a key element in the regulation of ECM remodeling, which modulates the degradation and turnover of ECM components.

Self-Assembling Polypeptide Hydrogels as a Platform to Recapitulate the Tumor Microenvironment.

The tumor microenvironment plays a critical role in modulating cancer cell migration, metabolism, and malignancy, thus, highlighting the need to develop in vitro culture systems that can recapitulate its abnormal properties. While a variety of stiffness-tunable biomaterials, reviewed here, have been developed to mimic the rigidity of the tumor extracellular matrix, culture systems that can recapitulate the broader extracellular context of the tumor microenvironment (including pH and temperature) remain comparably unexplored, partially due to the difficulty in independently tuning these parameters. Here, we investigate a self-assembled polypeptide network hydrogel as a cell culture platform and demonstrate that the culture parameters, including the substrate stiffness, extracellular pH and temperature, can be independently controlled.

G Protein-Coupled Estrogen Receptor Regulates Actin Cytoskeleton Dynamics to Impair Cell Polarization.

Mechanical forces regulate cell functions through multiple pathways. G protein-coupled estrogen receptor (GPER) is a seven-transmembrane receptor that is ubiquitously expressed across tissues and mediates the acute cellular response to estrogens. Here, we demonstrate an unidentified role of GPER as a cellular mechanoregulator.

The Planar Polarity Component VANGL2 Is a Key Regulator of Mechanosignaling.

VANGL2 is a component of the planar cell polarity (PCP) pathway, which regulates tissue polarity and patterning. The mutation causes lung branching defects due to dysfunctional actomyosin-driven morphogenesis. Since the actomyosin network regulates cell mechanics, we speculated that mechanosignaling could be impaired when VANGL2 is disrupted.

GPER Activation Inhibits Cancer Cell Mechanotransduction and Basement Membrane Invasion via RhoA.

The invasive properties of cancer cells are intimately linked to their mechanical phenotype, which can be regulated by intracellular biochemical signalling. Cell contractility, induced by mechanotransduction of a stiff fibrotic matrix, and the epithelial-mesenchymal transition (EMT) promote invasion. Metastasis involves cells pushing through the basement membrane into the stroma-both of which are altered in composition with cancer progression.

Where No Hand Has Gone Before: Probing Mechanobiology at the Cellular Level.

Physical forces and other mechanical stimuli are fundamental regulators of cell behavior and function. Cells are also biomechanically competent: they generate forces to migrate, contract, remodel, and sense their environment. As the knowledge of the mechanisms of mechanobiology increases, the need to resolve and probe increasingly small scales calls for novel technologies to mechanically manipulate cells, examine forces exerted by cells, and characterize cellular biomechanics.

Engineering the cellular mechanical microenvironment - from bulk mechanics to the nanoscale.

The field of mechanobiology studies how mechanical properties of the extracellular matrix (ECM), such as stiffness, and other mechanical stimuli regulate cell behaviour. Recent advancements in the field and the development of novel biomaterials and nanofabrication techniques have enabled researchers to recapitulate the mechanical properties of the microenvironment with an increasing degree of complexity on more biologically relevant dimensions and time scales. In this Review, we discuss different strategies to engineer substrates that mimic the mechanical properties of the ECM and outline how these substrates have been applied to gain further insight into the biomechanical interaction between the cell and its microenvironment.

Cost-effective rapid prototyping and assembly of poly(methyl methacrylate) microfluidic devices.

The difficulty in translating conventional microfluidics from laboratory prototypes to commercial products has shifted research efforts towards thermoplastic materials for their higher translational potential and amenability to industrial manufacturing. Here, we present an accessible method to fabricate and assemble polymethyl methacrylate (PMMA) microfluidic devices in a "mask-less" and cost-effective manner that can be applied to manufacture a wide range of designs due to its versatility. Laser micromachining offers high flexibility in channel dimensions and morphology by controlling the laser properties, while our two-step surface treatment based on exposure to acetone vapour and low-temperature annealing enables improvement of the surface quality without deformation of the device.