Physiologically, four major types of hepatic cells – the liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and hepatocytes – reside inside liver sinusoids and interact with flowing peripheral cells under blood flow. It is hard to mimic an in vivo liver sinusoid due to its complex multiple cell–cell interactions, spatiotemporal construction, and mechanical microenvironment. Here we developed an in vitro liver sinusoid chip by integrating the four types of primary murine hepatic cells into two adjacent fluid channels separated by a porous permeable membrane, replicating liver's key structures and configurations. Each type of cells was identified with its respective markers, and the assembled chip presented the liver-specific unique morphology of fenestration. The flow field in the liver chip was quantitatively analyzed by computational fluid dynamics simulations and particle tracking visualization tests. Intriguingly, co-culture and shear flow enhance albumin secretion independently or cooperatively, while shear flow alone enhances HGF production and CYP450 metabolism. Under lipopolysaccharide (LPS) stimulations, the hepatic cell co-culture facilitated neutrophil recruitment in the liver chip. Thus, this 3D-configured in vitro liver chip integrates the two key factors of shear flow and the four types of primary hepatic cells to replicate key structures, hepatic functions, and primary immune responses and provides a new in vitro model to investigate the short-duration hepatic cellular interactions under a microenvironment mimicking the physiology of a liver.

How appendages, such as plant leaves or animal limbs, develop asymmetric shapes remains a fundamental question in biology. Although ongoing research has revealed the genetic regulation of organ pattern formation, how gene activity ultimately directs organ shape remains unclear. Here, we show that leaf dorsoventral (adaxial-abaxial) polarity signals lead to mechanical heterogeneity of the cell wall, related to the methyl-esterification of cell-wall pectins in tomato and Arabidopsis. Numerical simulations predicate that mechanical heterogeneity is sufficient to produce the asymmetry seen in planar leaves. Experimental tests that alter pectin methyl-esterification, and therefore cell wall mechanical properties, support this model and lead to polar changes in gene expression, suggesting the existence of a feedback mechanism for mechanical signals in morphogenesis. Thus, mechanical heterogeneity within tissue may underlie organ shape asymmetry.

Cells sense various in vivo mechanical stimuli, which initiate downstream signaling to mechanical forces. While a body of evidences is presented on the impact of limited mechanical regulators in past decades, the mechanisms how biomechanical responses globally affect cell function need to be addressed. Complexity and diversity of in vivo mechanical clues present distinct patterns of shear flow, tensile stretch, or mechanical compression with various parametric combination of its magnitude, duration, or frequency. Thus, it is required to understand, from the viewpoint of mechanobiology, what mechanical features of cells are, why mechanical properties are different among distinct cell types, and how forces are transduced to downstream biochemical signals. Meanwhile, those in vitro isolated mechanical stimuli are usually coupled together in vivo, suggesting that the different factors that are in effect individually could be canceled out or orchestrated with each other. Evidently, omics analysis, a powerful tool in the field of system biology, is advantageous to combine with mechanobiology and then to map the full-set of mechanically sensitive proteins and transcripts encoded by its genome. This new emerging field, namely mechanomics, makes it possible to elucidate the global responses under systematically-varied mechanical stimuli. This review discusses the current advances in the related fields of mechanomics and elaborates how cells sense external forces and activate the biological responses.

Lymphocyte function–associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1) and their counterreceptors such as intercellular cell adhesion molecules (ICAM-1 and ICAM-2), junctional adhesion molecules (JAM-A, JAM-C), and receptors for advanced glycation end products (RAGE) are crucial for promoting polymorphonuclear leukocyte (neutrophil, PMN) recruitment. The underlying mechanisms of ligand-specific bindings in this cascade remain incompletely known. We compared the dynamic force spectra for various LFA-1/Mac-1–ligand bonds using single-molecule atomic force microscopy (AFM) and tested their functions in mediating PMN recruitment under in vitro shear flow. Distinct features of bond rupture forces and lifetimes were uncovered for these ligands, implying their diverse roles in regulating PMN adhesion on endothelium. LFA-1 dominates PMN adhesion on ICAM-1 and ICAM-2, while Mac-1 mediates PMN adhesion on RAGE, JAM-A, and JAM-C, which is consistent with their bond strength. All ligands can trigger PMN spreading and polarization, in which Mac-1 seems to induce outside-in signaling more effectively. LFA-1–ICAM-1 and LFA-1/Mac-1–JAM-C bonds can accelerate PMN crawling under high shear stress, presumably due to their high mechanical strength. This work provides new insight into basic molecular mechanisms of physiological ligands of β2 integrins in PMN recruitment.