Morphogenesis is a spatially and temporally regulated process involved in various physiological and pathological transformations. In addition to the associated biochemical factors, the physical regulation of morphogenesis has attracted increasing attention. However, the driving force of morphogenesis initiation remains elusive. Here, it is shown that during the growth of multilayered tissues, a morphogenetic process can be self-organized by the progression of compression gradient stemmed from the interfacial mechanical interactions between layers. In tissues with low fluidity, the compression gradient is progressively strengthened during growth and induces stratification by triggering symmetric-to-asymmetric cell division reorientation at the critical tissue size. In tissues with high fluidity, compression gradient is dynamic and induces cell rearrangement leading to 2D in-plane morphogenesis instead of 3D deformation. Morphogenesis can be tuned by manipulating tissue fluidity, cell adhesion forces, and mechanical properties to influence the progression of compression gradient during the development of cultured cell sheets and chicken embryos. Together, the dynamics of compression gradient arising from interfacial mechanical interaction provides a conserved mechanism underlying morphogenesis initiation and size control during tissue growth.

The mechanical microenvironments have profound effects on the morphology and mechanical properties of cells, which are required for their functions. Pluripotent stem cells (PSCs) grow as a multicellular colony and the coupling effects of cell-cell and cell-ECM interactions are complex, while they are necessary for formations and functions of tissues. We used the finite element method to develop a computational model of a pair of deformed PSCs in contact with each other in three dimensions, and the growth and depolymerization of actin filaments were considered. We demonstrated the effects of substrate stiffness on the morphology of cells and nuclei and the rearrangement of cytoskeleton. The results show that as the substrate becomes softer, the nuclei become loose and round, and the actin filaments are assembled at a lower level. These changes could promote the formation of compacted cell colony which have a positive effect on the maintenance of pluripotency and the efficiency of induced reprogramming. We also find that stronger activation of cytoskeleton contractility will compress the cytoplasm as well as the nuclei. The cell mechanical model proposed here provides a strategy to study the response of cell morphology and cytoskeleton of the two-cell system under different biophysical stimuli. Since the nuclear morphology affects the remodeling of chromatin and the transcription efficiency of pluripotent genes, it provides a fundament for a further study of more mechanical factors on cell pluripotency.

Extracellular matrix (ECM) stiffness has profound effects on the regulation of cell functions. DNA methylation is an important epigenetic modification governing gene expression. However, the effects of ECM stiffness on DNA methylation remain elusive. Here, it is reported that DNA methylation is sensitive to ECM stiffness, with a global hypermethylation under stiff ECM condition in mouse embryonic stem cells (mESCs) and embryonic fibroblasts compared with soft ECM. Stiff ECM enhances DNA methylation of both promoters and gene bodies, especially the 5’ promoter regions of pluripotent genes. The enhanced DNA methylation is functionally required for the loss of pluripotent gene expression in mESCs grown on stiff ECM. Further experiments reveal that the nuclear transport of DNA methyltransferase 3-like (DNMT3L) is promoted by stiff ECM in a protein kinase C 𝜶 (PKC𝜶)-dependent manner and DNMT3L can be binding to Nanog promoter regions during cell–ECM interactions. These findings unveil DNA methylation as a novel target for the mechanical sensing mechanism of ECM stiffness, which provides a conserved mechanism for gene expression regulation during cell–ECM interactions.

Metallic glasses are perfect materials for preparing nanostructures by dealloying, but the obtained nanostructures are commonly of porous structures. Through the combination of chemical dealloying and ultrasonic vibration, ultrathin Cu&Ag bimetallic nanoporous membranes (NPMs) have been prepared from a Zr48Cu36Ag8Al8 MG ribbon. Furthermore, by introducing oxygen into the Zr48Cu36Ag8Al8 MG ribbon to change the mechanism of the dealloying process, nanoporous (Cu&Ag)@Ag core-shell alloy was synthesized by the one-pot chemical dealloying of Zr–Cu–Ag–Al–O amorphous/crystalline composite, which provides a new way to prepare metallic core–shell nanostructures by a one-pot method. The introducing of oxygen can enable the dissolution and redeposition of Cu, and tunes the Cu&Ag NPM into the nanoporous (Cu&Ag)@Ag core-shell alloy. The nanoporous (Cu&Ag)@Ag core-shell alloy exhibits better and robust antibacterial activity against E. Coli DH5α due to its better oxidation resistance caused by the Ag skin. The present work provides important insights into the tuning of nanostructures through simple dealloying.

Endothelial cells arranged on the vessel lumen are constantly stimulated by blood flow, blood pressure and pressure induced cyclic stretch. These stimuli are sensed through mechanical sensory structures and converted into a series of functional responses through mechanotransduction pathways. The process will eventually affect vascular health. Therefore, there has been an urgent need to establish in vitro endothelial biomechanics and mechanobiology of models, which reproduce three-dimensional structure vascular system. In recent years, the rapid development in microfluidic technology makes it possible to replicate the key structural and functionally biomechanical characteristics of vessels. Here, we summarized the progress of microfluidic chips used for the investigation of endothelial biomechanics and mechanobiology of the vascular system. Firstly, we elucidated the contribution of shear stress and circumferential stress, to vascular physiology. Then, we reviewed some applications using microfluidic technology in angiogenesis and vasculogenesis, endothelial permeability and mechanotransduction, as well as the blood-brain barrier under these physical forces. Finally, we discussed the future obstacles in terms of the development and application of microfluidic vascular chips.

目的探究凹凸界面对体外培养的小鼠胚胎干细胞多能性维持的影响。方法制作凹凸不同的细胞外基质培养小鼠胚胎干细胞,观察细胞的克隆形态,并通过免疫荧光和碱性磷酸酶（alkaline phosphatase,ALP）染色,检测胚胎干细胞的多能性。结果在凹面和凸面基底上,胚胎干细胞的立体度和圆度均比平面基底高,但凹面基底更明显。凹面和凸面基底上干细胞的Oct4-GFP表达含量和ALP染色强度均明显高于平面基底,其中凹面基底更为显著。结论与平面基底相比,凹面基底和凸面基底均对胚胎干细胞的多能性维持有积极影响,能够有助于维持全能性,但凹面基底效果更好。通过改变细胞外基质曲率,可以帮助胚胎干细胞体外培养维持多能性。研究结果对胚胎干细胞的研究和临床应用有重要意义。

The closure of gaps within epithelia is an essential part of many physiological and pathological processes, such as embryonic development, organ remodeling and wound healing. Emerging evidence proved that the physical microenvironment plays important roles in cell behaviors. However, the effect of osmolarity of extracellular medium on gap closure is least understood. Using a gap closure model of epithelial cells, we found that hypotonic condition significantly facilitated the process of gap closure. Moreover, instead of actomyosin ring, enhanced migration leading by lamellipodia primarily contributed to the rapid gap closure in hypotonic condition. These findings provide insights for understanding the physiology of epithelial gap closure.

Mechanical factors play critical roles in mammalian development. Here, we report that colony-growing mouse embryonic stem cells (mESCs) generate significant tension on the colony surface through the contraction of a three-dimensional supracellular actomyosin cortex (3D-SAC). Disruption of the 3D- SAC, whose organization is dependent on the Rho/ Rho-associated kinase (ROCK) signals and E-cad- herin, results in mESC colony destruction. Recipro- cally, compression force, which is generated by the 3D-SAC, promotes colony growth and expression of Nanog and Oct4 in mESCs and blastocyst devel- opment of mouse embryos. These findings suggest that autonomous cell forces regulate embryonic stem cells fate determination and provide insight regarding the biomechanical regulation of embryonic development.

Engineered nanomaterials promise to transform medicine at the bio–nano interface. However,it is important to elucidate how synthetic nanomaterials interact with critical biologicalsystems before such products can be safely utilized in humans. Past evidence suggests thatpolyethylene glycol-functionalized (PEGylated) nanomaterials are largely biocompatibleand elicit less dramatic immune responses than their pristine counterparts. We here reportresults that contradict these findings. We find that PEGylated graphene oxide nanosheets(nGO-PEGs) stimulate potent cytokine responses in peritoneal macrophages, despite notbeing internalized. Atomistic molecular dynamics simulations support a mechanism by whichnGO-PEGs preferentially adsorb onto and/or partially insert into cell membranes, therebyamplifying interactions with stimulatory surface receptors. Further experiments demonstratethat nGO-PEG indeed provokes cytokine secretion by enhancing integrinb8-related signallingpathways. The present results inform that surface passivation does not always preventimmunological reactions to 2D nanomaterials but also suggest applications for PEGylatednanomaterials wherein immune stimulation is desired.

The closure of gaps within epithelia is an essential part of many physiological and pathological processes, such as embryonic development, organ remodeling and wound healing. Emerging evidence proved that the physical microenvironment plays important roles in cell behaviors. However, the effect of osmolarity of extracellular medium on gap closure is least understood. Using a gap closure model of epithelial cells, we found that hypotonic condition significantly facilitated the process of gap closure. Moreover, instead of actomyosin ring, enhanced migration leading by lamellipodia primarily contributed to the rapid gap closure in hypotonic condition. These findings provide insights for understanding the physiology of epithelial gap closure.

The closure of gaps within epithelia is an essential part of many physiological and pathological processes, such as embryonic development, organ remodeling and wound healing. Emerging evidence proved that the physical microenvironment plays important roles in cell behaviors. However, the effect of osmolarity of extracellular medium on gap closure is least understood. Using a gap closure model of epithelial cells, we found that hypotonic condition significantly facilitated the process of gap closure. Moreover, instead of actomyosin ring, enhanced migration leading by lamellipodia primarily contributed to the rapid gap closure in hypotonic condition. These findings provide insights for understanding the physiology of epithelial gap closure.

Metallic core–shell nanostructures have inspired prominent research interests due to their better performances in catalytic, optical, electric, and magnetic applications as well as the less cost of noble metal than monometallic nanostructures, but limited by the complicated and expensive synthesis approaches. Development of one-pot and inexpensive method for metallic core–shell nanostructures’ synthesis is therefore of great significance. A novel Cu network supported nanoporous Ag-Cu alloy with an Ag shell and an Ag-Cu core was successfully synthesized by one-pot chemical dealloying of Zr-Cu-Ag-Al-O amorphous/crystalline composite, which provides a new way to prepare metallic core–shell nanostructures by a simple method. The prepared nanoporous Ag-Cu@Ag core-shell alloy demonstrates excellent air-stability at room temperature and enhanced oxidative stability even compared with other reported Cu@Ag core-shell micro-particles. In addition, the nanoporous Ag-Cu@ Ag core-shell alloy also possesses robust antibacterial activity against E. Coli DH5α. The simple and low- cost synthesis method as well as the excellent oxidative stability promises the nanoporous Ag-Cu@Ag core-shell alloy potentially wide applications.

ABSTRACT Cell spreading is involved in many physiological and pathological processes. The spreading behavior of a cell significantly depends on its microenvironment, but the biochemomechanical mechanisms of geometry-confined cell spreading remain unclear. A dynamic model is here established to investigate the spreading of cells confined in a finite region with different geometries, e.g., rectangle, ellipse, triangle, and L-shape. This model incorporates both biophysical and biochemical mecha- nisms, including actin polymerization, integrin-mediated binding, plasma viscoelasticity, and the elasticity of membranes and microtubules. We simulate the dynamic configurational evolution of a cell under different geometric microenvironments, including the angular distribution of microtubule forces and the deformation of the nucleus. The results indicate that the posi- tioning of the cell-division plane is affected by its boundary confinement: a cell divides in a plane perpendicular to its minimal principal axis of inertia of area. In addition, the effects of such physical factors as the adhesive bond density, membrane tension, and microtubule number are examined on the cell spreading dynamics. The theoretical predictions show a good agreement with relevant experimental results. This work sheds light on the geometry-confined spreading dynamics of cells and holds potential applications in regulating cell division and designing cell-based sensors.

It is well established that extracellular matrix (ECM) stiffness plays a significant role in regulating the phenotypes and behaviors of many cell types. However, the mechanism underlying the sensing of mechanical cues and subsequent elasticity-triggered pathways remains largely unknown. We observed that stiff ECM significantly enhanced the expression level of several members of the Wnt/β-catenin pathway in both bone marrow mesenchymal stem cells and primary chondrocytes. The activation of β-catenin by stiff ECM is not dependent on Wnt signals but is elevated by the activation of integrin/ focal adhesion kinase (FAK) pathway. The accumulated β-catenin then bound to the wnt1 promoter region to up-regulate the gene transcription, thus constituting a positive feedback of the Wnt/β-catenin pathway. With the amplifying effect of positive feedback, this integrin-activated β-catenin/Wnt pathway plays significant roles in mediating the enhancement of Wnt signal on stiff ECM and contributes to the regulation of mesenchymal stem cell differentiation and primary chondrocyte phenotype maintenance. The present integrin-regulated Wnt1 expression and signaling contributes to the understanding of the molecular mechanisms underlying the regulation of cell behaviors by ECM elasticity.

Disturbance of the production and clearance of Aβ in the brain is the main cause of memory and cognition decline and contributes strongly to the development of AD. In human, APOE gene has three isoforms, e2, e3 and e4, with APOE e4 as the most risk gene among them. In the development of AD pathophysiology, ApoE4 is positively associated with Aβ plague formation, but the mechanisms are not clear. In this review, we proposed a hypothesis that the effect of ApoE4 on Aβ possibly involves three processes: 1) ApoE4 can directly interact with Aβ and interferes Aβ clearance. 2) ApoE4 can compete with Aβ for the same receptor, that hinds the cellular uptake pathways of Aβ. 3) ApoE4 also modulates other Aβ degrading proteases like IDE to downregulate Aβ degradation, but the mechanisms needs to be further investigated. These findings suggest that the effect of ApoE in AD pathogenesis is complicated and modulation of ApoE is an attractive strategy for AD therapy.

Nuclear actin assembly in somatic cells has been an enigma for a long time. Recently, with the advancement of novel F-actin probes, researchers have started to uncover this mystery. In this study, we investigated the actin dynamics in somatic cell nuclei using two probes: Lifeact and Utr230. Surprisingly, we observed that both Lifeact and Utr230 significantly interfered with actin dynamics in cell nuclei. Moreover, these two probes induced distinct patterns of nuclear actin assembly. While Lifeact induced filamentous actin assembly in cell nuclei, Utr230 led to various patterns of actin aggregates, including fibers, small puncta, and large patches. Moreover, the interference of actin dynamics by Lifeact was limited to nuclear actin, while Utr230 induced actin aggregation in both the nucleus and cytoplasm. Using time-lapse microscopy, we found that Lifeact-induced actin fibers remained steady over hours of observation, indicating a deficiency of nuclear F-actin reorganization. These results suggest that Lifeact and Utr230 both interfere with nuclear actin dynamics but with distinct mechanisms. This is an important finding for research on nuclear actin assembly and highlights the potential value of these two probes for exploring the native mechanisms underlying nuclear actin dynamics which appear to be altered in the presence of these probes. This article is protected by copyright. All rights reserved.

Here, we observed that integrin α1β1 and bone morphogenetic protein receptor (BMPR) IA formed a complex and co-localised in several cell types. However, the molecular interaction between these two molecules was not studied in detail to date and the role of the interaction in BMPR signalling remains unknown; thus, these were investigated here. In a steered molecular dynamics (SMD) simulation, the observed development of the rupture force related to the displacement between the A-domain of integrin α1 and the extracellular domain of BMPR IA indicated a strong molecular interaction within the integrin-BMPR complex. Analysis of the intermolecular forces revealed that hydrogen bonds, rather than salt bridges, are the major contributors to these intermolecular interactions. By using Enzyme-linked immunosorbent assay (ELISA) and co-immunoprecipitation (co-IP) experiments with site-directed mutants, we found that residues 85–89 in BMPR IA play the most important role for BMPR IA binding to integrin α1β1. These residues are the same as those responsible for bone morphogenetic protein 2 (BMP-2)/BMPR IA binding. In our experiments, we also found that the interference of integrin α1 up regulated the level of phosphorylated Smad1, 5, 8 which is the downstream of BMP/BMPR signalling. Therefore, our results suggest that integrin α1β1/BMPR IA may block BMP-2/BMPR IA complex information and interfere with the BMP-2 signalling pathway in cells.