More Like this

1. Molecular basis of conformational changes and mechanics of integrins

   https://doi.org/10.1098/rsta.2022.0243  

   Gaikwad, Hanmant K. ; Jaswandkar, Sharad V. ; Katti, Kalpana S. ; Haage, Amanda ; Katti, Dinesh R. ( July 2023 , Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences)

   Integrin, as a mechanotransducer, establishes the mechanical reciprocity between the extracellular matrix (ECM) and cells at integrin-mediated adhesion sites. This study used steered molecular dynamics (SMD) simulations to investigate the mechanical responses of integrinα_vβ₃with and without 10th type III fibronectin (FnIII₁₀) binding for tensile, bending and torsional loading conditions. The ligand-binding integrin confirmed the integrin activation during equilibration and altered the integrin dynamics by changing the interface interaction between β-tail, hybrid and epidermal growth factor domains during initial tensile loading. The tensile deformation in integrin molecules indicated that fibronectin ligand binding modulates its mechanical responses in the folded and unfolded conformation states. The bending deformation responses of extended integrin models reveal the change in behaviour of integrin molecules in the presence of Mn²⁺ion and ligand based on the application of force in the folding and unfolding directions of integrin. Furthermore, these SMD simulation results were used to predict the mechanical properties of integrin underlying the mechanism of integrin-based adhesion. The evaluation of integrin mechanics provides new insights into understanding the mechanotransmission (force transmission) between cells and ECM and contributes to developing an accurate model for integrin-mediated adhesion.

   This article is part of a discussion meeting issue ‘Supercomputing simulations of advanced materials’.

    

   more » « less
2. Mechanical feedback enables catch bonds to selectively stabilize scanning microvilli at T-cell surfaces

   https://doi.org/10.1091/mbc.E19-01-0048  

   Pullen, Robert H. ; Abel, Steven M. ; Weaver, Valerie Marie ( July 2019 , Molecular Biology of the Cell)

   T-cells use microvilli to search the surfaces of antigen-presenting cells for antigenic ligands. The active motion of scanning microvilli provides a force-generating mechanism that is intriguing in light of single-molecule experiments showing that applied forces increase the lifetimes of stimulatory receptor–ligand bonds (catch-bond behavior). In this work, we introduce a theoretical framework to explore the motion of a microvillar tip above an antigen-presenting surface when receptors on the tip stochastically bind to ligands on the surface and dissociate from them in a force-dependent manner. Forces on receptor-ligand bonds impact the motion of the microvillus, leading to feedback between binding and microvillar motion. We use computer simulations to show that the average microvillar velocity varies in a ligand-dependent manner; that catch bonds generate responses in which some microvilli almost completely stop, while others move with a broad distribution of velocities; and that the frequency of stopping depends on the concentration of stimulatory ligands. Typically, a small number of catch bonds initially immobilize the microvillus, after which additional bonds accumulate and increase the cumulative receptor-engagement time. Our results demonstrate that catch bonds can selectively slow and stabilize scanning microvilli, suggesting a physical mechanism that may contribute to antigen discrimination by T-cells. 

   more » « less
3. Effects of Cell-Adhesive Ligand Presentation on Pentapeptide Supramolecular Assembly and Gelation: Simulations and Experiments

   https://doi.org/10.1159/000534280  

   Thede, Andrew T. ; Tang, James D. ; Cocker, Clare E. ; Harold, Liza J. ; Amelung, Connor D. ; Kittel, Anna R. ; Taylor, Phillip A. ; Lampe, Kyle J. ( September 2023 , Cells Tissues Organs)

   The extracellular matrix (ECM) is a complex, hierarchical material containing structural and bioactive components. This complexity makes decoupling the effects of biomechanical properties and cell-matrix interactions difficult, especially when studying cellular processes in a 3D environment. Matrix mechanics and cell adhesion are both known regulators of specific cellular processes such as stem cell proliferation and differentiation. However, more information is required about how such variables impact various neural lineages that could, upon transplantation, therapeutically improve neural function after a central nervous system injury or disease. Rapidly Assembling Pentapeptides for Injectable Delivery (RAPID) hydrogels are one biomaterial approach to meet these goals, consisting of a family of peptide sequences that assemble into physical hydrogels in physiological media. In this study, we studied our previously reported supramolecularly-assembling RAPID hydrogels functionalized with the ECM-derived cell-adhesive peptide ligands RGD, IKVAV, and YIGSR. Using molecular dynamics simulations and experimental rheology, we demonstrated that these integrin-binding ligands at physiological concentrations (3–12 mm) did not impact the assembly of the KYFIL peptide system. In simulations, molecular measures of assembly such as hydrogen bonding and pi-pi interactions appeared unaffected by cell-adhesion sequence or concentration. Visualizations of clustering and analysis of solvent-accessible surface area indicated that the integrin-binding domains remained exposed. KYFIL or AYFIL hydrogels containing 3 mm of integrin-binding domains resulted in mechanical properties consistent with their non-functionalized equivalents. This strategy of doping RAPID gels with cell-adhesion sequences allows for the precise tuning of peptide ligand concentration, independent of the rheological properties. The controllability of the RAPID hydrogel system provides an opportunity to investigate the effect of integrin-binding interactions on encapsulated neural cells to discern how hydrogel microenvironment impacts growth, maturation, or differentiation.

    

   more » « less
4. Engineering human spinal microphysiological systems to model opioid-induced tolerance

   https://doi.org/10.1016/j.bioactmat.2022.10.007  

   Cai, Hongwei ; Ao, Zheng ; Tian, Chunhui ; Wu, Zhuhao ; Kaurich, Connor ; Chen, Zi ; Gu, Mingxia ; Hohmann, Andrea G. ; Mackie, Ken ; Guo, Feng ( April 2023 , Bioactive Materials)

   Jian Yang (Ed.)

   Dynamic regulation of cell-extracellular matrix (ECM)-material interactions is crucial for various biomedical applications. In this study, a light-activated molecular switch for the modulation of cell attachment/detachment behaviors was established on monolayer graphene (Gr)/n-type Silicon substrates (Gr/Si). Initiated by light illumination at the Gr/Si interface, pre-adsorbed proteins (bovine serum albumin, ECM proteins collagen-1, and fibronectin) underwent protonation to achieve negative charge transfer to Gr films (n-doping) through π-π interactions. This n-doping process stimulated the conformational switches of ECM proteins. The structural alterations in these ECM interactors significantly reduced the specificity of the cell surface receptor-ligand interaction (e.g., integrin recognition), leading to dynamic regulation of cell adhesion and eventual cell detachment. RNA-sequencing results revealed that the detached bone marrow mesenchymal stromal cell sheets from the Gr/Si system manifested regulated immunoregulatory properties and enhanced osteogenic differentiation, implying their potential application in bone tissue regeneration. This work not only provides a fast and feasible method for controllable cells/cell sheets harvesting but also gives new insights into the understanding of cell-ECM-material communications. 

   more » « less
5. Abalone populations are most sensitive to environmental stress effects on adult individuals

   https://doi.org/10.3354/meps13320  

   Aalto, EA ; Barry, JP ; Boch, CA ; Litvin, SY ; Micheli, F ; Woodson, CB ; De Leo, GA ( June 2020 , Marine Ecology Progress Series)

   null (Ed.)

   Marine organisms are exposed to stressors associated with climate change throughout their life cycle, but a majority of studies focus on responses in single life stages, typically early ones. Here, we examined how negative impacts from stressors associated with climate change, ocean acidification, and pollution can act across multiple life stages to influence long-term population dynamics and decrease resilience to mass mortality events. We used a continuous-size-structured density-dependent model for abalone ( Haliotis spp.), calcifying mollusks that support valuable fisheries, to explore the sensitivity of stock abundance and annual catch to potential changes in growth, survival, and fecundity across the organism’s lifespan. Our model predicts that decreased recruitment from lowered fertilization success or larval survival has small negative impacts on the population, and that stock size and fishery performance are much more sensitive to changes in parameters that affect the size or survival of adults. Sensitivity to impacts on subadults and juveniles is also important for the population, though less so than for adults. Importantly, likelihood of recovery following mortality events showed more pronounced sensitivity to most possible parameter impacts, greater than the effects on equilibrium density or catch. Our results suggest that future experiments on environmental stressors should focus on multiple life stages to capture effects on population structure and dynamics, particularly for species with size-dependent fecundity. 

   more » « less