Nimesh R. Chahare

selected publications

1. 

   Mechanics of epithelial tissue subjected to controlled pressure

   Nimesh R. Chahare

   2023

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   Epithelial sheets form specialized 3D structures suited to their physiological roles, such as branched alveoli in the lungs, tubes in the kidney, and villi in the intestine. To generate and maintain these structures, epithelia must undergo complex 3D deformations across length and time scales. How epithelial shape arises from active stresses, viscoelasticity, and luminal pressure remains poorly understood. To address this question, we developed a microfuidic chip and a computational framework to engineer 3D epithelial tissues with controlled shape and pressure. In the setup, an epithelial monolayer is grown on a porous surface with circular low adhesion zones. On applying hydrostatic pressure, the monolayer delaminates into a spherical cap from the circular zone. This simple shape allows us to calculate epithelial tension using Laplace’s law. Through this approach, we subject the monolayer to a range of lumen pressures at different rates and hence probe the relation between strain and tension in different regimes while computationally tracking actin dynamics and their mechanical effect at the tissue scale. Slow pressure changes relative to the actin dynamics allow the tissue to accommodate large strain variations. However, under sudden pressure reductions, the tissue develops buckling patterns and folds with different degrees of symmetry-breaking to store excess tissue area. These insights allow us to pattern epithelial folds through rationally directed buckling. Our study establishes a new approach for engineering epithelial morphogenetic events

   @phdthesis{chahare2023,
     author = {Chahare, Nimesh R.},
     title = {Mechanics of epithelial tissue subjected to controlled pressure},
     school = {Universitat Politècnica de Catalunya, Barcelona},
     year = {2023},
   }

2. 

   Mechanical force application to the nucleus regulates nucleocytoplasmic transport

   Ion Andreu, Ignasi Granero-Moya, Nimesh R. Chahare, Kessem Clein, and 7 more authors

   Nature Cell Biology 2022

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   Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied forces. Such forces can lead to the nuclear translocation of proteins, but whether force controls nucleocytoplasmic transport, and how, remains unknown. Here we show that nuclear forces differentially control passive and facilitated nucleocytoplasmic transport, setting the rules for the mechanosensitivity of shuttling proteins. We demonstrate that nuclear force increases permeability across nuclear pore complexes, with a dependence on molecular weight that is stronger for passive than for facilitated diffusion. Owing to this differential effect, force leads to the translocation of cargoes into or out of the nucleus within a given range of molecular weight and affinity for nuclear transport receptors. Further, we show that the mechanosensitivity of several transcriptional regulators can be both explained by this mechanism and engineered exogenously by introducing appropriate nuclear localization signals. Our work unveils a mechanism of mechanically induced signalling, probably operating in parallel with others, with potential applicability across signalling pathways.

   @article{andreu2022mechanical,
     title = {Mechanical force application to the nucleus regulates nucleocytoplasmic transport},
     author = {Andreu, Ion and Granero-Moya, Ignasi and Chahare, Nimesh R. and Clein, Kessem and Molina-Jord{\'a}n, Marc and Beedle, Amy EM and Elosegui-Artola, Alberto and Abenza, Juan F and Rossetti, Leone and Trepat, Xavier and others},
     journal = {Nature Cell Biology},
     pages = {1--10},
     year = {2022},
     publisher = {Nature Publishing Group},
     doi = {10.1038/s41556-022-00927-7},
     url = {https://doi.org/10.1038/s41556-022-00927-7},
   }

3. 

   The force loading rate drives cell mechanosensing through both reinforcement and cytoskeletal softening

   Ion Andreu, Bryan Falcones, Sebastian Hurst, Nimesh R. Chahare, and 7 more authors

   Nature communications 2021

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   Cell response to force regulates essential processes in health and disease. However, the fundamental mechanical variables that cells sense and respond to remain unclear. Here we show that the rate of force application (loading rate) drives mechanosensing, as predicted by a molecular clutch model. By applying dynamic force regimes to cells through substrate stretching, optical tweezers, and atomic force microscopy, we find that increasing loading rates trigger talin-dependent mechanosensing, leading to adhesion growth and reinforcement, and YAP nuclear localization. However, above a given threshold the actin cytoskeleton softens, decreasing loading rates and preventing reinforcement. By stretching rat lungs in vivo, we show that a similar phenomenon may occur. Our results show that cell sensing of external forces and of passive mechanical parameters (like tissue stiffness) can be understood through the same mechanisms, driven by the properties under force of the mechanosensing molecules involved.

   @article{andreu2021force,
     title = {The force loading rate drives cell mechanosensing through both reinforcement and cytoskeletal softening},
     author = {Andreu, Ion and Falcones, Bryan and Hurst, Sebastian and Chahare, Nimesh R. and Quiroga, Xarxa and Le Roux, Anabel-Lise and Kechagia, Zanetta and Beedle, Amy EM and Elosegui-Artola, Alberto and Trepat, Xavier and others},
     journal = {Nature communications},
     volume = {12},
     number = {1},
     pages = {1--12},
     year = {2021},
     publisher = {Nature Publishing Group},
     doi = {10.1038/s41467-021-24383-3},
     url = {https://doi.org/10.1038/s41467-021-24383-3},
   }