Biology subjects

Shenoy, V.

Publications and source records attributed to Shenoy, V..

22 records · Page 2Linked to original sources

bioRxiv2021

Dynamic Self-Reinforcement of Gene Expression Determines Acquisition and Retention of Cellular Mechanical Memory

Mechanotransduction describes activation of gene expression by changes in the cells physical microenvironment. Recent experiments show that mechanotransduction can lead to long-term "mechanical memory", where cells cultured on stiff substrates for sufficient time (priming phase) maintain altered phenotype after switching to soft substrates (dissipation phase), as compared to unprimed controls. The timescale of memory acquisition and retention is orders of magnitude larger than the timescale of mechanosensitive cellular signaling, and memory retention time changes continuously with priming time. We develop a model that captures these features by accounting for positive reinforcement in mechanical signaling. The sensitivity of reinforcement represents the dynamic transcriptional state of the cell composed of protein lifetimes and 3D chromatin organization. Our model provides a single framework connecting microenvironment mechanical history to cellular outcomes ranging from no memory to terminal differentiation. Predicting cellular memory of environmental changes can help engineer cellular dynamics through changes in culture environments.

systems biology↗

bioRxiv2020

Mechanical memory in cells emerges from mechanotransduction with transcriptional feedback and epigenetic plasticity

Emerging evidence shows that cells are able to sense and store a memory of their past mechanical environment. Since existing mechanotransduction models are based on adhesion and cytoskeletal dynamics that occurs over seconds and minutes, they do not capture memory observed over days or weeks. We postulate that transcriptional activity and epigenetic plasticity, upstream of adhesion-based signaling, need to be invoked to explain long-term mechanical memory. Here, we present a theory for mechanical memory in cells governed by three key components. First, cells on a stiff matrix are primed by a transcriptional reinforcement of cytoskeletal signaling. Second, longer stiff-priming progressively produces more memory-regulating factors and reduces epigenetic plasticity. Third, when stiff-primed cells move to soft matrix, the reduced epigenetic plasticity blocks new transcription required for cellular adaptation to the new matrix. This stalled transcriptional state gives rise to memory. We validate this model against previous experimental findings of memory storage and decay in epithelial cell migration and stem cell differentiation. We also predict wide-ranging memory responses for different cell types of varying protein kinetics and priming conditions. This theoretical framework for mechanical memory expands the timescales of mechanotransduction captured by conventional models by integrating cytoskeletal signaling with transcriptional activity and epigenetic plasticity. Our model predictions explain mechanical memory and propose new experiments to test spatiotemporal regulation of cellular memory in diverse contexts ranging from cell differentiation to migration and growth.

biophysics↗

bioRxiv2020

An Active Chemo-mechanical Model to Predict Adhesion and Microenvironmental Regulation of 3D Cell Shapes

Cell shapes are known to regulate cytoskeletal organization, stiffness and the ability of cells to migrate and proliferate. Yet a quantitative understanding of the fundamental biochemical and biophysical mechanisms that determine the cell shapes is currently not available. In this study, we developed a chemo-mechanical feedback model to predict how adhesions and the properties of the 3D microenvironment regulate cell shapes. We find that the cells in 3D collagen matrices remain round or adopt an elongated shape depending on the density of active integrins, the level of contractility regulated by mechanosensitive signaling pathways and the density and mechanics of the matrix. While the formation of actin fibers that run along the cell body mediated by integrins and matrix stiffness drive elongation of cells, the cortical and membrane tension resist elongation. Based on the competition between these mechanisms, we derive phase diagrams for cell shape in the space spanned by the density of active adhesions and the level of biochemical signaling that controls contractility. Our predictions are validated by studying the shapes of HT1080 cells cultured in collagen gels of varying densities and using pharmacological treatments to regulate adhesions and contractility. The predictions of the model are found to be in excellent agreement with our experiments and data reported on a number of cell types in the literature.

biophysics↗

bioRxiv2018

Balance of Mechanical Forces Drives Endothelial Gap Formation and May Facilitate Cancer and Immune-Cell Extravasation

The formation of gaps in the endothelium is a crucial process underlying both cancer and immune cell extravasation, contributing to the functioning of the immune system during infection, the unfavorable development of chronic inflammation and tumor metastasis. Here, we present a stochastic-mechanical multiscale model of an endothelial cell monolayer and show that the dynamic nature of the endothelium leads to spontaneous gap formation, even without intervention from the transmigrating cells. These gaps preferentially appear at the vertices between three endothelial cells, as opposed to the border between two cells. We quantify the frequency and lifetime of these gaps, and validate our predictions experimentally. Interestingly, we find experimentally that cancer cells also preferentially extravasate at vertices, even when they first arrest on borders. This suggests that extravasating cells, rather than initially signaling to the endothelium, might exploit the autonomously forming gaps in the endothelium to initiate transmigration.

bioengineering↗