Biology subjects

Tagay, Y.

Publications and source records attributed to Tagay, Y..

4 recordsLinked to original sources

bioRxiv2026

Dynein-microtubule forces drive nucleokinesis and transmigration in T cells

Beyond the mechanical capacity of canonical actomyosin-driven amoeboid motility in permissive extracellular environments, the nucleus becomes the principal barrier to T cell migration in confining tissues. We establish the dynein-microtubule (MT) force-transmission axis as an essential mechanism for nuclear translocation during confined T cell migration and transmigration. We argue that dynein acts both as a motor and as an F-actin-anchored force-transmission element (fulcrum), sliding MTs and the MT-coupled nucleus along the cell cortex to drive nucleokinesis and productive cell displacement. Dynein is the primary driver of nucleokinesis: its inhibition arrests nucleus movement independently of myosin II activity, while F-actin dynamics remain spatiotemporally decoupled from nuclear oscillations. During transmigration, dynein and actomyosin act cooperatively and non-redundantly, and only combined inhibition abolishes nuclear passage. Computational modeling demonstrates that dynein-mediated pulling, together with volume exclusion imposed by the nucleus, is sufficient to generate self-organized nuclear oscillations. Dynein inhibition in zebrafish Langerhans cells impairs protrusion dynamics in situ, identifying the dynein-MT axis as an evolutionarily conserved mechanobiological program. Collectively, these findings identify the dynein-MT mechanical unit as a potential target for engineering T cells with enhanced solid-tumor infiltration.

cell biology↗

bioRxiv2025

Immune Cell Migration Models Synergize Nuclear Piston, Uropod, and Microenvironment into Hydraulic Cell Engine

The nucleus and uropod are the largest and most mechanically distinct structures in migrating amoeboid lymphocytes, including NK, B, and T cells. The biophysical properties of these structures may shape the ability of immune cells to navigate dense tissue microenvironments during immune surveillance. Using bead-spring and agent-based cell models, we explore the biomechanical contributions of the nucleus, uropod, septin-templated cortical rings, actomyosin cytoskeleton, and extracellular matrix obstacles to lymphocyte migration. Our results support a migration model in which, following cell-matrix collisions, septins mediate the formation of cortical rings that hydraulically seal cytoplasmic compartments on each side of the passing nucleus, generating a pressure difference that propels the nucleus forward. This hydraulically driven nuclear piston actively enhances migration through confined spaces. Concurrently, the uropod emerging from the peristaltic collapse of rear compartments stabilizes directional persistence and prevents T cell repolarization. We show that such polarity stabilization boosts immune surveillance efficiency. Together, these models redefine the nucleus as an active component of the migratory engine and the uropod as a locomotion stabilizer. Furthermore, the models offer a predictive framework towards engineering of immune cell motility in complex tissue microenvironments with broad implications for cancer immunotherapy, aging, and regenerative medicine.

biophysics↗

bioRxiv2023

Dynamic neuroinflammatory profiles predict Alzheimer's disease pathology in microglia-containing cerebral organoids

Neuroinflammation and the underlying dysregulated immune responses of microglia actively contribute to the progression and, likely, the initiation of Alzheimers disease (AD). Fine-tuned therapeutic modulation of immune dysfunction to ameliorate disease cannot be achieved without the characterization of diverse microglial states that initiate unique, and sometimes contradictory, immune responses that evolve over time in chronic inflammatory environments. Because of the functional differences between human and murine microglia, untangling distinct, disease-relevant reactive states and their corresponding effects on pathology or neuronal health may not be possible without the use of human cells. In order to profile shifting microglial states in early AD and identify microglia-specific drivers of disease, we differentiated human induced pluripotent stem cells (iPSCs) carrying a familial AD PSEN2 mutation or its isogenic control into cerebral organoids and quantified the changes in cytokine concentrations over time with Luminex XMAP technology. We used partial least squares (PLS) modeling to build cytokine signatures predictive of disease and age to identify key differential patterns of cytokine expression that inform the overall organoid immune milieu and quantified the corresponding changes in protein pathology. AD organoids exhibited an overall reduction in cytokine secretion after an initial amplified immune response. We demonstrate that reduced synapse density observed in the AD organoids is prevented with microglial depletion. Crucially, these differential effects of dysregulated immune signaling occurred without the accumulation of pathological proteins. In this study, we used microglia-containing AD organoids to quantitatively characterize an evolving immune milieu, made up of a diverse of collection of activation patterns and immune responses, to identify how a dynamic, overall neuroinflammatory state negatively impacts neuronal health and the cell-specific contribution of microglia.

neuroscience↗

bioRxiv2023

Dynein-Powered Cell Locomotion Guides Metastasis of Breast Cancer

Metastasis is a principal cause of death in cancer patients, which remains an unresolved fundamental and clinical problem. Conventionally, metastatic dissemination is linked to the actomyosin-driven cell locomotion. However, locomotion of cancer cells often does not strictly line up with the measured actomyosin forces. Here, we identify a complementary mechanism of metastatic locomotion powered by the dynein-generated forces. These forces that arise within a non-stretchable microtubule network drive persistent contact guidance of migrating cancer cells along the biomimetic collagen fibers. We also show that dynein-powered locomotion becomes indispensable during invasive 3D migration within a tissue-like luminal network between spatially confining hydrogel microspheres. Our results indicate that the complementary contractile system of dynein motors and microtubules is always necessary and in certain instances completely sufficient for dissemination of metastatic breast cancer cells. These findings advance fundamental understanding of cell locomotion mechanisms and expand the spectrum of clinical targets against metastasis.

cell biology↗