Biology subjects

Tabdanov, E. D.

Publications and source records attributed to Tabdanov, E. D..

11 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↗

bioRxiv2025

Female Anterior Cruciate Ligaments Exhibit a Muted Mechanobiological Response to Mechanical Loading

Female athletes are significantly more likely to tear their anterior cruciate ligament (ACL) compared to their male counterparts. While there are several potential reasons for this, previous data from our lab demonstrated that female ACL explants have an impaired remodeling response to loading, which may prevent the repair of fatigue damage and lead to increased ACL rupture. The objective of this study was to identify the mechanisms driving the impaired remodeling of female ACLs to cyclic loading, including the role of estrogen. ACLs were harvested from male and female New Zealand white rabbits and cyclically loaded in a tensile bioreactor followed by bulk RNA-sequencing. Additional ACL explants treated with or without estradiol were analyzed using RT-qPCR to determine the regulatory effect of estrogen on markers for tissue remodeling and inflammatory cytokines with cyclic loading. We found that female ACLs exhibited significantly fewer differentially expressed genes (DEGs) in response to loading compared to male ACLs. Additionally, multiple mechanotransduction pathways were enriched with loading only in the male ACLs. While a few estrogen-related pathways were enriched in both male and female ACLs with loading, the expression of tissue remodeling markers was not different between estrogen treatment and vehicle control. Together, our findings highlight specific mechanotransduction pathways that may be responsible for the muted biological response of female ACLs to load, which provides a potential explanation for the increased rate of ACL tears in women.

bioengineering↗

bioRxiv2024

A non-muscle α-actinin is an intrinsic component of the cardiac Z-disc and regulates sarcomere turnover, contractility, and heart remodeling

Cardiac sarcomeres generate the fundamental forces behind each heartbeat and are thought to contain only muscle-specific cytoskeletal proteins. We show that a widely expressed actin cross-linking protein, -actinin 4 (ACTN4), is a sarcomere component of the human and zebrafish heart in vivo and in human iPSC-derived cardiac myocytes (CMs) in vitro. A confluence of biochemical experiments, immunofluorescence, and AI modeling suggest ACTN4 forms a heterodimeric complex with muscle-specific ACTN2 at the cardiac Z-disc, the cardiac sarcomere border. ACTN4 depletion from human iPSC-CMs stabilizes canonical sarcomere proteins and drives contractility-dependent cellular hypertrophy while ACTN4 overexpression destabilizes sarcomeres. ACTN4 depletion from zebrafish embryos specifically increases ventricular contractility which drives atrial enlargement, suggesting biomechanically driven atrial remodeling. ACTN4-associated phenotypes in both model systems lack hallmarks of cardiac disease models and an ACTN4 variant in humans is associated with reduced risk for disease. Our findings suggest a "non-muscle" actinin regulates heart contractility and influences clinical outcomes related to heart failure.

cell biology↗

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

Septins Enable T Cell Contact Guidance via Amoeboid-Mesenchymal Switch

Lymphocytes exit circulation and enter in-tissue guided migration toward sites of tissue pathologies, damage, infection, or inflammation. By continuously sensing and adapting to the guiding chemo-mechano-structural properties of the tissues, lymphocytes dynamically alternate and combine their amoeboid (non-adhesive) and mesenchymal (adhesive) migration modes. However, which mechanisms guide and balance different migration modes are largely unclear. Here we report that suppression of septins GTPase activity induces an abrupt amoeboid-to-mesenchymal transition of T cell migration mode, characterized by a distinct, highly deformable integrin-dependent immune cell contact guidance. Surprisingly, the T cell actomyosin cortex contractility becomes diminished, dispensable and antagonistic to mesenchymal-like migration mode. Instead, mesenchymal-like T cells rely on microtubule stabilization and their non-canonical dynein motor activity for high fidelity contact guidance. Our results establish septins GTPase activity as an important on/off switch for integrin-dependent migration of T lymphocytes, enabling their dynein-driven fluid-like mesenchymal propulsion along the complex adhesion cues. SIGNIFICANCE STATEMENTDeciphering mechanisms of guided lymphocyte migration paves the way towards effective immunotherapies for the extracellular matrix-rich tissues, such as solid tumors. Here we demonstrate that T cell septins GTPase activity regulates both actomyosin and microtubules, alternately enhancing either of these two major motor systems. Surprisingly, the suppression of septin GTPase activity also induces a highly guided integrin-dependent mesenchymal-like migration directed by the extracellular matrix proteins. The phenomenon of guided mesenchymal-like migration of T cells relies on the microtubules and microtubule-based dynein motors that are responsible for the force generation, powering guided T cell motility. This finding opens a new perspective for future studies of septin GTPases in a context of the optimisation of T cell-based immunotherapies for the solid tissues.

cell biology↗

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↗

bioRxiv2022

Cyclic Loading Induces Anabolic and Catabolic Gene Expression in ACLs in a Load-Dependent and Sex-Specific Manner

Anterior cruciate ligament (ACL) injuries are historically thought to be a result of a single acute overload or traumatic event. However, recent studies suggest that ACL failure may be a consequence of fatigue damage. Additionally, the remodeling response of ACLs to fatigue loading is unknown. Therefore, the objective of this study was to investigate the remodeling response of ACLs to cyclic loading. Furthermore, given that women have an increased rate of ACL rupture, we investigated whether this remodeling response is sex specific. ACLs were harvested from male and female New Zealand white rabbits and cyclically loaded in a tensile bioreactor mimicking the full range of physiological loading (2, 4, and 8 MPa). Expression of markers for anabolic and catabolic tissue remodeling, as well as inflammatory cytokines, was quantified using RT-qPCR. We found that the expression of markers for tissue remodeling of the ACL is dependent on the magnitude of loading and is sex specific. Male ACLs activated a tissue remodeling response to cyclic loading below 4 MPa loads but turned off remodeling at 8 MPa. These data support the hypothesis that noncontact ACL injury is a consequence of failed tissue remodeling and inadequate repair of microtrauma resulting from fatigue loading. Conversely, female ACLs downregulate genes responsible for tissue remodeling in response to cyclic loading at all magnitudes, which may explain the increased rate of ACL tears in women. Together, these data provide insight into the remodeling response of ACLs in vivo and potentially offer novel approaches for preventing ACL rupture.

bioengineering↗

bioRxiv2022

Septin-Mediated Mechanobiological Reprogramming of T Cell Transmigration and 3D Motility

The all-terrain motility of lymphocytes in tissues and tissue-like gels is best described as amoeboid motility. For amoeboid motility, lymphocytes do not require specific biochemical or structural modifications to the surrounding extracellular matrix. Instead, they rely on changing shape and steric interactions with the microenvironment. However, the exact mechanism of amoeboid motility remains elusive. Here we report that septins shape T cells for amoeboid motility. Specifically, septins form F-actin and alpha-actinin-rich cortical rings at the sites of cortex-indenting collisions of T cells with the extracellular matrix. Cortical rings compartmentalize cells into chains of spherical segments that are spatially conformed to the available lumens, forming transient hourglass-shaped steric locks onto the surrounding collagen fibers. The steric lock facilitates pressure-driven peristaltic propulsion of cytosolic content by individually contracting cell segments. Our results demonstrate that septins provide microenvironment-guided partitioning of actomyosin contractility and steric pivots for amoeboid motility of T cells in tissue-like microenvironments. GLOSSARYO_LISteric interactions - interactions by the means of their spatial collision dependent on objects shapes. C_LIO_LISteric guidance - cell navigation within crowded 3D environments, determined by the available passages around and between steric hindrances. C_LIO_LIPeristaltic treadmilling - locomotion mode by the means of a repeated sequence of polarized cell cortex extension, stabilization, and retraction, accompanied by translocation of nucleus and cytoplasm via circumferential cortex contractility. C_LI Significance StatementT cells can be highly motile, searching for cognate antigens or better yet targets in chimeric antigen receptor therapy settings. However, mechanisms of motility remain elusive for T cells migrating in structurally and biochemically diverse tissues. Here we address one pivotal question of basic and clinical immunology - How T cells achieve the all-terrain motility? Here we decipher and report septin-based T cell motility in a 3D tissue-like environment. Specifically, we show that septins facilitate cell morphological responsiveness to the steric obstacles, i.e., collagen fiber-wise partitioning of actomyosin cortex contractility and cell-obstacle steric interactions. These responses coordinate peristaltic propulsion of the lymphocytes cytosolic content along its individually contracting cell segments, forming the obstacle-avoiding motility, i.e., circumnavigation, shared across various tested lymphocytes.

biophysics↗

bioRxiv2021

Mechanical counterbalance of kinesin and dynein motors in microtubular network regulates cell mechanics, 3D architecture, and mechanosensing

Microtubules (MTs) and MT motor proteins form active 3D networks made of unstretchable cables with rod-like bending mechanics that provide cells with a dynamically changing structural scaffold. In this study, we report an antagonistic mechanical balance within the dynein-kinesin microtubular motor system. Dynein activity drives microtubular network inward compaction, while isolated activity of kinesins bundles and expands MTs into giant circular bands that deform the cell cortex into discoids. Furthermore, we show that dyneins recruit MTs to sites of cell adhesion increasing topographic contact guidance of cells, while kinesins antagonize it via retraction of MTs from sites of cell adhesion. Actin-to-microtubules translocation of septin-9 enhances kinesins-MTs interactions, outbalances activity of kinesins over dyneins and induces discoid architecture of cells. These orthogonal mechanisms of MT network reorganization highlight the existence of an intricate mechanical balance between motor activities of kinesins and dyneins that controls cell 3D architecture, mechanics, and cell-microenvironment interactions.

biophysics↗

bioRxiv2020

Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments

Defining the principles of T cell migration in structurally and mechanically complex tumor microenvironments is critical to understanding sanctuaries from antitumor immunity and optimizing T cell-related therapeutic strategies. To enhance T cell migration through complex microenvironments, we engineered nanotextured platforms that allowed us to define how the balance between T cell phenotypes influences migration in response to tumor-mimetic structural and mechanical cues and characterize a mechanical optimum for migration that can be perturbed by manipulating an axis between microtubule stability and force generation. In 3D environments and live tumors, we demonstrate that microtubules instability, leading to increased Rho pathway-dependent cell contractility, promotes migration while clinically used microtubule-targeting chemotherapies profoundly decrease effective migration. Indeed, we show that rational manipulation of the microtubule-contractility axis, either pharmacologically or through genome engineering, results in engineered T cells that more effectively move through and interrogate 3D matrix and tumor volumes. This suggests that engineering cells to better navigate through 3D microenvironments could be part of an effective strategy to enhance efficacy of immune therapeutics.

cancer biology↗