Biology subjects

Toth, J. M.

Publications and source records attributed to Toth, J. M..

3 recordsLinked to original sources

bioRxiv2026

Increased Expression and Altered Functional Activities of Immune Receptors TREM1, PD-L1, and Others on Hematopoietic Progenitor Cells in a Mouse Model of Rheumatoid Arthritis

Hematopoietic stem and progenitor cells (HSPCs) sustain the production of hundreds of billions of new cells per day to maintain our blood and immune system. In this process, HSPCs regulate the hematopoietic output by sensing and integrating diverse physiological cues. Thus, HSPCs express many receptors traditionally studied for their functions in the immune system, and this allows HSPCs to directly detect microbial compounds, endogenous danger signals, cytokines, and other inflammatory mediators. However, how the expression levels of such receptors on HSPCs change under chronic inflammation and how such changes alter HSPC functions and immune cell production remains unexplored. Working in a murine model of rheumatoid arthritis, we demonstrate the induction of microbial sensors TLR2 and CD14, orphan inflammatory receptor TREM1, and checkpoint receptor PD-L1 on HSPCs and particularly the myeloid progenitor cells in the arthritis-afflicted mice. Furthermore, we demonstrate that the stimulation of HSPCs through these receptors in culture can significantly alter the dynamics of cell expansion and differentiation, with distinct responses from HSPCs of arthritis-afflicted versus healthy control mice. We hypothesize that the induction and stimulation of HSPCs through these immune receptors under chronic inflammation may impact the output and functional properties of their immune cell progeny, positing HSPCs as central players in the pathogenic inflammatory responses of rheumatoid arthritis and potentially other chronic inflammatory diseases. HIGHLIGHTSO_LIHematopoietic progenitor cells in murine models of rheumatoid arthritis show an upregulation of immune receptors TREM1, PD-L1, TLR2, and CD14. C_LIO_LIStimulation of murine hematopoietic stem and progenitor cells through these receptors in culture alters the dynamics of their expansion and differentiation. C_LIO_LIIn such cultures, hematopoietic stem and progenitor cells from mice afflicted with rheumatoid arthritis show altered responses to stimulation as compared to healthy controls. C_LI

immunology↗

bioRxiv2024

Polymer Model Integrates Super-Resolution Imaging and Epigenomic Sequencing to Elucidate the Role of Epigenetic Reactions in Shaping 4D Chromatin Organization

Chromatin, with its complex spatial and temporal organization, plays a crucial role in regulating gene expression. Recent advancements in super-resolution microscopy have revealed that nanoscale domains of heterochromatin (repressed segments) embedded within a euchromatin (active segments) background are fundamental units of 3D chromatin organization. In tissue-resident cells, the size of these heterochromatin domains varies with the microenvironment, particularly its stiffness, and chromatin organization is also influenced by pharmacological and epigenetic drugs. However, the mechanisms governing heterochromatin domain size under various conditions and their impact on gene expression remain unclear. To address this knowledge gap, we have developed a dynamic, next-generation sequencing informed chromatin copolymer model. Our model simulates the spatiotemporal evolution of chromatin, driven by passive diffusion and active epigenetic reactions, which interconvert euchromatin and heterochromatin. By integrating chromatin-chromatin interaction energetics and diffusion-reaction dynamics, we predict the formation of nanoscale heterochromatin-rich domains and establish a scaling relationship between their size and the modulation of epigenetic reaction rates. Additionally, our model predicts that epigenetic and chromatin compaction changes in response to changes in global reaction rates occur predominantly at domain boundaries. We validated these predictions via Hi-C contact map analysis and super-resolution imaging of hyperacetylated melanoma cells. Subsequent RNA-seq analysis suggested a pivotal role of these epigenetic shifts in influencing the metastatic potential of these cells. We further validated our mesoscale findings against chromatin rearrangement in hMSCs, which exhibit sensitivity of epigenetic reaction rates to changes in microenvironmental stiffness. Finally, we evaluated the effects of cycling of epigenetic reaction rates in silico, mimicking the cellular transition to different extracellular conditions, and back again. This finding reveals a cell-type invariant mechanism driven by domain boundaries, whereby chromatin organization guides epigenetic memory formation. Our findings show that chromatin reorganization in response to changes in epigenetic reaction rates resulting from alterations in the microenvironment, drug exposure and disease progression impacts both immediate cellular responses and long-term epigenetic memory.

biophysics↗

bioRxiv2024

Mechano-metabolism of adherent cells in 2D and 3D microenvironments

Cells dynamically regulate their morphology, contractility, and metabolism in response to the mechano-chemical properties of their microenvironment. Here, we show matrix stiffness and ligand density jointly govern the bioenergetics of contractile cells through a nonequilibrium active chemo-mechanical model built around a newly introduced cellular metabolic potential. This concept links ATP hydrolysis to mechanosensitive signaling, quantifies the energetic cost of stress fiber assembly, and determines mechanically stable states. The metabolic potential enables quantitative prediction of cell contractility, morphology, and ATP consumption in different stiffness 2D and 3D environments, and we find quantitative agreement with experimental measurements in MDA-MB-231 breast cancer cells. The model further predicts activation of AMPK accompanies increased energetic demands in stiffer microenvironments which we experimentally validate and correlate with increased mitochondrial membrane potential, glucose uptake, and intracellular ATP levels. Together, these findings establish a predictive quantitative framework unifying mechanosensitive control of cell shape and contractility with the metabolic pathways sustaining cellular function across diverse mechanical environments. TeaserMatrix stiffness reshapes the cellular energy budget, driving metabolic adaptation to mechanical demand.

biophysics↗