Biology subjects

Nouri, S.

Publications and source records attributed to Nouri, S..

5 recordsLinked to original sources

bioRxiv2026

TGFB1-Engineered Induced Mesenchymal Stromal Cells Exhibit High Immunomodulatory Potency and Durably Reprogram Synovial Macrophages in Osteoarthritis

Clinical translation of mesenchymal stromal cell (MSC) therapies derived from primary tissue sources is limited by manufacturing inconsistencies driven by donor-to-donor variability, which reduces predictability of clinical response. Induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) offer a promising donor-independent, clonal alternative strategy that is also more amenable to engineering, but whether engineered iMSCs reproduce the potency attributes of primary MSCs remains unclear. Here, we benchmarked a doxycycline-inducible, hTERT-immortalized iMSC line engineered to overexpress TGFB1 (TGFB1-iMSCs), a key regulator of macrophage polarization, against multiple adipose tissue-derived MSC (MSC(AT)) donors across predefined immunomodulatory and angiogenic potency attributes. TGFB1-iMSCs were smaller and more circular with comparable or higher proliferative rates than primary MSC(AT) donors. Interestingly, they had a distinct angiogenic signature (EDIL3, EDN1, PDGFA), and nine differentially expressed microRNAs were predicted to target secretory trafficking and growth factor receptor signalling. Functionally, however, TGFB1-iMSCs secreted less VEGF and showed intermediate HUVEC tube formation, but matched or exceeded all primary MSC(AT) donors in a monocyte-macrophage transwell immunomodulatory assay. Notably, in a murine destabilization of the medial meniscus (DMM) model of post-traumatic osteoarthritis, a single intra-articular injection of TGFB1-iMSCs, but not MSC(AT), reduced total synovial macrophage numbers and lowered the MHCII/CD206 ratio at eight weeks, although it did not reduce cartilage degeneration, synovitis, or fibrosis. Together, these findings show that TGFB1-engineered iMSCs have a macrophage-directed potency profile distinct from that of primary MSC(AT). Immortalized iMSCs therefore provide a reproducible platform for mechanistically dissecting engineered MSC potency and its effects on the immune environment.

immunology↗

bioRxiv2025

Exploring Peptide-Based Nanodiscs Structure and Dynamics through Synergistic Approach of NMR Spectroscopy, SAS and MD Simulations

Peptide nanodiscs are promising anti-atherosclerosis therapeutics, drug delivery particles and structural biology tools. However, the lack of experimental methods for structural and dynamical characterization of these particles hinders their further development. Here we integrated nuclear magnetic resonance (NMR), small-angle x-ray scattering, and small-angle neutron scattering experiments with molecular dynamics (MD) simulations to investigate the structure and dynamics of peptide nanodiscs stabilized by the apolipoprotein A-I mimetic peptide 22A with therapeutic activity against atherosclerosis. This multi-technique approach takes advantage of combining average size and shape information from small-angle scattering, peptide site-specific information from NMR spectroscopy, and interpretative power of MD simulations. Our results reveal the intrinsic polydispersity in size of peptide nanodiscs, highlighting the importance of careful interpretation when using averaged experimental parameters. Our consensus model suggests that 22A peptides are predominantly in -helical configuration with a disordered inter-helical orientation around the lipid matrix. The terminal regions of the peptides display greater flexibility relative to the peptide core and an enhanced C-terminal exposure to solvent, which could facilitate interaction with the enzyme LCAT. Interestingly, our results indicate that peptides and lipids rotate together as a rigid body. The methodological approach described in this paper paves the way for the design of more stable and effective therapeutic nanodiscs and for the characterization of other biomolecular aggregates that are beyond the scope of current structural biology techniques. Significance StatementNanodiscs stabilized by 22A apoA-I mimetic peptides hold significant pharmaceutical potential for treating cardiovascular diseases by mimicking HDL functions, yet their development is hindered by the difficulty of characterizing disordered biomolecular systems. Standard structural biology techniques cannot readily resolve the structure and dynamics of these peptide nanodiscs, which is essential for rational therapeutic design. Here, we integrate complementary biophysical experiments with MD simulations to establish a consensus model of 22A peptide nanodisc structure, dynamics, and interactions with biological partners at molecular resolution. Beyond advancing peptide nanodisc design, our integrative methodology provides a generalizable framework for characterizing other disordered biomolecular assemblies that are similarly challenging to conventional structural approaches.

biochemistry↗

bioRxiv2025

Modifications of the 22A apoA-I mimetic peptide sequence improve the anti-atherosclerotic properties of synthetic HDL

Synthetic high-density lipoprotein (sHDL) constituted of apolipoprotein A-I (apoA-I) mimetic peptides and phospholipids are nanometer-scale particles designed to recreate biological functions of HDL particles in the context of cardiovascular disease. Particularly, the therapeutic efficacy of sHDL particles is attributed to their ability to promote reverse cholesterol transport (RCT), a process where accumulated cholesterol is transported from peripheral tissues to the liver for elimination. Here, we designed two novel apoA-I mimetic peptides (22A-F and 22A-P-18A) by modifying the sequence of the well-studied apoA-I mimetic peptide 22A. These modifications were intended to improve cholesterol efflux from macrophages in vitro and structural stability of sHDL particles in human plasma while preserving their ability to activate lecithin-cholesterol acyltransferase (LCAT). We performed a systematic examination of the potency of sHDL particles made with these peptides in cellular cholesterol efflux, activation of LCAT, plasma HDL remodeling and proteolytic stability. Our study highlights that these modifications improve cholesterol efflux and, in the case of 22A-P-18A, also cholesterol esterification rate by LCAT but they do not appear to influence HDL remodeling in human plasma. Nonetheless, the LCAT activity assay conducted in human plasma suggest that intact sHDL particles are present and are likely the primary contributors to the increased cholesterol esterification rate, rather than the pre-{beta} HDL fraction generated through HDL remodeling. These findings offer new mechanistic insights into how specific peptide modifications affect key steps in RCT, laying the groundwork for future studies to explore their functional relevance in atherosclerosis and HDL-based drug delivery applications.

pharmacology and toxicology↗

bioRxiv2024

Gliflozins, sucrose and flavonoids are allosteric activators of lecithin:cholesterol acyltransferase

Lecithin:cholesterol acyltransferase (LCAT) serves as a pivotal enzyme in preserving cholesterol homeostasis via reverse cholesterol transport, a process closely associated with the onset of atherosclerosis. Impaired LCAT function can lead to severe LCAT deficiency disorders for which no pharmacological treatment exists. LCAT-based therapies, such as small molecule positive allosteric modulators (PAMs), against LCAT deficiencies and atherosclerosis hold promise, although their efficacy against atherosclerosis remains challenging. Herein we utilized a quantitative in silico metric to predict the activity of novel PAMs and tested their potencies with in vitro enzymatic assays. As predicted, sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), sucrose and flavonoids activate LCAT. This has intriguing implications for the mechanism of action of gliflozins, which are commonly used in the treatment of type 2 diabetes, and for the endogenous activation of LCAT. Our results underscore the potential of molecular dynamics simulations in rational drug design.

biochemistry↗

bioRxiv2024

Microsaccade Selectivity as Discriminative Feature for Object Decoding

Microsaccades, a form of fixational eye movements, maintain visual stability during stationary observations. Previous studies have provided valuable insights into the relationship between microsaccade characteristics and external stimuli. However, the dynamic nature of microsaccades provides an opportunity to explore the mechanisms of information processing, particularly object decoding. This study examines the modulation of microsaccadic rates by different stimulus categories. Our experimental approach involves an analysis of microsaccade characteristics in monkeys and human subjects engaged in a passive viewing task. The stimulus categories comprised four primary categories: human, animal, natural, and man-made. We identified distinct microsaccade patterns across different stimulus categories, successfully decoding the stimulus category based on the microsaccade rate post-stimulus distribution. Our experiments demonstrate that stimulus categories can be classified with an average accuracy and recall of up to 85%. Our study found that microsaccade rates are independent of pupil size changes. Neural data showed that category classification in the inferior temporal (IT) cortex peaks earlier than microsaccade rates, suggesting a feedback mechanism from the IT cortex that influences eye movements after stimulus discrimination. These results exhibit potential for advancing neurobiological models, developing more effective human-machine interfaces, optimizing visual stimuli in experimental designs, and expanding our understanding of the capability of microsaccades as a feature for object decoding.

neuroscience↗