Biology subjects

Momen-Heravi, F.

Publications and source records attributed to Momen-Heravi, F..

4 recordsLinked to original sources

bioRxiv2026

Spatial transcriptomics reveals epithelial-immune remodeling preceding malignant transformation of oral premalignant lesions

Oral premalignant lesions (OPLs) are common; however, histopathological grading incompletely identifies lesions destined for cancer. To define tissue ecosystems that precede malignant transformation, we integrated single-cell-resolution Xenium spatial transcriptomics of 20 HPV-negative biospecimens from 16 patients, with independent single-cell RNA sequencing and immunofluorescence data from 38 patients with OPLs after quality control. Progressive OPLs exhibit a coordinated epithelial-immune program comprising MX1/NOTCH3-high KRT14+/KRT15+ basal epithelial states, S100A9-high inflammatory macrophages, TIGIT-high, exhaustion-associated T cells, and altered dendritic cell states. Spatial analyses showed that T cells and dendritic cells were displaced from the basal epithelial interface, and that epithelial neighborhoods were depleted of dendritic cells but enriched for TIGIT-high T cells, revealing immune reorganization not captured by cellular abundance alone. Independent single-cell and protein-level analyses reproduced basal epithelial interferon/stress programs, S100A9-associated myeloid inflammation, TIGIT-high, exhaustion-associated T-cell programs, and dendritic cell redistribution. Ligand-receptor inference suggested convergent myeloid and lymphoid signals linked to epithelial stress, checkpoint regulation, and extracellular matrix remodeling. Functionally, recombinant S100A9 accelerated wound closure in oral epithelial and cancer cells, whereas S100A9 and S100A8/S100A9 enhanced oral cancer cell proliferation. These responses were attenuated by pharmacologic inhibition of TLR4 or RAGE. Together, these data define a spatially organized, myeloid-skewed, checkpoint-enriched ecosystem present before invasion and suggest S100A9-TLR4/RAGE signaling and epithelial-immune geometry as candidate mechanisms and biomarkers for oral cancer interception.

immunology↗

bioRxiv2025

Distal Gene Expression Governed by Lamins and Nesprins via Chromatin Conformation Change

The nuclear lamina is a vital structural component of eukaryotic cells, playing a pivotal role in both physiological processes, such as cell differentiation, and pathological conditions, including laminopathies and cancer metastasis. Lamina associated proteins, particularly lamins and nesprins, are integral to mechanosensing, chromatin organization, and gene regulation. However, their precise contributions to gene regulation remain incompletely understood. This study explores the functions of lamin A, LMNA, and SYNE2 in gene expression, with a particular focus on their influence on distal chromatin interactions and conformational changes. Using inducible shRNA knockdown, RNA-seq analysis, and dCas9-mediated live imaging of chromosomes, we demonstrate that lamin A affects RNA synthesis, LMNA governs chromatin spatial organization, and SYNE2 regulates chromatin modifications. Furthermore, both lamins and nesprins enhance telomere dynamics. These findings elucidate nuclear envelope-associated mechanisms in gene regulation, offering valuable insights into chromatin dynamics under both physiological and pathological contexts.

cell biology↗

bioRxiv2024

Modeling epithelial homeostasis and perturbation in three-dimensional human esophageal organoids

BackgroundEsophageal organoids from a variety of pathologies including cancer are grown in Advanced Dulbeccos Modified Eagle Medium-Nutrient Mixture F12 (hereafter ADF). However, the currently available ADF-based formulations are suboptimal for normal human esophageal organoids, limiting the ability to compare normal esophageal organoids with those representing a given disease state. MethodsWe have utilized immortalized normal human esophageal epithelial cell (keratinocyte) lines EPC1 and EPC2 and endoscopic normal esophageal biopsies to generate three-dimensional (3D) organoids. To optimize ADF-based medium, we evaluated the requirement of exogenous epidermal growth factor (EGF) and inhibition of transforming growth factor-(TGF)-{beta} receptor-mediated signaling, both key regulators of proliferation of human esophageal keratinocytes. We have modeled human esophageal epithelial pathology by stimulating esophageal 3D organoids with interleukin (IL)-13, an inflammatory cytokine, or UAB30, a novel pharmacological activator of retinoic acid signaling. ResultsThe formation of normal human esophageal 3D organoids was limited by excessive EGF and intrinsic TGF{beta} receptor-mediated signaling. In optimized HOME0, normal human esophageal organoid formation was improved, whereas IL-13 and UAB30 induced epithelial changes reminiscent of basal cell hyperplasia, a common histopathologic feature in broad esophageal disease conditions including eosinophilic esophagitis. Conclusions: HOME0 allows modeling of the homeostatic differentiation gradient and perturbation of the human esophageal epithelium while permitting a comparison of organoids from mice and other organs grown in ADF-based media.

cell biology↗

bioRxiv2023

An exosome-based gene delivery platform for cell-specific CRISPR/Cas9 genome editing

Exosomes are naturally occurring vesicles that have the potential to be manipulated to become promising drug delivery vehicles for on-demand in vitro and in vivo gene editing. Here, we developed the modular safeEXO platform, a prototype exosome delivery vehicle that is mostly devoid of endogenous RNA and can efficaciously deliver RNA and ribonucleoprotein (RNP) complexes to their intended intracellular targets manifested by downstream biologic activity. We also successfully engineered producer cells to produce safeEXO vehicles that contain endogenous Cas9 (safeEXO-CAS) to effectively deliver efficient ribonucleoprotein (RNP)-mediated CRISPR genome editing machinery to organs or diseased cells in vitro and in vivo. We confirmed that safeEXO-CAS exosomes could co-deliver ssDNA, sgRNA and siRNA, and efficaciously mediate gene insertion in a dose-dependent manner. We demonstrated the potential to target safeEXO-CAS exosomes by engineering exosomes to express a tissue-specific moiety, integrin alpha-6 (safeEXO-CAS-ITGA6), which increased their uptake to lung epithelial cells in vitro and in vivo. We tested the ability of safeEXO-CAS-ITGA6 loaded with EMX1 sgRNAs to induce lung-targeted editing in mice, which demonstrated significant gene editing in the lungs with no signs of morbidity or detectable changes in immune cell populations. Our results demonstrate that our modular safeEXO platform represents a targetable, safe and efficacious vehicle to deliver nucleic acid-based therapeutics that successfully reach their intracellular targets. Furthermore, safeEXO producer cells can be genetically manipulated to produce safeEXO vehicles containing CRISPR machinery for more efficient RNP-mediated genome editing. This platform has the potential to improve current therapies and increase the landscape of treatment for various human diseases using RNAi and CRISPR approaches.

molecular biology↗