Biology subjects

De Domenico, E.

Publications and source records attributed to De Domenico, E..

7 recordsLinked to original sources

bioRxiv2026

A high-throughput cost-efficient in vitro platform for the screening of immune senomodulators

With advancing age, the immune systems capacity to effectively combat pathogens diminishes. This decline of the overall immune function impacts both the innate and adaptive compartments, contributing in many cases to a systemic state of chronic inflammation which further increases the risk of the most prevalent non-communicable diseases and severe infections. Given the increase in median life expectancy with a demographic development towards a larger number of elderly people, identifying interceptive strategies to mitigate the individual and societal impact of diseases related to immune aging is of paramount importance. We developed a molecularly defined strategy to guide interventions with the aim to reduce immune aging. We introduce an omics-based drug screening platform to identify and characterize the pharmacological profile of immune senomodulators applicable to cross-age human cohorts using human-derived peripheral immune cells. To this aim we developed a robust experimental approach to screen for effective anti-aging compounds directly on human cells. This methodology allows us to quickly screen for drug candidates at different scales: from cost-effective bulk transcriptomics for a broader high-throughput overview of cellular responses, down to single-cell resolution approaches for a more detailed look at gene expression and other molecular data. This in vitro screening method is designed to maximize the clinical relevance of our findings, providing a direct link between preclinical research and patient care. By analyzing how different compounds affect the immune cells of individual persons, we can identify treatments that are most likely to be effective against aging in a subject-specific manner--a key step toward personalized medicine. In short, our approach enables a faster translation of anti-aging immune treatments from the lab to the clinic, tailoring them to each individuals unique biological makeup.

systems biology↗

bioRxiv2026

Downregulation of Satb1 is required to prevent autoimmunity by maintaining Tfh homeostasis

T follicular helper (Tfh) cells are a specialized subset of CD4 T cells that localize to germinal centers (GC), where they provide critical help to B cells through the delivery of IL-21 and other cytokines. Here, we demonstrate that the tight control of the chromatin remodeler Special AT-rich sequence-binding protein 1 (Satb1) is key for this process, as overexpression of Satb1 drives lymphoproliferation and expansion of the T cell and B cell compartments in secondary lymphoid organs. Specifically, Satb1 overexpression induces a pronounced shift towards Tfh cell differentiation and increased GC formation accompanied by an increase in non-classed switched GC B cells and auto-antibody secretion. These findings highlight the importance of the precise regulation of Satb1 in fine-tuning CD4 T cells and B cells responses and suggest a potential role for dysregulation of Satb1 in the pathogenesis of autoimmune disease such as systemic lupus erythematodes (SLE).

immunology↗

bioRxiv2026

A reproducible human brain tissue model to study physiological and disease-associated microglia phenotypes

Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions under physiological and pathological conditions. However, harnessing this potential is impaired by low reproducibility, maturity, or cell-type diversity of existing models. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a 3D cortical brain tissue model (3BTM) containing neurons, astrocytes, and microglia with high reproducibility, maturity, and viability. 3BTMs show morphological, functional, and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions, and gene expression. Importantly, when engineered to model Alzheimers disease pathology, 3BTMs recapitulate key disease hallmarks including amyloid deposition, increased phospho-Tau levels, and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Together, our model offers unprecedented possibilities for studying physiological and pathological states of human brain tissue and translational applications.

neuroscience↗

bioRxiv2025

Tau interactions with inner nuclear envelope proteins modulates chromatin

Abstract/SummaryThe intracellular re-distribution of the neuronal microtubule-associated protein Tau, from the axon into the somatodendritic compartment, is a physiological stress-related event and occurs early in Alzheimers disease (AD). Nuclear envelope distortions have been linked to the presence and aggregation of pathological Tau near the nucleus in these diseases. How physiologically increased soma Tau levels, enabling Tau interactions with the nucleus, impact nuclear integrity and neuronal physiology is unclear. Combining proximity biotinylation interactomics with chromatin imaging and molecular assays, we show that soluble Tau interacts with proteins coordinating chromatin at the inner nuclear membrane, including lamin B receptor and SUN1. This interaction promotes nuclear envelope invaginations and damage and changes the coordination of DNA at the nuclear lamina. Increasing somatodendritic Tau is sufficient to upregulate the expression of multiple transcription factors implicated in AD pathogenesis and to reduce expression of genes involved in cholesterol biosynthesis, which seem coordinated at lamin associated domains. These nuclear envelope-related mechanisms suggest that physiological, neuronal stress-related somatodendritic Tau missorting can initiate chromatin-related cascades important for early changes in AD and tauopathies.

neuroscience↗

bioRxiv2025

Molecular determinants of brain-resident CD8+ T cell formation and function

Tissue-resident memory T (Trm) cells are strategically located to provide frontline protection upon antigen re-encounter while possessing tissue-specific transcriptional programs. Whether brain Trm cells similarly adapt to their tissue environment, and to what extent their molecular signature is altered in neuropathology, remains unclear. Here we profile brain Trm cells under homeostasis and in the contexts of aging, beta-amyloidosis, and systemic viral infection. From these studies, a tissue-specific CD8+ T cell landscape emerged, defined by the expression of the transcription factor TCF-1 and the inhibitory receptor PD-1. TCF-1 was critical for the formation and phenotypic maturation of brain CD8+ Trm cells, while PD-1 signaling was necessary for robust effector function and antigen-specific recall response. In addition, the cytokine transforming growth factor (TGF)-{beta} was required for the differentiation of brain CD8+ Trm cells and restricted their transition into effector-like cells upon antigenic rechallenge. These findings highlight common as well as tissue-specific features of brain CD8+ Trm cells and provide insights into the molecular mechanisms governing their formation and function.

immunology↗

bioRxiv2024

Characterizing human CMV-specific CD8+ T cells using multi-layer single-cell omics

In this study we established a comprehensive workflow to collect multi-omics single-cell data using a commercially available micro-well based platform. This included whole transcriptome, cell surface markers (targeted sequencing-based cell surface proteomics), T cell specificities, adaptive immune receptor repertoire (AIRR) profiles and sample multiplexing. With this technique we identified novel paired T cell receptor sequences for three prominent human CMV epitopes. In addition, we review the ability of dCODE dextramers to detect antigen-specific T cells at low frequencies by estimating sensitivities and specificities when used as reagents for single-cell multi-omics. MotivationIn this study, we report the first five-layer multi-omics dataset using the BD Rhapsody single-cell platform for the characterization of human antigen-specific T cells. Modalities include whole transcriptome, T cell receptor (TCR) sequences, T cell antigen specificity measured by dCODE dextramers, surface marker proteins and combinatorial sample multiplexing combining two distinct hashing approaches.

genomics↗

bioRxiv2024

Dysregulation of gene expression during gastrulation results in impaired primitive erythropoiesis and vascular development in Trim71-KO embryos

The transition of an embryo from gastrulation to organogenesis requires precisely coordinated changes in gene expression. The RNA-binding protein Trim71 is essential for embryonic survival, but its exact role in mammalian development in vivo remains poorly defined. Here we show that murine Trim71-KO embryos appear normal until embryonic day (E)8.5 but display severe defects in primitive erythropoiesis, yolk sac vasculature and heart function during the onset of organogenesis at E9.5 and E10.5. This led to an impaired vascular translocation of yolk sac-derived macrophage progenitors to the embryo head, independent of Trim71 expression in erythro-myeloid progenitors. The cardiovascular and erythropoiesis defects explain the embryonic lethality upon global Trim71-KO. Targeting Trim71 in hematoendothelial progenitors did not induce strong developmental defects, indicating an earlier developmental origin of these phenotypes in Trim71-KO embryos. ScRNA-seq of E7.5 Trim71-KO embryos revealed that transcriptomic changes arise already at gastrulation, showing a strong upregulation of the transcription factor Eomes. We identify Eomes as a direct target of Trim71-mediated mRNA repression via the NHL domain, demonstrating a functional link of Trim71 to a key regulator of mesodermal development. Taken together, our data suggest that Trim71-dependent control of gene expression at gastrulation establishes a framework for proper development during organogenesis.

developmental biology↗