Biology subjects

Borodina, T.

Publications and source records attributed to Borodina, T..

6 recordsLinked to original sources

bioRxiv2026

Distinct macrophage and T cell programs shape pancreatic inflammation during metabolic stress and aging

Type 2 diabetes is linked to systemic inflammation driven by metabolic stress and aging. Although pancreatic inflammation associated with these factors is well documented, the dynamics of immune cell populations and their molecular changes remain poorly understood. We characterized immune cell alterations in the pancreas and pancreatic islets during Western diet (WD) feeding and aging using imaging mass cytometry (IMC) and single-cell RNA sequencing (scRNA-seq). Spatial and transcriptional analyses were performed to define immune cell subtype composition, activation states, and inferred cell-cell communication programs under metabolic and age-related stress conditions. Our analyses identified expansion of an F4/80low macrophage subtype and activated effector-like CD8+ T cells throughout the pancreas during WD feeding and aging. Within pancreatic islets, single-cell RNA sequencing identified a type I interferon-responsive macrophage population with low F4/80 expression that expanded during overnutrition. Notably, the type I interferon responses elicited by these stressors diverged: aging was associated with a more canonical type I interferon response, whereas overnutrition induced a broader response that included STAT3-associated transcriptional programs. We further provide evidence for enhanced cytokine-mediated communication between macrophages and a CD8+ cytotoxic T-cell population under overnutrition and aging. These findings show that metabolic stress and aging remodel pancreatic inflammation through overlapping but distinct immune mechanisms, involving expansion of F4/80low macrophages, activation of divergent type I interferon programs, and enhanced macrophage-CD8+ T-cell communication. Together, these findings suggest that distinct therapeutic approaches may be required to preserve islet function in type 2 diabetes driven by metabolic stress versus aging. Article HighlightsO_LIMetabolic stress and aging remodel pancreatic inflammation through overlapping but distinct immune mechanisms. C_LIO_LISpatial and single-cell analyses identified conserved remodeling of pancreatic macrophage populations accompanied by activation of cytotoxic T-cell responses during metabolic stress and aging. C_LIO_LIIn pancreatic islets, macrophages exhibited distinct type I interferon-associated transcriptional programs, with aging showing a more canonical interferon response and metabolic stress eliciting a broader inflammatory program that included STAT3-associated transcriptional signatures. C_LIO_LIThese findings provide a framework for understanding how metabolic stress and aging differentially shape pancreatic inflammation. C_LI

cell biology↗

bioRxiv2026

Endothelial YAP/TAZ rewiring under cardiometabolic stress drives sex-divergent vascular remodeling in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is widely linked to endothelial dysfunction, yet the molecular pathways translating cardiometabolic stress into microvascular remodeling remain poorly defined. Here, we identify endothelial YAP/TAZ signaling as a mechanistic regulator of sex-divergent vascular responses in HFpEF. Plasma proteomics from the UK Biobank revealed elevated circulating YAP1 levels associated with heart failure and increased mortality, particularly in male patients, where YAP1 coincided with increased levels of the endothelial activation marker ESM1. In a hypertensive cardiorenal mouse model, endothelial YAP/TAZ deletion preserved cardiac function, whereas endothelial TAZ gain-of-function aggravated disease. Under cardiometabolic stress (TNF and high glucose), endothelial cells exhibited sex-specific rewiring of YAP/TAZ-dependent transcriptional programs. Male endothelial cells showed increased extracellular YAP1 release, angiogenic instability with impaired extracellular matrix remodeling, whereas female cells adopted an immune-primed, stress-adaptive phenotype. Mechanistically, cardiometabolic stress uncoupled canonical YAP-TEAD transcription and engaged alternative cofactors, including VGLL3 and VGLL4, thereby reshaping the endothelial secretome and propagating sex-divergent microvascular remodeling. These findings identify endothelial YAP/TAZ rewiring as a molecular switch that converts cardiometabolic stress into sex-divergent microvascular remodeling in HFpEF and connect this process to circulating YAP1 and ESM1 in patients.

cell biology↗

bioRxiv2025

circVDJ-seq for T cell clonotype detection in single-cell and spatial multi-omics

Monitoring T cell repertoires in human tissues provides important insights into immune response mechanisms in cancer, infectious diseases, and autoimmunity. However, retrieving VDJ information from single-cell and spatial transcriptomics workflows with 3-barcoding of cDNA remains resource-intensive or requires specialized sequencing equipment. Here, we introduce circVDJ-seq for simplified and cost-efficient T cell receptor (TCR) profiling from 3-directed workflows like single-cell or single-nucleus RNA sequencing, ATAC+RNA multi-omics, and spatial transcriptomics. Application of circVDJ-seq to freshly resected neuroblastomas and postmortem lymph nodes affected by pneumonia or COVID-19 reveals distinct immune microenvironments and T cell clonality patterns, highlighting broad utility across diverse clinical contexts.

genomics↗

bioRxiv2025

Epiproteomic control of the epitranscriptome drives cortical neurogenesis

Neurological conditions are the leading cause of ill health worldwide. Here, we show that the neurodevelopmental disorder-associated ubiquitin ligase UBE3C regulates the cellular composition of the murine cerebral cortex and human brain organoids, with its loss favoring neurogenesis and suppressing glial fate. Using genetic complementation, we demonstrate that disease-associated UBE3C mutations alter its autoubiquitination activity and disrupt cortical lamination. Proteomic profiling of UBE3C-deficient forebrains and organoids identifies Cbll1 as a UBE3C substrate, and we show that the UBE3C-Cbll1 duo drives N6-methyladenosine (m6A) mRNA methylation. Hyperactivation of m6A writers in UBE3C-deficient neural progenitors impairs cell cycle exit, a defect reversible in vivo by the METTL3 inhibitor STM2457. Our findings uncover an epiproteomic mechanism controlling m6A-mediated gene expression and define a regulatory axis linking ubiquitin signaling to epitranscriptomic control of neural fate. This work provides a mechanistic framework for understanding neurodevelopmental disorders and highlights potential therapeutic strategies.

cell biology↗

bioRxiv2021

De Novo Whole Genome Assembly of the Roborovski Dwarf Hamster (Phodopus roborovskii) Genome, an Animal Model for Severe/Critical COVID-19

The Roborovski dwarf hamster Phodopus roborovskii belongs to the Phodopus genus, one of seven within Cricetinae subfamily. Like other rodents such as mice, rats or ferrets, hamsters can be important animal models for a range of diseases. Whereas the Syrian hamster from the genus Mesocricetus is now widely used as a model for mild to moderate COVID-19, Roborovski dwarf hamster show a severe to lethal course of disease upon infection with the novel human coronavirus SARS-CoV-2.

genomics↗

bioRxiv2021

Diverse but unique astrocytic phenotypes during embryonic stem cell differentiation, culturing and aging

Astrocytes are resident glia cells of the central nervous system (CNS) that play complex and heterogeneous roles in brain development, homeostasis and disease. Since their vast involvement in health and disease is becoming increasingly recognized, suitable and reliable tools for studying these cells in vivo and in vitro are of utmost importance. One of the key challenges hereby is to adequately mimic their context-dependent in vivo phenotypes and functions in vitro. To better understand the spectrum of astrocytic variations in defined settings we performed a side-by-side-comparison of embryonic stem cell (ESC)-derived astrocytes as well as primary neonatal and adult astrocytes, revealing major differences on a functional and transcriptomic level, specifically on proliferation, migration, calcium signaling and cilium activity. Our results highlight the need to carefully consider the choice of astrocyte origin and phenotype with respect to age, isolation and culture protocols based on the respective biological question.

neuroscience↗