Biology subjects

Wagner, J. U. G.

Publications and source records attributed to Wagner, J. U. G..

4 recordsLinked to original sources

bioRxiv2026

Temporal AI model predicts drivers of cell state trajectories across human aging

Foundational AI models have recently shown promise for predicting the impact of perturbations on cell states. However, current models typically consider only one cell state at a time, limiting their ability to learn how cellular responses unfold over time, particularly across long trajectories such as diseases of aging. Here, we develop a temporal AI model, MaxToki, trained on nearly 1 trillion gene tokens including cell state trajectories across the human lifespan to generate cell states across long timelapses of human aging. MaxToki generalized to unseen trajectories through in-context learning and predicted novel age-modulating targets that were experimentally verified to influence age-related gene programs and functional decline in vivo. MaxToki represents a promising strategy for temporal modeling to accelerate the discovery of interventions for programming therapeutic cellular trajectories.

bioinformatics↗

bioRxiv2025

Endothelial expression of ZBTB16 protects against cardiac aging

Background and aimAging significantly increases the risk of cardiovascular diseases, characterized by progressive cardiac dysfunction. The vascular niche is crucial for maintaining cardiac homeostasis, yet endothelial cell (EC) impairment during aging remains poorly understood. This study investigates epigenetically regulated mechanisms mediating EC-dependent cardiac aging and identifies a critical role of Zinc finger and BTB domain-containing protein 16 (ZBTB16). MethodsChromatin accessibility (snATAC-seq) and transcriptomic (snRNA-seq) analyses were performed on aged hearts to identify age-related regulatory changes. Functional studies using genetic models, assessed cardiac aging phenotypes. In vitro assays examined EC senescence and secretory profiles, while co-culture experiments analyzed the impact of ZBTB16-deficient EC supernatants on fibroblasts, cardiomyocytes, and neurons. Overexpression experiments in vitro and in vivo tested the potential for ZBTB16 to mitigate aging-associated dysfunction. ResultsAged hearts exhibited decreased chromatin accessibility and expression of the transcription factor ZBTB16 in both human and mice. Loss of ZBTB16 in young mice, including Zbtb16 haploinsufficient and endothelial-specific knockout mice, led to premature aging, diastolic dysfunction, and increased secretion of pro-fibrotic and inflammatory factors. Supernatants from ZBTB16-deficient ECs activated fibroblasts, induced cardiomyocyte hypertrophy, and impaired neuronal sprouting. Overexpression of ZBTB16 reversed these effects in senescent ECs and aged mice and reduced diastolic dysfunction. Mechanistic studies identified key downstream targets of ZBTB16, including nuclear receptor-interacting protein 1 (NRIP1). ZBTB16 suppressed NRIP1 expression, limiting fibroblast activation and pro-fibrotic signaling. ConclusionsZBTB16 is a key regulator of endothelial function, maintaining vascular niche homeostasis and mitigating aging-associated cardiac dysfunction. Its loss promotes EC senescence and pro-fibrotic signaling, contributing to diastolic dysfunction. Overexpression of ZBTB16 presents a potential therapeutic strategy for preserving cardiac function during aging. These findings establish a novel role for ZBTB16 in endothelial aging and cardiovascular disease prevention. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/681100v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1a56e2org.highwire.dtl.DTLVardef@13e23fforg.highwire.dtl.DTLVardef@ad681eorg.highwire.dtl.DTLVardef@8eca8b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Vascular niches are the primary hotspots for aging within the multicellular architecture of cardiac tissue

BackgroundAging is a major, yet unmodifiable risk factor for cardiovascular diseases, leading to vascular alterations, increased cardiac fibrosis, and inflammation, all of which contribute to impaired cardiac function. However, the microenvironment inciting age-related alterations withing the multicellular architecture of the cardiac tissue is unknown. MethodsWe investigated local microenvironments in aged mice hearts applying an integrative approach combining single-nucleus RNA sequencing and spatial transcriptomics in 12-week-old and 18-month-old mice. We defined distinct cardiac niches and studied changes in their cellular composition and functional characteristics. ResultsIntegration of spatial transcriptomics data across young and aged hearts allowed us to identify 11 cardiac niches, which were characterized by distinct cellular composition and functional signatures. Aging did not alter the overall proportions of cardiac niches but leads to distinct regional changes, particularly in the left ventricle. Whereas cardiomyocyte-enriched niches show disrupted circadian clock gene expression, vascular niches showed major changes in pro-inflammatory and pro-fibrotic signatures and altered cellular composition. We particularly identified larger vessel-associated cellular niches as key hotspots for activated fibroblasts and macrophages in aged hearts, with interactions of both cell types through the C3:C3ar1 axis. These niches were also enriched in senescence cells exhibiting high expression of immune evasion mechanisms that may impair senescent cell clearance. ConclusionOur findings indicate that the microenvironment around the vasculature is particularly susceptible to age-related changes and serves as a primary site for inflammation-driven aging, so called "inflammaging". This study provides new insights into how aging reshapes cardiac cellular architecture, highlighting vessel-associated niches as potential therapeutic targets for age-related cardiac dysfunction.

physiology↗

bioRxiv2024

The aging-induced long non-coding RNA MIRIAL controls endothelial cell and mitochondrial function

AimsVascular aging is characterized by the progressive deterioration of endothelial function. Long non-coding RNAs (lncRNAs) are critical regulators of gene expression and protein function. However, their involvement in aging-related dysregulation of endothelial cell function remains largely unknown. Here, we aim to characterize the aging-regulated lncRNA MIRIAL in endothelial cells. Methods + ResultsWe identified Mirial as an aging-induced lncRNA in RNA-sequencing data of mouse cardiac endothelial cells. In human umbilical vein endothelial cells (HUVECs), gapmer-mediated knockdown of MIRIAL led to decreases in proliferation, migration and basal angiogenic sprouting. Additionally, MIRIAL knockdown led to increased mitochondrial mass, spare respiratory capacity, and vascular endothelial growth factor (VEGF)-stimulated sprouting. Mechanistically, we demonstrate that MIRIAL forms an RNA{middle dot}DNA:DNA triple helix (triplex) with a regulatory region of the quiescence-promoting Forkhead Box O1 (FOXO1) gene, thus inducing its expression. The formation of this triplex involves an Alu element within the MIRIAL transcript, representing a previously undescribed mechanism of action for a lncRNA. Further, we generated a global Mirial knockout mouse line of. Angiogenic sprouting of aortic rings from Mirial knockout mice was reduced under basal conditions, but increased after VEGF administration, validating the in vitro angiogenic phenotype. Importantly, cardiac contractile function after acute myocardial infarction is severely reduced in Mirial knockout mice, as compared to wild-type littermates. ConclusionsThe lncRNA MIRIAL is an aging-induced regulator of endothelial quiescence and metabolism. Translational PerspectiveLncRNAs often exhibit cell-type or tissue-specific expression and regulation, rendering them potentially druggable targets requiring lower doses and having fewer side effects compared to protein targets. Our current research highlights, that loss of Mirial correlates with adverse outcomes post-acute myocardial infarction in a murine model. Dysregulation of MIRIAL in various human pathological conditions, such as ischemic heart disease, abdominal aortic aneurysm, cancer, and aging, indicates its potential as a diagnostic marker. Mechanistically, MIRIAL regulates endothelial quiescence by modulating FOXO1 expression, suggesting it as a promising therapeutic target to counteract the age-related decline in endothelial cell function.

cell biology↗