Biology subjects

Ason, B.

Publications and source records attributed to Ason, B..

7 recordsLinked to original sources

bioRxiv2026

A Compact Regulatory Logic Governs Fibroblast Cell State Plasticity in Fibrosis

Fibroblast activation drives organ failure across human diseases, yet its regulatory basis remains largely undefined. Here, we repressed 280 conserved disease-activated enhancers using CRISPR droplet sequencing (CROP-seq) in ~550,000 fibroblasts, constructing a regulome of 15 gene programs governing the profibrotic state. Systematic TF perturbation converged on MEOX1 as a central regulator, and fibroblast-specific Meox1 deletion in mice improved cardiac function, reduced fibrosis, and rewired profibrotic fibroblasts toward quiescence in heart failure. Effector gene perturbation in human cardiac fibroblasts revealed distinct regulators of contractility, migration, and inflammatory signaling, and these programs were conserved across profibrotic states in human lung, liver, and skin. Simultaneous repression of just six enhancers using a multiplexed dCas12a-KRAB system collapsed the profibrotic network, suppressed migration and contraction, and rewired fibroblast paracrine signaling to attenuate macrophage inflammation. These findings define the regulatory logic of fibroblast plasticity and establish a new framework for reprogramming profibrotic cell states in disease.

genomics↗

bioRxiv2026

Collateral Immune Cell Signaling Compromises the Efficacy of T-cell Engaging Therapies for Cardiac Fibrosis

Cardiac fibrosis is causally linked to heart failure progression and survival. Currently, there are no approved treatments that directly target cardiac fibrosis. Recent studies have identified a subset of activated cardiac fibroblasts distinct from myofibroblasts that are marked by fibroblast activation protein (FAP) expression, emerge in the injured and diseased heart through inflammatory signaling, and contribute to fibrosis. Using a genetic mouse model, we demonstrate the potential benefits of FAP+ fibroblast depletion following myocardial infarction. Unexpectedly, while FAP targeted bispecific T-cell engaging antibodies (BiTE(R) molecules) effectively eliminate FAP+ fibroblasts from the heart, they surprisingly lead to accelerated deterioration of cardiac function, enhanced remodeling, and increased scar size. FAP BiTE(R) molecules elicit a robust cytokine response within the heart with prominent activation of interferon gamma (IFNg) and CD40 ligand pathways. Target cell killing was independent of IFNg; and CD40L signaling and blockade of these pathways was sufficient to unmask the protective therapeutic effects of FAP+ fibroblast depletion. Mechanistically, we reveal that IFNg; signaling to fibroblasts drives the differentiation of an independent lineage of activated fibroblasts not typically found in the infarcted heart, which are responsible for the harmful effects of FAP BiTE(R) molecules. Collectively, these findings highlight a previously unrecognized cardiac liability of BiTE(R) molecules and inform the design of the next generation of therapeutics.

immunology↗

bioRxiv2025

Targeting RUNX1 in Macrophages Facilitates Cardiac Recovery

Despite advances in disease treatment, our understanding of how damaged organs recover and the mechanisms governing this process remain poorly defined. Here, we mapped the transcriptional and regulatory landscape of human cardiac recovery using single cell multiomics. Macrophages emerged as the most reprogrammed cell type. Deep learning identified the transcription factor RUNX1 as a key regulator of this process. Macrophage-specific Runx1 deletion recapitulated the human cardiac recovery phenotype in a chronic heart failure model. Runx1 deletion reprogrammed macrophages to a reparative phenotype, reduced fibrosis, and promoted cardiomyocyte adaptation. RUNX1 chromatin profiling revealed a conserved regulon that diminished during recovery. Mechanistically, the epigenetic reader BRD4 controlled Runx1 expression in macrophages. Chromatin activity mapping, combined with CRISPR perturbations, identified the precise regulatory element governing Runx1 expression. Therapeutically, small molecule Runx1 inhibition was sufficient to promote cardiac recovery. Our findings uncover a druggable RUNX1 epigenetic mechanism that orchestrates recovery of heart function.

immunology↗

bioRxiv2025

Targeting Modulated Vascular Smooth Muscle Cells in Atherosclerosis via FAP-Directed Immunotherapy

Vascular smooth muscle cell (VSMC) and immune cell diversification play a central role in driving atherosclerotic coronary artery disease (CAD)1-3. However, the molecular mechanisms governing cell state transitions within the neo-intima in human CAD remain poorly understood, and no lipid-independent therapies are currently approved for its treatment. Here, we performed multi-omic single-cell gene expression profiling, epitope mapping, and spatial transcriptomics from 27 human coronary arteries. Our analysis identified fibroblast activation protein (FAP) as a marker of modulated VSMCs within the neo-intima. Genetic lineage tracing in mice confirmed that FAP cells in the plaque originate from medial VSMCs. Additionally, non-invasive positron emission tomography (PET) imaging in patients with CAD revealed focal FAP uptake in atherosclerotic lesions. Spatial transcriptomics further delineated the distinct localization of VSMC and immune cell subsets within plaques, with FAP states enriched in the neo-intima. To explore the therapeutic potential of targeting de-differentiated VSMCs, we developed an anti-FAP bispecific T-cell engager (BiTE) and demonstrated that it significantly reduced the plaque burden in multiple mouse models of atherosclerosis. Collectively, our study provides the first single-cell and spatially resolved map of human CAD, establishes FAP as a marker of modulated smooth muscle cells, and demonstrates the broader potential of immunotherapeutics for lipid independent targets in atherosclerotic CAD.

genomics↗

bioRxiv2024

Dissecting Regulatory Non-Coding Heart Disease GWAS Loci with High-Resolution 3D Chromatin Interactions Reveals Causal Genes with Pathophysiological Relevance to Heart Failure

Heart failure is caused in part by cardiac remodeling processes that include the death of cardiac myocytes and their replacement by cardiac fibroblasts. We hypothesized that these two cell types may harbor epigenetic contexts in which heart disease-associated non-coding SNPs perturb gene expression relevant to disease. Accordingly, we generated high-resolution Hi-C data layered with chromatin accessibility and transcriptomic information to annotate and link putative distal regulatory elements in heart disease-associated loci to gene promoters. Our analysis identified several target genes with established roles in cardiac fibrosis and/or heart disease (GJA1, TBC1D32, CXCL12, IL6R, and FURIN). Perturb-seq in cardiac fibroblasts to knock out putative regulatory elements confirmed regulatory relationships involving GJA1, CXCL12, and FURIN, as gene editing led to changes in transcriptomic signatures associated with fibroblasts in heart failure. Our results demonstrate how integrative multi-omic approaches can delineate pathophysiologically relevant regulatory circuits that connect protein-coding genes to non-coding genetic variants associated with disease.

genomics↗

bioRxiv2022

Targeting the Immune-Fibrosis Axis in Myocardial Infarction and Heart Failure

Cardiac fibrosis is causally linked to heart failure pathogenesis and adverse clinical outcomes. However, the precise fibroblast populations that drive fibrosis in the human heart and the mechanisms that govern their emergence remain incompletely defined. Here, we performed Cellular Indexing of Transcriptomes and Epitomes by sequencing (CITE-seq) in 22 explanted human hearts from healthy donors, acute myocardial infarction (MI), and chronic ischemic and non-ischemic cardiomyopathy patients. We identified a fibroblast trajectory marked by fibroblast activator protein (FAP) and periostin (POSTN) expression that was independent of myofibroblasts, peaked early after MI, remained elevated in chronic heart failure, and displayed a transcriptional signature consistent with fibrotic activity. We assessed the applicability of cardiac fibrosis models and demonstrated that mouse MI, angiotensin II/phenylephrine infusion, and pressure overload models were superior compared to cultured human heart and dermal fibroblasts in recapitulating cardiac fibroblast diversity including pathogenic cell states. Ligand-receptor analysis and spatial transcriptomics predicted interactions between macrophages, T cells, and fibroblasts within spatially defined niches. CCR2+ monocyte and macrophage states were the dominant source of ligands targeting fibroblasts. Inhibition of IL-1{beta} signaling to cardiac fibroblasts was sufficient to suppress fibrosis, emergence, and maturation of FAP+POSTN+ fibroblasts. Herein, we identify a human fibroblast trajectory marked by FAP and POSTN expression that is associated with cardiac fibrosis and identify macrophage-fibroblast crosstalk mediated by IL-1{beta} signaling as a key regulator of pathologic fibroblast differentiation and fibrosis.

immunology↗

bioRxiv2020

The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15

Cardiometabolic syndrome has become a global health issue. Heart failure is a common comorbidity of cardiometabolic syndrome. Successful drug development to prevent cardiometabolic syndrome and associated comorbidities requires preclinical models predictive of human conditions. To characterize the heart failure component of cardiometabolic syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in obese and lean ZSF1 20-to 22-week-old male rats. Cardiac function, exercise capacity, and left ventricular gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-seq results demonstrated changes in left ventricular gene expression associated with fatty acid and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly decreased body weight, food intake, blood glucose, and triglycerides and improved exercise capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model for human cardiometabolic syndrome with established heart failure with preserved ejection fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective effect in obese ZSF1 rats.

physiology↗