Biology subjects

Hartmann, N.

Publications and source records attributed to Hartmann, N..

9 recordsLinked to original sources

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↗

bioRxiv2026

Tricuspid valve regurgitation accelerates heart failure via a cardio-intestinal innate immune circuit

Activation of the immune system impacts the progression of heart failure (HF), but the underlying mechanisms remain incompletely understood. Here, we identify a cardio-intestinal innate immune axis that links systemic venous congestion to myocardial inflammation, fibrosis, and functional decline. Using single-cell and single-nucleus transcriptomic profiling in patients and mice with tricuspid regurgitation (TR), we demonstrate that TR disrupts intestinal barrier integrity and elicits expansion of circulating monocytes which in turn orchestrate pathological crosstalk between the right and left heart. Monocyte-derived Interleukin-6 (IL-6) emerged as a key mediator of TR-driven myocardial fibrosis and dysfunction. Blockade of IL-6 attenuated cardiac fibrosis and improved cardiac function. In patients, catheter-based repair of TR resulted in reduced IL-6 levels. Together, these findings establish cardio-intestinal innate immunity as a mechanism linking altered hemodynamics to left ventricular remodeling and nominate TR patients as a selective target population for IL-6-directed therapy in HF. One Sentence SummaryThis work mechanistically resolves the heart-gut axis in tricuspid valve regurgitation, and its impact on heart failure progression as mediated by Interleukin-6.

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

Quantum Cognition Machine Learning for Forecasting Chromosomal Instability

The accurate prediction of chromosomal instability from the morphology of circulating tumor cells (CTCs) enables real-time detection of CTCs with high metastatic potential in the context of liquid biopsy diagnostics. However, it presents a significant challenge due to the high dimensionality and complexity of single-cell digital pathology data. Here, we introduce the application of Quantum Cognition Machine Learning (QCML), a quantum-inspired computational framework, to estimate morphology-predicted chromosomal instability in CTCs from patients with metastatic breast cancer. QCML leverages quantum mechanical principles to represent data as state vectors in a Hilbert space, enabling context-aware feature modeling, dimensionality reduction, and enhanced generalization without requiring curated feature selection. QCML outperforms conventional machine learning methods when tested on out of sample verification CTCs, achieving higher accuracy in identifying predicted large-scale state transitions (pLST) status from CTC-derived morphology features. These preliminary findings support the application of QCML as a novel machine learning tool with superior performance in high-dimensional, low-sample-size biomedical contexts. QCML enables the simulation of cognition-like learning for the identification of biologically meaningful prediction of chromosomal instability from CTC morphology, offering a novel tool for CTC classification in liquid biopsy.

cancer biology↗

bioRxiv2024

Spatial omics of acute myocardial infarction reveals a novel mode of immune cell infiltration

Myocardial infarction (MI) continues to be a leading cause of death worldwide. Even though it is well-established that the complex interplay between different cell types determines the overall healing response after MI, the precise changes in the tissue architecture are still poorly understood. Here we generated an integrative cellular map of the acute phase after murine MI using a combination of imaging-based transcriptomics (Molecular Cartography) and antibody-based highly multiplexed imaging (Sequential Immunofluorescence), which enabled us to evaluate cell-type compositions and changes at subcellular resolution over time. One striking finding of these analyses was the identification of a novel mode of leukocyte accumulation to the infarcted heart via the endocardium - the inner layer of the heart. To investigate the underlying mechanisms driving this previously unknown infiltration route, we performed unbiased spatial proteomic analysis using Deep Visual Proteomics (DVP). When comparing endocardial cells of homeostatic hearts and infarcted hearts, DVP identified von Willebrand Factor (vWF) as an upregulated mediator of inflammation 24 hours post-MI. To further explore the immune mediating capabilities of vWF and its effect on tissue repair, we performed functional blocking of vWF during acute murine MI. This resulted in a reduced amount of infiltration by CCR2+ monocytes and worse cardiac function post-MI. Our study provides the first spatial map of acute murine MI with subcellular resolution and subsequently discovers a novel route of immune infiltration. Furthermore, we identified vWF as a critical immune mediating agent for endocardial immune cell infiltration.

systems biology↗

bioRxiv2023

The Tgf-β family member Gdf6Y determines the male sex in Nothobranchius furzeri by suppressing oogenesis-inducing genes

The short-lived African killifish Nothobranchius furzeri lives in seasonal freshwater ponds and has evolved remarkable traits to survive in this limited environment. One of those traits is a genetic XX/XY sex-determination system, which ensures an equal distribution of both sexes. Comparisons of female and male genomic sequences identified the Y-chromosomal copy of the TGF-{beta} family member gdf6 as the candidate male sex-determining (SD) gene, which was named gdf6Y in contrast to the X-chromosomal allele gdf6X. CRISPR/Cas9-mediated inactivation of gdf6Y in N. furzeri led to a complete male-to-female sex reversal in XY animals. The homozygous inactivation of gdf6X on the other hand led to a detrimental phenotype post-hatching. This phenotype was compensated by gdf6Y, revealing that the latter became the SD gene while retaining at least some of its original gdf6 function. Gdf6Y is expressed in testicular somatic cells already prior to hatching, where it represses the germ cell-intrinsic feminizing gene foxl2l. We have identified components of the TGF-{beta} signaling pathway, especially the inhibitor of DNA binding genes id1/2/3, and the mRNA decay activator zfp36l2, as Gdf6Y targets. We conclude that Gdf6Y exerts its function as the male sex-determining gene by suppressing female-specific genes in the developing gonad of male N. furzeri.

molecular biology↗

bioRxiv2023

Single-cell transcriptomics reveal distinctive patterns of fibroblast activation in murine heart failure with preserved ejection fraction

Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 next to basement membrane compounds. Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell-states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we found an expansion of pro-inflammatory Ly6Chigh macrophages in HFpEF, and we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNF[a]. Finally, a marker of murine HFpEF fibroblast activation, Angiopoietin-like 4, was elevated in plasma samples of HFpEF patients and associated with disease severity. Taken together, our study provides a comprehensive characterization of molecular fibroblast and macrophage activation patterns in murine HFpEF, as well as the identification of a novel biomarker for disease progression in patients.

cell biology↗

bioRxiv2021

Specialized subsets of innate-like T cells and dendritic cells protect from lethal pneumococcal infection in the lung

Innate-like T cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and {gamma}{delta} T cells, are present in various barrier tissues, including the lung. They carry out protective responses during infections, but the mechanisms for protection are not completely understood. Here, we investigated their roles during pulmonary infection with Streptococcus pneumoniae. Following infection, innate-like T cells rapidly increased in lung tissue, in part through recruitment, but TCR activation and cytokine production occurred mostly in IL-17-producing NKT17 and {gamma}{delta} T cells. NKT17 cells were preferentially located outside the vasculature prior to infection, as were CD103+ dendritic cells (cDC1), which were important both for antigen presentation to NKT17 cells and {gamma}{delta} T cell activation. Whereas IL-17A-producing {gamma}{delta} T cells also were numerous, GM-CSF was exclusive to NKT17 cells and contributed to iNKT cell-mediated protection. These studies demonstrate how particular cellular interactions and responses of functional subsets of innate-like T cells contribute to protection from pathogenic lung infection.

immunology↗

bioRxiv2021

Systems analysis reveals ageing-related perturbations in retinoids and sex hormones in Alzheimer's and Parkinson's diseases

Neurodegenerative diseases (NDDs), including Alzheimers (AD) and Parkinsons diseases (PD), are complex heterogeneous diseases with highly variable patient responses to treatment. Due to the growing evidence for ageing-related clinical and pathological commonalities between AD and PD, these diseases have recently been studied in tandem. In this study, we analyse transcriptomic data from AD and PD patients, and stratify these patients into three subclasses with distinct gene expression and metabolic profiles. Through integrating transcriptomic data with a genome-scale metabolic model and validating our findings by network exploration and co-analysis using a zebrafish ageing model, we identify retinoids as a key ageing-related feature in all subclasses of AD and PD. We also demonstrate that the dysregulation of androgen metabolism by three different independent mechanisms is a source of heterogeneity in AD and PD. Taken together, our work highlights the need for stratification of AD/PD patients and development of personalised and precision medicine approaches based on the detailed characterisation of these subclasses.

systems biology↗