Biology subjects

Gessner, A.

Publications and source records attributed to Gessner, A..

7 recordsLinked to original sources

bioRxiv2025

Differentiation hierarchy in adult B cell acute lymphoblastic leukemia at clonal resolution

While a differentiation hierarchy with leukemia-initiating stem cells (LICs) at the apex is well documented for acute myeloid leukemia, the existence of LICs and their trajectories in B cell acute lymphoblastic leukemia (B-ALL) are debated. B-ALL is a malignant disease displaying considerable phenotypical and functional heterogeneity, yet the underlying cellular organization remains largely elusive. This study aims to investigate the hierarchical landscape of B-ALL by combining barcoding and multiome single cell data to unveil the differentiation architecture and temporal dynamics of leukemic differentiation at clonal and single cell resolution in vivo. Single-cell transcriptome and AbSeq analysis of lentiviral barcoded and transplanted patient-derived B-ALL cells revealed interconnected subpopulations, which could be prospectively isolated via surface markers and exhibited distinct leukemogenicity. Barcode tracking demonstrated the ability of cells to differentiate from a source cluster into differentiated progeny. Using machine learning we identified expression patterns predicting their differentiation potential of each barcoded cell within the immature cell compartment. To determine the dynamical properties of clones, we have designed a mathematical model that simulates the development of these subpopulations from a clonally diverse stem cell compartment. The model confirmed the most likely cluster of origin, supporting our functional data, and revealed the variability in dynamical properties between clones, while largely excluding plasticity. Hence, our work demonstrates a unidirectional differentiation in B-ALL with an immature population exhibiting a high leukemogenic potential. Key pointsO_LIA differentiation hierarchy with distinct leukemogenesis potential in B-ALL is demonstrated via clonal tracing and mathematical modeling. C_LIO_LIClonal differentiation behavior, while heterogeneous, is cell intrinsically controlled and predictable, yet independent from expansion. C_LI

cancer biology↗

bioRxiv2025

A microbial metabolite protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in allo-HSCT patients. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DATs beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DATs dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

immunology↗

bioRxiv2025

TNF-α disrupts the malate-aspartate shuttle, driving metabolic rewiring in iPSC-derived enteric neural lineages from Parkinson's Disease patients

Gastrointestinal (GI) dysfunction emerges years before motor symptoms in Parkinsons disease (PD), implicating the enteric nervous system (ENS) in early disease progression. However, the mechanisms linking the PD hallmark protein, -synuclein (-syn), to ENS dysfunction - and whether these mechanisms are influenced by inflammation - remains elusive. Using iPSC-derived enteric neural lineages from patients with -syn triplications, we reveal that TNF- increases mitochondrial--syn interactions, disrupts the malate-aspartate shuttle, and forces a metabolic shift toward glutamine oxidation. These alterations drive mitochondrial dysfunction, characterizing metabolic impairment under cytokine stress. Interestingly, targeting glutamate metabolism with Chicago Sky Blue 6B restores mitochondrial function, reversing TNF--driven metabolic disruption. Our findings position the ENS as a central player in PD pathogenesis, establishing a direct link between cytokines, -syn accumulation, metabolic stress and mitochondrial dysfunction. By uncovering a previously unrecognized metabolic vulnerability in the ENS, we highlight its potential as a therapeutic target for early PD intervention.

neuroscience↗

bioRxiv2024

Inhibition of IAPs induces programmed cell death and inflammatory signaling in patient-derived metastatic breast cancer organoids

Breast cancer (BC) is the most common type of cancer among women worldwide and underlies relapse, disease progression and metastasis. Resistance to chemotherapy and programmed cell death (PCD), including apoptosis, strongly affects therapy success and remains a major challenge. Representative and translational models to understand, manipulate and cultivate advanced BC and to model PCD resistance are therefore urgently required. Smac mimetics are promising compounds to circumvent apoptosis resistance and are able to induce caspase-independent necroptosis, a lytic and inflammatory mode of PCD. Here, we apply primary, patient-derived human mammary organoids (hMOs) to investigate alternative forms of PCD to overcome apoptosis resistance. Using time lapse brightfield with immunofluorescent confocal microscopy, biochemistry and gene expression analysis, we demonstrate that Smac mimetics induce apoptosis in primary hMOs. By mimicking apoptosis resistance via caspase inhibition, hMOs undergo necroptosis, associated with expression and secretion of inflammatory mediators. Inhibition of linear ubiquitination by the LUBAC inhibitor HOIPIN-8 prevents necroptosis, as well as the expression and release of inflammatory mediators in hMOs. Our findings demonstrate that primary hMOs are effective models to model, study and manipulate PCD responses and inflammation in in primary BC organoids and open new therapeutic screening options for chemotherapy-resistant BC.

cancer biology↗

bioRxiv2024

Gut-specific H3R signaling orchestrates microglia-dependent resolution of peripheral inflammation

Chronic inflammatory diseases, like rheumatoid arthritis (RA) have been described to cause central nervous system (CNS) activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such factor. We show that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord and restore homeostatic microglia, thereby reducing inflammation in the joints. Selective histamine 3 receptor (H3R) signaling in the intestine is critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the SCFA propionate identified one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut-CNS-joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=109 HEIGHT=200 SRC="FIGDIR/small/603031v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@c217b8org.highwire.dtl.DTLVardef@a340ceorg.highwire.dtl.DTLVardef@1f3c1d8org.highwire.dtl.DTLVardef@3b6fc9_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIGut microbiota-derived histamine activates enteric neurons via H3R C_LIO_LILocal intestinal H3R activation induces shift to homeostatic microglia in the spinal cord C_LIO_LICNS controlled decrease in endothelial leakiness resolves synovial inflammation C_LI

immunology↗

bioRxiv2023

IgG4 serum levels are not elevated in cases of Post-COVID syndrome

Recently, unexpectedly high virus-specific IgG4 levels were reported after more than two mRNA vaccinations. Class switch towards IgG4 occurs after long-term antigen exposure, downregulates immune responses and is associated with several autoimmune diseases. Here, we examined differences in antigen-specific IgG subtypes in serum samples from 64 Post-COVID patients and an equally sized cohort of convalescent controls. In both cohorts, the relative amounts of spike protein-specific IgG subtypes were comparable. IgG1 was the most frequent, followed by IgG3, IgG2, and IgG4. A difference between cohorts was observed only for IgG2, which was significantly lower in the Post-COVID cohort. Further analysis of the reactive IgG4 revealed a small but significant difference for the spike protein receptor-binding domain but not for the spike ectodomain. Since the total IgG4 levels are very low, we do not expect a biologically relevant role in Post-COVID syndrome. However, reduced virus-specific IgG2 levels could contribute to the persistence of SARS-CoV-2, causing chronic inflammation in the setting of Post-COVID syndrome.

immunology↗

bioRxiv2023

Scorpionfish BPI is highly active against multiple drug-resistant Pseudomonas aeruginosa isolates from cystic fibrosis patients

Chronic pulmonary infection is a hallmark of cystic fibrosis (CF) and requires continuous antibiotic treatment. In this context, Pseudomonas aeruginosa (Pa) is of special concern since colonizing strains frequently acquire multiple drug resistance (MDR). Bactericidal/permeability-increasing protein (BPI) is a neutrophil-derived, endogenous protein with high bactericidal potency against Gram-negative bacteria. However, a significant range of CF patients produce anti-neutrophil cytoplasmic antibodies against BPI (BPI-ANCA) thereby neutralizing its bactericidal function. In accordance with literature, we describe that 54.3% of a total of 46 CF patients expressed BPI-ANCA. Importantly, an orthologous protein to human BPI (huBPI) derived from the scorpionfish Sebastes schlegelii (scoBPI) completely escaped recognition by these autoantibodies. Moreover, scoBPI exhibited high anti-inflammatory potency towards Pa LPS, and was bactericidal against MDR Pa derived from CF patients at nanomolar concentrations. In conclusion, our results highlight the potential of highly active orthologous proteins of huBPI in treatment of MDR Pa infections, especially in the presence of BPI-ANCA.

microbiology↗