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Spatial omics of acute myocardial infarction reveals a novel mode of immune cell infiltration
No full textMyocardial 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
Extension of the GRACE score for non-ST-elevation acute coronary syndrome: a development and validation study in ten countries
Get PDFBACKGROUND: The Global Registry of Acute Coronary Events (GRACE) scoring system guides the management of patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) according to current guidelines. However, broad validation of the sex-specific GRACE 3.0 in-hospital mortality model, and corresponding models for predicting long-term mortality and the personalised effect of early invasive management, are still needed. METHODS: We used data of 609 063 patients with NSTE-ACS from ten countries between Jan 1, 2005, and June 24, 2024. A machine learning model for 1-year mortality was developed in 400 054 patients from England, Wales, and Northern Ireland. Both the in-hospital mortality model and the new 1-year mortality model were externally validated in patients from Sweden, Switzerland, Germany, Denmark, Spain, the Netherlands, and Czechia. A separate machine learning model to predict the individualised effect of early versus delayed invasive coronary angiography and revascularisation on a composite primary outcome of all-cause death, non-fatal recurrent myocardial infarction, hospital admission for refractory myocardial ischaemia, or hospital admission for heart failure at a median follow-up of 4·3 years was developed and externally validated in participants from geographically different sets of hospitals in the Danish VERDICT trial. FINDINGS: The in-hospital mortality model (area under the receiver operating characteristic curve [AUC] 0·90, 95% CI 0·89-0·91) and the 1-year mortality model (time-dependent AUC 0·84, 95% CI 0·82-0·86) showed excellent discriminative abilities on external validation across all countries. Both models were well calibrated and decision curve analyses suggested favourable clinical utility. Compared with score version 2.0, both models provided improved discrimination and risk reclassification. The individualised treatment effect model effectively identified patients who would benefit from early invasive management on external validation. Patients with high predicted benefit had reduced risk of the composite outcome when randomly assigned to early invasive management (hazard ratio 0·60, 95% CI 0·41-0·88), whereas patients with no-to-moderate predicted benefit did not (1·06, 0·80-1·40; p(interaction)=0·014). The individualised treatment effect model suggested that the group of patients with NSTE-ACS who benefit from early intervention might be incompletely captured by current treatment strategies. INTERPRETATION: The updated GRACE 3.0 scoring system provides a validated, practical tool to support personalised risk assessment in patients with NSTE-ACS. Prediction of an individual's long-term cardiovascular benefit from early invasive management could refine future trial design
Astrocytic-OTUD7B ameliorates murine experimental autoimmune encephalomyelitis by stabilizing glial fibrillary acidic protein and preventing inflammation
Get PDFAstrocytes are central to the pathogenesis of multiple sclerosis (MS); however, their regulation by post-translational ubiquitination and deubiquitination is unresolved. This study shows that the deubiquitinating enzyme OTUD7B in astrocytes protects against murine experimental autoimmune encephalomyelitis (EAE), a model of MS, by limiting neuroinflammation. RNA-sequencing of isolated astrocytes and spatial transcriptomics show that in EAE, OTUD7B downregulates chemokine expression in astrocytes of inflammatory lesions, which is associated with reduced recruitment of encephalitogenic CD4(+) T cells. Furthermore, OTUD7B is necessary for glial fibrillary acidic protein (GFAP) expression of astrocytes bordering inflammatory lesions. Mechanistically, OTUD7B (i) restricts TNF-induced chemokine production of astrocytes by sequential K63- and K48-deubiquitination of RIPK1, which limits NF-κB and MAPK activation and (ii) enables GFAP protein expression by supporting GFAP mRNA expression and preventing its proteasomal degradation through K48-deubiquitination of GFAP. This dual action on TNF signaling and GFAP identifies OTUD7B as a central inhibitor of astrocyte-mediated inflammation
Zero-shot unsupervised motion estimation for motion-corrected cardiac T1 mapping
Get PDFOBJECTIVE: Cardiac quantitative MRI (qMRI) is a powerful imaging technique for diagnosing pathologies such as diffuse myocardial fibrosis. One main challenge is cardiac motion, which requires synchronization of data acquisition with the heartbeat, leading to long scan times. We present a novel deep learning-based image registration method for cardiac qMRI that enables non-rigid motion correction of data acquired continuously over multiple cardiac cycles, thereby reducing scan times. METHODS: Our method is a zero-shot approach that utilizes the physical qMRI signal model for accurate motion estimation. Non-rigid motion of dynamic images is estimated with a U-Net-based architecture. This exploits the intrinsic smoothness of cardiac motion, allowing sharing information between neighboring images. The approach is robust to undersampling artifacts, enabling motion estimation from dynamic images reconstructed from very few k-space data even without advanced image reconstruction methods. RESULTS: We evaluated the method for fast cardiac T1 mapping using a Golden radial sampling scheme on numerical simulations and in-vivo acquisitions. On numerical simulations, our method achieved a 61.64% improvement in T1 accuracy. On in-vivo data, our approach yielded a 45.13% improvement in sharpness of T1 maps, and temporal image alignment of motion-corrected dynamics improved on average by 11.78%. CONCLUSION: Our method enables accurate non-rigid motion correction of highly undersampled cardiac qMRI data obtained from continuously acquired data. SIGNIFICANCE: As our method is individually optimized for each scan without the need for training on large datasets, it can easily be adapted to other cardiac qMRI approaches
Cluster nanoarchitecture and structural diversity of PIEZO1 at rest and during activation in intact cells
Get PDFThe force- gated ion channel PIEZO1 confers mechanosensitivity to many cell types. While the structure and physiological roles of PIEZO1 are well- described, the subcellular distribution and the impact of the cellular microenvironment on PIEZO1 conformation and function are poorly understood. Here, using MINFLUX nanoscopy, we demonstrate that PIEZO1 channels accumulate in pit- shaped invaginations that are distinct from classical membrane invaginations such as clathrin- coated pits and caveolae, thereby possibly creating hotspots for mechanotransduction. Moreover, by measuring intramolecular distances in individual PIEZO1 channels with nanometer precision, we reveal subcellular compartment- specific differences in PIEZO1 conformation at rest and during activation that correlate with differences in PIEZO1 function and are possibly caused by differences in cytoskeletal architecture. Together, our data provide previously unrecognized insights into the complex interplay of forces that determine how PIEZO1 alters membrane shape and, vice versa, how the membrane together with the cytoskeleton affect the conformation and function of individual PIEZO1 channels
Integrated multimodel analysis of intestinal inflammation exposes key molecular features of preclinical and clinical IBD
Get PDFBACKGROUND: IBD is a chronic inflammatory condition driven by complex genetic and immune interactions, yet preclinical models often fail to fully recapitulate all aspects of the human disease. A systematic comparison of commonly used IBD models is essential to identify conserved molecular mechanisms and improve translational relevance.
OBJECTIVE: We performed a multimodel transcriptomic analysis of 13 widely used IBD mouse models to uncover coregulatory gene networks conserved between preclinical colitis/ileitis and human IBD and to define model-specific and conserved cellular, subcellular and molecular signatures.
DESIGN: We employed comparative transcriptomic analyses with curated and a priori statistical correlative methods between mouse models versus IBD patient datasets at both bulk and single-cell levels.
RESULTS: We identify IBD-related pathways, ontologies and cellular compositions that are translatable between mouse models and patient cohorts. We further describe a conserved core inflammatory signature of IBD-associated genes governing T-cell homing, innate immunity and epithelial barrier that translates into the new mouse gut Molecular Inflammation Score (mMIS). Moreover, specific mouse IBD models have distinct signatures for B-cell, T-cell and enteric neurons. We discover that transcriptomic relatedness of models is a function of the mode of induction, not the canonical immunotype (Th1/Th2/Th17). Moreover, the model compendium database is made available as a web explorer (http://trr241.hosting.rrze.uni-erlangen.de/SEPIA/).
CONCLUSION: This integrated multimodel approach provides a framework for systematically assessing the molecular landscape of intestinal inflammation. Our findings reveal conserved inflammatory circuits, refine model selection, offering a valuable resource for the IBD research community
Astrocytes distress triggers brain pathology through induction of δ secretase in a murine model of Alzheimer’s disease
Get PDFThe importance of astrocytes for Alzheimer’s disease (AD) pathology is increasingly appreciated, yet the mechanisms whereby this cell type impacts neurodegenerative processes remain elusive. Here we show that, in a genetic mouse model with diminished astrocyte stress response, even low levels of amyloid-β trigger astrocyte reactivity, resulting in brain inflammation and massive amyloid and tau pathologies. This dysfunctional response of astrocytes to amyloid-β acts through activation of δ secretase, a stress-induced protease implicated in both amyloid and tau-related proteolytic processing. Ourfindingsidentify a failed astrocyte stress response to amyloid-βas an early inducer of amyloid and tau co-morbidity, a noxious process in AD acting through a non-canonical secretase pathway
Resolving intra-tumor heterogeneity and clonal evolution of core-binding factor acute myeloid leukemia patients with single-cell resolution
Get PDFReconstructing and understanding intra-tumor heterogeneity, the coexistence of multiple genetically distinct subclones within the tumor of a patient, and tumor development is essential for resolving carcinogenesis and for identifying mechanisms of therapy resistance. While bulk sequencing can provide a broad view on tumoral complexity/heterogeneity of a patient, single-cell analysis remains essential to identify rare subclones that might drive chemotherapy resistance. In this study, we performed an integrated analysis of bulk and single-cell DNA sequencing data of core-binding factor acute myeloid leukemia patients, defined by the presence of a RUNX1::RUNX1T1 or CBFB::MYH11 fusion gene. By single-cell sequencing, we inferred tumor phylogenies for 8 patients at diagnosis including patient-specific somatic variants, somatic copy-number alterations and fusion genes, and studied clonal evolution under the pressure of chemotherapy for 3 patients. As a result, we developed an approach to reliably integrate subclonal somatic copy number alterations into phylogenetic trees and clonal evolution analysis, obtaining unprecedented resolution of intra-tumor heterogeneity in CBF AML. We were able to show that the fusion gene is among the earliest events of leukemogenesis at single-cell level. We identified remaining tumor clones in 6 patients with complete remission samples indicating incomplete eradication of the tumor clones. Here, we show that identifying the order of mutation acquisition can provide valuable insights into evolutionary history, offering a framework to improve drug selection in the era of targeted therapies
c-Jun inhibition mitigates chemotherapy-induced neurotoxicity in iPSC-derived sensory neurons
Get PDFChemotherapy-induced peripheral neuropathy (CIPN) affects up to two-thirds of cancer patients undergoing cytotoxic chemotherapy. Here, we used human iPSC-derived sensory neurons (iPSC-DSN) to model CIPN in vitro. Administration of various chemotherapeutic agents (i.e., paclitaxel, vincristine, bortezomib and cisplatin) at clinically applicable concentrations resulted in reduced cell viability, axonal degeneration, electrophysiological dysfunction and increased levels of phosphorylated c-Jun in iPSC-DSN. Transcriptomic analyses revealed that the upregulation of c-Jun strongly correlated with the expression of genes of neuronal injury, apoptosis and inflammatory signatures. To test whether c-Jun plays a central role in the development of CIPN, we applied the small molecule inhibitor of the Jun N-terminal kinase, SP600125, to iPSC-DSN treated with neurotoxic chemotherapy. c-Jun inhibition prevented chemotherapy-induced neurotoxicity by preserving cell viability, axonal integrity and electrophysiological function of iPSC-DSN. These findings identify c-Jun as a key mediator of CIPN pathophysiology across multiple drug types and present preclinical evidence that c-Jun inhibition is an attractive therapeutic target to prevent CIPN
Investigating the association between anthropometry and colorectal cancer survival: a two-sample Mendelian randomization analysis
Get PDFBACKGROUND: Observational epidemiologic studies on the association of anthropometric traits and colorectal cancer (CRC) survival provide inconsistent results, and potential limitations prohibit the investigation of causality. We examined the associations between seven genetically predicted anthropometric traits [height, body mass index (BMI), waist circumference (WC), hip circumference (HC), waist–hip circumference ratio, birth weight and body fat percentage] and CRC-specific mortality among CRC cases using two-sample Mendelian randomization (MR). METHODS: Analyses were performed using 16 964 CRC cases, out of which 4010 died due to their disease, from the Genetics and Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry. We further conducted stratified analyses by anatomical site and stage. We applied the inverse variance weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions and adjust for collider bias. RESULTS: One standard deviation (SD 13.4 cm) higher genetically predicted levels of WC were associated with worse CRC survival [hazard ratio (HR); 1.22, 95% confidence interval (CI); 1.02–1.47]. Positive associations were further observed for a SD higher genetically predicted BMI (SD; 4.8 kg/m(2), HR; 1.5, 95% CI; 1.15–1.95) and HC (SD; 9.2 cm, HR; 1.32, 95% CI; 1.02–1.73) and CRC-specific mortality in cases of stages II/III. The latter associations were generally robust to sensitivity analyses. Positive but imprecisely estimated associations were found for most other anthropometric traits. CONCLUSIONS: Despite the limitations of cancer survival research, our findings support that CRC cases should avoid obesity. Further research should inform the development of recommendations targeting overweight/obesity management during cancer surveillance