Biology subjects

Fischer, J. W.

Publications and source records attributed to Fischer, J. W..

5 recordsLinked to original sources

bioRxiv2026

The heart-liver axis controls platelet turnover by hepatic STAT3 phosphorylation and TPO regulation after acute myocardial infarction

Background: Platelets play a critical role in thrombo-inflammation following acute myocardial infarction (AMI). Objectives: Their impact on hepatic thrombopoietin (TPO) regulation after AMI remains poorly understood to date. Methods: Wildtype, thrombocytopenic or GPVI deficient mice underwent ischemia/reperfusion (I/R) injury. Platelet activation and turnover, and hepatic expression of different receptors involved in TPO regulation were analyzed. Results: Here, we identify a heart-liver axis that dynamically regulates platelet production post AMI. An elevated platelet turnover with increased reticulated as well as desialylated platelets early after AMI was detected. This was accompanied by the upregulation of specific receptors such as Asgr1/2 and IL-6R and increased phosphorylation of STAT3 in the liver and elevated numbers of megakaryocytes in spleen tissue. Consequently, increased TPO plasma levels at 24h post AMI were detected and platelet counts were rapidly restored after AMI. Platelet depletion induces a compensatory increase in hepatic TPO expression and plasma TPO levels, accompanied by dysregulated STAT3 signaling. This response contrasts with GPVI-deficient (Gp6-/-) mice, which exhibit no major alterations in TPO regulation, suggesting distinct mechanisms between acute thrombocytopenia and chronic platelet receptor deficiency in platelet homeostasis after AMI. These findings provide the first evidence of a direct heart-liver axis regulating platelet homeostasis after AMI, driven by inflammatory and hepatic signaling pathways. Conclusions: Our study highlights a previously unrecognized role of the heart-liver axis in controlling platelet turnover, with hepatic STAT3 signaling as a key mediator. These insights enhance our understanding of post AMI platelet homeostasis and may be critical for future therapeutic strategies.

molecular biology↗

bioRxiv2025

Obesity and diabetes related disturbances in systemic metabolism induce a cardiometabolic heart failure with preserved ejection fraction phenotype in a combined high-fat, high sucrose diet and streptozotocin mouse model

BackgroundDiabetes and obesity are associated with an increased incidence of heart failure with preserved ejection fraction (HFpEF), but the underlying pathophysiological mechanisms are poorly understood. A shortage of appropriate preclinical mouse models reflecting different pathophysiological disease aspects might contribute to this inadequate understanding of the complex and diverse HFpEF pathophysiology. We conducted a comprehensive analysis of a non-genetic, inducible T2DM mouse model with regard to its suitability as a preclinical model of cardiometabolic, diabetes-induced HFpEF. MethodsT2DM was induced in C57Bl/6 mice by high-fat/high-sucrose diet (HFHSD) combined with low-dose streptozotocin (STZ) treatment (DIO-STZ), control animals received standard chow (chow). As additional control groups, animals of a DIO group were solely fed HFHSD throughout the study, and a STZ group received solely STZ injections while maintained on a standard chow. Cardiac function was assessed in vivo by echocardiography and left ventricular catheterization, as well as in vitro using the isolated perfused heart model. Structural, molecular and bioenergetic disturbances were analyzed by immunohistochemistry, RNA-seq, qPCR, western blot, and extracellular flux analysis of myocardial tissue, among others. ResultsBlood glucose, fatty acids and ketone body levels were elevated, and insulin plasma level were reduced in DIO-STZ animals compared to chow. DIO-STZ mice showed a strong cardiometabolic HFpEF phenotype with reduced cardiac output, end-diastolic volume, and increased filling pressure. Neither STZ nor DIO mice showed signs of HFpEF development. No difference in myocardial fibrosis nor in in vitro myocardial stiffness was detected between DIO-STZ and chow. Myocardial RNA-Seq clearly pointed towards disturbances in lipid and ketone metabolism. Extracellular flux analysis in intact cardiac tissue slices revealed an increased fatty acid oxidation capacity without differences in glucose metabolism. Mitochondrial respirometry revealed no indication of general mitochondrial dysfunction or mitochondrial uncoupling, but a reduced capacity for {beta}-hydroxybutyrate oxidation. ConclusionsThe diabetic DIO-STZ mouse model showed a pronounced functional HFpEF phenotype. However, we show clear evidence that the underlying mechanism differs remarkably from the other HFpEF models making the DIO-STZ model a relevant extension of the range of HFpEF mouse models, especially for investigating molecular mechanisms or therapeutical interventions in diabetes associated HFpEF.

physiology↗

bioRxiv2024

Operational lessons learned from simulating an elimination response to a transboundary animal disease in wild animals

Transboundary animal disease (TAD) introductions can have myriad economic, ecological, and societal impacts. When TADs are introduced into wild species, rapid and intense control efforts to reduce wild animal host populations are sometimes needed to eliminate the disease and prevent endemicity and spillover to domestic animal populations. Yet, such intensive efforts are non-trivial, and the rarity of TAD introductions means that personnel rarely have direct experience with these types of operations. Thus, explicit assessments of operational challenges for these kinds of efforts can provide direction to build emergency response preparedness capacity. Here, we simulated a TAD control effort in response to initial detection of a hypothetical index case of a TAD in wild pigs (Sus scrofa) (e.g., African swine fever; ASF). We used three removal methods (aerial control, trapping, and an experimental toxic bait). Then, we conducted an after-action assessment to identify operational challenges for rapidly reducing a population of invasive wild pigs within a simulated outbreak zone. We also simulated carcass recoveries of dispatched pigs, similar to what might be conducted during a response to a TAD with carcass-based transmission (e.g., ASF virus). Here, we describe operational challenges identified during our effort, alongside technological development solutions and a priori strategy needs to improve TAD response operation outcomes.

ecology↗

bioRxiv2024

Platelets induce cell apoptosis of cardiac cells via FasL after acute myocardial infarction

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. Cell apoptosis in the myocardium plays an important role in ischemia and reperfusion (I/R) injury, leading to cardiac damage and dysfunction. Platelets are major players of hemostasis and play a crucial role in vessel occlusion, inflammation and cardiac remodeling after I/R. Here, we studied the impact of platelets on cell apoptosis in the myocardium using a close-chest mouse model of AMI. We found caspase-3 positive resident cardiac cells while leukocytes were negative for caspase-3. Using two different mouse models of thrombocytopenia, we detected a significant reduction of caspase-3 positive cells in the infarct border zone after I/R injury. Further, we identified platelet FasL to induce cell apoptosis via the extrinsic pathway of Fas receptor activation of target cells. Mechanistically, hypoxia triggers platelet adhesion to FasR suggesting that platelet induced apoptosis is elevated after I/R. Platelet-specific FasL knock-out mice showed reduced Bax and BcL-2 expression suggesting that platelets modulate the intrinsic and the extrinsic pathway of apoptosis leading to reduced infarct size after myocardial I/R injury. Therefore, platelet induced cardiac damage needs to be taken into account while optimizing antithrombotic/antiplatelet strategies for patients with AMI.

molecular biology↗

bioRxiv2021

Single-cell transcriptomics defines heterogeneity of epicardial cells and fibroblasts within the infarcted heart

In the adult heart, the epicardium becomes activated after injury, contributing to cardiac healing by secretion of paracrine factors. Here we analyzed by single-cell RNA sequencing combined with RNA in situ hybridization and lineage tracing of WT1+ cells the cellular composition, location, and hierarchy of epicardial stromal cells (EpiSC) in comparison to activated myocardial fibroblasts/stromal cells in infarcted mouse hearts. We identified 11 transcriptionally distinct EpiSC populations, that can be classified in three groups each containing a cluster of proliferating cells. Two groups expressed cardiac specification makers and sarcomeric proteins suggestive of cardiomyogenic potential. Transcripts of HIF-1 and HIF-responsive genes were enriched in EpiSC consistent with an epicardial hypoxic niche. Expression of paracrine factors was not limited to WT1+ cells but was a general feature of activated cardiac stromal cells. Our findings provide the cellular framework by which myocardial ischemia may trigger in EpiSC the formation of cardioprotective/regenerative responses.

cell biology↗