Biology subjects

Feuchtinger, A.

Publications and source records attributed to Feuchtinger, A..

7 recordsLinked to original sources

bioRxiv2025

Neural CXCR4 contributes to neuroimmune modulation of atherosclerosis in a cardio-metabolic Ldlr-/- mouse model

BackgroundAtherosclerosis is a chronic inflammatory disease characterized by metabolic and immune dysregulation. Emerging evidence suggests that specific central nervous system (CNS) regions modulate its progression via neuroimmune cardiovascular interfaces (NICIs). While the C-X-C motif chemokine receptor 4 (CXCR4) is known to participate in atherogenesis by regulating immune cell dynamics and vascular wall responses, the role of neural CXCR4 in atherosclerotic plaque formation remains unclear. MethodsWe generated a Nestin-Cre-mediated conditional Cxcr4 knockout mouse model on a low-density lipoprotein receptor-deficient (Ldlr-/-) background and fed these mice a western diet (WD) for up to 12 weeks to induce atherosclerosis. To evaluate the impact of neural CXCR4 function, we quantified atherosclerotic plaque burden, systemic metabolic parameters and circulating immune cell profiles, comparing neural Cxcr4-deficient mice with corresponding genetic controls. Spatial transcriptomics and RNAscope were employed to map Cxcr4 mRNA and its non-canonical ligand macrophage migration inhibitory factor (Mif) mRNA in neuroimmune-regulatory brain regions, and to assess diet-induced expression changes in relation to neuroinflammatory responses. ResultsNeural conditional deletion of Cxcr4 in Ldlr-/- mice significantly reduced atherosclerotic plaque formation in the aortic arch and aorta, without affecting body weight, lipid levels, glucose tolerance, or circulating immune cells. Cxcr4 gene expression was found to be uniformly low across hypothalamic subregions implicated in neuroimmune regulation of systemic inflammation and atherogenesis. Importantly, WD feeding did not modify this consistently low expression in male Ldlr-/- mice. In contrast, Mif mRNA expression was significantly upregulated in the PVN after 5-day WD feeding, but not after 8 weeks. Exploratory spatial transcriptomic analysis of PVN-containing coronal brain sections from male Ldlr-/- mice suggested that 5-day WD exposure is associated with MIF-CXCR4 signaling and downstream neuroinflammatory pathways in the PVN. ConclusionsThis study identifies neural CXCR4 as a component of neuroimmune modulation in atherosclerosis, exerting its effect independently of systemic metabolic or inflammatory changes. Short-term WD exposure activated gene expression of the CXCR4 ligand Mif in the PVN, pointing to a neuroimmune axis that may promote vascular inflammation and atherosclerotic plaque development. These findings establish a link between CNS CXCR4 and vascular disease and suggest that MIF-CXCR4-dependent neuroimmune pathways may play a role in cardiometabolic risk. Trial registrationNot applicable.

immunology↗

bioRxiv2024

Capture of Human Neuromesodermal and Posterior Neural Tube Axial Stem Cells

The spinal cord, nerves, and skeletal muscles arise from neuromesodermal progenitors (NMPs). We have developed a growth-factor screening strategy, utilizing ES and iPS cells, facilitating the indefinite self-renewal of two types of human axial stem cells (AxSCs), closely resembling mouse NMPs (NM-AxSCs) and posterior neural tube progenitors (N-AxSCs). Under specific regimens-- Wnt/CHIR99021, FGF2, and TGF-{beta} inhibitor SB431542 (CFS) and excluding FGF2 (CS), respectively--these AxSCs self-renew and sustain telomeres. Single cell transcriptomics and proteomics have revealed expression of posterior growth-zone and dorsoventral neural tube markers in NM-AxSCs, and correspondingly, differentiation to a wide spectrum of neural tube neurons and myocytes. N-AxSCs rapidly matured into dorsal sensory subsets and neural crest. Crucially, neither AxSC type produces teratomas, and analogous mouse NM-AxSCs integrated successfully into the neural tube and somites. Capturing of AxSCs from patient and GMP ES / iPS cells without transgenesis unveils ontogeny and promises modeling and therapy in neuropathies.

developmental biology↗

bioRxiv2022

Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism

The liver is the major metabolic hub, ensuring appropriate nutrient supply during fasting and feeding. In obesity, accumulation of excess nutrients hampers proper liver function and is linked to non-alcoholic fatty liver disease. Understanding the signaling mechanisms that enable hepatocytes to quickly adapt to dietary cues, might help to restore balance in liver diseases. Post-translational modification by attachment of the Small Ubiquitin-like Modifier (SUMO), allows for a dynamic regulation of numerous processes including transcriptional reprograming. Here, we demonstrate that the specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 was highly modified by SUMOylation on lysine 556 in the liver of ad libitum and re-fed mice, while this modification was strongly abolished upon fasting. In a context of diet-induced obesity, Prox1 SUMOylation became insensitive to fasting cues. Hepatocyte-selective knock in of a SUMOylation-deficient Prox1 mutant into mice fed a high fat/high fructose diet led to reduction of systemic cholesterol levels, associated with the induction of bile acid detoxifying pathways in mutant livers during fasting. As appropriate and controlled fasting protocols have been shown to exert beneficial effects on human health, tools to maintain the nutrient-sensitive SUMOylation switch on Prox1 may thus contribute to the development of "fasting-based" approaches for the maintenance of metabolic health.

physiology↗

bioRxiv2020

Functional multispectral optoacoustic tomography imaging of hepatic steatosis development in mice

The increasing worldwide prevalence of obesity, fatty liver diseases, as well as the emerging understanding of the importance of lipids in multi-faceted aspects of various other diseases is generating significant interest in lipid research. Lipid visualization in particular can play a critical role in understanding functional relations in lipid metabolism. In this study, we investigate the potential of multispectral optoacoustic tomography (MSOT) as a novel modality to non-invasively visualize lipids in laboratory mice. Using an obesity-induced non-alcoholic fatty liver disease (NAFLD) mouse model, we examined whether MSOT could detect and differentiate different grades of hepatic steatosis and monitor the accumulation of lipids in the liver quantitatively over time, without the use of contrast agents, i.e. in label free mode. Moreover, we demonstrate the efficacy of using the real-time clearance kinetics of indocyanine green (ICG) in the liver as a biomarker to evaluate the organs function and assess the severity of NAFLD. This study demonstrates MSOT as an efficient imaging tool for lipid visualization in preclinical studies, particularly for the assessment of NAFLD.

bioengineering↗

bioRxiv2020

Identification and characterization of distinct murine brown adipocyte lineages

Brown adipose tissue (BAT) plays an important role in the regulation of body weight and glucose homeostasis. While increasing evidence supports white adipose tissue heterogeneity, little is known about heterogeneity within murine BAT. Using single cell RNA sequencing of the stromal vascular fraction of murine BAT and analysis of 67 brown preadipocyte and adipocyte clones we unravel heterogeneity within brown preadipocytes. Statistical analysis of gene expression profiles from these clones identifies markers distinguishing brown adipocyte lineages. We confirm the presence of distinct brown adipocyte populations in vivo using three identified markers; Eif5, Tcf25, and Bin1. Functionally, we demonstrate that loss of Bin1 enhances UCP1 expression and mitochondrial respiration, suggesting that Bin1 marks a dormant brown adipocyte type. The existence of multiple brown adipocyte lineages suggests distinct functional properties of BAT depending on its cellular composition, with potentially distinct function in thermogenesis and the regulation of whole body energy homeostasis.

cell biology↗

bioRxiv2020

Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis

Reorganization of the extracellular matrix is a prerequisite for healthy adipose tissue expansion, whereas fibrosis is a key feature of adipose dysfunction and inflammation. However, very little is known about the direct effects of impaired cell-matrix interaction in adipocyte function and insulin sensitivity. Using adipose selective deletion of {beta}1 integrin (Itgb1adipo-cre) and Kindlin-2 (Kind2adipo-cre), we demonstrate here that active {beta}1 and {beta}3 integrins directly interact with the insulin receptor to regulate white adipocyte insulin action and systemic metabolism. Consequently, loss of adipose integrin activity, similar to loss of adipose insulin receptors, results in lipodystrophy and systemic insulin resistance. Conversely, we find that brown adipose tissue of Kind2adipo-cre and Itgb1adipo-cre mice is chronically hyperactivated, and has increased substrate delivery, reduced endothelial basement membrane thickness, and increased endothelial vesicular transport. Thus, we establish integrin-extracellular matrix interactions as key regulators of white and brown adipose tissue function and whole body metabolism.

physiology↗

bioRxiv2020

HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signaling

Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we show that Heart- and neural crest derivatives-expressed protein 2 (HAND2) is an obesity-linked adipocyte transcription factor regulated by glucocorticoids and required for adipocyte differentiation in vitro. In a large cohort of humans with obesity, white adipose tissue (WAT) HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes, induced early in differentiation and responded to dexamethasone, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in human multipotent adipose-derived stem cells (hMADS) or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Using a combinatorial RNAseq approach we identified gene clusters regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.

molecular biology↗