Biology subjects

Maas, S. L.

Publications and source records attributed to Maas, S. L..

4 recordsLinked to original sources

bioRxiv2026

Cyclin E/CDK2 deficiency links cell cycle control to intestinal barrier integrity and tight junction regulation

Background & Aims: The intestinal epithelium renews continuously through cell cycle-dependent turnover, yet it remains unknown whether core cell cycle regulators directly control intestinal barrier function. We investigated how loss of the Cyclin E1/Cyclin E2/CDK2 complex affects intestinal homeostasis. Based on the important role of this complex in compensatory liver regeneration, we hypothesized that its combined loss would impair epithelial renewal and barrier integrity. Methods: We generated Ccne2-/- mice and triple knockout (TKO) mice with intestinal epithelial cell (IEC)-specific deletion of Ccne1 and Cdk2 on a constitutive Ccne2-null background and characterized intestinal architecture, proliferation, and barrier function using histology, immunoblotting, qPCR, and FITC-dextran permeability assays. Mechanistic findings were validated in CRISPR/Cas9-generated Ccne2-deficient and CDK1-overexpressing MC38 colon carcinoma cells using transcriptomics and kinomics approaches. Results: Contrary to our hypothesis, TKO maintained and Ccne2-/- mice even enhanced cell cycle activity selectively in the colon, along with enhanced Cdk1 expression, had significantly lower serum FITC-dextran levels after oral administration, and increased Tjp1/ZO-1 expression, consistent with reduced intestinal permeability. Ccne2-deficient MC38 cells recapitulated the increase in ZO-1 and exhibited transcriptional enrichment of gene sets associated with tight junctions and cell cycle. CDK1 overexpression in MC38 cells increased ZO-1 protein abundance and was associated with activation of an AMPK-related kinase network. In TKO and Ccne2-/- colonic epithelium, CDK1, phosphorylated AMPK and ZO-1 showed partial colocalization at lateral epithelial cell-cell contacts. Conclusions: Loss of Cyclin E2, either alone or in combination with epithelial Cyclin E1/CDK2 deficiency, is associated with increased CDK1 expression and strengthens the colonic barrier integrity in mice. Findings from MC38 cells suggest that transcriptional reprogramming and enhanced CDK1 signaling in the context of Cyclin E2 deficiency may contribute to tight junction reinforcement and improved barrier function.

cell biology↗

bioRxiv2025

Uncovering an unconventional JAK1/2-STAT3 branch in macrophage IFNγ signaling

Interferon-{gamma} (IFN{gamma}) is a key cytokine in immune activation, especially anti-viral responses and driver of macrophage activation. It classically signals via JAK1/2-mediated STAT1 homodimers. Here, we identify an alternative, non-canonical signaling component in which IFN{gamma} simultaneously also activates STAT3. Our results show that IFN{gamma} activates STAT3 rapidly and directly through JAK1 and JAK2. We provide the first evidence that STAT3 can form heterodimers with STAT1 in this context and demonstrate that STAT3 is co-recruited to a subset of IFN{gamma}-induced, STAT1-bound regulatory elements. While IFN{gamma} directly activates STAT3, our results reveal that its contribution to gene regulation is limited, indicating that STAT1 easily substitutes the STAT1-STAT3 heterodimer for STAT1 homodimers when STAT3 is absent. These findings uncover STAT3 as a new unconventional player in macrophage IFN{gamma} signaling, underscoring the complex and context-dependent nature of cytokine signaling networks.

immunology↗

bioRxiv2024

Pneumonia induced rise in glucagon promotes endothelial damage and vascular thrombogenicity

BackgroundRecent studies have demonstrated a link between respiratory infections and increased short-term risk of cardiovascular disease (CVD). However, the molecular mechanisms underlying the increased cardiovascular risk after respiratory infections are only poorly understood. Here, we aimed to decipher pathophysiological circuits of pneumonia associated CVD in experimental models of bacterial pneumonia and vascular injury. MethodsC57BL/6J mice were exposed to intranasal inoculation with either Streptococcus pneumoniae (S. pneumoniae) serotype 4 (pneumonia group) or phosphate buffered saline (PBS) (control group). 24 hours post infectionem (p.i.) mice were treated with antibiotics until the end of the study. On day 7 p.i. carotid artery injury (CI) was induced by electric stimulation and vascular repair was analyzed 3 days after injury. Plasma proteomic analyses were performed by Olink Bioscience. Primary human aortic endothelial cells (HAECs) were used to study alterations of the endothelial functional properties, bioenergetic state and thrombogenic potential in vitro. Intravital fluorescence microscopy equipped with video recording was applied to measure thrombus formation in real-time. ResultsBacterial pneumonia impaired repair capacity of the endothelium after vascular injury. Proteomic analyses revealed significantly higher plasma levels of glucagon in mice after recovery from pneumonia relative to controls, which was further confirmed by ELISA detecting glucagon. Mechanistically, we found that glucagon impaired mitochondrial bioenergetics and migratory potential in HAECs and induced an inflammatory response. Moreover, glucagon fostered vascular thrombogenicity as demonstrated by increased thrombocyte adhesion to HAECs and accelerated carotid artery thrombus formation in vivo. Acute application of the glucagon-like peptide-1 receptor (GLP1-R) agonist liraglutide to lower blood glucagon levels, restored vascular repair potential and attenuated vascular thrombogenicity in mice with pneumonia. ConclusionsOur findings reveal a novel mechanism that associates elevated circulatory glucagon levels to dysfunctional endothelium and increased vascular thrombogenicity, suggesting glucagon signaling as a potential therapeutic target to prevent pneumonia-induced cardiovascular events. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/592488v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1dab59eorg.highwire.dtl.DTLVardef@1c9a033org.highwire.dtl.DTLVardef@34a566org.highwire.dtl.DTLVardef@56e33d_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

MicroRNA-26b protects against MASH development and can be efficiently targeted with lipid nanoparticles.

Background & AimsThe prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, urging more research into the underlying mechanisms. MicroRNA-26b (miR-26b) might play a role in several MASH-related pathways. Therefore, we aimed to determine the role of miR-26b in MASH and its therapeutic potential using miR-26b mimic-loaded lipid nanoparticles (LNPs). MethodsApoe-/-Mir26b-/-, Apoe-/-LysMcreMir26bfl/fl mice, and respective controls were fed a western-type diet to induce MASH. Plasma and liver samples were characterized regarding lipid metabolism, hepatic inflammation, and fibrosis. Additionally, miR-26b mimic-loaded LNPs were injected in Apoe-/-Mir26b-/- mice to rescue the phenotype and key results were validated in human precision-cut liver slices. Finally, kinase profiling was used to elucidate underlying mechanisms. ResultsApoe-/-Mir26b-/- mice showed increased hepatic lipid levels, coinciding with increased expression of scavenger receptor a and platelet glycoprotein 4. Similar effects were found in mice lacking myeloid-specific miR-26b. Additionally, hepatic TNF and IL-6 levels and amount of infiltrated macrophages were increased in Apoe-/- Mir26b-/- mice. Moreover, Tgfb expression was increased by the miR-26b deficiency, leading to more hepatic fibrosis. A murine treatment model with miR-26b mimic-loaded LNPs reduced hepatic lipids, rescuing the observed phenotype. Kinase profiling identified increased inflammatory signaling upon miR-26b deficiency, which was rescued by LNP treatment. Finally, miR-26b mimic-loaded LNPs also reduced inflammation in human precision-cut liver slices. ConclusionsOverall, our study demonstrates that the detrimental effects of miR-26b deficiency in MASH can be rescued by LNP treatment. This novel discovery leads to more insight into MASH development, opening doors to potential new treatment options using LNP technology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/580792v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@b8b5b8org.highwire.dtl.DTLVardef@a26333org.highwire.dtl.DTLVardef@11ed2a0org.highwire.dtl.DTLVardef@963208_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗