Interrogating mediators of single-cell transcriptional changes in the acute damaged cerebral cortex: Insights into endothelial-astrocyte interactionsde Jager, Soliman, Theus
Mol Cell Neurosci (2025) 133, 104003
Abstract: Traumatic brain injury (TBI) induces complex cellular and molecular changes, challenging recovery and therapeutic development. Although molecular pathways have been implicated in TBI pathology, the cellular specificity of these mechanisms remains underexplored. Here, we investigate the role of endothelial cell (EC) EphA4, a receptor tyrosine kinase receptor involved in axonal guidance, in modulating cell-specific transcriptomic changes within the damaged cerebral cortex. Utilizing single-cell RNA sequencing (scRNA-seq) in an experimental TBI model, we mapped transcriptional changes across various cell types, with a focus on astrocytes and ECs. Our analysis reveals that EC-specific knockout (KO) of EphA4 triggers significant alterations in astrocyte gene expression and shifts predominate subclusters. We identified six distinct astrocyte clusters (C0-C5) in the damaged cortex including as C0-Mobp/Plp1+; C1-Slc1a3/Clu+; C2-Hbb-bs/Hba-a1/Ndrg2+; C3-GFAP/Lcn2+; C4-Gli3/Mertk+, and C5-Cox8a+. We validate a new Sox9+ cluster expressing Mertk and Gas, which mediates efferocytosis to facilitate apoptotic cell clearance and anti-inflammatory responses. Transcriptomic and CellChat analyses of EC-KO cells highlights upregulation of neuroprotective pathways, including increased amyloid precursor protein (APP) and Gas6. Key pathways predicted to be modulated in astrocytes from EC-KO mice include oxidative phosphorylation and FOXO signaling, mitochondrial dysfunction and ephrin B signaling. Concurrently, metabolic and signaling pathways in endothelial cells-such as ceramide and sphingosine phosphate metabolism and NGF-stimulated transcription-indicate an adaptive response to a metabolically demanding post-injury hypoxic environment. These findings elucidate potential interplay between astrocytic and endothelial responses as well as transcriptional networks underlying cortical tissue damage.Copyright © 2025 Elsevier Inc. All rights reserved.
Sex-specific molecular hallmarks point to increased atherogenesis susceptibility in male senescence-accelerated miceGonzález-Moro, Herranz, Rodríguez de Lope
et alLife Sci (2025) 369, 123529
Abstract: The senescence-accelerated mouse (SAM) model has been extensively used to study neurological alterations associated with aging. The SAM model has also proved to be useful in the study of vascular aging, but there is still work to be done to better define its utility as a model of atherosclerosis, since contradictory data have been published and sex seems to play a crucial role in potential divergences.With this in mind, we aimed to decipher the molecular mechanisms underlying early vascular aging on SAMP8 mice, analyzing the aorta of 10 months-old animals by means of in-depth proteomic analysis, considering sex-specific differences. Validation of the results obtained were performed by western blot in an independent cohort of mice, as well as in human aortic smooth muscle cells (HASMC). Besides, an exhaustive lipoprotein and glycoprotein analysis was performed in blood plasma.Distinct proteomic, lipoprotein and glycoprotein profiles have been found in SAMP8 mice, according to sex. Male SAMP8 mice showed signs of increased atherogenesis susceptibility due to several sex-specific alterations: 1) increased number of VLDLs, as well as in their cholesterol and TG content; 2) upregulation of inflammatory glycoproteins in plasma; and 3) increased features of SASP and vascular calcification: upregulation of exocytic vesicular transport and downregulation of the protein Gas6. On the contrary, female mice showed a much better proteomic and lipoprotein profile.The results obtained suggest that male SAMP8 mice will be more susceptible to develop atherosclerosis under a HFD than female mice.Copyright © 2024. Published by Elsevier Inc.
AXL kinase inhibitor exhibits antitumor activity by inducing apoptotic cell death in triple-negative breast cancer cellsWoo, Kim, Karapurkar
et alBiochim Biophys Acta Mol Cell Res (2025) 1872 (4), 119928
Abstract: Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with a poor prognosis and decreased patient survival. It is intimately linked to AXL overexpression and AXL hyperactivation. Here, we explored the therapeutic potential of AX-0085, a small molecule AXL inhibitor. While AX-0085 was previously characterized in the context of lung adenocarcinoma, this study demonstrates its application in triple-negative breast cancer (TNBC) models. AX-0085 exhibited high binding affinity to the ATP binding site located beneath the conserved glycine-rich loop (P-loop) that links the β1 and β2 strands of the AXL kinase domain. Furthermore, it was demonstrated that the benzamide group of AX-0085 and LyS567's Nζ atom could generate a hydrogen bond. AX-0085 efficiently suppressed the AXL/GAS6 signaling pathway activation in TNBC cells in vitro, which in turn prevented AXL/GAS6 signaling-dependent pro-cancerous behavior like cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT). In TNBC, an AX-0085-induced cell cycle arrest that took place during the G1 phase reduced the expression of CYCLIN E and CDK2. Additionally, AX-0085 facilitated apoptotic cell death in TNBC. Treatment of AX-0085 on in vivo mouse xenografts transplanted with 4 T1 cells showed a significant tumor reduction. Thus, our findings demonstrate that AX-0085 has an effective therapeutic role in TNBC by inhibiting AXL activation.Copyright © 2025. Published by Elsevier B.V.
Vitamin K supports TGF-β1 depended in vitro human Langerhans cell differentiation and function via AxlBauer, Richter-Eder, Yasmin
et alFront Immunol (2025) 16, 1509228
Abstract: On the outermost edge of the body a dense network of dendritic cells (DCs), the so-called Langerhans cells (LCs), represents the first immune barrier. The establishment and maintenance of this epidermal network is dependent on the cytokine transforming growth factor-β1 (TGF-β1) expressed by keratinocytes (KC) and LCs. We recently identified a crucial downstream effector of TGF-β1, the receptor tyrosine kinase Axl. Axl belongs to the TAM receptor family, which also includes Tyro3 and Mer, and is activated through the vitamin K-dependent ligands Gas6 and Protein S.We have now established that TGF-β1 dependent in vitro human LC generation from CD34+ progenitor cells can be enhanced by Axl over-expression.Additionally, we supplemented vitamin K into serum-free human LC generation cultures in order to activate the endogenous ligands Gas6 and Protein S. Vitamin K exhibited supportive effects on LC differentiation and LC-associated gene expression. The vitamin K antagonist warfarin on the other hand, hindered efficient LC differentiation. Blocking antibodies against Axl abrogated the positive effect of vitamin K on LC differentiation. Lastly, vitamin K downregulated the immune activation marker CD86 during LC differentiation and blocked the upregulation of CD86 during LC activation in vitro, in an Axl independent manner.Taken together, we provide evidence for the supportive role of vitamin K in regulating skin immunity.Copyright © 2025 Bauer, Richter-Eder, Yasmin, Jurkin, Köffel and Strobl.
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