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Cells, Volume 14, Issue 16 (August-2 2025) – 6 articles

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Article
An Ex Vivo Intervertebral Disc Slice Culture Model for Studying Disc Degeneration and Immune Cell Interactions
by Eunha G. Oh, Li Xiao, Zhiwen Xu, Yuan Xing, Yi Zhang, Parastoo Anbaei, Jialun A. Chi, Li Jin, Rebecca R. Pompano and Xudong Li
Cells 2025, 14(16), 1230; https://doi.org/10.3390/cells14161230 (registering DOI) - 8 Aug 2025
Abstract
Intervertebral disc degeneration is a leading cause of back and leg pain and a major contributor to disability worldwide. Despite its prevalence, treatments remain limited due to incomplete understanding of its pathology. In vivo models pose challenges for controlled conditions, while in vitro [...] Read more.
Intervertebral disc degeneration is a leading cause of back and leg pain and a major contributor to disability worldwide. Despite its prevalence, treatments remain limited due to incomplete understanding of its pathology. In vivo models pose challenges for controlled conditions, while in vitro cell cultures lack key cell–cell and cell–matrix interactions. To address these limitations, we developed a novel tissue slice culture model of mouse discs, in which intact mouse discs were sliced down to 300 μm thickness with a vibratome and cultured ex vivo at various time points. The cell viability, matrix components, structure integrity, inflammatory responses, and macrophage interactions were evaluated with biochemistry, gene expression, histology, and 3D imaging analyses. Disc slices maintained structural integrity and cell viability, with preserved extracellular matrix in the annulus fibrosus (AF) and mild degeneration in nucleus pulposus (NP) by day 5. Interleukin-1 (IL-1) induced disc degeneration manifested by increased glycosaminoglycan release in media and reduced aggrecan and collagen II mRNA levels in disc cells. Cultured disc slices promoted macrophages towards pro-inflammatory phenotype with elevated mRNA levels of il-1α, il-6, and inos. Macrophage overlay and 3D imaging demonstrated macrophage infiltration into the NP and AF tissues up to ~100 µm in depth. The disc tissue slice model captures key features of intervertebral discs and can be used for investigating mechanisms of disc degeneration and therapeutic evaluation. Full article
16 pages, 3848 KiB  
Article
Reversing Preeclampsia Pathology: AXL Inhibition Restores Mitochondrial Function and ECM Balance
by Archarlie Chou, Benjamin Davidson, Paul R. Reynolds, Brett E. Pickett and Juan A. Arroyo
Cells 2025, 14(16), 1229; https://doi.org/10.3390/cells14161229 (registering DOI) - 8 Aug 2025
Abstract
Preeclampsia (PE) is a leading cause of maternal and fetal morbidity that affects 2–8% of pregnancies worldwide, driven by placental dysfunction and systemic inflammation. Growth arrest-specific protein 6 (Gas6) and its receptor AXL play pivotal roles in PE pathogenesis, promoting trophoblast impairment and [...] Read more.
Preeclampsia (PE) is a leading cause of maternal and fetal morbidity that affects 2–8% of pregnancies worldwide, driven by placental dysfunction and systemic inflammation. Growth arrest-specific protein 6 (Gas6) and its receptor AXL play pivotal roles in PE pathogenesis, promoting trophoblast impairment and vascular dysregulation. This study investigated the transcriptomic reversal effects of AXL Receptor Tyrosine Kinase (AXL) inhibition in a Gas6-induced rat model of PE using RNA sequencing (RNA-seq). Pregnant rats were administered Gas6 to induce PE-like symptoms such as hypertension and proteinuria; a subset also received the AXL inhibitor R428. RNA-seq of placental tissues revealed 2331 differentially expressed genes (DEGs) in Gas6-AXLi versus Gas6 (1277 upregulated, 1054 downregulated). Protein–protein interaction networks and Gene Ontology enrichment highlighted upregulated mitochondrial functions, including electron transport chain components (e.g., NDUFC2, COX5A), suggesting enhanced energy metabolism. In the secondary analysis that compared Gas6 to Control, Gas6-upregulated extracellular matrix proteins (e.g., COL4A1, LAMC1) linked to fibrosis were reversed by AXL inhibition, indicating ameliorated placental remodeling. AXL inhibition activated compensatory pathways beyond Gas6 blockade, unveiling novel mechanisms for PE resolution. These findings position AXL inhibitors as promising therapeutics, offering insights into mitochondrial and fibrotic targets to mitigate this enigmatic disorder. Full article
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35 pages, 1462 KiB  
Review
The Influence of Irisin on Selected Organs—The Liver, Kidneys, and Lungs: The Role of Physical Exercise
by Maria Ciałowicz, Marek Woźniewski, Eugenia Murawska-Ciałowicz and Piotr Dzięgiel
Cells 2025, 14(16), 1228; https://doi.org/10.3390/cells14161228 (registering DOI) - 8 Aug 2025
Abstract
In recent years, irisin has garnered significant interest among researchers. It is a myokine released by skeletal muscles during physical exercise. Its expression occurs not only in skeletal muscles but also in other organs such as the liver, kidneys, and lungs, where it [...] Read more.
In recent years, irisin has garnered significant interest among researchers. It is a myokine released by skeletal muscles during physical exercise. Its expression occurs not only in skeletal muscles but also in other organs such as the liver, kidneys, and lungs, where it fulfills important metabolic and protective functions. Irisin is involved in the regulation of energy homeostasis, promotes the browning of adipose tissue, plays a protective role, and influences the body’s adaptation to physical exercise. In the context of internal organ function, studies suggest its potential role in protecting the kidneys from damage, modulating inflammatory processes in the lungs, and supporting liver regeneration. This literature review focuses on analyzing the therapeutic effects of irisin in these organs in relation to the role of physical exercise. Full article
(This article belongs to the Section Tissues and Organs)
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22 pages, 2971 KiB  
Article
Pig Liver Esterase Hydrolysis of 2-Arachidonoglycerol Exacerbates PRRSV-Induced Inflammation via PI3K-Akt-NF-κB Pathway
by Yuelin Fu, Huiwen Zhu, Qiling Xiao, Qi Chen, Qiongqiong Zhou, Xiliang Wang and Deshi Shi
Cells 2025, 14(16), 1227; https://doi.org/10.3390/cells14161227 - 8 Aug 2025
Abstract
Inflammation is essential for host defense but requires strict regulation to prevent immunopathology. This study reveals how pig liver esterase (PLE) in alveolar macrophages (PAMs) modulates PRRSV-induced inflammation through endocannabinoid metabolism. We identified PLE6 as the dominant hydrolytically active subtype in PAMs. Functional [...] Read more.
Inflammation is essential for host defense but requires strict regulation to prevent immunopathology. This study reveals how pig liver esterase (PLE) in alveolar macrophages (PAMs) modulates PRRSV-induced inflammation through endocannabinoid metabolism. We identified PLE6 as the dominant hydrolytically active subtype in PAMs. Functional studies demonstrated that PLE promotes pro-inflammatory cytokine expression during PRRSV infection, while its substrate 2-arachidonoylglycerol (2-AG) exerts anti-inflammatory effects. Animal experiments confirmed that PLE inhibition reduces pulmonary inflammation and tissue damage in PRRSV-infected piglets. Transcriptomic and mechanistic analyses revealed that PLE hydrolyzes 2-AG to activate the PI3K-Akt-NF-κB pathway, particularly through enhanced phosphorylation of Akt and p65. These findings establish a novel pathological mechanism where PLE-mediated 2-AG degradation disrupts endocannabinoid homeostasis, amplifying PRRSV-induced inflammation. The study provides therapeutic insights for targeting endocannabinoid hydrolysis to control inflammatory diseases. Full article
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32 pages, 2379 KiB  
Article
A Better Understanding of Atrial-like and Ventricular-like Action Potentials in Stem Cell-Derived Cardiomyocytes: The Underestimated Role of the L-Type Ca2+ Current
by Arie O. Verkerk, Christiaan C. Veerman, Maaike Hoekstra, Harsha D. Devalla and Ronald Wilders
Cells 2025, 14(16), 1226; https://doi.org/10.3390/cells14161226 - 8 Aug 2025
Abstract
Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) tend to show a mixed population of action potential (AP) types, including atrial-like (A-like) and ventricular-like (V-like) APs. In the present study, we investigated the membrane currents underlying these two AP types in hESC-CMs. These were generated [...] Read more.
Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) tend to show a mixed population of action potential (AP) types, including atrial-like (A-like) and ventricular-like (V-like) APs. In the present study, we investigated the membrane currents underlying these two AP types in hESC-CMs. These were generated using standard (Std) and retinoic acid (RA)-based differentiation protocols. Patch clamp methodology was used to correlate AP morphology with major cardiac ion currents by applying alternating current and voltage clamp protocols to each cell, and to measure L-type Ca2+ current (ICa,L) and Na+-Ca2+ exchange current (INCX) in detail, whereas Ca2+ transients were measured ratiometrically using Indo-1. A- and V-like APs were found in both Std and RA-treated hESC-CMs and the AP plateau amplitude (APplat), as a measure of fast phase-1 repolarization, appeared the best AP criterion to separate these two AP types. Traditional voltage clamp experiments revealed a significantly smaller ICa,L density in RA-treated hESC-CMs, as well as larger densities of the transient outward and delayed rectifier K+ currents (Ito1 and IK, respectively), without changes in the inward rectifier K+ current (IK1). The APplat showed strong and moderate correlations with the densities of ICa,L and IK, respectively, in the absence of a clear-cut correlation with the density of Ito1. Using pre-recorded, typical A- and V-like APs, AP clamp demonstrated that the ICa,L-mediated Ca2+ influx during the V-like AP in Std hESC-CMs is 3.15 times larger than the influx during the A-like AP in RA-treated hESC-CMs. Ca2+ transients of A-like hESC-CMs have a lower diastolic and systolic level, as well as a lower amplitude, than those of Std hESC-CMs, while their duration is shorter due to enhanced SERCA activity. In conclusion, ICa,L is an important determinant of the differently shaped A- and V-like APs in hESC-CMs. Furthermore, the Ca2+ homeostasis differs between A- and V-like hESC-CMs due to the smaller ICa,L and enhanced SERCA activity during A-like APs, resulting in a strongly reduced Ca2+ influx, which will cause a substantial reduction in INCX, further contributing to the shorter A-like APs. Full article
(This article belongs to the Section Cells of the Cardiovascular System)
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27 pages, 651 KiB  
Review
From COPD to Smoke-Related Arteriopathy: The Mechanical and Immune–Inflammatory Landscape Underlying Lung Cancer Distant Spreading—A Narrative Review
by Giulia M. Stella, Francesco Rocco Bertuccio, Cristina Novy, Chandra Bortolotto, Ilaria Salzillo, Fabio Perrotta, Vito D’Agnano, Valentina Conio, Vittorio Arici, Pietro Cerveri, Andrea Bianco, Angelo Guido Corsico and Antonio Bozzani
Cells 2025, 14(16), 1225; https://doi.org/10.3390/cells14161225 - 8 Aug 2025
Abstract
Metastatic dissemination defines a complex phenomenon driven by genetic forces and, importantly, determined by interaction between cancer cells and the surrounding stroma. Although the biologic and immune reactions which characterize the process have been widely and extensively evaluated, fewer data are available regarding [...] Read more.
Metastatic dissemination defines a complex phenomenon driven by genetic forces and, importantly, determined by interaction between cancer cells and the surrounding stroma. Although the biologic and immune reactions which characterize the process have been widely and extensively evaluated, fewer data are available regarding the mechanical and physical forces to which circulating neoplastic clones are exposed. It should be hypothesized that this interaction can be modified in case of concomitant pathologic conditions, such as chronic vasculopathy, which frequently occurs in lung cancer patients. We here aim at analyzing and discussing the complex interplay between lung malignant transformation and arteriopathy, mainly focusing on the immune–inflammatory systemic reaction. Notably—in most instances—smoking-related fixed airflow obstruction, including but not limited to COPD, frequently coexists and contributes to both tumor progression and vascular complications. Attention is paid mainly to the analysis of the role of immune checkpoint inhibitors and their interaction with triple bronchodilation and antiaggregants. Understanding the biomechanical and molecular dynamics of lung cancer progression in altered vascular territories has several translational implications in defining risk stratification and in surgical planning and therapeutic targeting. Moreover, computational modeling of the physical forces which regulate the transit and extravasation of metastatic clones in altered contexts could be of help in deciphering the whole process and in determining more effective blockade strategies. Full article
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