Cells

16 pages, 5043 KiB

Open AccessArticle

Adaptive Optics-Transscleral Flood Illumination Imaging of Retinal Pigment Epithelium in Dry Age-Related Macular Degeneration

by Laura Kowalczuk, Rémy Dornier, Aurélie Navarro, Fanny Jeunet, Christophe Moser, Francine Behar-Cohen and Irmela Mantel

Cells 2025, 14(9), 633; https://doi.org/10.3390/cells14090633 - 24 Apr 2025

Abstract

Adaptive optics-transscleral flood illumination (AO-TFI) is a novel imaging technique with potential for detecting retinal pigment epithelium (RPE) changes in dry age-related macular degeneration (AMD). This single-center prospective study evaluated its ability to visualize pathological features in AMD. AO-TFI images were acquired using [...] Read more.

Adaptive optics-transscleral flood illumination (AO-TFI) is a novel imaging technique with potential for detecting retinal pigment epithelium (RPE) changes in dry age-related macular degeneration (AMD). This single-center prospective study evaluated its ability to visualize pathological features in AMD. AO-TFI images were acquired using the prototype Cellularis^® camera over six 5 × 5° macular zones in patients with good fixation and no exudative changes. Conventional imaging modalities, including spectral-domain optical coherence tomography (OCT), color fundus photography and fundus autofluorescence, were used for comparison. AO-TFI images were correlated with OCT using a custom method (Fiji software, v. 2.9). Eleven eyes of nine patients (70 ± 8.3 years) with early (n = 5), intermediate (n = 1) and atrophic (n = 5) AMD were analyzed. AO-TFI identified relevant patterns in dry AMD. RPE cell visibility was impaired in affected eyes, but AO-TFI distinguished cuticular drusen with hyporeflective centers and bright edges, large ill-defined drusen and stage 3 subretinal drusenoid deposits as prominent hyperreflective spots. It provided superior resolution for small drusen compared to OCT and revealed crystalline structures and hyporeflective dots in atrophic regions. Atrophic borders remained isoreflective unless RPE displacement was absent, allowing precise delineation. These findings highlight AO-TFI’s potential as a sensitive imaging tool for characterizing early AMD and clinical research. Full article

(This article belongs to the Special Issue Advances in the Discovery of Retinal Degeneration)

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21 pages, 2149 KiB

Open AccessArticle

The Efficacy of Targeted Monoclonal IgA Antibodies Against Pancreatic Ductal Adenocarcinoma

by Léon Raymakers, Elsemieke M. Passchier, Meggy E. L. Verdonschot, Mitchell Evers, Chilam Chan, Karel C. Kuijpers, G. Mihaela Raicu, I. Quintus Molenaar, Hjalmar C. van Santvoort, Karin Strijbis, Martijn P. W. Intven, Lois A. Daamen, Jeanette H. W. Leusen and Patricia A. Olofsen

Cells 2025, 14(9), 632; https://doi.org/10.3390/cells14090632 - 24 Apr 2025

Abstract

The efficacy of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) remains limited. The tumor microenvironment (TME), characterized by the accumulation of suppressive myeloid cells including neutrophils, attributes to immunotherapy resistance in PDAC. IgA monoclonal antibodies (mAbs) can activate neutrophils to kill tumor cells; this [...] Read more.

The efficacy of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) remains limited. The tumor microenvironment (TME), characterized by the accumulation of suppressive myeloid cells including neutrophils, attributes to immunotherapy resistance in PDAC. IgA monoclonal antibodies (mAbs) can activate neutrophils to kill tumor cells; this can be further enhanced by blocking the myeloid immune checkpoint CD47. In this study, we investigated the potential of this therapeutic strategy for PDAC. We determined the expression of tumor-associated antigens (TAAs) on PDAC cell lines and fresh patient samples, and the results showed that the TAAs epithelial cell adhesion molecule (EpCAM), trophoblast cell surface antigen 2 (TROP2) and mucin-1 (MUC1), as well as CD47 were consistently expressed on PDAC. In line with this, we showed that IgA mAbs against EpCAM can activate neutrophils to lyse various PDAC cell lines and tumor cells, which can be augmented by addition of CD47 blockade. In addition, we observed that neutrophils were present in patient tumors and expressed the receptor for IgA. In conclusion, our results indicate that a combination of IgA mAb with CD47 blockade is a promising preclinical treatment strategy for PDAC, which merits further investigation. Full article

(This article belongs to the Section Cellular Immunology)

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30 pages, 2540 KiB

Open AccessReview

Ion Channel Regulation in Caveolae and Its Pathological Implications

by Jianyi Huo, Liangzhu Mo, Xiaojing Lv, Yun Du and Huaqian Yang

Cells 2025, 14(9), 631; https://doi.org/10.3390/cells14090631 - 24 Apr 2025

Abstract

Caveolae are distinctive, flask-shaped structures within the cell membrane that play critical roles in cellular signal transduction, ion homeostasis, and mechanosensation. These structures are composed of the caveolin protein family and are enriched in cholesterol and sphingolipids, creating a unique lipid microdomain. Caveolae [...] Read more.

Caveolae are distinctive, flask-shaped structures within the cell membrane that play critical roles in cellular signal transduction, ion homeostasis, and mechanosensation. These structures are composed of the caveolin protein family and are enriched in cholesterol and sphingolipids, creating a unique lipid microdomain. Caveolae contribute to the functional regulation of various ion channels through both physical interactions and involvement in complex signaling networks. Ion channels localized within caveolae are involved in critical cellular processes such as the generation and propagation of action potentials, cellular responses to mechanical forces, and regulation of metabolism. Dysregulation of caveolae function has been linked to the development of various diseases, including cardiovascular disorders, neurodegenerative diseases, metabolic syndrome, and cancer. This review summarizes the ion channel function and regulation in caveolae, and their pathological implications, offering new insights into their potential as therapeutic targets for ion channel-related diseases. Full article

(This article belongs to the Special Issue Function and Dysfunction of the Caveolar Network in Cell Signaling and Human Disease: An Update after 70 Years of the Discovery of Caveolae)

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27 pages, 26805 KiB

Open AccessArticle

Combined Transplantation of Mesenchymal Progenitor and Neural Stem Cells to Repair Cervical Spinal Cord Injury

by Seok Voon White, Yee Hang Ethan Ma, Christine D. Plant, Alan R. Harvey and Giles W. Plant

Cells 2025, 14(9), 630; https://doi.org/10.3390/cells14090630 - 23 Apr 2025

Abstract

Mesenchymal progenitor cells (MPC) are effective in reducing tissue loss, preserving white matter, and improving forelimb function after a spinal cord injury (SCI). We proposed that by preconditioning the mouse by the intravenous delivery (IV) of MPCs for 24 h following SCI, this [...] Read more.

Mesenchymal progenitor cells (MPC) are effective in reducing tissue loss, preserving white matter, and improving forelimb function after a spinal cord injury (SCI). We proposed that by preconditioning the mouse by the intravenous delivery (IV) of MPCs for 24 h following SCI, this would provide a more favorable tissue milieu for an NSC intraspinal bridging transplantation at day three and day seven. In combination, these transplants will provide better anatomical and functional outcomes. The intravenous MSCs would provide cell protection and reduce inflammation. NSCs would provide a tissue bridge for axonal regeneration and myelination and reconnect long tract spinal pathways. Results showed that initial protection of the injury site by IV MPCs transplantation resulted in no increased survival of the NSCs transplanted at day seven. However, integration of transplanted NSCs was increased at the day three timepoint, indicating MPCs influence very early immune signaling. We show, in this study, that MPC transplantation resulted in a co-operative NSC cell survival improvement on day three post-SCI. In addition to increased NSC survival on day three, there was an increase in NSC-derived mature oligodendrocytes at this early timepoint. An in vitro analysis confirmed MPC-driven oligodendrocyte differentiation, which was statistically increased when compared to control NSC-only cultures. These observations provide important information about the combination, delivery, and timing of two cellular therapies in treating SCI. This study provides important new data on understanding the MPC inflammatory signaling within the host tissue and timepoints for cellular transplantation survival and oligodendroglia differentiation. These results demonstrate that MPC transplantation can alter the therapeutic window for intraspinal transplantation by controlling both the circulating inflammatory response and local tissue milieu. Full article

(This article belongs to the Special Issue Stem Cell, Differentiation, Regeneration and Diseases)

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14 pages, 2980 KiB

Open AccessReview

Inflammatory Factors: A Key Contributor to Stress-Induced Major Depressive Disorder

by Qian Liu, Baowen Nie, Xuemin Cui, Wang Wang and Dongxiao Duan

Cells 2025, 14(9), 629; https://doi.org/10.3390/cells14090629 - 23 Apr 2025

Abstract

Major depressive disorder (MDD) is a prevalent psychiatric disorder with a complex pathogenesis influenced by various factors. Recent research has highlighted a significant connection between psychological stress and MDD, with inflammation playing a central role in this relationship. Studies have demonstrated that peripheral [...] Read more.

Major depressive disorder (MDD) is a prevalent psychiatric disorder with a complex pathogenesis influenced by various factors. Recent research has highlighted a significant connection between psychological stress and MDD, with inflammation playing a central role in this relationship. Studies have demonstrated that peripheral immune changes in patients with MDD and in mouse models of social stress are closely linked to depressive symptoms. These findings suggest that targeting peripheral immune factors could represent a novel approach for treating stress-related neuropsychiatric disorders. Stress triggers a cascade of inflammatory responses, leading to disruptions in neurotransmitter metabolism and reduced synaptic plasticity. These changes exacerbate depression and contribute to cognitive decline. This study examines the bidirectional relationship between MDD and stress, focusing on the role of inflammation in this complex interplay. Recent studies have identified specific immune factors that are elevated in the serum of patients with MDD and stress-exposed mice, indicating a mechanism by which peripheral immune responses can affect central nervous system function and behavior. Furthermore, proteins, such as nuclear factor kappa-B (NF-κB), reportedly play a critical role in the regulation of stress hormones and are associated with depressive behaviors. Understanding these mechanisms is essential for advancing diagnostic, intervention, and treatment strategies for MDD. Full article

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11 pages, 4908 KiB

Open AccessBrief Report

The Influence of the COVID-19 Pandemic in NK Cell Subpopulations from CML Patients Enrolled in the Argentina Stop Trial

by María Belén Sanchez, Bianca Vasconcelos Cordoba, Carolina Pavlovsky, Beatriz Moiraghi, Ana Ines Varela, Isabel Giere, Mariana Juni, Nicolas Flaibani, José Mordoh, Julio Cesar Sanchez Avalos, Estrella Mariel Levy and Michele Bianchini

Cells 2025, 14(9), 628; https://doi.org/10.3390/cells14090628 - 23 Apr 2025

Abstract

Treatment-free remission (TFR) is a key therapeutic goal for chronic myeloid leukemia (CML) patients in deep molecular response (DMR). While predicting patient outcome remains challenging, different NK cell populations seem crucial. We conducted an immunological sub-study from the Argentina Stop Trial (AST), including [...] Read more.

Treatment-free remission (TFR) is a key therapeutic goal for chronic myeloid leukemia (CML) patients in deep molecular response (DMR). While predicting patient outcome remains challenging, different NK cell populations seem crucial. We conducted an immunological sub-study from the Argentina Stop Trial (AST), including 46 patients in 2019 (AST I) and 35 new patients between 2022 and 2023 (AST II). To characterize NK cell subsets in patients attempting TFR, peripheral blood mononuclear cell samples were collected before stopping treatment and phenotype and functional characteristics were assessed by flow cytometry. Non-relapsing patients from AST I exhibited NK cell subpopulations with cytomegalovirus-related memory features, high expression of cytotoxicity markers, and robust functionality. Remarkably, though clinical variables were very similar between cohorts, significant immune differences were observed. NK cell percentage and CD16 and CD57 receptor expression levels were significantly reduced in AST II (p = 0.0051; p = 0.0222; p = 0.0033, respectively), whereas NKp46, NKp44 and PD-1 expression levels were significantly increased (p = 0.0081; p < 0.0001; p < 0.0001, respectively). NK cells from AST II patients demonstrated higher overall functionality and more memory-like subpopulations, characterized mainly by the expression of CD57, NKG2C, NKp30 and NKp46 receptors among CD56^dim NK cells, also with enhanced functional performance. However, in AST II, we were unable to report an association with clinical outcome. Given the enrollment time of both cohorts and that they appear to be clinically homogeneous, we consider that COVID could be impacting the immune landscape; accordingly, serum samples from AST II, but not AST I, confirmed the presence of anti-SARS-CoV-2 IgG. The influence of the COVID pandemic and the different vaccine platforms on NK cells cannot be underestimated when evaluating the role of the immune system in cancer. Full article

(This article belongs to the Special Issue Emerging Insights into Natural Killer Cell Immunity in Infection and Cancer)

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27 pages, 4284 KiB

Open AccessArticle

Revitalizing the Epigenome of Adult Jaw Periosteal Cells: Enhancing Diversity in iPSC-Derived Mesenchymal Stem Cells (iMSCs)

by Felix Umrath, Valerie Wendt, Gilles Gasparoni, Yasser Narknava, Jörn Walter, Bernd Lethaus, Josefin Weber, Victor Carriel, Meltem Avci-Adali and Dorothea Alexander

Cells 2025, 14(9), 627; https://doi.org/10.3390/cells14090627 - 22 Apr 2025

Abstract

Induced pluripotent stem cells (iPSCs) are rapidly emerging as a transformative resource in regenerative medicine. In a previous study, our laboratory achieved a significant milestone by successfully reprograming jaw periosteal cells (JPCs) into iPSCs, which were then differentiated into iPSC-derived mesenchymal stem cells [...] Read more.

Induced pluripotent stem cells (iPSCs) are rapidly emerging as a transformative resource in regenerative medicine. In a previous study, our laboratory achieved a significant milestone by successfully reprograming jaw periosteal cells (JPCs) into iPSCs, which were then differentiated into iPSC-derived mesenchymal stem cells (iMSCs). Using an optimized protocol, we generated iMSCs with a remarkable osteogenic potential while exhibiting lower expression levels of the senescence markers p16 and p21 compared to the original JPCs. This study aimed to explore the epigenetic landscape by comparing the DNA methylation and transcription profiles of iMSCs with their JPC precursors, seeking to uncover key differences. Additionally, this analysis provided an opportunity for us to investigate the potential rejuvenation effects associated with cellular reprogramming. To assess the safety of the generated cells, we evaluated their ability to form teratomas through subcutaneous injection into immunodeficient mice. Our findings revealed that, while the methylation profile of iMSCs closely mirrored that of JPCs, distinct iMSC-specific methylation patterns were evident. Strikingly, the application of DNA methylation (DNAm) clocks for biological age estimation showed a dramatic reduction in DNAm age to approximately zero in iPSCs—a rejuvenation effect that persisted in the derived iMSCs. This profound reset in biological age, together with our transcriptome data, indicate that iMSCs could possess an enhanced regenerative potential compared to adult MSCs. Future in vivo studies should validate this hypothesis. Full article

(This article belongs to the Special Issue Updates of Stem Cell Applications in Bone Tissue Engineering)

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23 pages, 2416 KiB

Open AccessArticle

On the Quest for Biomarkers: A Comprehensive Analysis of Modified Nucleosides in Ovarian Cancer Cell Lines

by Daniel A. Mohl, Simon Lagies, Alexander Lonzer, Simon P. Pfäffle, Philipp Groß, Moritz Benka, Markus Jäger, Matthias C. Huber, Stefan Günther, Dietmar A. Plattner, Ingolf Juhasz-Böss, Clara Backhaus and Bernd Kammerer

Cells 2025, 14(9), 626; https://doi.org/10.3390/cells14090626 - 22 Apr 2025

Abstract

Ovarian carcinoma is a gynecological cancer with poor long-term survival rates when detected at advanced disease stages. Early symptoms are non-specific, and currently, there are no adequate strategies to identify this disease at an early stage when much higher survival rates can be [...] Read more.

Ovarian carcinoma is a gynecological cancer with poor long-term survival rates when detected at advanced disease stages. Early symptoms are non-specific, and currently, there are no adequate strategies to identify this disease at an early stage when much higher survival rates can be expected. Ovarian carcinoma is a heterogeneous disease, with various histotypes originating from different cells and tissues, and is characterized by distinct somatic mutations, progression profiles, and treatment responses. Our study presents a targeted metabolomics approach, characterizing seven different ovarian (cancer-) cell lines according to their extracellular, intracellular, and RNA-derived modified nucleoside profiles. Moreover, these data were correlated with transcriptomics data to elucidate the underlying mechanisms. Modified nucleosides are excreted in higher amounts in cancer cell lines due to their altered DNA/RNA metabolism. This study shows that seven different ovarian cancer cell lines, representing different molecular subtypes, can be discriminated according to their specific nucleoside pattern. We suggest modified nucleosides as strong biomarker candidates for ovarian cancer with the potential for subtype-specific discrimination. Extracellular modified nucleosides have the highest potential in the distinguishing of cell lines between control cell lines and themselves, and represent the closest to a desirable, non-invasive biomarker, since they accumulate in blood and urine. Full article

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17 pages, 2551 KiB

Open AccessArticle

Platelet-Derived Soluble CD40L and Its Impact on Immune Modulation and Anti-IL6R Antibody Treatment Outcome in Rheumatoid Arthritis

by Carlos Zamora, Cesar Diaz-Torne, Maria Angels Ortiz, Patricia Moya, Hye Sang Park, Concepció Pitarch, Elisabet Cantó, Ruben Osuna-Gomez, Maria Mulet, Maisa Garcia-Arguinzonis, Diego Collado, Hector Corominas and Silvia Vidal

Cells 2025, 14(9), 625; https://doi.org/10.3390/cells14090625 - 22 Apr 2025

Abstract

Background: Platelets (PLTs) from healthy donors (HD) modulate T lymphocyte responses but PLTs from rheumatoid arthritis (RA) patients contribute to persistent systemic inflammation. This suggests that PLTs from RA patients and HD have different immunomodulatory effects. Methods: Using cell culture, flow cytometry, proteomics, [...] Read more.

Background: Platelets (PLTs) from healthy donors (HD) modulate T lymphocyte responses but PLTs from rheumatoid arthritis (RA) patients contribute to persistent systemic inflammation. This suggests that PLTs from RA patients and HD have different immunomodulatory effects. Methods: Using cell culture, flow cytometry, proteomics, and ELISA, we compared PLTs from HD and RA patients and their effects on T lymphocyte activation and cytokine production. Results: HD PLTs suppressed T lymphocyte proliferation and IFNγ and TNF production, while RA PLTs exhibited reduced suppressive capacity. In the presence of RA PLTs, IFNγ levels correlated with T lymphocyte proliferation, greater disease activity, and anti-citrullinated protein antibodies (ACPA). Proteomic analysis revealed that RA PLTs show upregulation of proteins linked to acute-phase response and complement activation. RA PLTs secreted higher levels of soluble CD40L (sCD40L) and PDGF-BB that correlated with enhanced IFNγ production. Seropositive RA patients had higher levels of sCD40L, and these levels were predictive of disease remission in RA patients treated with anti-IL6R. sCD40L was found to enhance T lymphocyte activation and to contribute to increased pro-inflammatory cytokine production. Conclusions: This study highlights the diminished ability of RA PLTs to suppress T lymphocyte activation and that sCD40L can be a potential biomarker and therapeutic target in RA. Full article

(This article belongs to the Special Issue Molecular and Cellular Insights into Platelet Function)

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21 pages, 2478 KiB

Open AccessReview

Beyond Infection: The Role of Secreted Viral Proteins in Pathogenesis, Disease Severity and Diagnostic Applications

by Luis Herrera-Moro Huitron, Víctor Javier Cruz-Holguin, José Manuel Ulloa-Aguilar, Luis Adrián De Jesús-González, Juan Fidel Osuna-Ramos, Mario Guzmán-Huerta, Mercedes Piedad de León-Bautista, Guadalupe León-Reyes, Julio García-Cordero, Leticia Cedillo-Barrón, Jorge Francisco Cerna-Cortes and Moisés León-Juárez

Cells 2025, 14(9), 624; https://doi.org/10.3390/cells14090624 - 22 Apr 2025

Abstract

Secreted viral proteins are crucial in virus–host interactions, as they modify the host microenvironment to promote infection. These secreted proteins could alter immune and inflammatory responses, allowing viruses to evade defense mechanisms such as cytotoxic T cell activation and antibody neutralization. Some secreted [...] Read more.

Secreted viral proteins are crucial in virus–host interactions, as they modify the host microenvironment to promote infection. These secreted proteins could alter immune and inflammatory responses, allowing viruses to evade defense mechanisms such as cytotoxic T cell activation and antibody neutralization. Some secreted proteins mimic host molecules to suppress antiviral responses, making them valuable targets for antivirals and diagnostics. Notable examples include BARF1 from Epstein–Barr virus, associated with gastric cancer; vIL-10 from Epstein–Barr virus, which regulates immune responses and contributes to autoimmune diseases; NS1 from dengue virus, associated with vascular permeability and early diagnosis; and NSP4 from rotavirus as an enterotoxin, among others. The study of these proteins improves our understanding of viral pathogenesis and helps to develop innovative treatments for infectious and non-infectious diseases, taking advantage of the evolutionary adaptations of viruses. This review explores their impact on the infection cycle, disease progression, and key processes, such as cell cycle regulation, apoptosis, and cell signaling. Research on these proteins deepens our basic knowledge of virology and generates alternative methods for detecting biomarkers and creating more effective therapies, as well as implementing some emerging technologies, such as biosensors and plasmon resonance, for the diagnosis of viral diseases. Full article

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14 pages, 3340 KiB

Open AccessArticle

Let-7 Family microRNAs Regulate the Expression of the Urokinase-Receptor in Acute Myeloid Leukemia Cells

by Anna Li Santi, Mariaevelina Alfieri, Luigia Meo and Pia Ragno

Cells 2025, 14(9), 623; https://doi.org/10.3390/cells14090623 - 22 Apr 2025

Abstract

The urokinase-receptor (uPAR) exerts multiple functions supporting most cancer hallmarks. Increased uPAR expression is associated with an unfavorable prognosis in several cancer types, including hematologic malignancies. We previously reported that three oncosuppressor microRNAs (miRNAs) can target the 3′untranslated region (3′UTR) of the uPAR [...] Read more.

The urokinase-receptor (uPAR) exerts multiple functions supporting most cancer hallmarks. Increased uPAR expression is associated with an unfavorable prognosis in several cancer types, including hematologic malignancies. We previously reported that three oncosuppressor microRNAs (miRNAs) can target the 3′untranslated region (3′UTR) of the uPAR mRNA and that uPAR mRNA is a competitive endogenous RNA (ceRNA) able to recruit oncosuppressor miRs, thus impairing their activity. We now show that uPAR mRNA can also be targeted by oncosuppressor members of the let-7 miRNA family in acute myeloid leukemia (AML) cell lines. Indeed, let-7a, let7d and let-7g directly target the 3′UTR of uPAR mRNA, thus down-regulating uPAR expression. These let-7 miRNAs are expressed in KG1 and U937 AML cells; their levels are high in KG1 cells, which express low uPAR levels, and low in the U937 cell line, expressing high levels of uPAR. Overexpression of these miRNAs down-regulates uPAR expression and impairs the adhesion to fibronectin and migration of U937 cells, without affecting their proliferation. Accordingly, the overexpression of specific inhibitors targeting these let-7 miRNAs efficiently increases uPAR expression in KG1 cells. These results indicate that selected let-7 miRNAs regulate uPAR expression and impair the adhesion and migration of AML cells. Full article

(This article belongs to the Special Issue Non-Coding and Coding RNAs in Targeted Cancer Therapy)

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4 pages, 2369 KiB

Open AccessCorrection

Correction: Belisario et al. ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma. Cells 2020, 9, 647

by Dimas Carolina Belisario, Muhlis Akman, Martina Godel, Virginia Campani, Maria Pia Patrizio, Lorena Scotti, Claudia Maria Hattinger, Giuseppe De Rosa, Massimo Donadelli, Massimo Serra, Joanna Kopecka and Chiara Riganti

Cells 2025, 14(9), 622; https://doi.org/10.3390/cells14090622 - 22 Apr 2025

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas)

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22 pages, 4181 KiB

Open AccessArticle

Mimicking the Liver Sinusoidal Endothelial Cell Niche In Vitro to Enhance Fenestration in a Genetic Model of Systemic Inflammation

by Dibakar Borah, Oliwia Blacharczyk, Karolina Szafranska, Izabela Czyzynska-Cichon, Sara Metwally, Konrad Szymanowski, Wolfgang Hübner, Jerzy Kotlinowski, Ewelina Dobosz, Peter McCourt, Thomas Huser, Malgorzata Lekka and Bartlomiej Zapotoczny

Cells 2025, 14(8), 621; https://doi.org/10.3390/cells14080621 - 21 Apr 2025

Abstract

Liver sinusoidal endothelial cells (LSECs) play a crucial role in hepatic homeostasis, clearance, and microcirculatory regulation. Their fenestrations—patent transcellular pores—are essential for proper liver function, yet disappear in pathological conditions such as liver fibrosis and inflammation through a process known as defenestration. Defenestrated [...] Read more.

Liver sinusoidal endothelial cells (LSECs) play a crucial role in hepatic homeostasis, clearance, and microcirculatory regulation. Their fenestrations—patent transcellular pores—are essential for proper liver function, yet disappear in pathological conditions such as liver fibrosis and inflammation through a process known as defenestration. Defenestrated sinusoids are often linked to the liver stiffening that occurs through mechanotransduction-regulated processes. We performed a detailed characterization of polyacrylamide (PAA) hydrogels using atomic force microscopy (AFM), rheometry, scanning electron microscopy, and fluorescence microscopy to assess their potential as biomimetic substrates for LSECs. We additionally implemented AFM; quantitative fluorescence microscopy, including high-resolution structured illumination microscopy (HR-SIM); and an endocytosis assay to characterize the morphology and function of LSECs. Our results revealed significant local variations in hydrogel stiffness and differences in pore sizes. The primary LSECs cultured on these substrates had a range of stiffnesses and were analyzed with regard to their number of fenestrations, cytoskeletal organization, and endocytic function. To explore mechanotransduction in inflammatory liver disease, we investigated LSECs from a genetic model of systemic inflammation triggered by the deletion of Mcpip1 in myeloid leukocytes and examined their ability to restore their fenestrations on soft substrates. Our study demonstrates the beneficial effect of soft hydrogels on LSECs. Control cells exhibited a similar fenestrated morphology and function compared to cells cultured on plastic substrates. However, the pathological LSECs from the genetic model of systemic inflammation regained their fenestrations when cultured on soft hydrogels. This observation supports previous findings on the beneficial effects of soft substrates on LSEC fenestration status. Full article

(This article belongs to the Section Cell Microenvironment)

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24 pages, 6557 KiB

Open AccessArticle

LFA-1/ICAM-1 Interactions Between CD8⁺ and CD4⁺ T Cells Promote CD4⁺ Th1-Dominant Differentiation and CD8⁺ T Cell Cytotoxicity for Strong Antitumor Immunity After Cryo-Thermal Therapy

by Yichen Yao, Zelu Zhang, Shicheng Wang, Junjun Wang, Yuankai Hao, Ke Wang and Ping Liu

Cells 2025, 14(8), 620; https://doi.org/10.3390/cells14080620 - 21 Apr 2025

Abstract

CD4⁺ T cells have been well-regarded as “helper” cells in activating the cytotoxicity of CD8⁺ T cells for effective tumor eradication, while few studies have focused on whether CD8⁺ T cells regulate CD4⁺ T cells. Our previous studies provided [...] Read more.

CD4⁺ T cells have been well-regarded as “helper” cells in activating the cytotoxicity of CD8⁺ T cells for effective tumor eradication, while few studies have focused on whether CD8⁺ T cells regulate CD4⁺ T cells. Our previous studies provided evidence for an interaction between CD4⁺ and CD8⁺ T cells after cryo-thermal therapy, but the mechanism remains unclear, especially pertaining to how CD8⁺ T cells promote the Th1 differentiation of CD4⁺ T cells. This study revealed that activated CD4⁺ and CD8⁺ T cells are critical for CTT-induced antitumor immunity, and the interaction between activated T cells is enhanced. The reciprocal regulation of activated CD8⁺ and CD4⁺ T cells was through LFA-1/ICAM-1 interactions, in which CD8⁺ T cells facilitate Notch1-dependent CD4⁺ Th1-dominant differentiation and promote IL-2 secretion of CD4⁺ T cells. Meanwhile, IL-2 derived from CD4⁺ T cells enhances the cytotoxicity of CD8⁺ T cells and establishes a positive feedback loop via increasing the expression of LFA-1 and ICAM-1 on T cells. Clinical analyses further validated that LFA-1/ICAM interactions between CD4⁺ and CD8⁺ T cells are correlated with clinical outcomes. Our study extends the functions of the LFA-1/ICAM-1 adhesion pathway, indicating its novel role in the interaction of CD4⁺ and CD8⁺ T cells. Full article

(This article belongs to the Section Cell Signaling)

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48 pages, 5608 KiB

Open AccessReview

Induced Pluripotent Stem Cells-Based Regenerative Therapies in Treating Human Aging-Related Functional Decline and Diseases

by Peijie Yu, Bin Liu, Cheng Dong and Yun Chang

Cells 2025, 14(8), 619; https://doi.org/10.3390/cells14080619 - 21 Apr 2025

Abstract

A significant increase in life expectancy worldwide has resulted in a growing aging population, accompanied by a rise in aging-related diseases that pose substantial societal, economic, and medical challenges. This trend has prompted extensive efforts within many scientific and medical communities to develop [...] Read more.

A significant increase in life expectancy worldwide has resulted in a growing aging population, accompanied by a rise in aging-related diseases that pose substantial societal, economic, and medical challenges. This trend has prompted extensive efforts within many scientific and medical communities to develop and enhance therapies aimed at delaying aging processes, mitigating aging-related functional decline, and addressing aging-associated diseases to extend health span. Research in aging biology has focused on unraveling various biochemical and genetic pathways contributing to aging-related changes, including genomic instability, telomere shortening, and cellular senescence. The advent of induced pluripotent stem cells (iPSCs), derived through reprogramming human somatic cells, has revolutionized disease modeling and understanding in humans by addressing the limitations of conventional animal models and primary human cells. iPSCs offer significant advantages over other pluripotent stem cells, such as embryonic stem cells, as they can be obtained without the need for embryo destruction and are not restricted by the availability of healthy donors or patients. These attributes position iPSC technology as a promising avenue for modeling and deciphering mechanisms that underlie aging and associated diseases, as well as for studying drug effects. Moreover, iPSCs exhibit remarkable versatility in differentiating into diverse cell types, making them a promising tool for personalized regenerative therapies aimed at replacing aged or damaged cells with healthy, functional equivalents. This review explores the breadth of research in iPSC-based regenerative therapies and their potential applications in addressing a spectrum of aging-related conditions. Full article

(This article belongs to the Special Issue The Potential of Induced Pluripotent Stem Cells)

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24 pages, 1421 KiB

Open AccessReview

Mitochondrial Dysfunction: A New Hallmark in Hereditable Thoracic Aortic Aneurysm Development

by Daniel Marcos-Ríos, Antonio Rochano-Ortiz, Irene San Sebastián-Jaraba, María José Fernández-Gómez, Nerea Méndez-Barbero and Jorge Oller

Cells 2025, 14(8), 618; https://doi.org/10.3390/cells14080618 - 21 Apr 2025

Abstract

Thoracic aortic aneurysms (TAAs) pose a significant health burden due to their asymptomatic progression, often culminating in life-threatening aortic rupture, and due to the lack of effective pharmacological treatments. Risk factors include elevated hemodynamic stress on the ascending aorta, frequently associated with hypertension [...] Read more.

Thoracic aortic aneurysms (TAAs) pose a significant health burden due to their asymptomatic progression, often culminating in life-threatening aortic rupture, and due to the lack of effective pharmacological treatments. Risk factors include elevated hemodynamic stress on the ascending aorta, frequently associated with hypertension and hereditary genetic mutations. Among the hereditary causes, Marfan syndrome is the most prevalent, characterized as a connective tissue disorder driven by FBN1 mutations that lead to life-threatening thoracic aortic ruptures. Similarly, mutations affecting the TGF-β pathway underlie Loeys–Dietz syndrome, while mutations in genes encoding extracellular or contractile apparatus proteins, such as ACTA2, are linked to non-syndromic familial TAA. Despite differences in genetic origin, these hereditary conditions share central pathophysiological features, including aortic medial degeneration, smooth muscle cell dysfunction, and extracellular remodeling, which collectively weaken the aortic wall. Recent evidence highlights mitochondrial dysfunction as a crucial contributor to aneurysm formation in Marfan syndrome. Disruption of the extracellular matrix–mitochondrial homeostasis axis exacerbates aortic wall remodeling, further promoting aneurysm development. Beyond its structural role in maintaining vascular integrity, the ECM plays a pivotal role in supporting mitochondrial function. This intricate relationship between extracellular matrix integrity and mitochondrial homeostasis reveals a novel dimension of TAA pathophysiology, extending beyond established paradigms of extracellular matrix remodeling and smooth muscle cell dysfunction. This review summarizes mitochondrial dysfunction as a potential unifying mechanism in hereditary TAA and explores how understanding mitochondrial dysfunction, in conjunction with established mechanisms of TAA pathogenesis, opens new avenues for developing targeted treatments to address these life-threatening conditions. Mitochondrial boosters could represent a new clinical opportunity for patients with hereditary TAA. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Marfan Syndrome)

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16 pages, 5298 KiB

Open AccessArticle

Neuregulin-1 (NRG1) Binds to the Allosteric Binding Site (Site 2) and Suppresses Allosteric Integrin Activation by Inflammatory Cytokines: A Potential Mechanism of Anti-Inflammatory and Anti-Fibrosis Action of NRG1

by Yoko K. Takada and Yoshikazu Takada

Cells 2025, 14(8), 617; https://doi.org/10.3390/cells14080617 - 21 Apr 2025

Abstract

We showed that multiple inflammatory cytokines (e.g., CCL5, CXCL12, CX3CL1, CD40L, and FGF2) bind to the allosteric site (site 2) of integrins, distinct from the classical RGD-binding site (site 1), and allosterically activate integrins. A major inflammatory lipid mediator 25-hydroxycholesterol is known to [...] Read more.

We showed that multiple inflammatory cytokines (e.g., CCL5, CXCL12, CX3CL1, CD40L, and FGF2) bind to the allosteric site (site 2) of integrins, distinct from the classical RGD-binding site (site 1), and allosterically activate integrins. A major inflammatory lipid mediator 25-hydroxycholesterol is known to bind to site 2 and allosterically activates integrins and induces inflammatory signals (e.g., IL-6 and TNF secretion). Thus, site 2 is involved in inflammatory signaling. Neuregulin-1 (NRG1) is known to suppresses the progression of inflammatory diseases, fibrosis, and insulin resistance. But, the mechanism of anti-inflammatory action of NRG1 is unclear. We previously showed that NRG1 binds to the classical RGD-binding site (site 1). Mutating the 3 Lys residues that are involved in site 1 binding (NRG1 3KE mutant) is defective in binding to site 1 and in ErbB3-mediated mitogenic signals. Docking simulation predicted that NRG1 binds to site 2. We hypothesized that NRG1 acts as an antagonist of site 2 and blocks allosteric activation by multiple cytokines. Here, we describe that NRG1 binds to site 2 but does not activate soluble αvβ3 or αIIbβ3 in 1 mM Ca²⁺, unlike inflammatory cytokines. Instead, NRG1 suppressed integrin activation by several inflammatory cytokines, suggesting that NRG1 acts as a competitive inhibitor of site 2. Wild-type NRG1 is not suitable for long-term treatment due to its mitogenicity. We showed that the non-mitogenic NRG1 3KE mutant still bound to site 2 and inhibited allosteric activation of soluble and cell-surface integrins, suggesting that NRG1 3KE may have potential as a therapeutic. Full article

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18 pages, 2372 KiB

Open AccessReview

LncRNAs Regulate Vasculogenic Mimicry in Human Cancers

by Eloísa Ibarra-Sierra, Mercedes Bermúdez, Carlos Esteban Villegas-Mercado, Macrina B. Silva-Cázares and César López-Camarillo

Cells 2025, 14(8), 616; https://doi.org/10.3390/cells14080616 - 20 Apr 2025

Abstract

Vasculogenic mimicry (VM) has recently been discovered as an alternative mechanism for nourishing cancer cells in vivo. During VM, tumor cells align and organize themselves into three-dimensional (3D) channel-like structures to transport nutrients and oxygen to the internal layers of tumors. This mechanism [...] Read more.

Vasculogenic mimicry (VM) has recently been discovered as an alternative mechanism for nourishing cancer cells in vivo. During VM, tumor cells align and organize themselves into three-dimensional (3D) channel-like structures to transport nutrients and oxygen to the internal layers of tumors. This mechanism mainly occurs in aggressive solid tumors and has been associated with poor prognosis in oncologic patients. Long non-coding RNAs (lncRNAs) are essential regulators of protein-encoding genes involved in cancer development and progression. These single-stranded RNA molecules regulate critical cellular functions in cancer cells including cell proliferation, apoptosis, angiogenesis, VM, therapy response, migration, invasion, and metastasis. Recently, high-throughput RNA-sequencing technologies have identified thousands of lncRNAs, but only a small percentage of them have been functionally characterized in human cancers. The vast amount of data about its genomic expression in tumors can allow us to dissect their functions in cancer biology and make them suitable biomarkers for cancer diagnosis and prognosis. In this study, we reviewed the current knowledge about the role of lncRNAs in regulating VM in cancer. We also examined the molecular mechanisms of lncRNAs and highlight several commonalities in the cellular functions associated with VM between diverse cancer types. Future directions for research focused on deciphering their function in VM are delineated. Finally, the potential of selected lncRNAs as novel therapeutic targets in RNA-based molecular interventions is also discussed. Full article

(This article belongs to the Special Issue Non-Coding and Coding RNAs in Targeted Cancer Therapy)

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24 pages, 2785 KiB

Open AccessArticle

A Mimetic Assay of Neutrophil Extracellular Trap Degradation Using YOYO-1-Stained DNA-Histone Surface Webs

by Katherine H. Nguyen, Midori L. Wasielewski, Srilakshmi Yalavarthi, Xianggui Qu, Jason S. Knight and Shuichi Takayama

Cells 2025, 14(8), 615; https://doi.org/10.3390/cells14080615 - 19 Apr 2025

Abstract

Neutrophil extracellular traps (NETs) are not only promising biomarkers of disease, but also potential therapeutic targets. Overproduction or the improper clearance of NETs has been linked to disease severity. In vitro NET degradation assays can reveal mechanisms and degradation efficiency differences in diseased [...] Read more.

Neutrophil extracellular traps (NETs) are not only promising biomarkers of disease, but also potential therapeutic targets. Overproduction or the improper clearance of NETs has been linked to disease severity. In vitro NET degradation assays can reveal mechanisms and degradation efficiency differences in diseased serum samples. There is a need for more convenient assays to increase the speed of NET degradation studies. This paper describes a simplified, lower variability mimetic assay with DNA–histone structures, referred to as surface webs, that performs functionally similarly to traditional NET degradation assays with increased scalability, ease of use, shorter preparation time, and lowered costs. The surface webs are created and dehydrated in a 96-well microplate that is shelf-stable, transportable, and viable for 30 days of storage at room temperature. The surface webs, compared to NETs, have similar shapes and distribution but lower intraplate variability while degrading with healthy serum and DNase I within the same timeframe. The assay can identify patient serum with reduced degradation capabilities. This assay opens new opportunities for NET-targeted drug discovery and studies on the role of NETs as modulators of disease. Full article

(This article belongs to the Special Issue Formation, Aggregation, Persistence, and Maturation of NETs)

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