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Cells

Cells is an international, peer-reviewed, open access journal on cell biology, molecular biology, and biophysics, published semimonthly online by MDPI. The Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH) and Society for Regenerative Medicine (Russian Federation) (RPO) are affiliated with Cells and their members receive discounts on the article processing charges.

Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, MEDLINE, PMC, CAPlus / SciFinder, and other databases.
Journal Rank: JCR - Q2 (Cell Biology) / CiteScore - Q1 (General Biochemistry, Genetics and Molecular Biology)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 17 days after submission; acceptance to publication is undertaken in 2.6 days (median values for papers published in this journal in the second half of 2024).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Sections: published in 21 topical sections.
Companion journal: Organoids.

Impact Factor: 5.1 (2023); 5-Year Impact Factor: 6.0 (2023)

Imprint Information Journal Flyer Open Access ISSN: 2073-4409

Latest Articles

17 pages, 10990 KiB

Open AccessArticle

Rotavirus Spreads in a Spatially Controlled Manner

by Gianna V. Passarelli, Patricio Doldan, Camila Metz-Zumaran, Yagmur Keser, Steeve Boulant and Megan L. Stanifer

Cells 2025, 14(4), 313; https://doi.org/10.3390/cells14040313 (registering DOI) - 19 Feb 2025

Rotavirus is an enteric virus that leads to 200,000 deaths worldwide every year. The live-cell imaging evaluating rotavirus infection of MA104 cells revealed that rotavirus replication and spread occurs in a spatially controlled manner. Specifically, following initial rotavirus infection, the infected cells die, [...] Read more.

Rotavirus is an enteric virus that leads to 200,000 deaths worldwide every year. The live-cell imaging evaluating rotavirus infection of MA104 cells revealed that rotavirus replication and spread occurs in a spatially controlled manner. Specifically, following initial rotavirus infection, the infected cells die, and the second round of infection occurs in the restricted area surrounding the initially infected cell. Interestingly, we found that the time required to establish the secondary infection is shorter compared to the time required for the initial infection. To determine if this increase in the kinetic of secondary infection was due to the early release of viruses or priming of the cells that are infected during the secondary infection, we used a combination of live-cell microscopy, trypsin neutralization assays, and the pharmacological inhibition of calcium signaling. Together, our results show that the second round of infection required rotavirus to be released and accessible to extracellular proteases. In addition, we found that the calcium wave induced upon rotavirus infection was critical for initial infection but did not play a role in the establishment of a secondary infection. Finally, we uncovered that high viral titers released from the initial infection were sufficient to accelerate the rate of the secondary infection. Full article

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21 pages, 15816 KiB

Open AccessReview

Exploratory Review and In Silico Insights into circRNA and RNA-Binding Protein Roles in γ-Globin to β-Globin Switching

by Alawi Habara

Cells 2025, 14(4), 312; https://doi.org/10.3390/cells14040312 (registering DOI) - 19 Feb 2025

β-globin gene cluster regulation involves complex mechanisms to ensure proper expression and function in RBCs. During development, switching occurs as γ-globin is replaced by β-globin. Key regulators, like BCL11A and ZBTB7A, repress γ-globin expression to facilitate this transition with other factors, like KLF1, [...] Read more.

β-globin gene cluster regulation involves complex mechanisms to ensure proper expression and function in RBCs. During development, switching occurs as γ-globin is replaced by β-globin. Key regulators, like BCL11A and ZBTB7A, repress γ-globin expression to facilitate this transition with other factors, like KLF1, LSD1, and PGC-1α; these regulators ensure an orchestrated transition from γ- to β-globin during development. While these mechanisms have been extensively studied, circRNAs have recently emerged as key contributors to gene regulation, but their role in β-globin gene cluster regulation remains largely unexplored. Although discovered in the 1970s, circRNAs have only recently been recognized for their functional roles, particularly in interactions with RNA-binding proteins. Understanding how circRNAs contribute to switching from γ- to β-globin could lead to new therapeutic strategies for hemoglobinopathies, such as sickle cell disease and β-thalassemia. This review uses the circAtlas 3.0 database to explore circRNA expressions in genes related to switching from γ- to β-globin expression, focusing on blood, bone marrow, liver, and spleen. It emphasizes the exploration of the potential interactions between circRNAs and RNA-binding proteins involved in β-globin gene cluster regulatory mechanisms, further enhancing our understanding of β-globin gene cluster expression. Full article

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12 pages, 1895 KiB

Open AccessArticle

Comparison Between Signal Transduction Pathway Activity in Blood Cells of Sepsis Patients and Laboratory Models

by Wilbert Bouwman, Reinier Raymakers, Tom van der Poll and Anja van de Stolpe

Cells 2025, 14(4), 311; https://doi.org/10.3390/cells14040311 (registering DOI) - 19 Feb 2025

Sepsis represents a serious disease burden that lacks effective treatment. Drug development for sepsis requires laboratory models that adequately represent sepsis patients. Simultaneous Transcriptome-based Activity Profiling of Signal Transduction Pathway (STAP-STP) technology quantitatively infers STP activity from mRNA levels of target genes of [...] Read more.

Sepsis represents a serious disease burden that lacks effective treatment. Drug development for sepsis requires laboratory models that adequately represent sepsis patients. Simultaneous Transcriptome-based Activity Profiling of Signal Transduction Pathway (STAP-STP) technology quantitatively infers STP activity from mRNA levels of target genes of the STP-associated transcription factor. Here, we used STAP-STP technology to compare STP activities between sepsis patients and lipopolysaccharide (LPS)-based models. Activity scores of Androgen Receptor (AR), TGFβ, NFκB, JAK-STAT1/2, and JAK-STAT3 STPs were calculated based on publicly available transcriptome data. Peripheral blood mononuclear cells (PBMCs) from patients with Gram-negative sepsis, nor PBMCs stimulated with LPS in vitro, showed altered STP activity. Increased NFκB, JAK-STAT1/2, and JAK-STAT3 STP activity was found in whole blood stimulated with LPS in vitro, and in whole blood obtained after intravenous injection of LPS in humans in vivo; AR and TGFβ STP activity only increased in the in vivo LPS model. These results resembled previously reported STP activity in whole blood of sepsis patients. We provide the first comparison of STP activity between patients with sepsis and laboratory model systems. Results are of use for the refinement of sepsis model systems for rational drug development. Full article

(This article belongs to the Section Cell Signaling)

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28 pages, 7761 KiB

Open AccessArticle

Therapeutic Targeting of the Galectin-1/miR-22-3p Axis Regulates Cell Cycle and EMT Depending on the Molecular Subtype of Breast Cancer

by Ju Yeon Kim, Jun Ho Lee, Eun Jung Jung, Young Sim Son, Hee Jin Park, Jae Myung Kim, Taejin Park, Sang-Ho Jeong, Jinkwon Lee, Tae Han Kim, Seon Min Lee and Jeong Doo Heo

Cells 2025, 14(4), 310; https://doi.org/10.3390/cells14040310 - 19 Feb 2025

Breast cancer is a highly heterogeneous disease; hence, it is crucial to understand its biology and identify new targets for the development of effective treatments. Galectin-1 is known to play an oncogenic role in breast cancer progression. It is known that oncogenic factors [...] Read more.

Breast cancer is a highly heterogeneous disease; hence, it is crucial to understand its biology and identify new targets for the development of effective treatments. Galectin-1 is known to play an oncogenic role in breast cancer progression. It is known that oncogenic factors can influence cancer progression through interactions with miRNAs. The purpose of this study is to identify the clinical significance and biological role of galectin-1 and miR-22-3p in cancer progression according to the molecular subtype of breast cancer. We analyzed the expression of galectin-1 and miR-22-3p using cancer tissues and the correlation with clinical pathological characteristics. In addition, we investigated the regulation of the cell cycle and EMT processes of cancer progression through the galectin-1/miR-22-3p axis using cell lines of different breast cancer subtypes. miR-22-3p negatively regulates galectin-1 expression and the two molecules have opposite patterns of oncogenic and tumor-suppressive functions, respectively; furthermore, these two molecules are associated with metastasis-free survival. Cell experiments showed that miR-22-3p overexpression and galectin-1 knockdown inhibited the proliferation and invasion of breast cancer cells. Galectin-1 regulates different cancer progression pathways depending on the molecular subtype. In hormone receptor-positive breast cancer cells, galectin-1 knockdown mainly inhibited cell cycle-related substances and induced G0/G1 arrest, whereas in triple-negative breast cancer cells, it suppressed molecules related to the epithelial–mesenchymal transition pathway. In conclusion, the miR-22-3p/galectin-1 axis regulates different cancer metastasis mechanisms depending on the specific molecular subtype of breast cancer, and miR-22-3p/galectin-1 axis modulation may be a novel target for molecular subtype-specific personalized treatment. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Breast Cancer)

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17 pages, 1432 KiB

Open AccessReview

The CD39/CD73/Adenosine and NAD/CD38/CD203a/CD73 Axis in Cutaneous T-Cell Lymphomas

by Liyun Lin, Gabriele Roccuzzo, Yuliya Yakymiv, Sara Marchisio, Erika Ortolan, Ada Funaro, Rebecca Senetta, Valentina Pala, Martine Bagot, Adèle de Masson, Maxime Battistella, Emmanuella Guenova, Simone Ribero and Pietro Quaglino

Cells 2025, 14(4), 309; https://doi.org/10.3390/cells14040309 - 19 Feb 2025

Cutaneous T-cell lymphoma (CTCL), characterized by malignant T-cell proliferation primarily in the skin, includes subtypes such as mycosis fungoides (MF) and Sézary syndrome (SS). The tumor microenvironment (TME) is central to their pathogenesis, with flow cytometry and histology being the gold standards for [...] Read more.

Cutaneous T-cell lymphoma (CTCL), characterized by malignant T-cell proliferation primarily in the skin, includes subtypes such as mycosis fungoides (MF) and Sézary syndrome (SS). The tumor microenvironment (TME) is central to their pathogenesis, with flow cytometry and histology being the gold standards for detecting malignant T cells within the TME. Alongside emerging molecular markers, particularly clonality analysis, these tools are indispensable for accurate diagnosis and treatment planning. Of note, adenosine signaling within the TME has been shown to suppress immune responses, affecting various cell types. The expression of CD39, CD73, and CD38, enzymes involved in adenosine production, can be elevated in MF and SS, contributing to immune suppression. Conversely, the expression of CD26, part of the adenosine deaminase/CD26 complex, that degrades adenosine, is often lost by circulating tumoral cells. Flow cytometry has demonstrated increased levels of CD39 and CD73 on Sézary cells, correlating with disease progression and prognosis, while CD38 shows a variable expression, with its prognostic significance remaining under investigation. Understanding these markers’ roles in the complexity of TME-mediated immune evasion mechanisms might enhance diagnostic precision and offer new therapeutic targets in CTCL. Full article

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

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14 pages, 409 KiB

Open AccessReview

Ultraviolet Radiation-Induced Tolerogenic Dendritic Cells in Skin: Insights and Mechanisms

by Gelare Ghajar-Rahimi, Nabiha Yusuf and Hui Xu

Cells 2025, 14(4), 308; https://doi.org/10.3390/cells14040308 - 18 Feb 2025

Ultraviolet (UV) radiation has profound effects on the immune system, including the induction of tolerogenic dendritic cells (DCs), which contribute to immune suppression and tolerance. This review explores the roles of conventional CD11c⁺ DCs, as well as cutaneous Langerhans cells and CD11b⁺ myeloid [...] Read more.

Ultraviolet (UV) radiation has profound effects on the immune system, including the induction of tolerogenic dendritic cells (DCs), which contribute to immune suppression and tolerance. This review explores the roles of conventional CD11c⁺ DCs, as well as cutaneous Langerhans cells and CD11b⁺ myeloid cells, in UV-induced immune modulation. Two key mechanisms underlying the immunosuppressive relationship between UV and DCs are discussed: the inactivation of DCs and the induction of tolerogenic DCs. DCs serve as a critical link between the innate and adaptive immune systems, serving as professional antigen-presenting cells. In this context, we explore how UV-induced DCs influence the activity of specific T cell subsets, including regulatory T lymphocytes and T helper cells, and shape immune outcomes. Finally, we highlight the implications of UV-induced tolerogenic DCs in select dermatologic pathologies, including cutaneous lupus, polymorphic light eruption, and skin cancer. Understanding the mechanisms by which UV radiation alters DC function offers insights into the complex interplay between environmental factors and immune regulation, providing potential avenues for preventive and therapeutic intervention in UV-induced skin diseases. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)

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23 pages, 3781 KiB

Open AccessReview

The Emerging Role of the Histone H2AK13/15 Ubiquitination: Mechanisms of Writing, Reading, and Erasing in DNA Damage Repair and Disease

by Qi Shu, Yun Liu and Huasong Ai

Cells 2025, 14(4), 307; https://doi.org/10.3390/cells14040307 (registering DOI) - 18 Feb 2025

Histone modifications serve as molecular switches controlling critical cellular processes. The ubiquitination of histone H2A at lysines 13 and 15 (H2AK13/15ub) is a crucial epigenetic modification that coordinates DNA repair and genome stability during the DNA damage response (DDR). This epigenetic mark is [...] Read more.

Histone modifications serve as molecular switches controlling critical cellular processes. The ubiquitination of histone H2A at lysines 13 and 15 (H2AK13/15ub) is a crucial epigenetic modification that coordinates DNA repair and genome stability during the DNA damage response (DDR). This epigenetic mark is dynamically regulated by three functional protein groups: “writer” enzymes (e.g., E3 ubiquitin ligase RNF168 that catalyzes H2AK13/15ub formation), “reader” proteins (including 53BP1 and BRCA1-BARD1 that recognize the mark to guide DNA repair), and “eraser” deubiquitinases (such as USP3 and USP16 that remove the modification). Dysregulation of the precisely coordinated network of H2AK13/15ub is strongly associated with various diseases, including RIDDLE syndrome, neurodegenerative disorders, immune deficiencies, and breast cancer. This review systematically analyzes the dynamic regulation of H2AK13/15ub in DDR and explores its therapeutic potential for disease intervention. Full article

(This article belongs to the Section Cell Microenvironment)

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20 pages, 3756 KiB

Open AccessArticle

Prenatal Exposure to Metals Is Associated with Placental Decelerated Epigenetic Gestational Age in a Sex-Dependent Manner in Infants Born Extremely Preterm

by Katelyn K. Huff, Kyle R. Roell, Lauren A. Eaves, Thomas Michael O’Shea and Rebecca C. Fry

Cells 2025, 14(4), 306; https://doi.org/10.3390/cells14040306 - 18 Feb 2025

Prenatal exposure to metals can influence fetal programming via DNA methylation and has been linked to adverse birth outcomes and long-term consequences. Epigenetic clocks estimate the biological age of a given tissue based on DNA methylation and are potential health biomarkers. This study [...] Read more.

Prenatal exposure to metals can influence fetal programming via DNA methylation and has been linked to adverse birth outcomes and long-term consequences. Epigenetic clocks estimate the biological age of a given tissue based on DNA methylation and are potential health biomarkers. This study leveraged the Extremely Low Gestational Age Newborn (ELGAN) study (n = 265) to evaluate associations between umbilical cord tissue concentrations of 11 metals as single exposures as well as mixtures in relation to (1) placental epigenetic gestational age acceleration (eGAA) and the (2) methylation status of the Robust Placental Clock (RPC) CpGs. Linear mixed effect regression models were stratified by infant sex. Both copper (Cu) and manganese (Mn) were significantly associated with a decelerated placental eGA of −0.98 (95% confidence interval (CI): −1.89, −0.07) and −0.90 weeks (95% CI: −1.78, −0.01), respectively, in male infants. Cu and Mn levels were also associated with methylation at RPC CpGs within genes related to processes including energy homeostasis and inflammatory response in placenta. Overall, these findings suggest that prenatal exposures to Cu and Mn impact placental eGAA in a sex-dependent manner in ELGANs, and future work could examine eGAA as a potential mechanism mediating in utero metal exposures and later life consequences. Full article

(This article belongs to the Special Issue Molecular Advances in Prenatal Exposure to Environmental Toxicants)

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17 pages, 5006 KiB

Open AccessReview

The Terminal Segment of the Seminiferous Tubule: The Current Discovery of Its Morphofunctional Importance in Mammals

by Vicente Seco-Rovira, Ester Beltrán-Frutos, Jesús Martínez-Hernández, Juan Francisco Madrid and Luis Miguel Pastor

Cells 2025, 14(4), 305; https://doi.org/10.3390/cells14040305 - 18 Feb 2025

The morphophysiology of intratesticular sperm pathways in mammals, including humans, is poorly understood. The seminiferous tubule is continuous with the straight tubule; however, its final portion—the terminal segment (TS)—has a different tissue composition. This paper reviews the most important histological results from mammal [...] Read more.

The morphophysiology of intratesticular sperm pathways in mammals, including humans, is poorly understood. The seminiferous tubule is continuous with the straight tubule; however, its final portion—the terminal segment (TS)—has a different tissue composition. This paper reviews the most important histological results from mammal studies from the last decades of the 20th century, including the different nomenclatures given to the TS. The TS presents a loss of spermatogenesis and is lined mainly with modified Sertoli cells. There is no unanimity among authors when it comes to naming and defining TS. In the last ten years, studies on rats and mice have highlighted the importance of this testicular zone, proposing that there is a high proliferation of modified Sertoli cells with an undifferentiated cellular profile associated with stem spermatogonia. In hamsters, an immunohistochemical study showed the existence of heterogeneity between these cells, and the surrounding interstitium presents numerous Leydig cells that are ultrastructurally different from those of the rest of the testis rest. In conclusion, we have only just begun to understand the tissue biology of TS. Emerging research is very promising; it can potentially modify our current knowledge of testicular biology and be very useful in promoting the advancement of male fertility restoration therapies in andrology. Full article

(This article belongs to the Special Issue Advances in Spermatogenesis)

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25 pages, 1622 KiB

Open AccessFeature PaperReview

NEMO Family of Proteins as Polyubiquitin Receptors: Illustrating Non-Degradative Polyubiquitination’s Roles in Health and Disease

by Chuan-Jin Wu

Cells 2025, 14(4), 304; https://doi.org/10.3390/cells14040304 - 18 Feb 2025

The IκB kinase (IKK) complex plays a central role in many signaling pathways that activate NF-κB, which turns on a battery of genes important for immune response, inflammation, and cancer development. Ubiquitination is one of the most prevalent post-translational modifications of proteins and [...] Read more.

The IκB kinase (IKK) complex plays a central role in many signaling pathways that activate NF-κB, which turns on a battery of genes important for immune response, inflammation, and cancer development. Ubiquitination is one of the most prevalent post-translational modifications of proteins and is best known for targeting substrates for proteasomal degradation. The investigations of NF-κB signaling pathway primed the unveiling of the non-degradative roles of protein ubiquitination. The NF-κB-essential modulator (NEMO) is the IKK regulatory subunit that is essential for IKK activation by diverse intrinsic and extrinsic stimuli. The studies centered on NEMO as a polyubiquitin-binding protein have remarkably advanced understandings of how NEMO transmits signals to NF-κB activation and have laid a foundation for determining the molecular events demonstrating non-degradative ubiquitination as a major driving element in IKK activation. Furthermore, these studies have largely solved the enigma that IKK can be activated by diverse pathways that employ distinct sets of intermediaries in transmitting signals. NEMO and NEMO-related proteins that include optineurin, ABIN1, ABIN2, ABIN3, and CEP55, as non-degradative ubiquitin chain receptors, play a key role in sensing and transmitting ubiquitin signals embodied in different topologies of polyubiquitin chains for a variety of cellular processes and body responses. Studies of these multifaceted proteins in ubiquitin sensing have promoted understanding about the functions of non-degradative ubiquitination in intracellular signaling, protein trafficking, proteostasis, immune response, DNA damage response, and cell cycle control. In this review, I will also discuss how dysfunction in the NEMO family of protein-mediated non-degradative ubiquitin signaling is associated with various diseases, including immune disorders, neurodegenerative diseases, and cancer, and how microbial virulence factors target NEMO to induce pathogenesis or manipulate host response. A profound understanding of the molecular bases for non-degradative ubiquitin signaling will be valuable for developing tailored approaches for therapeutic purposes. Full article

(This article belongs to the Special Issue Non-Traditional Roles of Protein Ubiquitination in Cellular Processes and Health)

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22 pages, 4264 KiB

Open AccessArticle

Seasonal Influences on Human Placental Transcriptomes Associated with Spontaneous Preterm Birth

by Khondoker M. Akram, Eleanor Dodd and Dilly O. C. Anumba

Cells 2025, 14(4), 303; https://doi.org/10.3390/cells14040303 - 18 Feb 2025

Demographic studies have revealed a strong association between exposure to high ambient temperatures during pregnancy and increased risks of preterm birth (PTB). The mechanism underlying this association is unclear, but it is plausible that altered placental function may contribute to it. In this [...] Read more.

Demographic studies have revealed a strong association between exposure to high ambient temperatures during pregnancy and increased risks of preterm birth (PTB). The mechanism underlying this association is unclear, but it is plausible that altered placental function may contribute to it. In this study, we conducted differential gene expression analysis, gene set enrichment analysis (GSEA), and gene ontology (GO) analysis on bulk RNA-seq data from human placentas delivered at term and preterm during the warmer months compared to placentas delivered at term and preterm during the colder months in the UK. We detected 48 differentially expressed genes in preterm placentas delivered during the warmer months compared to preterm placentas delivered during the colder months, the majority of which were inflammatory cytokines and chemokines, including SERPINA1, IL1B, CCL3, CCL3L3, CCL4, CCL4L2, CCL20, and CXCL8. The GSEA positively enriched 17 signalling pathways, including the NF-κB, IL17, Toll-like receptor, and chemokine signalling pathways in preterm placentas delivered during warmer months. These results were not observed in the placentas delivered at term during the same times of the year. The GO analysis revealed several enhanced biological processes, including neutrophil, granulocyte, monocyte, and lymphocyte chemotaxis, as well as inflammatory and humoral immune responses in preterm placentas, but not in placentas delivered at term in the summer. We conclude that maternal exposure to warm environmental temperatures during pregnancy likely alters the placental transcriptomes towards inflammation and immune regulation, potentially leading to PTB. Full article

(This article belongs to the Special Issue Molecular Insight into the Pathogenesis of Spontaneous Preterm Birth)

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32 pages, 3557 KiB

Open AccessArticle

Secretome Analysis of Human and Rat Pancreatic Islets Co-Cultured with Adipose-Derived Stromal Cells Reveals a Signature with Enhanced Regenerative Capacities

by Erika Pinheiro-Machado, Bart J. de Haan, Marten A. Engelse and Alexandra M. Smink

Cells 2025, 14(4), 302; https://doi.org/10.3390/cells14040302 - 18 Feb 2025

Pancreatic islet transplantation (PIT) is a promising treatment for type 1 diabetes (T1D) but faces challenges pre- and post-transplantation. Co-transplantation with mesenchymal stromal cells (MSCs), known for their regenerative properties, has shown potential in improving PIT outcomes. This study examined the secretome of [...] Read more.

Pancreatic islet transplantation (PIT) is a promising treatment for type 1 diabetes (T1D) but faces challenges pre- and post-transplantation. Co-transplantation with mesenchymal stromal cells (MSCs), known for their regenerative properties, has shown potential in improving PIT outcomes. This study examined the secretome of islets cultured alone compared to the secretomes of islets co-cultured with adipose-derived stromal cells (ASCs), a subtype of MSCs, under transplantation-relevant stressors: normoxia, cytokines, high glucose, hypoxia, and combined hypoxia and high glucose. Islet co-culture with ASCs significantly altered the proteome, affecting pathways related to energy metabolism, angiogenesis, extracellular matrix organization, and immune modulation. Key signaling molecules (e.g., VEGF, PDGF, bFGF, Collagen I alpha 1, IL-1α, and IL-10) were differentially regulated depending on culture conditions and ASC presence. Functional assays demonstrated that the co-culture secretome could enhance angiogenesis, collagen deposition, and immune modulation, depending on the stress conditions. These findings highlight possible mechanisms through which ASCs may support islet survival and function, offering insights into overcoming PIT challenges. Moreover, this work contributes to identifying biomarkers of the post-transplantation microenvironment, advancing therapeutic strategies for T1D and regenerative medicine. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells: Current Applications and Future Directions)

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13 pages, 1406 KiB

Open AccessArticle

Humanized FcεRI Expressed on Mouse Eosinophils Mediates IgE-Facilitated Eosinophil Antigen Presentation

by Haibin Wang, Jean-Pierre Kinet and Peter F. Weller

Cells 2025, 14(4), 301; https://doi.org/10.3390/cells14040301 - 18 Feb 2025

High-affinity IgE receptors (FcεRI) are expressed on human blood eosinophils and may be upregulated on eosinophils at sites of allergic inflammation including atopic dermatitis and allergic asthma. FcεRI engagement, however, fails to elicit “effector” responses from eosinophils. Thus, a functional role for FcεRI [...] Read more.

High-affinity IgE receptors (FcεRI) are expressed on human blood eosinophils and may be upregulated on eosinophils at sites of allergic inflammation including atopic dermatitis and allergic asthma. FcεRI engagement, however, fails to elicit “effector” responses from eosinophils. Thus, a functional role for FcεRI on eosinophils has been uncertain. We evaluated the role of FcεRI in enhancing eosinophil antigen presentation in vivo by using humanized FcεRI α chain (hFcεRIα) transgenic mice. Eosinophils from hFcεRIα transgenic mice expressed humanized FcεRIα, with higher levels of eosinophils from the bronchoalveolar lavage of experimental asthma than those from polymyxin-elicited peritoneal lavage. The hFcεRIα-bearing eosinophils instilled intratracheally (i.t.) into recipient wild-type mice migrated from airways into paratracheal lymph nodes (pLNs) and spleens. Eosinophils, pretreated in vitro with nitrophenyl-ovalbumin ((NP)-OVA) and anti-NP human IgE complexes and instilled i.t., presented NP antigen via hFcεRIα to T cells more effectively than those pretreated with NP-OVA only, as assessed by pLN cell proliferation. IgE/FcεRIα-facilitated eosinophil antigen presentation resulted in increased IL-4 but not INF-γ production by pLN cells, with a bias towards Th2 cytokine production. Furthermore, cross-linking hFcεRIα on eosinophils increased eosinophil expressions of T cell costimulatory proteins CD40, CD80, and CD86. Humanized FcεRIα on murine eosinophils functions to enhance eosinophil antigen presentation capacities by mediating IgE-facilitated antigen presentation and upregulating expression of requisite T cell costimulatory proteins. Thus, a functional, non-“effector” role for FcεRI on eosinophils is revealed through identifying a means by which IgE may act on eosinophils to mediate their immunomodulatory, enhanced antigen presentation capabilities. Full article

(This article belongs to the Special Issue Eosinophils and Their Role in Allergy and Related Diseases)

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17 pages, 2028 KiB

Open AccessArticle

Dual Roles of Plasma miRNAs in Myocardial Injuries After Polytrauma: miR-122-5p and miR-885-5p Reflect Inflammatory Response, While miR-499a-5p and miR-194-5p Contribute to Cardiomyocyte Damage

by Jiaoyan Han, Liudmila Leppik, Larissa Sztulman, Roberta De Rosa, Victoria Pfeiffer, Lewin-Caspar Busse, Elena Kontaxi, Elisabeth Adam, Dirk Henrich, Ingo Marzi and Birte Weber

Cells 2025, 14(4), 300; https://doi.org/10.3390/cells14040300 - 18 Feb 2025

Cardiac injury after severe trauma is associated with higher mortality in polytrauma patients. Recent evidence suggests that miRNAs play a key role in cardiac pathophysiology and could serve as potential markers of cardiac damage after polytrauma. To explore this hypothesis, plasma miRNA profiles [...] Read more.

Cardiac injury after severe trauma is associated with higher mortality in polytrauma patients. Recent evidence suggests that miRNAs play a key role in cardiac pathophysiology and could serve as potential markers of cardiac damage after polytrauma. To explore this hypothesis, plasma miRNA profiles from polytrauma patients (ISS ≥ 16) with and without cardiac injury, stratified by troponin T levels (TnT, > 50 pg/mL vs. < 12 pg/mL), were analysed using NGS and validated via RT-qPCR. Five miRNAs (miR-122-5p, miR-424-5p, miR-885-5p, miR-194-5p, and miR-499a-5p) were found to be significantly upregulated in polytrauma patients with elevated TnT levels. miR-122-5p was associated with markers of right ventricular dysfunction (TAPSE) and left ventricular hypertrophy (IVS/LVPW), while miR-885-5p correlated with left ventricular hypertrophy (IVS/LVPW) and diastolic dysfunction (E/E’ ratio). In vitro, miR-194-5p mimic and miR-499a-5p mimic exhibited more active roles in cardiomyocyte injury by increasing caspase-3/7 activity and/or enhancing caspase-1 activity. Notably, the miR-194-5p mimic significantly enhanced the cytotoxic effects of the polytrauma cocktail, while miR-499a-5p boosted effects of LPS/nigericin stimulation in cardiomyocytes. Our findings identify miR-122-5p and miR-885-5p as potential biomarkers reflecting the cardiomyocyte response to polytrauma-induced inflammation, while miR-499a-5p and miR-194-5p appear to play a direct role in myocardial injury after polytrauma. Full article

(This article belongs to the Special Issue Advances in Cardiomyocyte and Stem Cell Biology in Heart Disease)

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4 pages, 904 KiB

Open AccessCorrection

Correction: Singh et al. Stat3 Inhibitors TTI-101 and SH5-07 Suppress Bladder Cancer Cell Survival in 3D Tumor Models. Cells 2024, 13, 1463

by Surya P. Singh, Gopal Pathuri, Adam S. Asch, Chinthalapally V. Rao and Venkateshwar Madka

Cells 2025, 14(4), 299; https://doi.org/10.3390/cells14040299 - 18 Feb 2025

In the original publication [...] Full article

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23 pages, 2955 KiB

Open AccessArticle

Radiation Retinopathy: Microangiopathy-Inflammation-Neurodegeneration

by Anja-Maria Davids, Inga-Marie Pompös, Norbert Kociok, Jens Heufelder, Sergej Skosyrski, Nadine Reichhart, Antonia M. Joussen and Susanne A. Wolf

Cells 2025, 14(4), 298; https://doi.org/10.3390/cells14040298 - 18 Feb 2025

Purpose: Proton irradiation is used to treat choroidal melanoma of the eye. The impact on non-malignant retinal cells is currently understudied. Therefore, we here report a mouse model to investigate the impact of proton irradiation on the retina. Methods: We performed a proton [...] Read more.

Purpose: Proton irradiation is used to treat choroidal melanoma of the eye. The impact on non-malignant retinal cells is currently understudied. Therefore, we here report a mouse model to investigate the impact of proton irradiation on the retina. Methods: We performed a proton beam irradiation of 5–15 Cobalt-Gray-Equivalent (CGE) of the eyes of female C57Bl6/J (Cx3cr1^+/+), Cx3cr1^gfp/+ and Cx3cr1^gfp/gfp mice mimicking the clinical situation and evaluated the structure, function and cellular composition of the retina up to 24 weeks after irradiation. Results: Proton beam irradiation of the eye with 15 CGE leads to cataract formation after 24 weeks without affecting the gross anatomy of the retinal vasculature as shown by Fundus imaging in all genotypes respectively. However, 10 and 15 CGE, lead to a significant decrease in NG2 positive cell numbers and all three dosages induced an increase in GFAP immunoreactivity. At 24 weeks a dosage of 15 CGE resulted in functional impairment and a decrease of NG2 positive cells in both WT and Cx3cr1 animals. Iba1 cell immunoreactivity was increased in all genotypes. However, in the Cx3cr1 animals the invasion of Iba1 cells into the deep vascular layer was partially prevented. This was accompanied by a less severe functional impairment in the irradiated Cx3cr1^gfp/gfp vs. WT. Conclusions: Although the gross anatomy of the retina does not seem to be affected by proton beam irradiation, the cellular composition and retinal function changed significantly in both WT and Cx3cr1 mice reflecting the clinical situation. Moreover, cataract formation was one of the major long-term effects of irradiation. We conclude that the murine model (WT and Cx3cr1 genotype) can be used to investigate proton-beam associated side effects in vivo as well as to test prospective interventions. Moreover, the loss of Cx3cr1 seems to be partially protective. Full article

(This article belongs to the Special Issue Radiation-Induced Brain Injury: Molecular Mechanisms and Therapeutic Strategies)

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18 pages, 641 KiB

Open AccessArticle

Selected Elements of the Tumor Microenvironment (MMP-2, MMP-7, TIMP-2, CXCL-9, CXCL-10) in the Serum of Pediatric Patients with Acute Lymphoblastic Leukemia

by Aleksandra Kaczorowska, Natalia Miękus-Purwin, Anna Owczarzak, Anna Gabrych, Małgorzata Wojciechowska, Ninela Irga-Jaworska, Sylwia Małgorzewicz, Małgorzata Rąpała and Joanna Stefanowicz

Cells 2025, 14(4), 297; https://doi.org/10.3390/cells14040297 - 17 Feb 2025

In recent years, researchers have been paying special attention to the tumor microenvironment (TME). One of the most important factors contributing to the development and progression of cancer is the destruction of elements of the extracellular matrix (ECM). The most important substances involved [...] Read more.

In recent years, researchers have been paying special attention to the tumor microenvironment (TME). One of the most important factors contributing to the development and progression of cancer is the destruction of elements of the extracellular matrix (ECM). The most important substances involved in regulating the extracellular matrix degradation process are extracellular matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). In the process of cancer cell migration, chemokines secreted by target tissues, as well as the profile of chemokine receptors presented on cancer cells, play a key role. In the presented work, five components of the TME were selected: MMP-2, MMP-7, TIMP-2, CXCL-9, and CXCL-10. In the years 2018–2021, peripheral blood samples were collected before the start of treatment and then on day 33 of intensive treatment from 31 patients diagnosed with ALL. The results indicate that the levels of MMP-2, MMP-7, and TIMP-2 did not statistically significantly change before and during treatment of ALL patients. The decrease in CXCL-9 and CXCL-10 levels in the patients’ serum on the 33rd day of therapy turned out to be statistically significant. Our study indicates that serum is also a valuable material for the evaluation of these substances. Conclusions: CXCL-9 and CXCL-10 could be used as one of markers for monitoring the response to treatment and a potential marker of ALL recurrence in pediatric patients. The role of MMP-2, MMP-7, and TIMP-2 in the assessment of response to therapy in children with ALL has not been confirmed. Full article

(This article belongs to the Special Issue Role of Matrix in Cancers)

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13 pages, 2730 KiB

Open AccessCommunication

Generation of a Transgenic Mouse Model for Investigating Mitochondria in Sperm

by Hironmoy Sarkar, Suryaprakash R. Batta, Neerja Wadhwa, Subeer S. Majumdar and Bhola Shankar Pradhan

Cells 2025, 14(4), 296; https://doi.org/10.3390/cells14040296 - 17 Feb 2025

Mitochondria play a crucial role in sperm development; however, the mechanisms regulating their function in sperm remain poorly understood. Developing a method to regulate the expression of a target gene within the mitochondria of sperm is a vital step in this area of [...] Read more.

Mitochondria play a crucial role in sperm development; however, the mechanisms regulating their function in sperm remain poorly understood. Developing a method to regulate the expression of a target gene within the mitochondria of sperm is a vital step in this area of research. In this study, we aimed to create a system for expressing a transgene in the mitochondria of sperm. As a proof of concept, we generated transgenic mice that express green fluorescent protein (GFP) fused with a mitochondrial localization signal (MLS) driven by the phosphoglycerate kinase 2 (PGK2) promoter, which facilitates the transgene expression in the sperm. Although the PGK2 promoter has previously shown to drive gene expression in spermatocytes and spermatids, the novelty of our approach lies in the combination of PGK2-driven MLS-GFP expression to study mitochondria in vivo. We established two founder lines of transgenic mice through pronuclear microinjection, and MLS-GFP expression was confirmed in the mitochondria of sperm cells using fluorescence microscopy and flow cytometry. Consequently, we provide a novel platform for investigating mitochondrial function in sperm, where GFP can be substituted with other genes of interest to examine their effects on mitochondria. This system specifically targets sperm mitochondria, offering an innovative approach for studying mitochondrial function in vivo. Full article

(This article belongs to the Special Issue Sperm Biology and Reproductive Health—Second Edition)

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21 pages, 2160 KiB

Open AccessArticle

Phenolic Compounds from Haskap Berries Have Structure, Combination, and Cell Line-Dependent Impacts on the Longevity-Associated Deacetylase Sirtuin 1

by Morgan A. Fleming, Nicholas H. Low and Christopher H. Eskiw

Cells 2025, 14(4), 295; https://doi.org/10.3390/cells14040295 - 17 Feb 2025

It is well established that phenolic compounds from plant sources impact readouts of cell health such as reduced radical and reactive oxygen species. However, it is unclear if specific phenolic structures impact other cellular processes or proteins, such as the evolutionary conserved deacetylase [...] Read more.

It is well established that phenolic compounds from plant sources impact readouts of cell health such as reduced radical and reactive oxygen species. However, it is unclear if specific phenolic structures impact other cellular processes or proteins, such as the evolutionary conserved deacetylase Sirtuin 1 (SIRT1), and if phenolic combinations interact synergistically to do so. We observed that structurally diverse haskap berry phenolics (caffeic acid, cyanidin, kaempferol-3-O-glucoside, and gentisic acid) differentially impacted normal primary human fibroblast growth, which has been linked to SIRT1. These results were consistent with previous work from our lab indicating that haskap phenolic extracts/fractions impact human cell growth via SIRT1-dependent mechanisms. Therefore, we furthered the investigation into SIRT1 and phenolic structure and observed that the individual phenolics or their combinations had no observable impact on SIRT1 transcript abundance or cellular localization. We also observed that select phenolics decreased SIRT1 protein abundance and increased SIRT1 activity. The catechol-containing phenolics outperformed those that lack a catechol group, indicating potential structure-dependent impact(s). Potential synergy between the specific phenolics analyzed was observed in Western blot, and potential antagonism was identified in the SIRT1 activity assay. Results were concomitant with the presence of different phenolic structures, phenolic combinations, and cell type (sex and/or individual differences). These results highlight the possible significance of the catechol structure and indicate that phenolics have the potential to impact cell processes, which the authors hypothesize to be due to mechanisms that are independent of antioxidant activity. Full article

(This article belongs to the Section Cellular Aging)

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25 pages, 3378 KiB

Open AccessArticle

Salicylate-Elicited Activation of AMP-Activated Protein Kinase Directly Triggers Degradation of C-Myc in Colorectal Cancer Cells

by Ana Laura S. A. Matos, Ashley J. Ovens, Emil Jakobsen, Diego Iglesias-Gato, Jacob M. Bech, Stine Friis, Lasse Kristoffer Bak, Gunvor I. Madsen, Jonathan S. Oakhill, Pietri Puustinen and José M. A. Moreira

Cells 2025, 14(4), 294; https://doi.org/10.3390/cells14040294 - 17 Feb 2025

Aspirin has consistently shown preventive effects in some solid cancers, notably colorectal cancer. However, the precise molecular mechanisms underlying this positive effect have remained elusive. In this study, we used an azoxymethane-induced mouse model of colon carcinogenesis to identify aspirin-associated molecular alterations that [...] Read more.

Aspirin has consistently shown preventive effects in some solid cancers, notably colorectal cancer. However, the precise molecular mechanisms underlying this positive effect have remained elusive. In this study, we used an azoxymethane-induced mouse model of colon carcinogenesis to identify aspirin-associated molecular alterations that could account for its cancer-preventive effect. Transcriptomic analysis of aspirin-treated mice showed a strong reduction in c-Myc protein levels and effects on the Myc-dependent transcriptional program in colonic cells. Proto-oncogene c-Myc cooperates with AMP-activated protein kinase (AMPK) to control cellular energetics. Here, we show that salicylate, the active metabolite of aspirin, reduces c-Myc protein expression levels through multiple mechanisms that are both AMPK dependent and independent. This effect is cell-type dependent and occurs at both the transcriptional and post-translational levels. Salicylate-induced AMPK activation leads to the phosphorylation of c-Myc at Thr400, as well as its destabilization and degradation. Our results reveal a complex, multilayered, negative effect of salicylate on c-Myc protein abundance and suggest that chronic depletion of c-Myc can counteract the neoplastic transformation of colorectal epithelium, underpinning the preventive effect of aspirin on colorectal cancer. Full article

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