Cells

18 pages, 2976 KB

Open AccessArticle

Reorganization of Spinal Cord Microarchitecture by Bioluminescent Optogenetic and Rehabilitative Interventions

by Tatyana Ageeva, Rezeda Shigapova, Aizilya Bilalova, Elizaveta Plotnikova, Amina Akmanova, Albert Rizvanov and Yana Mukhamedshina

Cells 2026, 15(6), 571; https://doi.org/10.3390/cells15060571 - 23 Mar 2026

Viewed by 904

Abstract

Spinal cord injury (SCI) induces persistent locomotor deficits that are closely associated with maladaptive structural plasticity of spinal neuronal circuits. Although motor rehabilitation improves functional outcomes, the cellular substrates underlying rehabilitation-induced recovery remain incompletely understood, particularly in relation to activity-dependent neuromodulation strategies. Here, [...] Read more.

Spinal cord injury (SCI) induces persistent locomotor deficits that are closely associated with maladaptive structural plasticity of spinal neuronal circuits. Although motor rehabilitation improves functional outcomes, the cellular substrates underlying rehabilitation-induced recovery remain incompletely understood, particularly in relation to activity-dependent neuromodulation strategies. Here, we investigated how treadmill-based motor training (TMT) and its combination with bioluminescent optogenetic (BL-OG) stimulation of Hb9 (homebox 9)-positive motoneurons and excitatory interneurons selectively modulate microarchitectural plasticity in the injured rat spinal cord. At the level of gross locomotor assessment, Basso, Beattie and Bresnahan (BBB) scores were comparable between the BL-OG and SCI+TMT groups. Although no statistically significant differences in the total score in rung ladder were observed at 28 days post-injury, animals in the BL-OG group showed a tendency toward a higher ratio of successful hindlimb placements, indicating improved step accuracy. BL-OG stimulation was associated with a slightly greater attenuation of SCI-induced spine abnormalities compared to TMT alone, with significant differences between the experimental groups detected specifically in laminae VIII and IX. These lamina-specific alterations in dendritic integration and dendritic spine composition were accompanied by preservation of wisteria floribunda agglutinin WFA-positive perineuronal net (PNN) architecture. Against this background, reduced glypican-4 (GPC-4) expression and attenuated WFA/GPC-4 colocalization were observed in the SCI+BL-OG group relative to SCI in laminae VII–IX, consistent with activity-dependent modulation of PNN-associated synaptic organization in Hb9-positive neuronal populations. Together, these findings indicate that motor rehabilitation and bioluminescent optogenetic stimulation engage distinct but partially overlapping mechanisms of activity-dependent microarchitectural remodeling, preferentially targeting synaptic and perineuronal net-associated substrates rather than inducing large-scale circuit reorganization. Further studies are warranted to elucidate the mechanisms underlying these distinct plasticity profiles. Full article

(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Third Edition)

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29 pages, 967 KB

Open AccessReview

Cell–Cell Interactome-Based Pathogenesis and Therapies for Osteosarcoma

by Sriya Neelam, Abdulaziz Hakeem, Yang Yang and Shuying Yang

Cells 2026, 15(6), 570; https://doi.org/10.3390/cells15060570 - 23 Mar 2026

Viewed by 1087

Abstract

Osteosarcoma (OS), the most common primary malignant bone tumor in children and young adults, is characterized by aggressive behavior, frequent metastasis, and resistance to chemotherapy, resulting in poor clinical outcomes. Increasing evidence indicates that OS progression is not solely driven by tumor-intrinsic factors [...] Read more.

Osteosarcoma (OS), the most common primary malignant bone tumor in children and young adults, is characterized by aggressive behavior, frequent metastasis, and resistance to chemotherapy, resulting in poor clinical outcomes. Increasing evidence indicates that OS progression is not solely driven by tumor-intrinsic factors but is strongly influenced by dynamic interactions within the tumor microenvironment (TME). This literature review synthesizes current research on the roles of endothelial cells, fibroblasts, mesenchymal stromal cells, immune populations, and osteoclasts in OS pathogenesis, with emphasis on cell–cell interactions mediated by direct contact, soluble factors, and extracellular vesicles. The studies demonstrate that these interactions promote tumor proliferation, immune evasion, extracellular matrix remodeling, metastatic dissemination, and therapeutic resistance. Adaptive responses of both tumor and stromal cells to environmental stressors contribute to chemoresistance and disease progression. Collectively, our findings highlight the multifactorial nature of OS driven by complex cellular crosstalk within the TME. Understanding these mechanisms highlights the limitations of conventional chemotherapy and encourages the development of combined therapeutic approaches, including targeted therapies, immunomodulation, and microenvironmental interventions. Continued investigation into tumor–microenvironment interactions may facilitate the identification of actionable targets and improve personalized treatment approaches for OS. Full article

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17 pages, 3356 KB

Open AccessArticle

Glycolytic Enzymes Are Part of an Oncogenic Network in AML

by Stefan Nagel, Corinna Meyer and Claudia Pommerenke

Cells 2026, 15(6), 569; https://doi.org/10.3390/cells15060569 - 23 Mar 2026

Viewed by 649

Abstract

Erythroid acute myeloid leukemia (AML) cell line OCI-M2 expresses a particular oncogenic network: IRF6, in concert with ETV2 and HEY1, aberrantly activates NKL homeobox gene NKX2-4, which in turn represses megakaryocytic lineage factor FLI1. Interestingly, in keratinocytes, IRF6 is able to bind glucose [...] Read more.

Erythroid acute myeloid leukemia (AML) cell line OCI-M2 expresses a particular oncogenic network: IRF6, in concert with ETV2 and HEY1, aberrantly activates NKL homeobox gene NKX2-4, which in turn represses megakaryocytic lineage factor FLI1. Interestingly, in keratinocytes, IRF6 is able to bind glucose which promotes IRF6-dimerization and thus alters its binding site selection. Here, we used OCI-M2 as a model to investigate the role of glucose level and IRF6 in leukemogenesis. Treatment of OCI-M2 with high glucose or 2-deoxy-glucose resulted in the downregulation of IRF6 and NKX2-4, and the upregulation of FLI1, indicating that glucose-mediated dimerization of IRF6 altered its reported autoactivation. The screening of this cell line for genes encoding glycolytic enzymes identified aberrant overexpression of glucose-6-phosphate isomerase (GPI) and phosphofructokinase L (PFKL), which were targeted by genomic amplification and chromothripsis-like alterations, respectively. Furthermore, GPI was activated by NKX2-4 and ETV2, and PFKL by ETV2. Finally, siRNA-mediated downregulation of PFKL resulted in elevated glucose levels, suppressed expression of IRF6 and NKX2-4, and activated FLI1. Thus, we connected an oncogenic regulatory network with deregulated glycolytic enzymes and glucose metabolism, thereby establishing a new in vitro model to develop novel therapeutic avenues in AML subsets. Full article

(This article belongs to the Special Issue Hematopoietic Cell Lines as Models for Leukemia and Lymphoma)

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17 pages, 1519 KB

Open AccessArticle

Cell-Free DNA as Biomarker in Oral Squamous Cell Carcinoma: Dynamics, Mutational Landscape and Clinical Implications

by Pedro Veiga, Leonor Barroso, Luís Miguel Pires, Carolina Mano, Francisco Caramelo, Isabel Marques Carreira, Ilda Patrícia Ribeiro and Joana Barbosa de Melo

Cells 2026, 15(6), 568; https://doi.org/10.3390/cells15060568 - 23 Mar 2026

Viewed by 959

Abstract

Oral squamous cell carcinoma (OSCC) is a prevalent form of head and neck cancer that typically develops on the lip or within the oral cavity. Although there have been advances in early detection and treatment, the prognosis for patients, particularly those with advanced-stage [...] Read more.

Oral squamous cell carcinoma (OSCC) is a prevalent form of head and neck cancer that typically develops on the lip or within the oral cavity. Although there have been advances in early detection and treatment, the prognosis for patients, particularly those with advanced-stage disease, remains poor. Liquid biopsy, particularly through the analysis of cell-free DNA (cfDNA) in plasma and urine, has emerged as a promising tool for non-invasive cancer detection and monitoring. This study assessed cfDNA concentration dynamics in plasma and urine samples from 32 OSCC patients, with 5 undergoing genomic characterization by targeted next-generation sequencing (NGS). CfDNA levels were higher in patients compared to healthy controls and showed transient increases following treatment initiation, likely reflecting tumor cell death, followed by a gradual return to baseline. However, cfDNA concentrations were not significantly associated with tumor stage, recurrence, or progression-free survival. Targeted NGS analysis revealed a heterogeneous mutational landscape, identifying 76 variants across tumor tissue and initial cfDNA, with 30.3% shared between both sources. Recurrent hotspot mutations were detected in several important genes, including TP53, PIK3CA, KRAS, APC, and FBXW7. Urine cfDNA also captured several mutations absent from plasma or tissue, supporting its complementary value. These findings demonstrate that cfDNA analysis can dynamically reflect treatment response and capture tumor heterogeneity in OSCC. While informative, cfDNA quantification alone offers limited prognostic reliability, reinforcing the need for a multidimensional approach that includes genomic and clinical evaluation. Overall, this study supports the potential of liquid biopsy as a real-time, non-invasive tool for molecular monitoring and personalized management of OSCC patients. Full article

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19 pages, 2175 KB

Open AccessReview

EPCR in Wound Healing: Mechanisms of Action and Therapeutic Potential

by Hui Wang, Lyn March, Christopher J. Jackson, Marita Cross and Meilang Xue

Cells 2026, 15(6), 567; https://doi.org/10.3390/cells15060567 - 22 Mar 2026

Viewed by 744

Abstract

The endothelial protein C receptor (EPCR) is an important component of the protein C (PC) system, recognised for its diverse roles in blood coagulation, inflammation, and stem cell regulation. Wound healing is a complex physiological process that can be divided into four distinct [...] Read more.

The endothelial protein C receptor (EPCR) is an important component of the protein C (PC) system, recognised for its diverse roles in blood coagulation, inflammation, and stem cell regulation. Wound healing is a complex physiological process that can be divided into four distinct but overlapping phases: haemostasis, inflammation, proliferation and remodelling. Recently, EPCR has emerged as a key regulator in wound repair and regeneration. During haemostasis, EPCR enhances the conversion of PC to its activated form (APC) to optimise local and systemic anticoagulation. In the inflammatory phase, EPCR modulates immune cell activity, inhibits inflammatory factors, and maintains tissue barrier integrity. As the process transitions to the proliferative phase, EPCR promotes endothelial and epithelial cell proliferation, migration, neovascularisation and re-epithelization, and mediates the expression of matrix metalloproteinases to facilitate tissue reconstruction. Finally, during the remodelling phase, EPCR exerts a potential antifibrotic effect by regulating fibroblast activation and collagen deposition via the Transforming growth factor (TGF)-β1/Smad3 pathway, ensuring functional repair. While therapeutic potential has been shown in animal models, translating EPCR-mediated therapies to clinical application faces many challenges, including wound heterogeneity, dosage control, targeted delivery, and potential bleeding risks. Studies have shown that local drug delivery strategies, non-anticoagulant APC variants, and individualised treatment based on EPCR expression will be the key directions for future development. Additionally, EPCR may serve as a potential biomarker for assessing wound severity and guiding personalised interventions. Full article

(This article belongs to the Special Issue Cutaneous Regeneration and Tissue Engineering: From Hair Follicle Regeneration to Skin Restoration)

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26 pages, 4272 KB

Open AccessArticle

Modeling Chronic BaP Exposure in Bronchial Epithelial Cells Reveals Multi-Scale Drivers of Early Preneoplastic Reprogramming

by Cristian Andrade-Madrigal, Cecilia Rojas-Fuentes, Javier Díaz-Mijares, Gloria M. Calaf, Pablo M. Santoro, Alejandro H. Corvalán, Francisca J. Medina, Cristian G. Torres, Paula Romero-Vicencio, Julio C. Tapia, Mónica L. Acevedo, Ricardo Soto-Rifo, Enrique Boccardo and Francisco Aguayo

Cells 2026, 15(6), 566; https://doi.org/10.3390/cells15060566 - 22 Mar 2026

Viewed by 1455

Abstract

Chronic exposure to benzo[a]pyrene (BaP), a Group 1 IARC carcinogen, is a major driver of lung carcinogenesis; however, how sustained subcytotoxic exposure reprograms bronchial epithelium toward preneoplastic states remains poorly defined. Here, we subjected BEAS-2B human bronchial epithelial cells to 12 weeks of [...] Read more.

Chronic exposure to benzo[a]pyrene (BaP), a Group 1 IARC carcinogen, is a major driver of lung carcinogenesis; however, how sustained subcytotoxic exposure reprograms bronchial epithelium toward preneoplastic states remains poorly defined. Here, we subjected BEAS-2B human bronchial epithelial cells to 12 weeks of continuous BaP at environmentally relevant concentrations (0.1 and 1.0 µM) and interrogated the resulting phenotypes using an integrated multi-scale framework encompassing functional toxicology, RT-qPCR, RNA-seq, phospho-kinase/NF-κB arrays, and organotypic air–liquid interface (ALI) cultures. Cells maintained metabolic competence throughout, evidenced by sustained CYP1A1 and CYP1B1 induction at both acute (4 h) and chronic (12-week) timepoints, while accumulating genotoxic stress as demonstrated by dose-dependent nuclear γ-H2AX foci formation and ATM phosphorylation (Ser1981). RNA-seq revealed a dose-dependent transcriptional shift: 0.1 µM BaP yielded 119 differentially expressed genes (DEGs; |log2FC| ≥ 1, FDR < 0.05), whereas 1.0 µM generated 255 DEGs. Downregulated transcripts were enriched for extracellular matrix and cell-adhesion programs (COL14A1, ADAMTS2, CSMD3, CADM3), while upregulated genes encompassed inflammatory, calcium-signaling, and vesicle-trafficking modules (NFATC4, CSF2RA, SYT1, PCLO). Phospho-kinase/NF-κB arrays confirmed a p53/NF-κB signaling nexus, with concurrent activation of MAPK/ERK (Thr202/Tyr204) and PI3K/Akt (Ser473) pathways. Despite persistent genotoxic stress, cells did not acquire anchorage-independent growth and remained non-tumorigenic in vivo. Critically, ALI organotypic cultures derived from BaP-exposed cells exhibited histological dysplasia, nuclear pleomorphism, and disrupted apical-basal polarity. These findings mechanistically link chronic BaP exposure to an initiation-like preneoplastic state and establish a validated 2D/3D multi-omics platform for PAH-driven lung carcinogenesis research. Full article

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24 pages, 7903 KB

Open AccessArticle

Protein Kinase D2 Regulates GRASP65 Phosphorylation and Golgi Ribbon Unlinking During G2/M Transition

by Inmaculada Ayala, Daniela Spano and Antonino Colanzi

Cells 2026, 15(6), 565; https://doi.org/10.3390/cells15060565 - 21 Mar 2026

Viewed by 663

Abstract

The Golgi complex undergoes dynamic remodeling during the cell cycle, as ribbon unlinking in G2 is required for proper mitotic progression. Failure to fragment the ribbon leads to G2 arrest, whereas forced mitotic entry with intact ribbons results in multipolar spindle formation. Phosphorylation [...] Read more.

The Golgi complex undergoes dynamic remodeling during the cell cycle, as ribbon unlinking in G2 is required for proper mitotic progression. Failure to fragment the ribbon leads to G2 arrest, whereas forced mitotic entry with intact ribbons results in multipolar spindle formation. Phosphorylation of the Golgi matrix protein GRASP65 at serine 277 (S277) in rat (S274 in human) by JNK2 is essential for ribbon unlinking, but its upstream regulation has remained unclear. Here, we generated and validated a phospho-specific antibody recognizing human GRASP65 phosphorylated at S274, enabling accurate detection of this modification. Using this tool, we identify protein kinase D2 (PKD2) as a critical upstream regulator required for GRASP65 phosphorylation and Golgi unlinking. GRASP65-S274 phosphorylation increases during G2 and is markedly reduced upon PKD2 inhibition or depletion, resulting in decreased Golgi unlinking and delayed G2/M transition. Conversely, PKD2-activating stimuli, including phorbol esters and nocodazole, enhance GRASP65 phosphorylation in a PKD2-dependent manner. These findings define PKD2 as a key regulator of the JNK2–GRASP65 signaling axis controlling Golgi disassembly at the G2/M transition. Moreover, the phospho-specific GRASP65 antibody described here provides a valuable tool to dissect upstream signaling mechanisms and to identify the initial triggers driving Golgi unlinking at G2 entry. Full article

(This article belongs to the Section Intracellular and Plasma Membranes)

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22 pages, 816 KB

Open AccessReview

Understanding Eosinophil Heterogeneity: The Known and Unknown

by Alexander Ruzic, Michael Trus, Roma Sehmi and Manali Mukherjee

Cells 2026, 15(6), 564; https://doi.org/10.3390/cells15060564 - 21 Mar 2026

Viewed by 1449

Abstract

Eosinophils are multifunctional granulocytes with central roles in the pathobiology of chronic airway diseases. While systemic eosinophilia (>300 cells/μL) is a well-established biomarker to guide therapeutic decision-making, accumulating evidence indicates that eosinophils are not a uniform population but instead exhibit substantial phenotypic and [...] Read more.

Eosinophils are multifunctional granulocytes with central roles in the pathobiology of chronic airway diseases. While systemic eosinophilia (>300 cells/μL) is a well-established biomarker to guide therapeutic decision-making, accumulating evidence indicates that eosinophils are not a uniform population but instead exhibit substantial phenotypic and functional heterogeneity across biological compartments, inflammatory states, and disease contexts. In this review, we synthesize the current understanding of eosinophil heterogeneity in airway diseases and critically evaluate the strengths and limitations of surface marker-based approaches, with emphasis on CD62L/L-selectin-defined subpopulations. Although CD62L-based stratification has provided valuable insight into eosinophil activation and tissue localization, its limited specificity, inconsistent clinical associations, and reliance on murine models restrict its utility as a framework for eosinophil subtyping in humans. We highlight how transcriptomic and proteomic profiling has transformed the field by revealing that peripheral blood eosinophils are largely quiescent, whereas disease-relevant functional specialization is predominantly acquired within inflamed tissues in response to cues from the local microenvironment. These molecular studies support a model in which eosinophil heterogeneity represents a continuum of activation rather than discrete, fixed subsets. A refined, integrative approach to understanding eosinophil heterogeneity is critical for improving patient stratification, predicting therapeutic responsiveness, and optimizing precision medicine strategies in chronic airway diseases. Full article

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

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23 pages, 3504 KB

Open AccessReview

Oxidative Stress and the KEAP1/NRF2 Axis in Saphenous Vein: Implications for Graft Patency

by Georgia R. Layton, Em Marston, Hannah L. Musa, Shameem Ladak, Alice Copperwheat, Akintoye Oluwanifemi, Ibrahim Antoun and Mustafa Zakkar

Cells 2026, 15(6), 563; https://doi.org/10.3390/cells15060563 - 20 Mar 2026

Cited by 1 | Viewed by 985

Abstract

Vein graft disease remains a significant limitation to the long-term patency of venous conduits following coronary artery bypass grafting. Early oxidative stress, triggered by ischaemia–reperfusion injury and haemodynamic changes following the implantation of veins into the arterial circulation, disrupts endothelial integrity and initiates [...] Read more.

Vein graft disease remains a significant limitation to the long-term patency of venous conduits following coronary artery bypass grafting. Early oxidative stress, triggered by ischaemia–reperfusion injury and haemodynamic changes following the implantation of veins into the arterial circulation, disrupts endothelial integrity and initiates inflammation, apoptosis, and maladaptive remodelling. The KEAP1-NRF2 axis is a central regulator of cellular antioxidant responses; however, its role in the development of vein graft disease remains poorly defined. This narrative review aimed to summarise what is known about NRF2/KEAP1 signalling in modulating vein graft pathology. Methods: A systematic search of PubMed was conducted to identify original research studies examining the NRF2/KEAP1 pathway in human saphenous vein tissue in vivo or ex vivo. Narrative synthesis was performed due to limited evidential availability and study heterogeneity. Results: Only one study has directly evaluated NRF2 pathway activation directly in human saphenous vein tissue, and it demonstrated that Protandim (a herbal dietary supplement) treatment increased antioxidant enzyme activity and reduced oxidative stress markers, including superoxide and 4-hydroxynonenal, both known activators of MAPK-dependent smooth muscle proliferation. Adjacent studies in other cells and tissues reveal that NRF2 intersects with multiple pathways central to vein graft pathology: it suppresses NFκB-mediated inflammation, modulates eNOS-NO signalling, inhibits NADPH oxidase expression, regulates MAPK activation, and influences angiogenic responses. However, context-dependent activation of NRF2 under arterial cyclic stretch can paradoxically drive proliferation through p62-mediated KEAP1 sequestration and enhanced glutathione synthesis. Conclusions: The NRF2/KEAP1 pathway serves as a central integrator of oxidative stress responses that directly intersect with established mechanisms of intimal hyperplasia and pathological angiogenesis. Post-translational KEAP1 inhibition may offer a targeted intervention point to limit these processes. Critical gaps remain regarding our understanding of the role of NRF2 in human saphenous vein under physiological arterial conditions and sex-specific pathway regulation. Mechanistic studies in vein-specific models are essential for advancing our understanding and any potential therapeutic translation. Full article

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17 pages, 1698 KB

Open AccessReview

Making Mobile Leaflets: Biomechanical Forces in Atrioventricular Valve Formation

by Anji Yang and Renee Wei-Yan Chow

Cells 2026, 15(6), 562; https://doi.org/10.3390/cells15060562 - 20 Mar 2026

Viewed by 732

Abstract

Atrioventricular valves prevent the backward flow of blood from the ventricles to the atria and are essential for the efficient pumping of blood throughout the body. Errors in development can lead to congenital atrioventricular valve disease. Atrioventricular valve formation is a multi-step process [...] Read more.

Atrioventricular valves prevent the backward flow of blood from the ventricles to the atria and are essential for the efficient pumping of blood throughout the body. Errors in development can lead to congenital atrioventricular valve disease. Atrioventricular valve formation is a multi-step process that involves endocardial cushion formation, valve progenitor cell proliferation, valve sinus formation, valve elongation, and extracellular matrix remodeling. Increasing evidence suggests that hemodynamic cues are required across multiple steps. Here, we compare atrioventricular valve formation in different in vivo models and review how biomechanical forces regulate atrioventricular valve formation. Full article

(This article belongs to the Section Cells of the Cardiovascular System)

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28 pages, 970 KB

Open AccessReview

Precision Immunotherapeutics for Glioblastoma: Current Approaches and Emerging Strategies in 2026

by James Poe, Claire Kim, Campbell Coleman, Hieu Nguyen, Vaithish Velazhahan, Brandon Bergsneider, Vivek Sanker, Samuel Kim, Yijiang Chen, Matthew Abikenari, John Choi and Michael Lim

Cells 2026, 15(6), 561; https://doi.org/10.3390/cells15060561 - 20 Mar 2026

Cited by 2 | Viewed by 3667

Abstract

Glioblastoma (GBM) persists as one of the greatest challenges in the treatment of human cancer, despite extensive efforts to leverage the therapeutic potential of immunotherapy. While checkpoint blockade and other forms of immunotherapy have revolutionized the treatment of various cancers, their therapeutic efficacy [...] Read more.

Glioblastoma (GBM) persists as one of the greatest challenges in the treatment of human cancer, despite extensive efforts to leverage the therapeutic potential of immunotherapy. While checkpoint blockade and other forms of immunotherapy have revolutionized the treatment of various cancers, their therapeutic efficacy in GBM has been hindered by the profound immunosuppressive environment, spatial heterogeneity, and dynamic immune metabolic challenges associated with the tumor microenvironment. In this review, we will synthesize recent advances and insights to develop a next-generation framework for GBM immunotherapy based on systems biology approaches to understanding the complex interplay between GBM and the immune system, as opposed to single-axis approaches to immune activation and modulation. We will discuss how the functional competence of the interferon system, myeloid antigen presentation status, T-cell clone status, spatial organization of the immune microenvironment, and resource competition between GBM and the immune system dictate therapeutic responsiveness. Furthermore, the current paper elucidates how recent advances in spatial transcriptomics, single-cell analysis, and high-parameter imaging enable us to understand how immune phenotype status varies across GBM regions and treatment status, and how this information can be used to develop predictive and pharmacodynamic biomarkers of therapeutic efficacy and failure. We will then discuss how these advances form the basis for rational combination approaches to GBM immunotherapy, which involve the integration of checkpoint blockade with metabolic reprogramming, myeloid modulation, and interferon system reactivation, and how artificial intelligence-based analytics and adaptive clinical trial design can guide the development of biomarker-based therapeutic selection approaches. Full article

(This article belongs to the Special Issue Decoding Cancer Metabolism: Recent Insights and Future Directions)

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6 pages, 193 KB

Open AccessEditorial

Gene and Cell Therapy in Regenerative Medicine—Second Edition

by Albert A. Rizvanov and Ayşegül Doğan

Cells 2026, 15(6), 560; https://doi.org/10.3390/cells15060560 - 20 Mar 2026

Viewed by 950

Abstract

Gene and cell therapies have expanded the toolbox of regenerative medicine by enabling (i) targeted modulation of tissue repair programs, (ii) replacement of damaged or missing cell populations, and (iii) durable correction of molecular defects that prevent regeneration [...] Full article

(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Second Edition)

20 pages, 2827 KB

Open AccessArticle

Mitochondrial Dynamic Proteins MiD49 and MiD51 as Novel Targets of Cardioprotection

by Parisa Samangouei, Gustavo E. Crespo-Avilan, Andrew R. Hall, Sauri Hernandez-Resendiz, J. Maeve Elder, Laura D. Osellame, Nicole G. Z. Tee, Khairunnisa Katwadi, Sang-Bing Ong, Xiu-Yi Kwek, Siavash Beikoghli Kalkhoran, Niall Burke, Derek M. Yellon and Derek J. Hausenloy

Cells 2026, 15(6), 559; https://doi.org/10.3390/cells15060559 - 20 Mar 2026

Viewed by 850

Abstract

Novel therapeutic strategies are required to protect the heart from acute ischaemia-reperfusion injury (IRI) and improve outcomes in patients with acute myocardial infarction (AMI). Mitochondria play a critical role in determining cardiomyocyte fate following acute IRI, with genetic and pharmacological inhibition of Drp1-mediated [...] Read more.

Novel therapeutic strategies are required to protect the heart from acute ischaemia-reperfusion injury (IRI) and improve outcomes in patients with acute myocardial infarction (AMI). Mitochondria play a critical role in determining cardiomyocyte fate following acute IRI, with genetic and pharmacological inhibition of Drp1-mediated mitochondrial fission limiting cardiomyocyte death. We investigated the role of the mitochondrial Drp1 receptors, MiD49 and MiD51, as novel targets for cardioprotection. In cardiac cell lines subjected to simulated IRI, dual genetic knockdown of both MiD49 and MiD51 reduced cell death, inhibited mitochondrial fission, prevented mitochondrial permeability transition pore opening, and attenuated mitochondrial calcium overload compared with wild-type cells. However, individual knockdown of either MiD49 or MiD51 did not induce mitochondrial elongation or inhibit MPTP opening. Whole-body genetic ablation of MiD49 in adult mice modestly altered mitochondrial morphology but did not affect myocardial infarct size or cardiac function following AMI. Together with the in vitro protection seen with dual MiD49/51 knockdown, these findings suggest that MiD49 deficiency alone is insufficient and that coordinated inhibition of MiD49 and MiD51 may be required for cardioprotection. Full article

(This article belongs to the Special Issue Myocardial Ischemia/Reperfusion Injury: Mechanisms and New Directions in Cardioprotection)

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20 pages, 8911 KB

Open AccessArticle

SGK1 Is Upregulated in Retained Placenta and Mediates Estradiol Effects in Bovine Endometrial Cells

by Ruiqing Wang, Meng Wei, Wei Niu, Jingxiao Chen, Jinghong Nan, Yong Zhang, Xingxu Zhao and Qi Wang

Cells 2026, 15(6), 558; https://doi.org/10.3390/cells15060558 - 20 Mar 2026

Viewed by 625

Abstract

Retained placenta (RP) is a significant postpartum complication in dairy cows. Although abnormal estradiol (E₂) levels are implicated, the underlying cellular mechanisms remain poorly defined. Through RNA-seq analysis of postpartum blood from cows with or without RP, we identified Serum and [...] Read more.

Retained placenta (RP) is a significant postpartum complication in dairy cows. Although abnormal estradiol (E₂) levels are implicated, the underlying cellular mechanisms remain poorly defined. Through RNA-seq analysis of postpartum blood from cows with or without RP, we identified Serum and Glucocorticoid-regulated Kinase 1 (SGK1) as a differentially expressed gene candidate. Analysis of fetal cotyledonary tissues revealed that SGK1 expression was significantly elevated in these tissues, concomitant with markers of suppressed apoptosis, increased levels of tight junction proteins, and an inhibited epithelial–mesenchymal transition (EMT) phenotype. To explore a potential mechanistic link between E₂ and these cellular alterations, we investigated the E₂-SGK1 axis in bovine endometrial epithelial cells in vitro. E₂ treatment upregulated SGK1 expression, reduced apoptosis, increased tight junction protein levels, and suppressed EMT. Conversely, SGK1 knockdown induced apoptosis, disrupted tight junctions, and impaired EMT. Notably, E₂ could not rescue the apoptosis and EMT alterations in SGK1-knockdown cells, indicating that SGK1 is a critical mediator of these E₂ effects in this cellular model. Based on these initial correlative findings in tissues, combined with the subsequent mechanistic experiments in cells, we propose a novel model whereby dysregulation of the E₂- SGK1 axis could contribute to RP pathogenesis by stabilizing the placental interface. Our findings provide the first experimental evidence linking SGK1 to RP and establish a foundation for future in vivo validation. Full article

(This article belongs to the Special Issue Advances in Reproductive Biology: Cellular and Molecular Mechanisms)

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19 pages, 3768 KB

Open AccessArticle

CISAT, a CoPP-Induced lncRNA, Improves Cardiac Mesenchymal Progenitor Cell Survival and Myocardial Repair via SFPQ/NRF2/p38 Redox Regulation

by Xiuchun Li, Xiao-Liang Wang, Sofia Lopez, Jill Wang and Chuanxi Cai

Cells 2026, 15(6), 557; https://doi.org/10.3390/cells15060557 - 20 Mar 2026

Viewed by 600

Abstract

Cellular therapy using human cardiac mesenchymal progenitor cells (hMPCs) for regenerative medicine is hindered by poor cell survival and senescence. Long non-coding RNAs (lncRNAs) are critical regulators of cellular processes, yet their role in cardiac aging remains underexplored. Here, lncRNA microarray profiling identified [...] Read more.

Cellular therapy using human cardiac mesenchymal progenitor cells (hMPCs) for regenerative medicine is hindered by poor cell survival and senescence. Long non-coding RNAs (lncRNAs) are critical regulators of cellular processes, yet their role in cardiac aging remains underexplored. Here, lncRNA microarray profiling identified a novel lncRNA, XLOC_002543, upregulated in hMPCs preconditioned with cobalt protoporphyrin (CoPP), which was named CoPP-Induced and SFPQ-Associated RNA Transcript (CISAT) due to its interaction with splicing factor proline and glutamine rich (SFPQ), confirmed via RNA pull-down and immunoprecipitation. CISAT was the only highly expressed transcript among seven lnc-ANKMY1-5 variants in hMPCs, as shown by RT-PCR. Notably, CISAT expression decreased in aging/senescent hMPCs, correlating with elevated p16^INK4A, a senescence marker. Overexpression of CISAT reduced p16^INK4A levels; enhanced hMPC survival, proliferation, and migration; and increased antioxidant and anti-apoptotic protein expression, while CISAT knockdown reduced resistance to H₂O₂-induced oxidative stress. In vivo, intramyocardial transplantation of CISAT-overexpressed hMPCs in an immune-deficient murine myocardial infarction model reduced fibrosis, promoted angiogenesis, and preserved cardiac function. Mechanistically, CISAT interacts with SFPQ to regulate NRF2-mediated redox homeostasis and inhibits p38 MAPK phosphorylation, mitigating senescence and enhancing cell survival. These findings suggest that targeting CISAT to modulate redox signaling and p38 MAPK pathways in aging hMPCs could improve their therapeutic efficacy for myocardial repair in heart disease. Full article

(This article belongs to the Special Issue The Role of Oxidative Stress in Cardiovascular Diseases—2nd Edition)

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2 pages, 618 KB

Open AccessCorrection

Correction: Alhajlah et al. Overexpression of Reticulon 3 Enhances CNS Axon Regeneration and Functional Recovery After Traumatic Injury. Cells 2021, 10, 2015

by Sharif Alhajlah, Adam M Thompson and Zubair Ahmed

Cells 2026, 15(6), 556; https://doi.org/10.3390/cells15060556 - 20 Mar 2026

Viewed by 397

Abstract

In the original manuscript [...] Full article

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15 pages, 965 KB

Open AccessReview

Molecular and Functional Platelet Abnormalities in Myeloproliferative Neoplasms

by Ann X. Wang, Belinda B. Guo and Matthew D. Linden

Cells 2026, 15(6), 555; https://doi.org/10.3390/cells15060555 - 19 Mar 2026

Viewed by 961

Abstract

Blood platelets are derived from megakaryocytes with functions extending beyond hemostasis to inflammation, immunity, and cancer. Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders driven by somatic mutations affecting JAK-STAT signaling, leading to excessive myeloid proliferation. Thrombosis affects approximately one-fifth of patients at [...] Read more.

Blood platelets are derived from megakaryocytes with functions extending beyond hemostasis to inflammation, immunity, and cancer. Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders driven by somatic mutations affecting JAK-STAT signaling, leading to excessive myeloid proliferation. Thrombosis affects approximately one-fifth of patients at diagnosis and remains elevated throughout the disease course, while the paradoxical coexistence of bleeding further complicates clinical management. In addition, MPNs may progress to advanced disease stages, including bone marrow fibrosis and transformation to acute myeloid leukemia, leading to ineffective hematopoiesis, worsening symptom burden, and poor clinical outcomes. This review outlines how peripherally circulating platelets provide a unique window into MPN pathophysiology, with emphasis on their functional and molecular abnormalities. We summarize current understanding of platelet-mediated hemostatic imbalance across MPN subtypes. We discuss the potential of platelet transcriptomics and proteomics to reveal disease-specific signatures. We further highlight emerging platelet-associated candidates with potential utility as dynamic biomarkers for both the pathological marrow niche and thrombotic and bleeding risk. Together, these insights underscore the potential of platelet-based approaches to complement existing diagnostic and prognostic strategies in MPNs. Full article

(This article belongs to the Special Issue Molecular and Cellular Insights into Platelet Function, 2nd Edition)

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21 pages, 1439 KB

Open AccessReview

The Role of Protein Post-Translational Modifications in the Pathogenesis of Nephrolithiasis: Mechanistic Insights and Translational Potential

by Wenlong Wan, Baokang Wang, Junyi Yang, Yang Xun and Xiao Yu

Cells 2026, 15(6), 554; https://doi.org/10.3390/cells15060554 - 19 Mar 2026

Viewed by 764

Abstract

Nephrolithiasis is a prevalent urological disorder worldwide, whose pathogenesis involves a complex network of crystal formation, cellular injury, and microenvironmental dysregulation. As a critical mechanism for regulating cellular functions, protein post-translational modifications (PTMs) have been increasingly implicated in multiple facets of kidney stone [...] Read more.

Nephrolithiasis is a prevalent urological disorder worldwide, whose pathogenesis involves a complex network of crystal formation, cellular injury, and microenvironmental dysregulation. As a critical mechanism for regulating cellular functions, protein post-translational modifications (PTMs) have been increasingly implicated in multiple facets of kidney stone formation, including crystal–cell interactions, oxidative stress responses, and inflammatory signaling pathways. This review systematically synthesizes the biochemical foundations of PTMs, the molecular microenvironment of nephrolithiasis, and the roles of key modifications such as phosphorylation and acetylation in the pathogenesis of calculi. It further explores the translational potential of PTM detection technologies in clinical practice. Current evidence indicates that PTMs influence the nucleation, growth, and aggregation of crystals by modulating the activity of pro-/anti-lithogenic proteins, the expression of cell adhesion molecules, and inflammatory pathways. Consequently, therapeutic strategies targeting PTMs may offer novel avenues for the prevention and management of kidney stones. Future research should focus on integrating multi-omics approaches with functional validation to elucidate the dynamic regulatory networks of PTMs within the stone microenvironment, thereby advancing the development of precision medicine. Full article

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30 pages, 1387 KB

Open AccessReview

The Role of A-Kinase Anchoring Proteins for Inhibitory cAMP Signalling in Platelets

by Shannon Barkey and Albert Smolenski

Cells 2026, 15(6), 553; https://doi.org/10.3390/cells15060553 - 19 Mar 2026

Viewed by 874

Abstract

Platelets are small circulating blood cells that mediate haemostasis and thrombosis. Platelets respond to vascular damage by adhesion, granule release, and aggregation. Healthy endothelial cells inhibit platelets through prostacyclin-induced cAMP signalling. Intracellular cAMP activates protein kinase A (PKA), a tetrameric kinase composed of [...] Read more.

Platelets are small circulating blood cells that mediate haemostasis and thrombosis. Platelets respond to vascular damage by adhesion, granule release, and aggregation. Healthy endothelial cells inhibit platelets through prostacyclin-induced cAMP signalling. Intracellular cAMP activates protein kinase A (PKA), a tetrameric kinase composed of two regulatory (R) and two catalytic (C) subunits. cAMP-binding triggers dissociation of C subunits from the PKA complex and phosphorylation of substrate proteins, which mediate platelet inhibition. The R subunits of PKA are known to be attached to A-kinase anchoring proteins (AKAPs), which enable subcellular compartmentalisation of cAMP signalling. Proteomics have identified 22 AKAPs in platelets, but only a few of these have been studied in detail. This review summarises current knowledge about platelet AKAPs, including studies done regarding other cells. Possible integration of AKAPs into platelet signalling is explored with a focus on subcellular localisation, interaction partners, and PKA-mediated substrate phosphorylation. As main platelet compartments, the plasma membrane, endosomes, mitochondria, the Golgi, the dense tubular system, and the cytoskeleton are considered. Potential roles of individual AKAPs in platelet inhibition are discussed, and open questions in the field are defined. Full article

(This article belongs to the Special Issue Molecular and Cellular Insights into Platelet Function, 2nd Edition)

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23 pages, 7333 KB

Open AccessArticle

Quercetin Alleviates Cerebral Ischemia-Induced Neuroinflammation by Inhibiting Microglia-Mediated NLRP3/Caspase-1/GSDMD Pathway

by Da Shen, Weiao Kong, Haoke Qiu, Huiling Yuan, Wanyi Wu, Lefan Huang, Zixin Yin, Lisheng Chu and Lijun Ge

Cells 2026, 15(6), 552; https://doi.org/10.3390/cells15060552 - 19 Mar 2026

Cited by 1 | Viewed by 915

Abstract

In the pathological cascade of cerebral ischemia, the pyroptosis axis mediated by the NLRP3 inflammasome in activated microglia is a core link driving neuroinflammation and secondary brain injury. Quercetin has been proven to possess multi-target neuroprotective activity, and its anti-inflammatory effect has attracted [...] Read more.

In the pathological cascade of cerebral ischemia, the pyroptosis axis mediated by the NLRP3 inflammasome in activated microglia is a core link driving neuroinflammation and secondary brain injury. Quercetin has been proven to possess multi-target neuroprotective activity, and its anti-inflammatory effect has attracted particular attention. However, direct molecular evidence is lacking regarding how quercetin precisely regulates the NLRP3/Caspase-1/GSDMD core pyroptosis axis in microglia in cerebral ischemia models and whether it can directly target NLRP3 to inhibit this axis, thereby alleviating cerebral ischemic injury. This study aimed to investigate the molecular mechanism by which quercetin alleviates cerebral ischemic injury through inhibiting the pyroptosis axis, combining cellular and animal models with molecular docking and molecular dynamics simulations. The oxygen-glucose deprivation (OGD) model of BV2 microglia and the photothrombotic (PT) model of focal cortical ischemia in male C57BL/6 mice were used to detect the ameliorative effect of quercetin on cerebral ischemia-related injury through cellular and animal experiments. AutoDock Vina 1.5.7 and GROMACS 2025.3 software were employed for molecular docking and molecular dynamics simulations, respectively, to analyze the binding mode and complex stability between quercetin and the NLRP3 protein. The results showed that quercetin could significantly ameliorate OGD-induced injury in BV2 cells and downregulate the expression of pyroptosis and inflammation-related proteins and factors. Meanwhile, it relieved motor dysfunction in PT mice, attenuated cortical neuronal injury, and inhibited the activation of the cerebral pyroptosis axis. At the molecular level, molecular simulation predictions indicated that quercetin might specifically bind to the NACHT domain of the NLRP3 protein, forming a complex with a stable conformation, and van der Waals interactions served as the main driving force for binding. This study confirmed that quercetin can directly bind to the NLRP3 protein and alleviate cerebral ischemia-induced inflammatory injury by inhibiting the activation of the NLRP3/Caspase-1/GSDMD pyroptosis axis and the release of downstream inflammatory factors. Combined with the molecular simulation results, a predictive hypothesis is proposed: direct binding of quercetin to the NLRP3 protein is one of its core mechanisms of action. These findings provide direct experimental evidence for the development of NLRP3-based drugs against ischemic brain injury. Full article

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29 pages, 1226 KB

Open AccessReview

Plasminogen Activator Inhibitor 1, Cell Senescence, and Aging-Related Diseases

by Rui-Ming Liu and Mary F. Nakamya

Cells 2026, 15(6), 551; https://doi.org/10.3390/cells15060551 - 19 Mar 2026

Viewed by 1421

Abstract

Cellular senescence, including replicative senescence (RS) and stress-induced premature senescence (SIPS), is a state of the permanent arrest of cell growth, which can occur in proliferative cells and post-mitotic cells. Cellular senescence is believed to contribute importantly to aging and aging-related diseases. Although [...] Read more.

Cellular senescence, including replicative senescence (RS) and stress-induced premature senescence (SIPS), is a state of the permanent arrest of cell growth, which can occur in proliferative cells and post-mitotic cells. Cellular senescence is believed to contribute importantly to aging and aging-related diseases. Although several hypotheses, including telomere shortening, oncogene activation, oxidative stress, DNA damage, and mitochondrial dysfunction, have been proposed, the mechanisms underlying cellular senescence in either physiological or pathological conditions remain poorly understood. Plasminogen activator inhibitor 1 (PAI-1), a physiological inhibitor of tissue type and urokinase type of plasminogen activators (tPA and uPA), has multiple functions. PAI-1 expression increases with age and in many aging-related diseases. Importantly, increased PAI-1 expression is not only a marker but also a mediator of cell senescence induced by different stimuli in vitro and in vivo. This review focuses on the recent advance in the role of PAI-1 in cell senescence during aging and in aging-related diseases as well as the potential mechanisms by which PAI-1 promotes cell senescence. Full article

(This article belongs to the Special Issue The Role of Cellular Senescence in Health, Disease, and Aging)

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27 pages, 3750 KB

Open AccessArticle

SMR Peptide Modulates Tumor-Derived Extracellular Vesicles microRNA and Inflammatory Transcript Signatures in TNBC

by Ming-Bo Huang, Fengxia Yan, Uswa Jadoon, Jennifer Y. Wu, Dara Brena, Erica L. Johnson, Jonathan Stiles, Lily Yang, Brian M. Rivers and Vincent C. Bond

Cells 2026, 15(6), 550; https://doi.org/10.3390/cells15060550 - 19 Mar 2026

Viewed by 851

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies and characterized by pronounced heterogeneity and widespread dysregulation of microRNAs (miRNAs) that influence epithelial-to-mesenchymal transition (EMT) and metastasis. Tumor-derived extracellular vesicles (tEVs) further contribute to TNBC progression by transporting oncogenic cargo that [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies and characterized by pronounced heterogeneity and widespread dysregulation of microRNAs (miRNAs) that influence epithelial-to-mesenchymal transition (EMT) and metastasis. Tumor-derived extracellular vesicles (tEVs) further contribute to TNBC progression by transporting oncogenic cargo that can enhance pro-inflammatory signaling. The synthetic SMRwt peptide has been suggested to modulate oncogenic pathways; however, its effects on EV miRNA composition and inflammatory transcript profiles in TNBC remain unclear. Here, we investigated whether SMRwt alters tEV-associated miRNAs and cytokine transcript signatures relevant to EMT and inflammasome-linked pathways. Extracellular vesicles were isolated from SMR-treated and untreated MDA-MB-231 cells, followed by nanoparticle tracking analysis and small RNA sequencing. SMRwt treatment enriched 11 tumor-suppressive miRNAs (including Let-7a-5p, Let-7b-5p, miR-24-3p, miR-26b-5p, miR-92a-3p, miR-93-5p, and miR-496) previously associated with the regulation of proliferation, EMT, migration, and metastasis. We also observed modest, non-significant decreases (1.01–1.27-fold) in oncogenic miR-1200, miR-374a-5p, and miR-937-3p, which have been implicated in the progression of breast, lung, and bone malignancies. Complementary transcriptomic profiling using the NanoString nCounter Breast Cancer 360 Gene Expression Panel (NanoString Technologies, Inc., Seattle, CA, USA) demonstrated reduced expression of inflammasome-associated cytokines in TNBC cells relative to non-tumorigenic controls, including a log₂ fold change of −1.15 for IL 1β (MDA-MB-231 vs. MCF10A). These transcript-level changes suggest potential modulation. Additionally, SMRwt suppresses ASC-mediated caspase-1 activation and reduces IL-1β secretion, thereby inhibiting NLRP3 inflammasome signaling. Therefore, we infer that SMRwt simultaneously restores tumor-suppressive miRNA networks and suppresses inflammasome-driven inflammation, supporting its potential as a dual-target therapeutic strategy for TNBC. Full article

(This article belongs to the Special Issue Research on Extracellular Vesicles in Health and Disease)

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26 pages, 1160 KB

Open AccessArticle

Inherent Lipid Composition Abnormalities in Astrocytes Associated with Late-Onset Alzheimer’s Disease (LOAD)

by Bruce M. Cohen, Eunjung Koh, Kandice R. Levental, Ilya Levental and Kai-Christian Sonntag

Cells 2026, 15(6), 549; https://doi.org/10.3390/cells15060549 - 19 Mar 2026

Viewed by 1072

Abstract

Lipid abnormalities have been observed in brain, cerebrospinal fluid (CSF), and blood in association with late-onset Alzheimer’s disease (LOAD). It is unknown which of these abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be [...] Read more.

Lipid abnormalities have been observed in brain, cerebrospinal fluid (CSF), and blood in association with late-onset Alzheimer’s disease (LOAD). It is unknown which of these abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived brain cells. These cells lack markers associated with aging and environmental exposures. The iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Astrocytes are crucial to neural activity and health, and altered astrocyte functions are associated with LOAD pathology. Lipidomics analyses were performed on whole-cell and mitochondria-enriched fractions. Large reductions in cholesterol esters (CEs) and imbalances in fatty acids (FAs) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids. The findings identify abnormalities in CEs, as well as in FAs, as inherent abnormalities and likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD. Full article

(This article belongs to the Special Issue Lipids and Lipidomics in Neurodegenerative Diseases)

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21 pages, 527 KB

Open AccessReview

Current Understanding of SIRT7 Function and Its Emerging Roles in the Central Nervous System

by Yuchen Jiao, Chuangui Wang and Shengping Zhang

Cells 2026, 15(6), 548; https://doi.org/10.3390/cells15060548 - 19 Mar 2026

Viewed by 893

Abstract

SIRT7is an NAD⁺-dependent deacetylase predominantly localized in the nucleolus, where it plays important roles in chromatin regulation, transcriptional control, and cellular stress response. Accumulating evidence has revealed that SIRT7 participates in multiple molecular processes, including ribosomal RNA transcription, histone modification, DNA [...] Read more.

SIRT7is an NAD⁺-dependent deacetylase predominantly localized in the nucleolus, where it plays important roles in chromatin regulation, transcriptional control, and cellular stress response. Accumulating evidence has revealed that SIRT7 participates in multiple molecular processes, including ribosomal RNA transcription, histone modification, DNA damage repair, metabolic regulation, and inflammatory signaling pathways. Through these mechanisms, SIRT7 contributes to the pathogenesis of various human diseases, particularly cancer and metabolic disorders. In recent years, emerging studies have begun to uncover the roles of SIRT7 in the central nervous system (CNS). Although research in this area remains limited, available evidence suggests that SIRT7 may be involved in neuronal homeostasis, glial function, neuroinflammation, and responses to brain injury. Furthermore, dysregulation of SIRT7 has been implicated in CNS-related pathologies. In this review, we summarize the understanding of SIRT7 molecular mechanisms and its implications in human disease, with special emphasis on its emerging roles in the CNS. We also address unresolved questions and propose future research directions to facilitate a deeper understanding of SIRT7 in neurological physiology and pathology. Full article

(This article belongs to the Special Issue State-of-the-Art Research on Histone Deacetylases (HDACs) and Histone Acetyltransferases (HATs))

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23 pages, 7014 KB

Open AccessArticle

Empowerment of CAR-T Cells by IL-7 and IL-15 Boosts Their Efficacy Against HER2-Positive Tumors with Enhanced Expansion and Persistence

by Zhehong Cheng, Henning Kirchgessner, Beate Jahraus, Emre Balta and Yvonne Samstag

Cells 2026, 15(6), 547; https://doi.org/10.3390/cells15060547 - 19 Mar 2026

Viewed by 1458

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in B cell malignancies. However, its efficacy in solid tumors remains limited, in part due to suboptimal expansion, persistence, and restrained effector function. Strategies that promote durable CAR-T cell fitness are therefore [...] Read more.

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in B cell malignancies. However, its efficacy in solid tumors remains limited, in part due to suboptimal expansion, persistence, and restrained effector function. Strategies that promote durable CAR-T cell fitness are therefore required to overcome these barriers. In this study, we generated HER2-CAR-T cells targeting human breast cancer cells and evaluated the impact of different cytokine supplementation strategies on CAR-T cell phenotype and function. We analyzed gene expression patterns and performed repetitive tumor killing assays to assess the ability of CAR-T cells expanded with IL-2 + IL-7 + IL-15 compared with IL-2 alone to maintain proliferation and cytotoxic function across multiple rounds of tumor cell exposure. Compared with IL-2 alone, supplementation with IL-7 and IL-15 significantly enhanced CAR-T cell expansion, preserved stem cell-like features prior to antigen encounter, and promoted superior proliferative capacity. Moreover, CAR-T cells cultured with IL-7+15 or IL-2+7+15 maintained sustained cytotoxicity and exhibited increased antitumor cytokine production during repeated tumor challenges. Notably, IL-7 and IL-15 supplementation induced a CD57⁺ CAR-T cell population that, unlike the immunosenescent CD57⁺ cells reported previously, retained full proliferative and cytotoxic capacity, with CD57 expression being dynamically downregulated upon antigen stimulation. Collectively, these findings demonstrate that incorporation of IL-7 and IL-15 into CAR-T cell manufacturing protocols substantially improves expansion, persistence, and effector function, supporting their use as a strategy to enhance CAR-T cell performance against solid tumors. Full article

(This article belongs to the Special Issue Tumor Immune Responsiveness in the Era of T Cell Immunotherapy)

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26 pages, 4149 KB

Open AccessArticle

Inflammation-Driven Downregulation of CYP2E1 Is Associated with Attenuated Diethylnitrosamine (DEN)-Induced Hepatocarcinogenesis

by Yoshihiro Tsuchiya, Yusuke Sotomaru, Akinori Kanai, Shin Maeda and Hideaki Kamata

Cells 2026, 15(6), 546; https://doi.org/10.3390/cells15060546 - 19 Mar 2026

Viewed by 1130

Abstract

Inflammation is widely viewed as a driver of hepatocellular carcinoma (HCC), yet inflammatory signaling also reshapes hepatic xenobiotic metabolism. Here, we established transgenic (Tg) IKKβ^Δhep mice (Tg-IKKβ^Δhep), which combine hepatocyte-specific IKKβ deletion with liver expression of a nuclear, kinase-inactive IKKβ [...] Read more.

Inflammation is widely viewed as a driver of hepatocellular carcinoma (HCC), yet inflammatory signaling also reshapes hepatic xenobiotic metabolism. Here, we established transgenic (Tg) IKKβ^Δhep mice (Tg-IKKβ^Δhep), which combine hepatocyte-specific IKKβ deletion with liver expression of a nuclear, kinase-inactive IKKβ mutant (NLS-IKKβKN). Tg-IKKβ^Δhep mice developed spontaneous chronic hepatitis and progressive fibrosis but were strikingly resistant to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, with markedly reduced tumor multiplicity and total tumor burden. Despite persistent inflammatory injury, DEN-triggered oxidative DNA damage and p53 activation were markedly attenuated, compatible with reduced tumor initiation. Transcriptomic and biochemical analyses revealed broad repression of xenobiotic-metabolizing cytochrome P450 genes, including the pericentral enzyme CYP2E1, accompanied by reduced CYP2E1 protein abundance. This was associated with impaired HNF4α–PXR–CAR transcriptional output and reduced HNF4α occupancy at target promoters. Acute TNFα or IL-1β exposure recapitulated this repression, in part through reduced PGC-1α expression and decreased RNA polymerase II recruitment to target promoters. In parallel, pericentral xenobiotic metabolism was blunted, a change that could plausibly diminish DEN bioactivation and genotoxic stress. Together, these findings support a “metabolic gatekeeping” model in which chronic inflammation can constrain chemical hepatocarcinogenesis by attenuating carcinogen-metabolizing capacity. Full article

(This article belongs to the Topic Signaling Pathways in Liver Disease 2nd Edition)

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37 pages, 1783 KB

Open AccessReview

Multifaceted Role of Copper Homeostasis in Gut Health: From Molecular Mechanisms to Therapeutic Interventions

by Fucheng Lu, Xuchen Wang, Xiaoyan Xue, Liqiang Liu, Dongmei Li, Anfang Liu, Simeng Qin and Lingbin Liu

Cells 2026, 15(6), 545; https://doi.org/10.3390/cells15060545 - 19 Mar 2026

Cited by 2 | Viewed by 1631

Abstract

Intestinal copper homeostasis governs gut health through its dual roles as an enzymatic cofactor and signaling mediator. This review discusses the molecular basis of copper absorption/transport, genetic regulation, and its functional impacts. Copper-dependent enzymes maintain intestinal barrier function and metabolism, while copper availability [...] Read more.

Intestinal copper homeostasis governs gut health through its dual roles as an enzymatic cofactor and signaling mediator. This review discusses the molecular basis of copper absorption/transport, genetic regulation, and its functional impacts. Copper-dependent enzymes maintain intestinal barrier function and metabolism, while copper availability shapes the composition of gut microbiota and mucosal immunity. The dysregulation of copper homeostasis, specifically pathological accumulation, contributes to the development of CRC by inducing dysbiosis of gut microbiota, chronic inflammation, and metastasis. This review systematically evaluates copper-targeted therapies and the associated unresolved challenges. Future efforts should prioritize defining cell-specific copper handling, metal interaction networks, and the copper–gut microbiota–immune axis in non-cancer pathologies. Moreover, future studies should also focus on developing stratified biomarker panels and spatially precise interventions to harness copper biology for diagnostic and therapeutic innovation. Full article

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20 pages, 4060 KB

Open AccessArticle

Harnessing Gut Endocrine Cell Plasticity to Restore Insulin Production

by Chaïma Ayachi, Tiziana Napolitano, Serena Silvano, Sophie Giorgetti-Peraldi, Ahmed Mansouri, Raphaël Rapetti-Mauss, Hugo Fofo, Valentin Lepage, Laura Etasse, Caroline Treins, Loan Tran and Patrick Collombat

Cells 2026, 15(6), 544; https://doi.org/10.3390/cells15060544 - 19 Mar 2026

Viewed by 690

Abstract

Type 1 diabetes (T1D) results from autoimmune-mediated destruction of pancreatic β-cells, leading to insulin deficiency and chronic hyperglycemia. β-cell replacement represents a promising therapeutic strategy, yet the identification of a sustainable and immune-compatible cell source remains a major challenge. Here, we explore the [...] Read more.

Type 1 diabetes (T1D) results from autoimmune-mediated destruction of pancreatic β-cells, leading to insulin deficiency and chronic hyperglycemia. β-cell replacement represents a promising therapeutic strategy, yet the identification of a sustainable and immune-compatible cell source remains a major challenge. Here, we explore the potential of the gastrointestinal (GI) epithelium as an alternative source of β-cells through in vivo cellular reprogramming. Given the large size and highly regenerative nature of the GI tract, partial reprogramming could provide a renewable source of insulin-producing (insulin⁺) cells. We demonstrate that ectopic expression of Pax4 is sufficient to convert gut endocrine L-cells into insulin⁺ cells in vivo. Phenotypic analyses reveal that these gut-derived cells express key β-cell markers, components of the glucose-sensing machinery, and properly process proinsulin into mature insulin. Functional studies using organoids derived from Pax4-expressing gut epithelium further demonstrate that these cells display glucose-responsive insulin secretion. Collectively, our findings highlight the plasticity of gut endocrine cells and support the feasibility of generating β-like cells from the GI epithelium, providing a potential avenue for the development of alternative cell-based therapies for T1D. Full article

(This article belongs to the Collection Research Advances in Cellular Metabolism)

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13 pages, 6941 KB

Open AccessArticle

Establishment of an Immortalized Canine Hippocampal Neural Stem Cell Line via SV40LT Retroviral Transduction

by Yankun Ke, Zixin Li, Huaiyu Wang, Yixuan Zhang, Shiyu Xu and Longlong Zhang

Cells 2026, 15(6), 543; https://doi.org/10.3390/cells15060543 - 19 Mar 2026

Viewed by 945

Abstract

Dogs represent a promising animal model for analyzing human neurodegenerative diseases, owing to their similarities to humans in nervous system architecture and behavioral phenotypes. Neural stem cells (NSCs) serve as a highly valuable in vitro experimental model for investigating neurogenesis, neurodegenerative disease pathogenesis, [...] Read more.

Dogs represent a promising animal model for analyzing human neurodegenerative diseases, owing to their similarities to humans in nervous system architecture and behavioral phenotypes. Neural stem cells (NSCs) serve as a highly valuable in vitro experimental model for investigating neurogenesis, neurodegenerative disease pathogenesis, and neural molecular biology; however, studies on immortalized canine neural stem cell lines remain scarce. Herein, we successfully established an immortalized canine hippocampal neural stem cell line that can be continuously passaged in vitro via SV40 large T antigen (SV40LT) viral infection and subsequent cellular transformation. Both the immortalized NSCs and their normal parental counterparts differentiated into neuronal and glial lineages under induced differentiation conditions. Normal canine hippocampal NSCs can be passaged for no more than 10 generations, whereas the immortalized line can be passaged indefinitely while maintaining a normal karyotype. This immortalized canine hippocampal NSC line can act as a critical experimental tool for future research into neural differentiation mechanisms and stem cell-derived therapeutic strategies for neurological disorders in dogs. Full article

(This article belongs to the Section Stem Cells)

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22 pages, 1122 KB

Open AccessReview

Calcific Aortic Valve Disease: Mechanism and Future Therapeutic Strategies

by Giwon Hwang, Soyoung Jo, Hyeshin Kwon, Minjeong Kwon, Ilwhea Ku, Jae-kwan Song and Yong Hwa Jo

Cells 2026, 15(6), 542; https://doi.org/10.3390/cells15060542 - 18 Mar 2026

Viewed by 1816

Abstract

Calcific aortic valve disease (CAVD) is an active pathological process driven by complex cellular and molecular mechanisms rather than passive aging. The disease is characterized by endothelial dysfunction, lipid infiltration, inflammation, extracellular matrix remodeling, and osteogenic differentiation of valvular interstitial cells, ultimately leading [...] Read more.

Calcific aortic valve disease (CAVD) is an active pathological process driven by complex cellular and molecular mechanisms rather than passive aging. The disease is characterized by endothelial dysfunction, lipid infiltration, inflammation, extracellular matrix remodeling, and osteogenic differentiation of valvular interstitial cells, ultimately leading to hydroxyapatite deposition and progressive valve calcification. Key signaling pathways, including Notch, Wnt/β-catenin, BMP2, and TGF-β, play critical roles in osteogenic reprogramming, while inflammatory cytokines such as IL-6, IL-1β, and TNF-α contribute to a pro-calcific microenvironment. To summarize current knowledge on CAVD pathophysiology and emerging therapeutic strategies, relevant preclinical studies were identified through searches of PubMed, and clinical trials were identified through ClinicalTrials.gov. Evidence indicates that extracellular matrix remodeling, fibrosis, and dysregulated phosphate metabolism, particularly involving TNAP and DPP-4, further accelerate disease progression. Despite advances in understanding disease mechanisms, effective pharmacological therapies remain limited, with the current treatment largely restricted to valve replacement. Emerging therapeutic approaches targeting molecular pathways, including enzyme inhibition, RNA-based therapeutics, and advanced drug delivery systems, may offer promising strategies for disease modification. A deeper understanding of CAVD pathophysiology may facilitate the development of targeted therapies to delay or prevent disease progression. Full article

(This article belongs to the Special Issue Advancements in Cardiac Metabolism)

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