Cells

35 pages, 4368 KB

Open AccessArticle

Trichostatin A Modulates Ethanol Consumption and Reveals Dose- and Sex-Specific Transcriptomic Signatures in the Nucleus Accumbens Shell

by Yi Zou, Sheketha R. Hauser, Teresa J. Raba, Richard L. Bell, Zhao Lai and Tiebing Liang

Cells 2026, 15(16), 1494; https://doi.org/10.3390/cells15161494 - 19 Aug 2026

Abstract

Background: Histone deacetylase inhibitors (HDACis) such as Trichostatin A (TSA) have emerged as promising epigenetic modulators of addiction-related behaviors. TSA treatment has been previously shown to decrease alcohol (ethanol) consumption with dose and sex differences. However, molecular mechanisms underlying TSA’s effects on [...] Read more.

Background: Histone deacetylase inhibitors (HDACis) such as Trichostatin A (TSA) have emerged as promising epigenetic modulators of addiction-related behaviors. TSA treatment has been previously shown to decrease alcohol (ethanol) consumption with dose and sex differences. However, molecular mechanisms underlying TSA’s effects on ethanol consumption remain poorly understood. Method: We collected the nucleus accumbens shell (NAcSh) of HAD1 rats, which has been used to investigate the impact of TSA treatment on ethanol consumption. RNA-seq profiling of NAcSh followed by IPA and GSEA analysis were conducted. Results: Gene profiling identified differentially expressed genes (DEGs) with sex- and dose-specific effects, with some genes demonstrating high fold change (FC). Males showed significantly increased Oxt and decreased Ttr expression following 1 mg/kg TSA treatment. In females, Pmch expression significantly decreased following 1 mg/kg TSA treatment, whereas Tmem179 expression increased following 2 mg/kg TSA treatment. Pathways centered on Hdac and Fkbp5 in males, and Bdnf and estrogen receptor in females were significantly enriched following TSA treatment, with distinct pathways identified at the 1 mg/kg and 2 mg/kg doses. IL1β and β-estradiol are common upstream regulators among all groups. Unexpectedly, some common DEGs between male and female comparisons have opposite responses to the same dose of TSA. GSEA analysis has identified additional gene sets, hallmark genes and microRNAs, and functions including immune response, metabolism, and estrogen response significantly associated with TSA treatment. Conclusions: This study successfully identified gene expression evidence that TSA treatment is sex- and dose-specific, underscoring the importance of considering both variables in the development of HDAC-targeted therapies for alcohol use disorders. Full article

(This article belongs to the Special Issue Epigenetic Regulation in Neuronal Development, Neurodegeneration and Regeneration)

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22 pages, 3278 KB

Open AccessArticle

Human Mesenchymal Stromal Cells Attenuate Hyperoxia-Induced Cellular Impairment of Immature Oligodendrocyte and Neurons

by Meray Serdar, Karina Kempe, Josephine Herz, Francesca Ricci, Ursula Felderhoff-Müser and Ivo Bendix

Cells 2026, 15(16), 1493; https://doi.org/10.3390/cells15161493 - 19 Aug 2026

Abstract

Preterm infants are at high risk of developing long-term brain injury such as encephalopathy of prematurity (EoP). Hyperoxia is a major contributor to EoP, affecting white and grey matter, with immature oligodendrocytes and hippocampal neurons being particularly vulnerable. While no causal therapy is [...] Read more.

Preterm infants are at high risk of developing long-term brain injury such as encephalopathy of prematurity (EoP). Hyperoxia is a major contributor to EoP, affecting white and grey matter, with immature oligodendrocytes and hippocampal neurons being particularly vulnerable. While no causal therapy is available, mesenchymal stromal cells (MSCs) show therapeutic potential and are considered a promising candidate, although their effector mechanisms remain incompletely understood. Primary oligodendrocytes were isolated from mixed glial cultures of P0–P2 rats and hippocampal neurons from E16 rat embryos. On day 3 (oligodendrocytes) and day 5 (neurons) after isolation, cells were exposed to hyperoxia for 8 h and subsequently co-cultured indirectly with naive or hypoxic-preconditioned human MSCs (hMSCs) for 48 h under standard culture conditions. Degeneration, proliferation, differentiation and mitochondrial respiration were assessed in both cell types. Both naive and hypoxic-preconditioned hMSCs attenuated hyperoxia-induced degeneration, reduced proliferation and mitochondrial respiration failure. Although oligodendrocyte differentiation, assessed by myelin basic protein (MBP) expression, was modulated neither by hyperoxia nor by hMSC treatment, the dendritic structure in hippocampal neurons was impaired by hyperoxia and improved by hMSC treatment. Notably, hypoxic-preconditioned hMSCs showed a stronger therapeutic effect than naive hMSCs on hyperoxia-damaged hippocampal neurons. These findings indicate that indirect hMSC co-culture mitigates hyperoxia-induced impairment of immature oligodendrocytes and hippocampal neurons and that hypoxic preconditioning may modulate this effect in a cell type-specific manner. Full article

(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)

57 pages, 3719 KB

Open AccessReview

Metabolic Outputs of the Gut Microbiome: Implications for Epilepsy

by Allison Gallucci, Xi Guo, Devika Shukla and Susan L. Campbell

Cells 2026, 15(16), 1492; https://doi.org/10.3390/cells15161492 - 19 Aug 2026

Abstract

Background: Microbiome-based mechanisms have emerged as a key area of investigation in epilepsy, given the growing recognition that gut microbial communities can modulate central nervous system (CNS) function through the gut–brain axis. Epilepsy is a common chronic neurological disorder affecting more than 65 [...] Read more.

Background: Microbiome-based mechanisms have emerged as a key area of investigation in epilepsy, given the growing recognition that gut microbial communities can modulate central nervous system (CNS) function through the gut–brain axis. Epilepsy is a common chronic neurological disorder affecting more than 65 million people worldwide, and despite the availability of anti-seizure medications (ASMs), approximately 30% of patients develop drug-resistant epilepsy. Current ASMs primarily suppress seizures rather than prevent disease progression, highlighting the need for alternative therapeutic strategies. In this context, increasing evidence supports a role for microbiota-dependent pathways in modulating seizure activity and treatment responsiveness. However, the mechanistic basis of these interactions remains incompletely understood. Methods: This narrative review synthesizes findings from the existing literature to examine the role of microbiota-derived metabolites, including neurotransmitters, vitamins, and the polyphenol metabolite S-equol, in gut–brain communication relevant to epilepsy. Evidence was drawn from both preclinical animal models and clinical studies to provide an integrated, mechanistic perspective on how these pathways may influence central nervous system function and seizure susceptibility. Emphasis was placed on studies describing molecular, metabolic, and signaling mechanisms linking the gut microbiome to epileptogenesis and treatment response. Results: Current evidence indicates that communication between the gut and CNS occurs through neural pathways, such as the vagus nerve, as well as through circulating microbial metabolites. These metabolites can cross the intestinal barrier and, in some cases, the blood–brain barrier (BBB), serving as key mediators of host–microbiota signaling. Emerging studies suggest that while some microbial metabolites may directly influence neuronal hyperexcitability and seizure susceptibility, others likely exert secondary or modulatory effects through broader metabolic and immune pathways. However, the precise mechanisms underlying these interactions remain incompletely understood. Conclusions: Some microbial-derived metabolites may serve as promising biomarkers and mechanistic mediators of epilepsy; however, further investigation is needed to define the molecular and cellular pathways through which these metabolites influence seizure susceptibility and epileptogenesis. Full article

(This article belongs to the Section Cellular Metabolism)

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23 pages, 7893 KB

Open AccessArticle

Derivative Texture Analysis of Tumor Histology for Evaluating Ultrasound Nanobubble-Driven Radiation Enhancement

by Yingqi Zhang, Lakshmanan Sannachi, Kai Xuan Leong, Wenyi Yang, Deepa Sharma, Ryan Yang and Gregory J. Czarnota

Cells 2026, 15(16), 1491; https://doi.org/10.3390/cells15161491 - 19 Aug 2026

Abstract

Microbubbles (MBs) have been used as a radiosensitizer, and their combination with ultrasound (US) has emerged as a promising strategy to improve radiotherapy outcomes in tumor treatment. Nanobubbles (NBs), which are about 1000 times smaller than MB and have enhanced stability, have been [...] Read more.

Microbubbles (MBs) have been used as a radiosensitizer, and their combination with ultrasound (US) has emerged as a promising strategy to improve radiotherapy outcomes in tumor treatment. Nanobubbles (NBs), which are about 1000 times smaller than MB and have enhanced stability, have been considered to have the potential for further radiosensitization enhancement. In this study, tumor-bearing models were treated with and without nanobubble–ultrasound (NBUS) treatment before radiotherapy (XRT) to evaluate the radiosensitization. The time intervals between the NB injection and US exposure, and between US and XRT, were optimized to maximize the therapeutic efficacy. A derivative texture analysis was applied to extract microstructural features from haematoxylin and eosin (H&E)-stained images. A one-way ANOVA test combined with a k-NN classifier and Tukey’s Honestly Significant Difference (HSD) test was used to identify the best features for assessing treatment outcomes. These were applied to H&E-stained tumor sections for evaluating microstructural alterations associated with NB-driven radiosensitization. The results indicated that both the 2 Gy and 8 Gy radiation groups showed enhanced treatment outcomes when NBUS therapy was administered before radiotherapy. Notably, NBUS + 2 Gy could achieve outcomes comparable to 8 Gy only. Additionally, a derivative texture analysis was demonstrated to be a promising and powerful technique for analyzing H&E images. This study provides a quantitative framework for assessing nanobubble-enhanced radiotherapy. Full article

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23 pages, 4195 KB

Open AccessArticle

Stimulation of Adult Muscle Stem Cells with BMPs Results in Direct Activation of Notch Pathway Genes

by Birthe Katrin Alexandra Lange, Ioanna Polydorou, Viktoriia Huryn, Angelina M. Georgieva, Shanshan You, Thomas Müller, Susanne Morales-Gonzalez, Bettina Brandt, Carmen Birchmeier, Helge Amthor and Markus Schuelke

Cells 2026, 15(16), 1490; https://doi.org/10.3390/cells15161490 - 19 Aug 2026

Abstract

Muscle stem cells (MuSCs) are the cellular source for the generation and regeneration of skeletal muscle. Proper muscle growth requires precise control over the differentiation and self-renewal of MuSCs. Signaling systems, such as bone morphogenetic proteins (BMPs) and Notch, suppress the myogenic differentiation [...] Read more.

Muscle stem cells (MuSCs) are the cellular source for the generation and regeneration of skeletal muscle. Proper muscle growth requires precise control over the differentiation and self-renewal of MuSCs. Signaling systems, such as bone morphogenetic proteins (BMPs) and Notch, suppress the myogenic differentiation of MuSCs. This allows the expansion of the progenitor pool necessary for muscle growth. To better understand the molecular mechanisms and target genes of BMPs during myogenesis, we examined the response of adult mouse MuSCs to BMP6. BMP6 stimulation of freshly isolated MuSCs suppressed myogenic differentiation. Short-term stimulation (one hour) rapidly increased the expression of classical BMP target genes, such as Id1, as well as Notch pathway genes, including Hes1, Hey1, Lfng, and Snai1. We used Cleavage Under Targets and Tagmentation (CUT&Tag) to generate whole-genome binding profiles for pSMAD1/5/9 and SMAD4, which are transcriptional effectors of the BMP pathway. This method detected dynamic binding in promoters and regulatory elements of direct BMP targets, including Notch pathway genes. Our data demonstrate that BMP6 is a potent suppressor of MuSC differentiation and reveal that a subset of well-characterized anti-myogenic genes (i.e., Hes1 and Hey1) are shared targets of the BMP and Notch pathways. Full article

(This article belongs to the Special Issue Skeletal Muscle Aging and Regeneration: Mitochondrial Health, Molecular Signaling, and Therapeutic Interventions)

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18 pages, 18052 KB

Open AccessArticle

Stage-Dependent Transmural Redistribution of NET-Associated Structures and Altered DNA Architecture in Acute Appendicitis

by Jonas Pachmann, Malik Szep, Pia Meyer zu Himmern, Max Rickes, Sara Al-Madhi, Mihailo Andric, Mirhasan Rahimli, Jessica Stockheim, Katrin Hippe, Franziska S. Karras, Ulf D. Kahlert, Roland S. Croner, Martin Herrmann and Maximilian Dölling

Cells 2026, 15(16), 1489; https://doi.org/10.3390/cells15161489 - 19 Aug 2026

Abstract

Neutrophil extracellular traps (NETs) contribute to antimicrobial defense but may promote tissue damage when produced in excess or insufficiently cleared. Acute appendicitis is characterized by neutrophil-driven inflammation, but NET-associated structures and their compartment-specific dynamics have not yet been systematically evaluated. We analyzed appendiceal [...] Read more.

Neutrophil extracellular traps (NETs) contribute to antimicrobial defense but may promote tissue damage when produced in excess or insufficiently cleared. Acute appendicitis is characterized by neutrophil-driven inflammation, but NET-associated structures and their compartment-specific dynamics have not yet been systematically evaluated. We analyzed appendiceal tissue across histopathological stages of adult appendicitis patients (n = 60), including layer-specific assessment of citrullinated histone H3 (CitH3), myeloperoxidase (MPO), B-DNA and modified DNA. In addition, we quantified NET-associated markers in the circulation of patients with histopathologically staged appendicitis (up to n = 52) and controls without appendicitis (n = 29). CitH3- and MPO-positive deposits increased with histopathological severity, formed large patches, and showed increasing involvement of the submucosa and muscularis in advanced stages. In parallel, the DNA ratio shifted toward modified DNA conformations, while B-DNA decreased. Circulating CitH3, MPO-DNA complexes, and cfDNA increased with disease stage and distinguished acute appendicitis from non-appendicitis controls. These findings suggest that acute appendicitis is not only defined by neutrophil transmigration but also by spatial and structural remodeling of NET-associated extracellular chromatin. The shift in DNA conformational patterns most likely reflects altered extracellular chromatin processing and, consequently, differential persistence of extracellular DNA. Whether circulating NET-associated markers can support diagnosis and severity stratification of appendicitis requires further validation. Full article

(This article belongs to the Special Issue Ripening and Degradation Mechanisms of Neutrophil Extracellular Traps)

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1 pages, 137 KB

Open AccessCorrection

Correction: Shin et al. Exosomal Plasminogen Activator Inhibitor-1 Induces Ionizing Radiation-Adaptive Glioblastoma Cachexia. Cells 2022, 11, 3102

by Eunguk Shin, Hyunkoo Kang, Haksoo Lee, Sungmin Lee, Jaewan Jeon, Kimoon Seong, Hyesook Youn and Buhyun Youn

Cells 2026, 15(16), 1488; https://doi.org/10.3390/cells15161488 - 19 Aug 2026

Abstract

In the original publication [...] Full article

27 pages, 5397 KB

Open AccessArticle

Isoserine Improves Spatial Memory and Remodels Synaptic and Inflammatory Gene-Expression Programs in APP/PS1 Mice

by Alessandra Saitta, Rossella Basilotta, Marika Lanza, Michele Scuruchi, Giovanna Casili, Pietro Giovani, Agata Copani, Emanuela Esposito, Salvatore Oddo and Antonella Caccamo

Cells 2026, 15(16), 1487; https://doi.org/10.3390/cells15161487 - 18 Aug 2026

Abstract

Synaptic dysfunction is a major contributor to cognitive decline in Alzheimer’s disease (AD) and represents an attractive therapeutic target. Here, we investigated whether chronic isoserine treatment improves cognition and alters the expression of synaptic-related genes in APP/PS1 mice. Isoserine was well tolerated and [...] Read more.

Synaptic dysfunction is a major contributor to cognitive decline in Alzheimer’s disease (AD) and represents an attractive therapeutic target. Here, we investigated whether chronic isoserine treatment improves cognition and alters the expression of synaptic-related genes in APP/PS1 mice. Isoserine was well tolerated and did not adversely affect body weight. In the Morris water maze, isoserine improved probe-trial performance in APP/PS1 mice, significantly reducing latency to the first platform-location crossing, while time spent in the target quadrant showed a directionally consistent but non-significant increase. To identify molecular correlates, we profiled 84 synaptic-related genes using a targeted RT² Profiler PCR Array. Gene-level factorial analyses identified several nominal treatment-associated effects, but no individual isoserine effect in APP/PS1 mice remained significant after false-discovery-rate correction. In contrast, module-level analyses identified False-discovery rate (FDR)-significant changes in NF-κB/inflammatory, synaptic-maintenance, and glutamatergic-signaling gene-expression modules, with significant genotype × treatment interactions for the NF-κB/inflammatory and synaptic-maintenance modules. Exploratory heatmap and principal component analyses further illustrated disease-context-dependent expression patterns. Western blot analyses showed that isoserine reduced nuclear factor kappa B (NF-κB p65) and NMDA receptor subunit GluN2B (GluN2B) and increased postsynaptic density protein 95 (PSD-95) levels in APP/PS1 mice. These findings suggest that isoserine improves spatial memory retention and coordinately remodels synaptic and inflammatory molecular programs in APP/PS1 mice. Full article

(This article belongs to the Section Cellular Neuroscience)

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43 pages, 1595 KB

Open AccessReview

Cellular and Microcircuit Mechanisms of Anesthetic Disruption of Conscious-State Organization

by Bernard Kordas

Cells 2026, 15(16), 1486; https://doi.org/10.3390/cells15161486 - 18 Aug 2026

Abstract

The reversible effects of general anesthesia can be used to examine how brain activity changes during transitions into and out of altered conscious states. Such changes are commonly tracked using behavioral responses, electroencephalographic recordings, and measures of functional connectivity. These measures, however, reflect [...] Read more.

The reversible effects of general anesthesia can be used to examine how brain activity changes during transitions into and out of altered conscious states. Such changes are commonly tracked using behavioral responses, electroencephalographic recordings, and measures of functional connectivity. These measures, however, reflect processes occurring at lower levels of organization, including the activity of pyramidal neurons, dendritic integration, interneuron function, thalamocortical signaling, and glial regulation of the extracellular environment. Anesthesia does not affect all neural processes equally. Propofol and volatile agents interfere with synaptic transmission and apical dendritic integration, as well as cortical feedback and thalamocortical signaling. The resulting activity is not necessarily absent or uniformly weaker. It is often more stereotyped, temporally restricted, and poorly coordinated between regions. Ketamine produces a different organization. Substantial neural activity and complex cortical responses may persist after behavioral responsiveness has been lost, although deeper anesthesia also produces slower and less complex activity. Responsiveness, environmental connectedness, memory, reportability, and conscious content may therefore become partly uncoupled. Ketamine produces a dissociative state that cannot be interpreted simply as another form of the predominantly restrictive state produced by propofol or volatile anesthetics. This narrative review synthesizes evidence identified through a structured PubMed search to examine how anesthesia reshapes conscious processing and why unresponsiveness or absent recall may not indicate absent experience. Full article

(This article belongs to the Special Issue Brain Function and Structure: Mapping Complexity in Neuronal Cells)

33 pages, 1890 KB

Open AccessReview

Urine and Blood-Derived MicroRNAs in Patients with Kidney Cancer: A Review of Clinical Utility and Recent Developments

by Samuel Y. R. Chen, Serina Quach, Vladislav Nikitin, Jennifer A. Linehan and Matias A. Bustos

Cells 2026, 15(16), 1485; https://doi.org/10.3390/cells15161485 - 18 Aug 2026

Abstract

Renal cell carcinoma (RCC) is frequently detected incidentally, and no widely adopted noninvasive biomarkers are available for RCC diagnosis or prognosis. In this regard, cell-free microRNAs (cfmiRs) have emerged as promising candidates due to their stability in biological fluids. In this narrative review, [...] Read more.

Renal cell carcinoma (RCC) is frequently detected incidentally, and no widely adopted noninvasive biomarkers are available for RCC diagnosis or prognosis. In this regard, cell-free microRNAs (cfmiRs) have emerged as promising candidates due to their stability in biological fluids. In this narrative review, we summarize translational studies published from 2010 to 2025 that evaluated serum, plasma, or urinary cfmiRs for RCC diagnosis, prognosis, recurrence surveillance, or treatment-response monitoring. Forty-two studies met inclusion criteria, comprising 3454 patients with RCC and 2445 healthy donors. Twenty-nine studies assessed diagnostic performance, fewer evaluated prognostic applications, and none examined treatment-response monitoring. Multi-miRNA panels generally reported higher performance than single-miRNA assays. Serum was the most frequently studied biofluid in this review (n = 26), followed by urine (n = 12) and plasma (n = 4). Urinary biomarkers demonstrated high specificity and the practical advantage of noninvasive collection. Although limited in number, prognostic studies identified associations between cfmiRs and overall survival, recurrence-free survival, metastasis-free survival, and other clinically relevant outcomes. However, substantial heterogeneity in study design, assay methods, and reporting limited comparisons across studies. Current evidence supports continued evaluation of cfmiRs as adjunctive biomarkers alongside imaging or histopathology, but multicenter validation, standardized methods, and more robust evidence are required before clinical implementation. Full article

(This article belongs to the Special Issue MicroRNAs: Regulators of Cellular Fate)

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15 pages, 2550 KB

Open AccessArticle

Dihydroquinine Enhances Radiosensitivity in Cervical Cancer Cells Accompanied by Radiation-Induced Cellular Responses

by Ausanai Prapan, Pimvaree Aissara, Peerawit Soonthornchookiat, Chanyatip Suwannasing, Jirapas Jongjitwimol, Chatrawut Pattaweerakul, Yu Xiong, Saranya Chaiwaree and Hans Bäumler

Cells 2026, 15(16), 1484; https://doi.org/10.3390/cells15161484 - 18 Aug 2026

Abstract

Radiosensitizers are being investigated to improve the therapeutic efficacy of radiotherapy by enhancing tumor cell sensitivity while minimizing damage to normal tissues. Dihydroquinine (DHQ), a naturally occurring Cinchona alkaloid with diverse biological activities, has not previously been evaluated for radiosensitizing potential. In this [...] Read more.

Radiosensitizers are being investigated to improve the therapeutic efficacy of radiotherapy by enhancing tumor cell sensitivity while minimizing damage to normal tissues. Dihydroquinine (DHQ), a naturally occurring Cinchona alkaloid with diverse biological activities, has not previously been evaluated for radiosensitizing potential. In this study, human cervical cancer (HeLa) cells were pretreated with an IC20 concentration of DHQ and exposed to 6 MV X-ray irradiation. Clonogenic survival was assessed after irradiation at 2, 4, and 6 Gy, while intracellular ROS, γ-H2AX immunofluorescence, and apoptosis were evaluated following DHQ pretreatment and 2 Gy irradiation. DHQ pretreatment reduced clonogenic survival, yielding sensitizer enhancement ratio values of 1.37 and 1.55 at surviving fractions of 0.20 and 0.37, respectively, indicating modest-to-moderate enhancement of radiosensitivity. DHQ was also associated with increased ROS production, elevated γ-H2AX positivity, and enhanced apoptosis compared with irradiation alone. These findings suggest that DHQ enhances the radiation response in HeLa cells and is associated with increased radiation-induced cellular responses. Although the radiosensitizing effect was modest, the consistent findings across multiple biological endpoints support further investigation of DHQ as a potential adjunct to radiotherapy. Further studies are warranted to validate these findings in more clinically relevant preclinical models. Full article

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26 pages, 2010 KB

Open AccessReview

From Degeneration to Regeneration: The Evolving Landscape of Cell-Based Tendon Repair

by Ines Wang, Brett D. Owens and Jay Trivedi

Cells 2026, 15(16), 1483; https://doi.org/10.3390/cells15161483 - 18 Aug 2026

Abstract

Tendinopathies represent a major clinical challenge. Vasculature, neuromuscular junctions, low cellularity, and slow extracellular matrix (ECM) turnover restrict endogenous repair and predispose injured tendons to fibrosis, mechanical weakness, and reinjury. Current therapeutic strategies including rehabilitation protocols, anti-inflammatory medications, platelet-rich plasma (PRP) injections, and [...] Read more.

Tendinopathies represent a major clinical challenge. Vasculature, neuromuscular junctions, low cellularity, and slow extracellular matrix (ECM) turnover restrict endogenous repair and predispose injured tendons to fibrosis, mechanical weakness, and reinjury. Current therapeutic strategies including rehabilitation protocols, anti-inflammatory medications, platelet-rich plasma (PRP) injections, and surgical repair primarily address symptoms or structural deficits without correcting the underlying biological limitations of tendon healing. Cell-based therapies have emerged as a promising regenerative approach aimed at restoring tissue homeostasis through modulation of angiogenesis, collagen synthesis, immune responses, and tenogenic differentiation. Mesenchymal stem cells (MSCs), adipose-derived stem cells (ADSCs), tendon-derived stem cells (TDSCs), induced pluripotent stem cells (iPSCs), differentiated tenocytes, and extracellular vesicle (EV)-based products have demonstrated the ability to enhance vascularization, promote type I collagen remodeling, suppress excessive inflammation, and stimulate tenocyte lineage commitment. These effects are mediated through paracrine signaling, growth factor secretion, and activation of key pathways, including HIF-1α, TGF-β/SMAD, NF-κB, and PI3K/Akt signaling. Despite promising preclinical data, significant translational challenges remain, including limited cell survival at the injury site, variability in cell sources and dosing, immunogenicity, risk of misdifferentiation, and lack of standardization across clinical protocols. Emerging strategies such as genetic modification, hypoxic preconditioning, scaffold-based delivery systems, and extracellular vesicle engineering aim to enhance therapeutic efficacy and reproducibility. This review synthesizes current evidence on cell-based tendon repair, critically evaluates mechanistic insights, clinical trials, and translational barriers, and outlines future directions toward biologically informed regenerative therapies. Full article

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

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22 pages, 14172 KB

Open AccessArticle

Inflammation-Associated Changes in Piezo1 Expression, Mitophagy-Related Markers, and Matrix Dysregulation in an LPS-Stimulated Co-Culture Organoid System

by Kavitha Raja, Dineshwary Grace Suresh, Jamila Khalid Albeshri, Surendra Singh Rawat, Ivan James Prithishkumar, Thomas Nau and Nerissa Naidoo

Cells 2026, 15(16), 1482; https://doi.org/10.3390/cells15161482 - 18 Aug 2026

Abstract

Osteoarthritis (OA) is a progressive joint disease characterized by cartilage degeneration, chronic low-grade inflammation, and disruption of tissue homeostasis. Although the mechanosensitive ion channel Piezo1 has been implicated in OA pathogenesis, its expression may also be modulated by inflammatory stimuli independently of applied [...] Read more.

Osteoarthritis (OA) is a progressive joint disease characterized by cartilage degeneration, chronic low-grade inflammation, and disruption of tissue homeostasis. Although the mechanosensitive ion channel Piezo1 has been implicated in OA pathogenesis, its expression may also be modulated by inflammatory stimuli independently of applied mechanical loading. This study established a scaffold-free three-dimensional co-culture organoid model comprising human bone marrow-derived mesenchymal stem cell-derived chondrocyte-like cells and M-CSF/RANKL-differentiated RAW264.7-derived osteoclast-like cells to investigate Piezo1-associated molecular responses, inflammatory signaling, and mitophagy-related markers under lipopolysaccharide (LPS)-induced inflammatory conditions. Osteoclast-like differentiation was validated in parallel monolayer cultures by tartrate-resistant acid phosphatase staining and the presence of multinucleated cells before the corresponding differentiated cultures were used for organoid generation. Histological staining, immunofluorescence, CellTiter-Glo 3D viability assay, lactate dehydrogenase cytotoxicity assay, RT-qPCR, and Western blotting were used to evaluate extracellular matrix formation and inflammatory, catabolic, and mitochondrial quality-control-associated markers. LPS stimulation increased the expression of Piezo1, HIF-1α, phosphorylated CaMKII, NLRP3, cleaved Caspase-1, and MMP13, together with alterations in mitophagy- and autophagy-associated markers. Among the evaluated compounds, curcumin produced the greatest improvement in viability relative to the LPS-treated group and was selected for subsequent molecular analyses. Curcumin treatment was associated with reduced inflammatory and catabolic marker expression and partial preservation of cartilage-associated matrix markers. These findings demonstrate inflammation-associated changes in Piezo1 expression and related molecular markers but do not establish mechanically activated Piezo1 signaling or Piezo1-dependent causality. The organoid system therefore represents an exploratory LPS-induced inflammatory model exhibiting selected OA-relevant molecular and matrix-associated features. Full article

(This article belongs to the Section Stem Cells)

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23 pages, 6378 KB

Open AccessArticle

Sepsis-Induced Exosomal Transfer of MAFB mRNA Reprograms Hepatocytes via a miR-155–Jarid2–H3F3A Epigenetic Cascade

by Gizaw Mamo Gebeyehu, Milorad Zjalic, Rita Bognár, Benjámin Farkas, Shima Rashidiani, Géza Makkai, Tibor Z. Jánosi, Péter Urbán, József Kun, Attila Gyenesei, Marianna Pap, Željko Debeljak, Marija Heffer and Tibor A. Rauch

Cells 2026, 15(16), 1481; https://doi.org/10.3390/cells15161481 - 18 Aug 2026

Abstract

Exosomes carry bioactive macromolecules driving sepsis pathogenesis, but the mechanisms underlying macrophage-to-hepatocyte communication during systemic inflammation remain poorly understood. We investigated how sepsis-induced macrophage exosomes are involved in remote intercellular crosstalk with hepatic cells via transcription factor-encoding mRNA cargo. Human monocytic THP-1 macrophages [...] Read more.

Exosomes carry bioactive macromolecules driving sepsis pathogenesis, but the mechanisms underlying macrophage-to-hepatocyte communication during systemic inflammation remain poorly understood. We investigated how sepsis-induced macrophage exosomes are involved in remote intercellular crosstalk with hepatic cells via transcription factor-encoding mRNA cargo. Human monocytic THP-1 macrophages were stimulated with lipopolysaccharide (LPS), followed by exosome isolation, recipient cell uptake verification, and high-throughput RNA sequencing cargo analysis. To functionally reconstruct downstream signaling in recipient cells, exosome-enriched MAFB mRNA was transiently overexpressed in a HepG2 cell model, with subsequent expression changes mapped at both the transcript and protein levels using quantitative PCR and Western blot analyses. This ectopic MAFB expression directly upregulates the expression of microRNA-155 (miR-155). Crucially, elevated miR-155 acts as a post-transcriptional repressor that directly targets and downregulates JARID2 and H3F3A mRNAs and their corresponding protein products within the liver cells, orchestrating a “repressor-of-repressors” disinhibition cascade that drives net chromatin remodeling and activation of downstream hepatic target genes. This study demonstrates that sepsis alters exosomal transcription factor mRNA cargo and delineates a mechanistic downstream pathway—MAFB → ↑miR155 → ↓Jarid2 & ↓H3F3A → Chromatin Remodeling → Downstream Hepatic Gene Activation pathway—that provides novel, specific molecular checkpoints for therapeutic intervention in sepsis-induced liver injury. Full article

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18 pages, 2865 KB

Open AccessArticle

Functional and Structural Determinants of Human Sperm Cryoresistance: Insights from Motility, Mitochondrial and Chromatin Integrity Analyses

by Eva Tvrdá, Temidayo S. Omolaoye, Michal Ďuračka, Fawzia AlObeidli and Stefan S. Du Plessis

Cells 2026, 15(16), 1480; https://doi.org/10.3390/cells15161480 - 18 Aug 2026

Abstract

Sperm cryopreservation is essential for fertility preservation and assisted reproduction; however, post-thaw sperm quality varies markedly between individuals despite standardized protocols. This exploratory study investigated whether good and poor freezers differ in cellular, sub-cellular, and molecular features associated with cryoresistance. One ejaculate from [...] Read more.

Sperm cryopreservation is essential for fertility preservation and assisted reproduction; however, post-thaw sperm quality varies markedly between individuals despite standardized protocols. This exploratory study investigated whether good and poor freezers differ in cellular, sub-cellular, and molecular features associated with cryoresistance. One ejaculate from each of 100 normozoospermic donors was assessed before cryopreservation and after thawing. Samples were classified after thawing as good freezers (GFs; n = 50) or poor freezers (PFs; n = 50) according to post-thaw motility performance, using total motility ≥ 42% and progressive motility ≥ 30% as thresholds. Sperm quality was evaluated using computer-assisted sperm analysis, membrane and acrosome integrity assays, mitochondrial membrane potential, capacitation-associated patterns, membrane lipid disorder and DNA/chromatin integrity tests. Post-thaw thermoresistance was assessed at 37 °C for 60 and 120 min. An exploratory Western blot panel was performed only on fresh pre-freeze samples from a selected subset of 4 GF and 4 PF samples. Cryopreservation reduced sperm quality in both groups; however, PF samples showed significantly greater declines in total and progressive motility, sperm viability, membrane and acrosome integrity, mitochondrial membrane potential and thermoresistance. Exploratory Western blot data showed GF-favoring patterns for proAKAP4, SPAG6, proACR and the proACR/ACR ratio, whereas PF samples showed relatively higher ACR abundance; these molecular findings require validation in larger cohorts. Our data indicate that human sperm cryoresistance is a coordinated multi-level phenomenon involving membrane, mitochondrial, acrosomal, chromatin and flagellar resilience. This study identifies candidate functional and molecular indicators associated with cryoresistance and supports future development of pre-freeze screening strategies rather than providing a validated predictive model or clinical cut-off values. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Male Fertility)

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20 pages, 1629 KB

Open AccessReview

Transcription Factor Regulation of Epidermal Differentiation and Inflammation

by Uyanga Batzorig, Grace Zhang and George L. Sen

Cells 2026, 15(16), 1479; https://doi.org/10.3390/cells15161479 - 18 Aug 2026

Abstract

The epidermis is far more than a mechanical shield; it is a dynamic immunological interface whose structural integrity and immune homeostasis are co-regulated by interconnected transcriptional networks. This review examines how epidermal differentiation promoting transcription factors coordinate terminal keratinocyte maturation, skin barrier formation, [...] Read more.

The epidermis is far more than a mechanical shield; it is a dynamic immunological interface whose structural integrity and immune homeostasis are co-regulated by interconnected transcriptional networks. This review examines how epidermal differentiation promoting transcription factors coordinate terminal keratinocyte maturation, skin barrier formation, immune suppression, lipid metabolism, and tissue repair. In particular, Zinc finger protein 750 (ZNF750), grainyhead-like transcription factor 3 (GRHL3), and ovo-like transcriptional repressor 1 (OVOL1) integrate epidermal differentiation with the suppression of inflammatory signaling by regulating lipid metabolism, innate immune sensors, stress-response pathways, and environmentally responsive transcriptional programs. Disruption of these regulatory nodes impairs barrier integrity, amplifies inflammatory signaling, and predisposes to chronic skin diseases, including psoriasis and atopic dermatitis. Full article

(This article belongs to the Special Issue Gene Regulation in Epithelial Cells)

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12 pages, 1712 KB

Open AccessArticle

Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway

by Dao-Fu Dai, Ines Martins, Nastaran Daneshgar, Meng Gao, Benjamin Rodriguez, Mohd Mabood Khan, Antentor Jr. Hinton, Peter A. Crawford and Chad Grueter

Cells 2026, 15(16), 1478; https://doi.org/10.3390/cells15161478 - 18 Aug 2026

Abstract

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in heart failure, but the mechanisms remain incompletely understood. Metabolic remodeling has been proposed as a key mediator. Methods and Results: Myocardial infarction (MI) was induced in cardiomyocyte-specific BDH1 knockout (BDH1-KO) wild-type (WT) mice and in [...] Read more.

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in heart failure, but the mechanisms remain incompletely understood. Metabolic remodeling has been proposed as a key mediator. Methods and Results: Myocardial infarction (MI) was induced in cardiomyocyte-specific BDH1 knockout (BDH1-KO) wild-type (WT) mice and in liver-specific Fibroblast Growth Factor-21 knockout (FGF21-KO) mice. Following confirmation of reduced ejection fraction (EF), mice were randomized to empagliflozin (Empa, 10 mg/kg/day) or saline. After 4 weeks, untreated WT mice demonstrated progressive systolic dysfunction (ΔEF: −11.6 ± 6.3%), whereas Empa-treated WT mice showed significant improvement (ΔEF: 9.9 ± 4.3%). This benefit was completely abolished in BDH1-KO mice (ΔEF: −10.5 ± 2.8%) or FGF21-KO mice, suggesting that FGF21 regulation and cardiomyocyte ketone oxidation are required for Empa cardioprotection. In WT and hepatocyte-specific FGF21-KO mice, 1 week of Empa treatment increased cardiac BDH1 expression in WT but not FGF21-deficient mice. In human iPSC-cardiomyocytes, FGF21 induced BDH1 expression, whereas Empa had no direct effect on BDH1. In HepG2 liver cells, Empa increased both FGF21 and BDH1 expression. Conclusions: Empa activates the liver–heart metabolic axis. Loss of cardiomyocyte BDH1 or FGF21 production by the liver abolishes Empa-mediated improvement in post-MI cardiac function, identifying FGF21/ketone metabolism as a key mechanism of SGLT2 inhibitor cardioprotection. Full article

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

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17 pages, 2004 KB

Open AccessArticle

Cellular Senescence-Associated Gene Expression in Circulating CD4⁺, CD8⁺, CD19⁺ Lymphocytes of HNSCC Patients: Associations with Clinical Parameters

by Kamila Ostrowska, Patryk Niewinski, Igor Piotrowski, Agata Kubicka, Julia Ostapowicz, Julia Kozikowska, Aleksandra Jazikowska, Karolina Czochór, Joanna Marchlewska, Danuta Procyk, Ewa Leporowska, Wiktoria M. Suchorska, Matthew J. Yousefzadeh, Michal M. Masternak and Wojciech Golusiński

Cells 2026, 15(16), 1477; https://doi.org/10.3390/cells15161477 - 18 Aug 2026

Abstract

Senescence-associated secretory phenotype (SASP) signaling, along with key markers such as P16^INK4a/CDKN2A and LMNB1, has not been systematically studied in circulating lymphocyte subsets in head and neck squamous cell carcinoma (HNSCC). This study aimed to evaluate SASP-related genes and senescence [...] Read more.

Senescence-associated secretory phenotype (SASP) signaling, along with key markers such as P16^INK4a/CDKN2A and LMNB1, has not been systematically studied in circulating lymphocyte subsets in head and neck squamous cell carcinoma (HNSCC). This study aimed to evaluate SASP-related genes and senescence markers in peripheral CD4⁺, CD8⁺, and CD19⁺ cells and assess their clinical relevance. Expression of IL-6, IL-1β, TNFα, CXCL1, P16^INK4a/CDKN2A, and LMNB1 was measured by RT-qPCR in sorted lymphocytes from 58 HNSCC patients at baseline, 31 post-treatment, and 13 controls. Statistical analyses included nonparametric tests, correlation analyses, and survival models (Kaplan–Meier, Cox regression). In the results, LMNB1 was significantly upregulated in all lymphocyte subsets of HNSCC patients. IL-6, CXCL1, and IL-1β were elevated in CD4⁺ T cells. A coordinated co-expression network involving IL-6, CXCL1, IL-1β, P16^INK4a/CDKN2A, and LMNB1 was observed. Clinically, IL-6 in CD8⁺ T cells was associated with higher nodal stage and worse survival, while CXCL1 in CD19⁺ B cells independently predicted survival. No differences were found between pre- and post-treatment samples. Circulating lymphocytes in HNSCC display coordinated expression of selected senescence-associated genes, with IL-6 and CXCL1 as candidate prognostic biomarkers linked to tumor progression that warrant further validation. Full article

(This article belongs to the Special Issue Emerging Mechanisms and Therapeutic Strategies in Head and Neck Cancer)

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22 pages, 23671 KB

Open AccessArticle

Live-Cell Imaging of Telocyte-like Cells in Primary Liver Cell Cultures

by Nikolaus Bresgen and Hubert H. Kerschbaum

Cells 2026, 15(16), 1476; https://doi.org/10.3390/cells15161476 - 18 Aug 2026

Abstract

Telocytes are small mesenchymal cells with unknown hepatic functions. In primary cultures of rat hepatocytes and non-parenchymal liver cells (NPLC), we observed, at a very low incidence, small-sized, highly motile cells. Because these cells fulfill ultrastructural/morphological ‘telocytes hallmarks’, foremost their minuteness and the [...] Read more.

Telocytes are small mesenchymal cells with unknown hepatic functions. In primary cultures of rat hepatocytes and non-parenchymal liver cells (NPLC), we observed, at a very low incidence, small-sized, highly motile cells. Because these cells fulfill ultrastructural/morphological ‘telocytes hallmarks’, foremost their minuteness and the presence of very thin telopodia, we refer to them as hepatic telocyte-like cells (hTCLs). Unique among hepatic cells and beyond these telocyte characteristics is their high motility and pronounced cell plasticity. Surprisingly, hTCLs display an exceptional exploratory behavior by moving along/between cell borders as well as beneath cells. Their fast motility apart, hTCLs share structural and behavioral similarities with Kupffer cells/macrophages in NPLC cultures, suggesting a relationship between both cell types that needs to be addressed by further investigation. In EGF/insulin-treated hepatocyte cultures, hTCLs’ motility declines, and the cells adopt an extremely small cell body with very long processes. In cultured hepatocyte monolayers, hTCLs associate with dividing hepatocytes, especially during advanced mitosis (cytokinesis). In conclusion, our observations demonstrate the presence of a small population of highly mobile, telocyte-like cells in liver-derived cell cultures, and a correlative association between hTCLs and hepatocytes, hypothetically accounting for an integrative function of this cell type. Full article

(This article belongs to the Special Issue Physiology of Telocytes)

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