Cells

11 pages, 1733 KB

Open AccessArticle

Effects of Age on Intervertebral Disc Tissue Morphology and Gene Expression in the ADAM8-Inactivation Mouse

by Lutian Yao, Huan Wang, Zuozhen Tian, Frances S. Shofer, Ling Qin and Yejia Zhang

Cells 2026, 15(8), 730; https://doi.org/10.3390/cells15080730 - 20 Apr 2026

Purpose: To determine which age of mice should be used to compare the effects of ADAM8 mutation on intervertebral disc (IVD) responses to injury. Methods: IVDs of ADAM8 mutant (Adam8^EQ) and wild type (WT) mice, aged 3, 10 [...] Read more.

Purpose: To determine which age of mice should be used to compare the effects of ADAM8 mutation on intervertebral disc (IVD) responses to injury. Methods: IVDs of ADAM8 mutant (Adam8^EQ) and wild type (WT) mice, aged 3, 10 and 18 months were injured. IVD tissues were harvested 1 week post injury for histological and molecular studies. Results: Histological scores increased with aging in intact IVDs, and there were no differences between Adam8^EQ and WT mice (n = 11–28; p > 0.05). Safranin O-staining was less intense in 10-month than in 3-month-old mice, in both intact and injured IVDs (n = 3–15; p < 0.05). Cxcl1, Il6, and Adam8 gene expression levels were higher in the injured tail IVDs of 3-month-old Adam8^EQ than WT mice (n = 18–30; p < 0.05); the injury-related differences diminished with increasing age. Conclusions: No histological differences were found between Adam8^EQ and WT mouse IVDs at 3, 10 or 18 months of age, in the intact or injured discs. The differences in inflammatory marker gene expression were detectable at age 3 months, but were less evident when the injury occurred at age 10 or 18 months. Therefore, to identify differences in injury responses between WT and Adam8^EQ mouse IVDs, 3-month-old mice are superior to older mice. Full article

(This article belongs to the Special Issue Novel Insights into Mechanism and Treatment of Degenerative Disc Disease)

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16 pages, 3108 KB

Open AccessArticle

Single-Cell Transcriptomics Reveals Immune Modulation by Telmisartan in Colorectal Cancer

by Jinxin Li, Decao Yang, Xiaoyue Wang, Runqing Ju, Shaomeng Chen, Jingyi Zhao, Jiaxing Xu, Jiaxin Chen, Jiayu Ye, Baohui Xu, Qianqian Yin and Yan Wang

Cells 2026, 15(8), 729; https://doi.org/10.3390/cells15080729 - 20 Apr 2026

Abstract

Telmisartan, an angiotensin II type 1 receptor blocker with established anti-inflammatory and antihypertensive properties, has been reported to inhibit tumor cell proliferation, yet its impact on the tumor immune microenvironment remains poorly understood. In this study, we evaluated the immunomodulatory effects of telmisartan [...] Read more.

Telmisartan, an angiotensin II type 1 receptor blocker with established anti-inflammatory and antihypertensive properties, has been reported to inhibit tumor cell proliferation, yet its impact on the tumor immune microenvironment remains poorly understood. In this study, we evaluated the immunomodulatory effects of telmisartan using a syngeneic MC38 colorectal cancer model in C57BL/6 mice. Daily intragastric administration of telmisartan significantly suppressed tumor growth and reduced endpoint tumor weight compared with controls. To elucidate the underlying mechanisms, we performed single-cell RNA sequencing on tumor-infiltrating CD45⁺ immune cells and revealed a macrophage-dominated immune landscape comprising multiple transcriptionally distinct subclusters. Telmisartan broadly downregulated pro-tumoral and M2-associated macrophage programs, including decreased expression of genes such as Mrc1 and Spp1, while also suppressing cell proliferation-related pathways. In contrast to its overall suppressive impact on macrophages, telmisartan increased the proportion of cytotoxic CD8⁺ T cells, reduced regulatory T cell counts, and enhanced major histocompatibility complex class I antigen presentation, consistent with an immune-activating effect. These results indicate that telmisartan reshapes the colorectal tumor immune microenvironment by simultaneously attenuating tumor-promoting macrophage activity and augmenting cytotoxic T cell responses. Overall, this study provides a single-cell framework to understand how angiotensin receptor blockade reshapes tumor-infiltrating immune programs, highlighting the translational potential of repurposing telmisartan for novel cancer immunotherapy strategies. Full article

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12 pages, 703 KB

Open AccessBrief Report

Three-Phase Serum Concentration Kinetics of FGF23 in a Clinical Model of Acute Myocardial Infarction

by Nora Strack, Praveen Gajawada, Christoph Liebetrau, Oliver Dörr, Till Keller, Yeong-Hoon Choi and Manfred Richter

Cells 2026, 15(8), 728; https://doi.org/10.3390/cells15080728 - 20 Apr 2026

Abstract

Background: Fibroblast growth factor-23 (FGF23) is a key regulator of phosphate homeostasis and an emerging biomarker in cardiovascular disease. Emerging data suggest that FGF23 may also contribute to the pathophysiology of myocardial infarction (MI), but existing studies have largely focused on non-acute stages. [...] Read more.

Background: Fibroblast growth factor-23 (FGF23) is a key regulator of phosphate homeostasis and an emerging biomarker in cardiovascular disease. Emerging data suggest that FGF23 may also contribute to the pathophysiology of myocardial infarction (MI), but existing studies have largely focused on non-acute stages. To address this gap, we investigated early FGF23 regulation by characterizing serum concentration kinetics over the first 24 h following MI, using both a clinical MI model (TASH) and a cohort of patients with ST-elevation myocardial infarction (STEMI). Methods: Circulating FGF23 concentrations (cFGF23; RU/mL) were determined by C-terminal ELISA in patients with preserved renal function (eGFR > 30 mL/min/1.73 m²). TASH (transcoronary septal ablation) was carried out in patients with hypertrophic obstructive cardiomyopathy (n = 38). Venous serum samples were taken at baseline (pre-TASH) and at 30′, 60′, 2 h, 4 h and 24 h post-TASH. For the STEMI cohort (n = 18), serum was sampled immediately before and 3 h after coronary recanalization. All samples were processed using standardized procedures prior to analysis. Changes over time were assessed using the Friedman test with Bonferroni-corrected pairwise Wilcoxon comparisons. Results: FGF23 concentrations changed significantly over time after TASH (Friedman test, p < 0.000001, Kendall’s W = 0.518). Baseline FGF23 was 28.9 (19.4–71.0) RU/mL and increased significantly at 30′ (68.2 (36.2–178.7) RU/mL, adjusted p < 0.0001 **) after TASH. Concentrations remained elevated at 60′ (54.8 (31.6–118.3) RU/mL; adjusted p = 0.0019 *), returned to baseline at 2 h (30.9 (20–71.2) RU/mL; adjusted p = 1.0 vs. baseline) and decreased significantly below baseline at 4 h (24 (12.13–37.5) RU/mL, adjusted p = 0.0215 *). By 24 h, FGF23 had returned to baseline levels (28.8 (12.8–57.3) RU/mL; adjusted p = 1.0 vs. baseline). Although concentrations were numerically higher than at the 4 h nadir, this recovery did not reach statistical significance (adjusted p = 0.136 vs. 4 h). In STEMI patients, a non-significant decrease was observed from baseline (27 (15.5–35.75) RU/mL) to 3 h after recanalization (15.5 (6.75–34.25) RU/mL; p = 0.074, effect size r = 0.422). In an exploratory normalized analysis, the decline reached significance (p = 0.0241). Conclusions: The triphasic kinetics of circulating FGF23 in TASH patients—characterized by an early rise, transient undershoot, and a recovery toward baseline with a continuing upward trend—are consistent with a dynamic release-and-clearance pattern following myocardial injury. These findings are hypothesis-generating and warrant further investigation in larger cohorts with additional biomarkers to elucidate the source, regulation, and potential functional significance of FGF23 in the acute phase of myocardial infarction. Full article

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20 pages, 2560 KB

Open AccessArticle

Hypomagnetic Field Enhances U2OS Cell Proliferation and Migration by Promoting β-Catenin Phosphorylation and Upregulating FN1 and LOX Expression

by Taotao Gao, Wenfeng Zhong, Mengli Tao, Yu Guo, Kun Yang, Yaohui He, Guosheng Hu, Long Li, Xiangyan Kong, Fulai Li and Yufen Zhao

Cells 2026, 15(8), 727; https://doi.org/10.3390/cells15080727 - 19 Apr 2026

Abstract

Accumulating evidence indicates that a hypomagnetic field (HMF, <5 μT) has a significant impact on various organ systems in animals. However, the cellular and molecular mechanisms underlying these biological effects remain unclear. Understanding the molecular mechanisms underlying mammalian responses to a HMF is [...] Read more.

Accumulating evidence indicates that a hypomagnetic field (HMF, <5 μT) has a significant impact on various organ systems in animals. However, the cellular and molecular mechanisms underlying these biological effects remain unclear. Understanding the molecular mechanisms underlying mammalian responses to a HMF is crucial for addressing health and safety concerns associated with HMF exposure. In this study, we investigated the changes in intracellular protein phosphorylation under HMF conditions and validated the functional mechanisms by which HMF-induced protein phosphorylation affects cell behavior. We found that U2OS cells can rapidly sense changes in magnetic fields, leading to alterations in protein phosphorylation levels within the cell. The quantitative phosphoproteomics results revealed that the exposure of U2OS cells to the HMF environment for 0.5 h and 3 days resulted in the alteration of 1101 and 1543 phosphosites, respectively. Notably, HMF exposure enhanced the phosphorylation of β-Catenin at Ser552, and this increased phosphorylation-promoted U2OS proliferation and migration. Furthermore, quantitative proteomics showed that exposure to a HMF for 3 days upregulated the expression of LOX and FN1, while the knockdown of LOX or FN1 suppressed the proliferation and migration of the U2OS cells. These results suggest that a HMF enhances U2OS cell proliferation and migration by promoting β-Catenin phosphorylation and upregulating FN1 and LOX expression. Full article

(This article belongs to the Section Cellular Biophysics)

18 pages, 1633 KB

Open AccessArticle

Alterations in Circulating Progenitor Cell Composition in Rheumatoid Arthritis

by Eva Camarillo-Retamosa, Jan Devan, Camino Calvo-Cebrián, Alexandra Khmelevskaya, Kristina Bürki, Raphael Micheroli, Adrian Ciurea, Stefan Dudli and Caroline Ospelt

Cells 2026, 15(8), 726; https://doi.org/10.3390/cells15080726 - 19 Apr 2026

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent joint inflammation and systemic immune dysregulation. While bone marrow activation has been linked to RA pathogenesis, direct access to bone marrow tissue for progenitor analysis remains limited by ethical and technical constraints. [...] Read more.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent joint inflammation and systemic immune dysregulation. While bone marrow activation has been linked to RA pathogenesis, direct access to bone marrow tissue for progenitor analysis remains limited by ethical and technical constraints. Analysis of progenitor cells in peripheral blood can serve as a surrogate reflecting bone marrow activation. In this study, we analysed peripheral blood cells from 12 RA patients and 9 healthy controls using high-dimensional spectral flow cytometry with a nine-marker panel (CD45, CD31, CD235, CD133, CD34, CD105, CD271, CD90, PDPN). Flow Self-Organizing Map (FlowSOM) clustering identified 20 distinct cell populations. Additionally, a complementary flow cytometry panel was used to assess CD31 expression on immune subsets in peripheral mononuclear cells (PBMCs) from 9 RA and 9 healthy donors of this cohort. RA patients showed increased CD45⁺CD31⁻ immune cells, but not their putative progenitors. Conversely, putative CD45⁺CD31^int progenitors and CD45⁺CD31^int mature cells were reduced, along with CD31 expression on T cells. Levels of CD235a⁺ putative erythroid precursors and CD45⁺CD31⁺ progenitors were significantly increased in RA patients. Three putative stromal cell populations were detected in circulation. Together, these findings reveal expanded erythroid precursor populations and reduced CD31 expression on T cells in RA. Our data underscore broad systemic alterations in cellular homeostasis in RA patients. In conclusion, our results suggest that the loss of CD31 expression on immune cell precursors plays a role in age-associated immune remodelling and immune activation in RA and provides the rationale for further studies on erythroblast differentiation and the functional role of erythroblasts in chronic inflammation. Full article

(This article belongs to the Section Cellular Immunology)

18 pages, 3664 KB

Open AccessReview

Retinal Pigment Epithelium Ageing: Cellular and Molecular Mechanisms of Long-Term Homeostasis and Age-Related Dysfunction

by Yijing Yang, Pei Liu, Jiangwei Li, Ying Deng, Li Xiao, Qinghua Peng and Jun Peng

Cells 2026, 15(8), 725; https://doi.org/10.3390/cells15080725 - 19 Apr 2026

Abstract

The retinal pigment epithelium (RPE) is a long-lived, highly polarised epithelial monolayer that performs essential functions in retinal homeostasis, including outer blood–retina barrier maintenance, visual cycle activity, metabolic exchange, phagocytic clearance of photoreceptor outer segments, and regulation of oxidative and immune balance. Because [...] Read more.

The retinal pigment epithelium (RPE) is a long-lived, highly polarised epithelial monolayer that performs essential functions in retinal homeostasis, including outer blood–retina barrier maintenance, visual cycle activity, metabolic exchange, phagocytic clearance of photoreceptor outer segments, and regulation of oxidative and immune balance. Because RPE cells persist for decades under conditions of sustained oxidative, metabolic, and phagocytic stress, this tissue provides a valuable model for examining how long-lived post-mitotic cells preserve function over time and how age-related dysfunction emerges when that balance weakens. Although much of the current literature on RPE ageing has been shaped by age-related macular degeneration (AMD), age-dependent change in the RPE should not be understood solely as a preclinical stage of disease. Rather, the ageing RPE offers a broader framework for studying cellular maintenance under chronic physiological load. In this review, we synthesise current evidence on RPE ageing across four interrelated domains: structural remodelling, mitochondrial and metabolic imbalance, proteostatic and lysosomal burden, and chronic inflammatory dysregulation. Across these processes, ageing in the RPE is expressed less as widespread cell loss than as progressive decline in cellular organisation, buffering capacity, and functional precision. Structural irregularity, altered mitochondrial regulation, incomplete degradative clearance, and persistent low-grade inflammatory signalling together reduce the ability of the RPE to maintain long-term homeostasis and increase vulnerability to age-related retinal dysfunction. We further argue that ageing in the RPE is best understood not as abrupt failure of isolated pathways, but as gradual loss of system coherence among interacting homeostatic systems that remain active while operating under increasing constraint. This view helps integrate diverse cellular and molecular findings and highlights the RPE as an informative model for understanding ageing in long-lived post-mitotic tissues. Full article

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

18 pages, 3423 KB

Open AccessArticle

Human iPSC-Derived Dorsal Root Ganglion Organoid Modeling of Chemotherapy-Induced Peripheral Neuropathy

by Sybil C. L. Hrstka, Maya Jahnke, Kylie Meng-Lin, Sarah Lindorfer, Henry Noma, Ronald F. Hrstka and Nathan P. Staff

Cells 2026, 15(8), 724; https://doi.org/10.3390/cells15080724 - 19 Apr 2026

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity affecting 30–40% of patients treated with neurotoxic chemotherapy. Sensory symptoms arise from injury to dorsal root ganglion (DRG) neurons and their axons; yet, the underlying mechanisms remain incompletely understood. While human induced pluripotent stem cell [...] Read more.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity affecting 30–40% of patients treated with neurotoxic chemotherapy. Sensory symptoms arise from injury to dorsal root ganglion (DRG) neurons and their axons; yet, the underlying mechanisms remain incompletely understood. While human induced pluripotent stem cell (iPSC)-derived sensory neuron (iSN) monolayers have provided mechanistic insight, they lack the three-dimensional architecture and cellular heterogeneity of native DRG tissue. Here, we generated human iPSC-derived DRG organoids (iDRGOs) containing mixed neuronal and peripheral glial populations and established a quantitative neurite outgrowth assay to model chemotherapy-induced neurotoxicity in a 3D context. iDRGOs from three healthy donors were exposed to bortezomib, vincristine, or paclitaxel. All three drugs caused dose-dependent neurite outgrowth impairment without significant short-term changes in organoid size, consistent with early axonal injury. Vincristine reduced MAP2 levels when normalized to total protein, whereas bortezomib and paclitaxel showed divergent microtubule-associated responses compared to monolayer cultures. The developmental stage significantly influenced the baseline neurite outgrowth, highlighting the need for age standardization. These results establish iDRGOs as a physiologically relevant human platform that complements monolayer models for mechanistic studies and therapeutic screening in CIPN. Full article

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

21 pages, 1652 KB

Open AccessReview

Thyroid Dysfunction as a Component of an Immuno-Metabolic Depression—A Possible Role of Gut Microbiota and a Rationale for Future Studies

by Karolina Michno, Mateusz Kapela, Dominik Strzelecki and Oliwia Gawlik-Kotelnicka

Cells 2026, 15(8), 723; https://doi.org/10.3390/cells15080723 - 19 Apr 2026

Abstract

Depression is one of the most prevalent psychiatric disorders worldwide, with a steadily increasing incidence and complex, multifactorial pathophysiology. Beyond classical neurochemical mechanisms, growing evidence points to the role of systemic low-grade inflammation and immuno-metabolic disturbances in its development. Gut microbiota dysbiosis has [...] Read more.

Depression is one of the most prevalent psychiatric disorders worldwide, with a steadily increasing incidence and complex, multifactorial pathophysiology. Beyond classical neurochemical mechanisms, growing evidence points to the role of systemic low-grade inflammation and immuno-metabolic disturbances in its development. Gut microbiota dysbiosis has emerged as a key factor linking metabolic, immune, and neuroendocrine pathways, potentially exacerbating neuroinflammation and contributing to the onset and progression of depressive symptoms. Immune activation, which is a result of gut dysbiosis, may play a crucial role in the pathogenesis of immuno-metabolic depression. Thyroid dysfunction appears to be an important, yet insufficiently understood component of this network. Thyroid hormones play a crucial role in regulating metabolism, immune responses, and central nervous system function. Alterations in thyroid function, even within subclinical ranges, have been associated with mood disturbances and may share common inflammatory and metabolic pathways with depression. Furthermore, emerging data suggest that gut microbiota may influence thyroid hormone metabolism, including deiodinase activity, linking dysbiosis with thyroid axis dysregulation. Despite these insights, the integrated interactions between thyroid function, gut microbiota, metabolic syndrome, and inflammation in depression remain largely unexplored. This review explores current evidence to highlight gaps in existing research and synthesizes current knowledge, aiming to clarify mechanisms underlying immuno-metabolic depression. Understanding these relationships may provide a rationale for redefining depression as an immuno-metabolic disorder and support the development of more integrative therapeutic strategies targeting not only the brain, but also the gut-thyroid axis. Full article

(This article belongs to the Special Issue Gut Dysbiosis in Inflammatory Diseases)

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24 pages, 5657 KB

Open AccessArticle

Circulating miR-22 Early Predicts TACE Non-Response and Targets WEE1 in Hepatocellular Carcinoma

by Laura Gramantieri, Clara Vianello, Ilaria Leoni, Giuseppe Galvani, Elisa Monti, Marco Bella, Giorgia Marisi, Irene Salamon, Manuela Ferracin, Gloria Ravegnini, Catia Giovannini, Claudio Stefanelli, Maria Laura Lazzari, Fabio Piscaglia, Camelia A. Coada, Cristian Bassi, Massimo Negrini, Andrea Casadei-Gardini, Giuseppe Francesco Foschi, Davide Trerè and Francesca Fornari Show full author list Hide full author list

Cells 2026, 15(8), 722; https://doi.org/10.3390/cells15080722 - 19 Apr 2026

Abstract

Transarterial chemoembolization (TACE) is the standard treatment for patients with intermediate-stage hepatocellular carcinoma (HCC), yet nearly half of treated patients fail to achieve durable benefit, and reliable biomarkers enabling early therapeutic stratification are still lacking. Treatment response is typically assessed by imaging one [...] Read more.

Transarterial chemoembolization (TACE) is the standard treatment for patients with intermediate-stage hepatocellular carcinoma (HCC), yet nearly half of treated patients fail to achieve durable benefit, and reliable biomarkers enabling early therapeutic stratification are still lacking. Treatment response is typically assessed by imaging one month after TACE and at three-month intervals, potentially delaying timely access to alternative therapies in non-responding patients. Circulating microRNAs (miRNAs) represent promising biomarkers due to their stability in body fluids and ease of detection. Here, we evaluated circulating miR-22 as an early predictor of TACE non-responder status and as a mechanistically relevant therapeutic target. Circulating miR-22 levels were measured by microarray and quantitative RT–PCR in three independent cohorts of early-to-intermediate-stage HCC patients undergoing TACE. Circulating miR-22 increased significantly in non-responders as early as 48 h after treatment, and fold changes consistently predicted treatment failure across two independent validation cohorts. Mechanistically, we identified the G2/M checkpoint kinase WEE1 as a direct functional target of miR-22. Modulation of the miR-22/WEE1 axis affected cell-cycle progression, proliferation, apoptosis, and DNA damage response in HCC cell lines and xenograft models. Under hypoxia-mimicking conditions combined with doxorubicin exposure, pharmacological inhibition of WEE1 induced mitotic catastrophe in highly proliferative miR-22-silenced cells. Collectively, these findings identify early post-TACE elevation of circulating miR-22 as a biomarker of non-response and highlight the miR-22/WEE1 axis as a potential target for precision treatment strategies in HCC. Full article

(This article belongs to the Special Issue Advances in Liquid Biopsy for Early Detection and Monitoring of Cancer)

25 pages, 1624 KB

Open AccessArticle

Stemness and Survival: CD117⁺/CD133⁺ Subpopulations Sustain PI3K Signaling and Drive Imatinib Resistance in Head and Neck Mucosal Melanoma

by Sofie-Yasmin Hassan, Simeon Santourlidis, Thomas W. Flanagan, Sarah-Lilly Hassan, He Zhou, Morna F. Schmidt, Claudio Cacchi, Matthias Ferdinand Lammert, Mossad Megahed, Amir Sadegh Yazdi, Danny David Jonigk, Marcos J. Araúzo-Bravo, Robert T. Brodell, Sybille Facca, Youssef Haikel and Mohamed Hassan

Cells 2026, 15(8), 721; https://doi.org/10.3390/cells15080721 - 19 Apr 2026

Abstract

Head and neck mucosal melanoma (HNMM) arises in the nasal and oral cavities and has the propensity to metastasize to local and distant body sites. HNMM is also notable for its resistance to available therapeutics. The rarity of this disease makes it difficult [...] Read more.

Head and neck mucosal melanoma (HNMM) arises in the nasal and oral cavities and has the propensity to metastasize to local and distant body sites. HNMM is also notable for its resistance to available therapeutics. The rarity of this disease makes it difficult to conduct large-scale clinical studies to develop standard treatment protocols. In contrast to cutaneous melanoma, c-Kit-dependent pathways are well studied in HNNMM and provide a potential therapeutic target. We identified and isolated genetically distinct subpopulations with stem cell characteristics in HNMM samples bearing Kit wild-type and mutations. Functional analysis of these subpopulations reveals that, in addition to expressing the stem cell marker proteins CD20, CD117, CD133, and CD166, these subpopulations are characterized by self-renewal potential, migratory capacity, and resistance to Kit inhibitors such as Imatinib. Immunofluorescence staining and inhibition experiments demonstrate that the maintenance and resistance of HHMM subpopulations to Kit inhibitors is mediated by the Kit signal to the PI3K signaling pathway. The KIT signal to the PI3K signaling pathway does not result exclusively from a KIT mutation localized to Exon 17, but can also be triggered by mutations localized to Exons 11 and 13. In the present study, we identify and characterize an HNMM subpopulation with stemness properties in patients with c-Kit wild-type and mutation, and demonstrate for the first time the mechanisms by which the CD117⁺/CD133⁺ HNMM subpopulations survive and confer resistance to the specific inhibitor of c-Kit mutation. Full article

32 pages, 2163 KB

Open AccessReview

Gene Editing Strategies for Neurological and Mental Disorders: Advances in Delivery, Methodology, and Clinical Translation

by Amer Elias and Shani Stern

Cells 2026, 15(8), 720; https://doi.org/10.3390/cells15080720 - 19 Apr 2026

Abstract

Neurological and mental disorders are among the main causes of disability worldwide, affecting over three billion people and increasing the socioeconomic burden. Advances in molecular genetics and genome engineering have led to gene-targeted therapies that address root causes rather than just symptoms. This [...] Read more.

Neurological and mental disorders are among the main causes of disability worldwide, affecting over three billion people and increasing the socioeconomic burden. Advances in molecular genetics and genome engineering have led to gene-targeted therapies that address root causes rather than just symptoms. This review covers current genome-editing tools, including CRISPR/Cas, base editing, and prime editing. The focus is on the benefits of gene editing in the central nervous system, where post-mitotic neurons allow lasting effects after a single treatment. It also discusses emerging delivery platforms such as viral vectors, nanoparticles, and exosome systems, as well as methods to bypass the blood–brain barrier. Recent clinical progress in spinal muscular atrophy, Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease is highlighted, with promising preclinical results for autism, bipolar disorder, epilepsy, and other neurogenetic conditions. The review concludes with regulatory issues, market trends, and ongoing clinical trials, underscoring the potential of gene therapies to transform disease management and provide long-term solutions. Full article

(This article belongs to the Special Issue New Trends and Advances in Induced Neural Cells and iPSC Technologies)

23 pages, 519 KB

Open AccessReview

Microphthalmia/Transcription factor E (MiT/TFE) Pathways in Pulmonary Diseases: Current Evidence and Emerging Mechanisms

by Priyanka Singh, Evans Kwabena Abor and Wei Shi

Cells 2026, 15(8), 719; https://doi.org/10.3390/cells15080719 - 18 Apr 2026

Abstract

The MiT/TFE family transcription factors play a critical role in lysosomal biogenesis, autophagy, mitochondrial turnover and lipid catabolism by regulating the Coordinated Lysosomal Expression and Regulation (CLEAR)gene network. The dysregulation of MiT/TFE activity has been implicated in the onset and progression of cancer [...] Read more.

The MiT/TFE family transcription factors play a critical role in lysosomal biogenesis, autophagy, mitochondrial turnover and lipid catabolism by regulating the Coordinated Lysosomal Expression and Regulation (CLEAR)gene network. The dysregulation of MiT/TFE activity has been implicated in the onset and progression of cancer and neurodegeneration, but its functions in association with pulmonary diseases remain poorly understood. In this review, we systematically summarize the findings from human pulmonary diseases and associated genetic disorders, such as asthma, cancer, Birt–Hogg–Dube (BHD) syndrome, and lung injury models that implicate MiT/TFE dysregulation in pathogenic progression. We also discussed MiT/TFE regulation and signaling through pathways involving mTORC1, AMPK, and lysosomal stress in different cellular contexts. Finally, we discussed significant mechanistic gaps, such as the absence of in vivo models targeting the combined activity of TFEB and TFE3 in disease progression and prevention. In conclusion, these insights seek to offer a comprehensive framework for understanding MiT/TFE signaling in human lung diseases and could present a promising opportunity for directing future mechanistic and translational research. Full article

(This article belongs to the Special Issue Kidney and Lung Disorders: The Role of Tubular and Alveolar Epithelia in Health, Disease, Infection, and Organ Crosstalk)

16 pages, 1263 KB

Open AccessArticle

Epigenetics as Biomarkers of Cumulative Physical Performance in Community-Dwelling Adults: A Cross-Sectional Feasibility Study

by Maayan Insler, Maxim Shapiro, Vered Hermush, Naama M. Kopelman, Gil Atzmon and Shmuel Springer

Cells 2026, 15(8), 718; https://doi.org/10.3390/cells15080718 - 18 Apr 2026

Abstract

With global life expectancy steadily rising, promoting healthy aging is becoming a critical objective of public health. Physical function tends to decline gradually, often beginning in midlife, when subtle changes start to occur and accumulate undetected until later years. This study examines the [...] Read more.

With global life expectancy steadily rising, promoting healthy aging is becoming a critical objective of public health. Physical function tends to decline gradually, often beginning in midlife, when subtle changes start to occur and accumulate undetected until later years. This study examines the feasibility of using DNA methylation-based epigenetic clocks as biomarkers for cumulative physical performance in 24 community-dwelling adults aged 39 years and older. Our findings reveal that several epigenetic age estimators, particularly DNAmAgeHannum, are significantly associated with a novel composite score criterion derived from standardized motor function assessments (DNAmAge: ρ = −0.48, p < 0.026; DNAmPhenoAge: ρ = −0.48, p < 0.026) with DNAmAgeHannum (ρ = −0.59, p < 0.005). These findings support the potential of using epigenetic aging markers to detect early physiological decline, even in relatively healthy, midlife populations, offering a promising tool for the early identification of age-related functional deterioration. Full article

17 pages, 2232 KB

Open AccessArticle

Extracellular Vesicles Derived from VEGF mRNA-Engineered Mesenchymal Stem Cells Promote Endothelial Cell Survival

by Cuiping Zhang, Peng Huang, Matthew Pak, Jennifer A. Korchak and Abba C. Zubair

Cells 2026, 15(8), 717; https://doi.org/10.3390/cells15080717 - 18 Apr 2026

Abstract

Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) exhibit great therapeutic potential in ischemia-associated conditions and diseases such as myocardial infarction, ischemic stroke, and wound healing. Enhancing the therapeutic efficacy of MSC-EVs could advance their clinical application. Diverse cargos (proteins, mRNA, microRNA, etc.) [...] Read more.

Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) exhibit great therapeutic potential in ischemia-associated conditions and diseases such as myocardial infarction, ischemic stroke, and wound healing. Enhancing the therapeutic efficacy of MSC-EVs could advance their clinical application. Diverse cargos (proteins, mRNA, microRNA, etc.) in MSC-EVs contribute to the therapeutic effects in various diseases. Vascular endothelial growth factor (VEGF) is one of the primary driving molecules in promoting angiogenesis and protecting endothelial cells lining blood vessels from apoptosis. In this study, we explored the feasibility of engineering parent MSCs with VEGF mRNA to potentiate therapeutic effects of their derived EVs. We first detected elevated levels of VEGF mRNA and protein in transfected MSCs and demonstrated the bioactivity of secreted VEGF by an angiogenesis assay. Furthermore, EVs derived from VEGF mRNA-engineered MSCs (VEGF-MSC-EVs) contained high levels of VEGF mRNA and protein and showed superior ability to protect human umbilical vein endothelial cells (HUVECs) from apoptosis compared to EVs derived from control MSCs (control MSC-EVs). To our knowledge, this is the first report demonstrating that VEGF-MSC-EVs boost therapeutic efficacy by promoting endothelial cell survival. Our findings offer a novel approach for cell-free therapy in ischemia-associated conditions and diseases. Full article

20 pages, 11779 KB

Open AccessArticle

Effect of Vitrification on Lipidomics in Porcine Cumulus–Oocyte Complexes After In Vitro Maturation

by Xinyu Huang, Zhen He, Decai Xiang, Jing Fu, Xuemei Li, Junyu Jiang, Guobo Quan, Guoquan Wu and Baoyu Jia

Cells 2026, 15(8), 716; https://doi.org/10.3390/cells15080716 - 18 Apr 2026

Abstract

Due to its high efficiency and safety, oocyte vitrification finds broad application in many fields of life sciences, such as clinical assisted reproduction and conservation of animal genetic resources. However, vitrification may cause cellular damage and reduce the quality of oocytes and their [...] Read more.

Due to its high efficiency and safety, oocyte vitrification finds broad application in many fields of life sciences, such as clinical assisted reproduction and conservation of animal genetic resources. However, vitrification may cause cellular damage and reduce the quality of oocytes and their cumulus cells (CCs), which could be closely related to disorders in lipid metabolism. At present, the impact of vitrification upon the lipid profile of oocytes and CCs has not been systematically elucidated. In this study, we used porcine germinal vesicle cumulus–oocyte complexes (COCs) as a model to analyze their lipid characteristics after vitrification and in vitro maturation (IVM), utilizing untargeted lipid metabolomics. Our results showed that an overall count of 37 down-regulated and 8 up-regulated differential lipids was identified in the vitrified oocytes. Pathway analysis confirmed the enrichment in glycerophospholipid metabolism and fat digestion and absorption, etc. Combined with transcriptomic analysis, three enriched pathways were revealed, including the AMPK signaling pathway, metabolic pathways, and fatty acid elongation. On the other hand, a total of four down-regulated and eight up-regulated differential lipids were detected in the vitrified CCs. Pathway enrichment implicated autophagy, glycerophospholipid metabolism, etc. A joint analysis of metabolomic and transcriptomic data revealed four enrichment pathways, including cholesterol metabolism, fat digestion and absorption, regulation of lipolysis in adipocytes, and metabolic pathways. Notably, the supplementation of lysophosphatidylcholine during IVM attenuated oxidative stress, enhanced mitochondrial activity, and enhanced the viability and embryonic development of cryopreserved porcine oocytes. The results indicate that vitrification alters lipids in oocytes and CCs, and the supplementation of lipids plays a role in improving the quality of vitrified oocytes. Full article

25 pages, 11976 KB

Open AccessArticle

Exosomal microRNAs from Alveolar Macrophages Reveal a Protective Role of the Lung Microbiome Against Oncogenic Signaling During PAH Exposure

by Harish Chandra, Brijesh Yadav, Damaris Kuhnell, Scott Langevin, Jacek Biesiada, Mario Medvedovic and Jagjit S. Yadav

Cells 2026, 15(8), 715; https://doi.org/10.3390/cells15080715 - 18 Apr 2026

Abstract

Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are major risk factors for lung cancer and other diseases, acting through the aryl hydrocarbon receptor (AHR). Alveolar macrophages (AMs) help regulate the lung microenvironment by responding to inhaled toxicants and resident microbiota. Although small [...] Read more.

Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are major risk factors for lung cancer and other diseases, acting through the aryl hydrocarbon receptor (AHR). Alveolar macrophages (AMs) help regulate the lung microenvironment by responding to inhaled toxicants and resident microbiota. Although small extracellular vesicles (sEVs, aka exosomes) released by AMs mediate intercellular communication and immune responses, the influence of lung microbiota on sEV biogenesis and the mechanisms underlying sEV dysregulation during PAH exposure remain unknown. Here, we investigated the interplay between AMs, B[a]P, and lung microbiota, focusing on sEV-associated miRNAs (exo-miRNAs). Murine AMs (MH-S) were exposed to varying B[a]P concentrations in the presence or absence of murine lung microbiota with or without an AHR antagonist. sEVs from each condition were characterized and profiled for miRNA. Distinct miRNA signatures emerged: high-dose B[a]P enriched miRNAs linked to cancer progression, whereas lung microbiota alone or with low-dose B[a]P induced tumor-suppressor miRNAs that limit proliferation and metastasis and promote apoptosis, an effect enhanced by AHR antagonism. Lung microbiota appeared to counteract high-dose B[a]P by modulating tumor-suppressive exo-miRNAs. This study demonstrates that lung microbiota-induced exo-miRNAs critically shape AM-derived sEV-miRNA signaling during PAH exposure. The identified exosomal miRNAs could serve as important exposure biomarkers and therapeutic targets for mitigating B[a]P-induced toxicity and cancer development. Full article

(This article belongs to the Section Cellular Immunology)

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16 pages, 1874 KB

Open AccessArticle

Maternal Inflammation Alters Nuclear and Mitochondrial DNA Methylation Patterns in Neonatal Brain Monocytes

by Andrew T. Ebenezer, Jonathan R. Hicks, Brooke Hollander, Alexander Hone, Mona Batish, Robert Akins, Adam Marsh and Elizabeth Wright-Jin

Cells 2026, 15(8), 714; https://doi.org/10.3390/cells15080714 - 18 Apr 2026

Abstract

Neonatal hypoxic ischemic encephalopathy (HIE) is a common birth complication that can cause death or lifelong disabling conditions like cerebral palsy, epilepsy, and autism. It is well established that maternal infection and inflammation are significant risk factors for HIE but reasons for this [...] Read more.

Neonatal hypoxic ischemic encephalopathy (HIE) is a common birth complication that can cause death or lifelong disabling conditions like cerebral palsy, epilepsy, and autism. It is well established that maternal infection and inflammation are significant risk factors for HIE but reasons for this increase in neurological risk to the offspring remain unknown. Inflammation or infection are associated with epigenetic changes and may contribute to the increased risk of neurodevelopmental disability in exposed offspring. Here, we analyzed and compared DNA methylation patterns in brain monocytes isolated from control, maternal immune activation (MIA), and an inflammation sensitized HIE (IS-HIE) CF-1 mouse model at postnatal day 7. We found that maternal inflammation induced significant methylation differences in neonates relative to control samples in both MIA and IS-HIE samples with no significant differences identified between the MIA and IS-HIE groups. MIA samples showed hypermethylation at loci involving craniofacial development and transcription factors important for regulating neurodevelopment and immune function. MIA samples also demonstrated significant hypermethylation at multiple mitochondrial genome CpGs. These findings suggest that maternal inflammation induces epigenetic alterations in fetal brain immune cells that are detectable in neonates. These changes may contribute to heightened neurodevelopmental risk in offspring following hypoxic injury, highlighting potential molecular pathways for future therapeutic targeting. Full article

(This article belongs to the Special Issue Inflammation in the Brain: From Molecular and Cellular Mechanisms to Therapeutic Strategies)

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12 pages, 881 KB

Open AccessArticle

Elevation of Mitochondrial Ca²⁺ Above a Plateau Level Impairs Force Production and Accelerates Fatigue in Mouse Soleus Muscle

by Joseph Bruton and Kent Jardemark

Cells 2026, 15(8), 713; https://doi.org/10.3390/cells15080713 - 17 Apr 2026

Abstract

Soleus muscle fibres display modest changes in tetanic force and [Ca²⁺]_i during repeated contractions. In this study, we investigate whether increasing mitochondrial Ca²⁺ load during repeated contractions could induce premature fatigue. Intact, single fibres were dissected from the soleus [...] Read more.

Soleus muscle fibres display modest changes in tetanic force and [Ca²⁺]_i during repeated contractions. In this study, we investigate whether increasing mitochondrial Ca²⁺ load during repeated contractions could induce premature fatigue. Intact, single fibres were dissected from the soleus muscles of adult mice. Mitochondrial Ca²⁺ was measured with rhod-2 in intact fibres. Fatigue was induced by 70 Hz, 350 ms tetani given at 2 s intervals in the absence and presence of 10 µM CGP-37157, a potent inhibitor of the mitochondrial Na⁺-Ca²⁺ exchanger. In soleus fibres fatigued in the absence of CGP-37157, tetanic force was significantly reduced by about 30% at the end of the fatiguing stimulation, while mitochondrial [Ca²⁺] increased to a maximum after about 50 tetani and returned to its resting level within 20 min after the end of the stimulation. In the presence of CGP-37157, the maximal mitochondrial [Ca²⁺] increase was more than twice that in control fibres. In addition, fatigue developed more rapidly and force remained depressed after the end of the stimulation. No difference in mitochondrial membrane potential or ROS production was seen between control and CGP-37157 conditions. We conclude that while modest increases in mitochondrial Ca² may be beneficial, excessive mitochondrial Ca² loading depresses muscle function. Full article

18 pages, 4696 KB

Open AccessArticle

An Inducible hiPSC-Derived Human Podocyte Model for Functional Analysis of TRPC6 Variants Associated with FSGS

by Lilas Batool, Krithika Hariharan, Gabriel Stölting, Tingting Zhong, Dimitry Tsvetkov, Manfred Gossen and Andreas Kurtz

Cells 2026, 15(8), 712; https://doi.org/10.3390/cells15080712 - 17 Apr 2026

Abstract

Podocyte injury is a characteristic feature of focal segmental glomerulosclerosis (FSGS) that leads to the development of nephrosis as its loss causes proteinuria and progressive glomerulosclerosis. The physiological function of podocytes is critically dependent on proper intracellular calcium levels; an excess or shortage [...] Read more.

Podocyte injury is a characteristic feature of focal segmental glomerulosclerosis (FSGS) that leads to the development of nephrosis as its loss causes proteinuria and progressive glomerulosclerosis. The physiological function of podocytes is critically dependent on proper intracellular calcium levels; an excess or shortage of calcium influx in these cells may result in foot process effacement, apoptosis, and nephron degeneration. A key protein responsible for the regulation of calcium flux is the canonical transient receptor potential 6 (TRPC6) expressed in podocytes. Several mutations in the TRPC6 gene have been associated with FSGS. Here we present a systematically optimized inducible FSGS model system in human induced pluripotent stem cells (hiPSCs). We generated and phenotypically characterized three transgenic hiPSC lines with regulatable overexpression of TRPC6 wild-type and FSGS-associated gain-of-function (GoF, P112Q) and loss-of-function (LoF, G757D) mutations. Moreover, these cell lines were differentiated into induced podocytes (ipodocytes). We assessed the impact of TRPC6 GoF and LoF mutants on calcium influx in combination with TRPC6 agonists and antagonists. Our data showed relative calcium responses consistent with the GoF and LoF phenotypes. Transgenic iPSC-based models, like the one presented here, are instrumental to studying disease mechanisms in vitro and investigating the outcomes of, and possible therapeutic interventions for, this complex disease. Full article

(This article belongs to the Section Stem Cells)

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