Cells

22 pages, 9969 KB

Open AccessArticle

Immune Cell Modulation of Patient-Matched Organoid Drug Response in Precision Cancer Medicine Platform

by Silje Kjølle, Mario Presti, Jéssica de Pina Roque, Lina Hua Bisgaard, Darío Beceiro Ramos, Kamilla Westarp Zornhagen, Christina Westmose Yde, Ane Yde Schmidt, Perrine Verdys, Martin Højgaard, Ulrik Lassen, Inge Marie Svane, Kristoffer Staal Rohrberg, Marco Donia and Janine T. Erler

Cells 2026, 15(3), 259; https://doi.org/10.3390/cells15030259 - 29 Jan 2026

Abstract

Cancer is one of the leading causes of death worldwide, and the majority of cancer-related deaths are caused by cancer that has spread to other organs. Precision cancer medicine (PCM) holds potential to improve outcomes and relies on molecularly matched therapies based on [...] Read more.

Cancer is one of the leading causes of death worldwide, and the majority of cancer-related deaths are caused by cancer that has spread to other organs. Precision cancer medicine (PCM) holds potential to improve outcomes and relies on molecularly matched therapies based on cancer cell specific molecular alterations. The tumor immune microenvironment plays an important role beyond response to therapy; however, this is generally not considered in current PCM platforms. We established patient-matched organoids and immune cell cultures for drug testing in mono- and co-culture treatment setups using three distinct treatment strategies (pretreatment, co-culture treatment, and T-cell bispecific antibody testing). Response to treatment and impact of immune cells were evaluated by tumor cell viability assays and flow cytometry analysis. Phenotypic analysis showed high heterogeneity of tumor-infiltrating lymphocytes (TILs) across the patients and low immune cell portions of organoids, emphasizing the need for a patient-matched co-culture PCM approach. Our in-depth study of three patients revealed an effect of the patients’ immune cells on drug response and T-cell bispecific antibody treatment in vitro. Here, we illustrate a state-of-the-art co-culture PCM pipeline for patient-matched organoids and immune cells replicating patient response to treatment at the time of biopsy. Full article

(This article belongs to the Special Issue Novel Insights into Cancer Immune Responsiveness)

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24 pages, 2020 KB

Open AccessReview

From Structure to Vulnerability: Mitochondrial Supercomplexes in Cancer Cells

by Corinne E. Griguer, Susanne Flor and Claudia R. Oliva

Cells 2026, 15(3), 258; https://doi.org/10.3390/cells15030258 - 29 Jan 2026

Abstract

Mitochondrial respiratory supercomplexes are emerging as key regulators of bioenergetics, redox homeostasis, and metabolic plasticity in cancer. Their assembly enhances electron transport efficiency, limits reactive oxygen species production, and supports the high oxidative and biosynthetic demands of tumor growth. Cancer cells remodel supercomplex [...] Read more.

Mitochondrial respiratory supercomplexes are emerging as key regulators of bioenergetics, redox homeostasis, and metabolic plasticity in cancer. Their assembly enhances electron transport efficiency, limits reactive oxygen species production, and supports the high oxidative and biosynthetic demands of tumor growth. Cancer cells remodel supercomplex organization in response to hypoxia, nutrient limitation, and therapeutic stress, enabling rapid metabolic adaptation. Multiple assembly factors—including COX subunits, HIGD1A/2A, COX7A2L (SCAF1), cardiolipin remodeling enzymes, and Complex I assembly factors such as NDUFAF1 and NDUFAF2—contribute to supercomplex stabilization and can be dysregulated in malignancy. Alterations in these factors enhance respiratory flexibility and therapy resistance, particularly in aggressive tumors such as glioblastoma. However, critical gaps remain, including incomplete understanding of the molecular mechanisms controlling supercomplex assembly and remodeling, limited validation of functional findings in primary patient-derived cells or clinical samples, and uncertainty regarding the contribution of supercomplex to therapy resistance and metabolic adaptation across tumor types. Advances in structural biology and functional imaging have uncovered tumor-specific vulnerabilities within supercomplex architecture that may be exploited therapeutically. Targeting supercomplex assembly, cardiolipin–protein interactions, or electron flux through individual supercomplex modules represents a promising approach to disrupt cancer metabolism and sensitize tumors to treatment. This review synthesizes current knowledge on supercomplex regulation, function, and therapeutic potential in cancer, and outlines key unanswered questions that remain to be addressed. Full article

(This article belongs to the Section Mitochondria)

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2 pages, 151 KB

Open AccessRetraction

RETRACTED: Ikram et al. Cycloastragenol, a Triterpenoid Saponin, Regulates Oxidative Stress, Neurotrophic Dysfunctions, Neuroinflammation and Apoptotic Cell Death in Neurodegenerative Conditions. Cells 2021, 10, 2719

by Muhammad Ikram, Myeung Hoon Jo, Kyonghwan Choe, Amjad Khan, Sareer Ahmad, Kamran Saeed, Min Woo Kim and Myeong Ok Kim

Cells 2026, 15(3), 257; https://doi.org/10.3390/cells15030257 - 29 Jan 2026

Abstract

The journal retracts the article titled “Cycloastragenol, a Triterpenoid Saponin, Regulates Oxidative Stress, Neurotrophic Dysfunctions, Neuroinflammation and Apoptotic Cell Death in Neurodegenerative Conditions” [...] Full article

25 pages, 55049 KB

Open AccessArticle

Reduced CHMP7 Expression Compromises Telomere Integrity in Mammalian Cells

by Romina Burla, Mattia La Torre, Klizia Maccaroni, Stefano Tacconi, Luciana Dini and Isabella Saggio

Cells 2026, 15(3), 256; https://doi.org/10.3390/cells15030256 - 29 Jan 2026

Abstract

During open mitosis, reassembly of the nuclear envelope requires the coordinated recruitment of the ESCRT machinery, initiated by the chromatin-associated factor BAF1 and the nuclear-envelope-associated factor LEM2. Because telomeres are enriched at the reforming envelope, we investigated whether ESCRT factors contribute to telomere [...] Read more.

During open mitosis, reassembly of the nuclear envelope requires the coordinated recruitment of the ESCRT machinery, initiated by the chromatin-associated factor BAF1 and the nuclear-envelope-associated factor LEM2. Because telomeres are enriched at the reforming envelope, we investigated whether ESCRT factors contribute to telomere integrity. Reduction in the pivotal nuclear ESCRT factor CHMP7 caused DNA damage, heterochromatin disorganization, and telomere defects, including sister telomere associations and telomere free ends. Extending this analysis, we found that additional ESCRT components, including TSG101, VPS28, CHMP4B, and the ESCRT-associated factor AKTIP/Ft1, also contribute to telomere integrity, although with different strengths. Genetic interaction analyses suggest that CHMP7 converges in a common pathway with CHMP4B and AKTIP/Ft1, while it functions in parallel routes to TNKS1, a telomere-specific regulator of the shelterin TRF1. More genetic analyses indicated that BAF1 and LEM2 contribute to safeguarding of telomeres during nuclear envelope reassembly. Because defects in nuclear envelope dynamics and chromatin–membrane coupling are hallmarks of disorders associated with nuclear deformation and fragility, including aging and cancer, our findings contribute a new angle into these conditions and suggest potential targets for selectively modulating telomere maintenance pathways. Full article

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3 pages, 483 KB

Open AccessCorrection

Correction: Kim et al. Transcriptomic Analysis of Air–Liquid Interface Culture in Human Lung Organoids Reveals Regulators of Epithelial Differentiation. Cells 2024, 13, 1991

by Jieun Kim, Eun-Young Eo, Bokyong Kim, Heetak Lee, Jihoon Kim, Bon-Kyoung Koo, Hyung-Jun Kim, Sukki Cho, Jinho Kim and Young-Jae Cho

Cells 2026, 15(3), 255; https://doi.org/10.3390/cells15030255 - 29 Jan 2026

Abstract

In the original publication [...] Full article

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22 pages, 1763 KB

Open AccessReview

Peroxisomes in Aging: Guardians of Cellular Resilience and Function

by Artuur Vercaemst, Mingming Zhao, Ruizhi Chai, Celien Lismont and Marc Fransen

Cells 2026, 15(3), 254; https://doi.org/10.3390/cells15030254 - 28 Jan 2026

Abstract

Peroxisomes are multifunctional organelles that play essential roles in lipid metabolism, redox regulation, and cellular signaling. An expanding body of evidence implicates peroxisomal dysfunction as a key contributor to aging and age-related diseases. Aging is accompanied by progressive declines in key peroxisomal functions, [...] Read more.

Peroxisomes are multifunctional organelles that play essential roles in lipid metabolism, redox regulation, and cellular signaling. An expanding body of evidence implicates peroxisomal dysfunction as a key contributor to aging and age-related diseases. Aging is accompanied by progressive declines in key peroxisomal functions, including catalase activity, fatty acid β-oxidation, plasmalogen biosynthesis, and the metabolism of bile acids and docosahexaenoic acid, resulting in increased oxidative stress, lipid dysregulation, and alterations in membrane composition. Impaired pexophagy further exacerbates these defects by allowing the accumulation of damaged peroxisomes and compromising cellular homeostasis. Through extensive metabolic and signaling crosstalk with mitochondria, the endoplasmic reticulum, and lysosomes, peroxisomal dysfunction can propagate oxidative and metabolic disturbances throughout the cell. In addition, peroxisome-derived signaling molecules, such as hydrogen peroxide and bioactive lipids, link peroxisomal activity to cellular stress responses and organismal metabolic homeostasis. We propose that aging-associated impairments in peroxisomal protein import, redox regulation, and selective turnover progressively shift peroxisomes from adaptive metabolic signaling hubs toward sources of chronic oxidative and lipid stress. In this context, current studies highlight peroxisomal homeostasis as a potential determinant of healthy aging and point to peroxisomal pathways as emerging targets for intervention in age-related disease. Full article

(This article belongs to the Special Issue Understanding Aging Mechanisms to Prevent Age-Related Diseases: 2nd Edition)

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19 pages, 8567 KB

Open AccessArticle

Temporal and Spatial Gene Expression Dynamics in Neonatal HI Hippocampus with Focus on Arginase

by Michael A. Smith, Eesha Natarajan, Carlos Lizama-Valenzuela, Thomas Arnold, David Stroud, Amara Larpthaveesarp, Cristina Alvira, Jeffrey R. Fineman, Donna M. Ferriero, Emin Maltepe, Fernando Gonzalez and Jana K. Mike

Cells 2026, 15(3), 253; https://doi.org/10.3390/cells15030253 - 28 Jan 2026

Abstract

Background: Hypoxic–ischemic (HI) brain injury triggers a dynamic, multi-phase response involving early microglial efferocytosis followed by extracellular matrix (ECM) deposition and scar formation. Arginase-1 (ARG1), a key enzyme in tissue repair, is implicated in both processes, yet its role in neonatal microglia remains [...] Read more.

Background: Hypoxic–ischemic (HI) brain injury triggers a dynamic, multi-phase response involving early microglial efferocytosis followed by extracellular matrix (ECM) deposition and scar formation. Arginase-1 (ARG1), a key enzyme in tissue repair, is implicated in both processes, yet its role in neonatal microglia remains poorly defined. We characterize ARG1-linked pathways in neonatal microglia, identifying distinct efferocytic and fibrotic phases post-HI. Methods: HI was induced in P9 mice using the Vannucci model, and brains were collected at 24 h (D1) and 5 days (D5). Spatially resolved single-cell transcriptomics (seqFISH) was performed using a targeted panel enriched for microglial, ARG1-pathway, efferocytosis, and profibrotic genes. Cell segmentation, clustering, and spatial mapping were conducted using Navigator and Seurat. Differential expression, GSEA, and enrichment analyses were used to identify time- and injury-dependent pathways. Results: Spatial transcriptomics identified 12 transcriptionally distinct cell populations with preserved neuroanatomical organization. HI caused the expansion of microglia and astrocytes and the loss of glutamatergic neurons by D5. Microglia rapidly activated regenerative and profibrotic programs—including TGF-β, PI3K–Akt, cytoskeletal remodeling, and migration—driven by early DEGs such as Cd44, Reln, TGF-β1, and Col1a2. By D5, microglia adopted a collagen-rich fibrotic state with an upregulation of Bgn, Col11a1, Anxa5, and Npy. Conclusion: Neonatal microglia transition from early efferocytic responses to later fibrotic remodeling after HI, driven by the persistent activation of PI3K–Akt, TGF-β, and Wnt/FZD4 pathways. These findings identify microglia as central regulators of neonatal scar formation and highlight therapeutic targets within ARG1-linked signaling. Full article

(This article belongs to the Section Cellular Neuroscience)

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36 pages, 2310 KB

Open AccessReview

Unpacking the Tumor Protein D52-like Family: Roles in Intracellular Trafficking and Cancer Progression

by Emma L. Dorward, Michael Ortiz, Claire M. Weekley, Kay K. Myo Min, Pascal H. G. Duijf, S. George Barreto, Michael W. Parker and Claudine S. Bonder

Cells 2026, 15(3), 252; https://doi.org/10.3390/cells15030252 - 28 Jan 2026

Abstract

There is growing evidence that dysregulation of vesicle-mediated intracellular trafficking pathways leads to the development of various diseases, including cancer. Cancer exploits the intracellular trafficking pathways to modulate the protein flow, alter cell surface protein expression, and drive the hallmarks of cancer progression, [...] Read more.

There is growing evidence that dysregulation of vesicle-mediated intracellular trafficking pathways leads to the development of various diseases, including cancer. Cancer exploits the intracellular trafficking pathways to modulate the protein flow, alter cell surface protein expression, and drive the hallmarks of cancer progression, such as sustained proliferation signaling and evading immune surveillance. As such, there is increasing interest in understanding the proteins that regulate these processes to better understand cancer biology and to identify novel ways to hinder disease progression. A group of small proteins, known as the Tumor Protein D52 (TPD52)-like family, has been identified and is increasingly recognized for its roles in intracellular trafficking within cancer cells. This family consists of four members: TPD52, TPD53, TPD54, and TPD55. Herein, we review the current literature on the TPD52-like family in cancer and detail the current known cellular functions (e.g., intracellular trafficking roles, lipid biogenesis, cell proliferation, and cell cycle regulation). Overexpression of family members, notably TPD52 and TPD54, has been heavily implicated in tumorigenic roles such as cell migration, invasion, proliferation, and protein–protein interactions. Additionally, there is mounting evidence that this family also has isoform-specific and/or tissue-specific functions, which is of clinical interest. A better understanding of the mechanistic actions of this protein family holds the promise of identifying novel therapeutic targets that exploit the broader multi-target nature of intracellular trafficking regulators to disrupt oncogenic processes. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Tumor Pathogenesis)

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24 pages, 7422 KB

Open AccessArticle

Cytotoxic Effect of a β1,4-Galactosyltransferase Inhibitor in Hepatic Carcinoma Cells

by Zhe Dai, Ming Sun, Lihang Chen, Xueqi Fu, Wenfu Yan, Yin Gao and Inka Brockhausen

Cells 2026, 15(3), 251; https://doi.org/10.3390/cells15030251 - 28 Jan 2026

Abstract

The incidence and mortality of hepatocellular carcinoma (HCC) are increasing worldwide, underscoring the need for novel therapeutic strategies. Synthetic 2-naphthyl 2-butanamido-2-deoxy-1-thio-β-d-glucopyranoside (612) is a selective inhibitor of β1,4-galactosyltransferase 1 (β4GalT1). In this study, we investigated the cytotoxic effects of [...] Read more.

The incidence and mortality of hepatocellular carcinoma (HCC) are increasing worldwide, underscoring the need for novel therapeutic strategies. Synthetic 2-naphthyl 2-butanamido-2-deoxy-1-thio-β-d-glucopyranoside (612) is a selective inhibitor of β1,4-galactosyltransferase 1 (β4GalT1). In this study, we investigated the cytotoxic effects of 612 across multiple cancer cell lines, with a focus on HCC, and explored the underlying mechanisms. We demonstrate that 612 preferentially exhibits cytotoxicity toward cancer cells with elevated expression of β4GalT family members, while human umbilical vein endothelial cells and immortalized human embryonic kidney epithelial cells are comparatively less sensitive. Treatment with 612 suppresses cancer cell migration and invasion and induces pronounced endoplasmic reticulum and Golgi stress, accompanied by G2/M cell cycle arrest. Furthermore, 612 activates apoptosis through ER stress–associated pathways by downregulating the anti-apoptotic protein Bcl-2 and upregulating pro-apoptotic proteins Bax and Bak, along with activation of caspase-3, -8, and -9. Collectively, these findings identify 612 as a promising anti-cancer candidate targeting β4GalTs-overexpressing HCC cells and warrant further therapeutic development. Full article

(This article belongs to the Special Issue Glycosylation and Glycoproteins in Human Disease)

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15 pages, 3181 KB

Open AccessArticle

Development and Characterization of a Rat Model of Blast Polytrauma and Hemorrhagic Shock for Evaluating Innate Immunotherapies During Prolonged Damage Control Resuscitation

by Milomir Simovic, Qingwei Zhao, Zhangsheng Yang, Leopoldo C. Cancio and Yansong Li

Cells 2026, 15(3), 250; https://doi.org/10.3390/cells15030250 - 28 Jan 2026

Abstract

Background: A major challenge in developing effective immunological damage-control therapies for traumatic hemorrhage (TH) is the lack of animal models that accurately reproduce the immune and pathophysiological responses observed in humans. In this study, we established a clinically relevant rat model that combines [...] Read more.

Background: A major challenge in developing effective immunological damage-control therapies for traumatic hemorrhage (TH) is the lack of animal models that accurately reproduce the immune and pathophysiological responses observed in humans. In this study, we established a clinically relevant rat model that combines blast injury with hemorrhagic shock in a simulated prolonged damage control resuscitation environment. Methods: Male Sprague Dawley rats were anesthetized and subjected to moderate blast overpressure, followed by controlled hemorrhage equivalent to 40% of the estimated total blood volume. Animals then received hypotensive resuscitation with Plasma-Lyte A at twice the shed blood volume. Plasma-Lyte A was used in our study to correct hypovolemia and electrolyte imbalances, thereby helping to standardize the traumatic hemorrhage model. Results: Four of six rats in the blast-plus-hemorrhage (B + H) group survived the 25 h observation period. During resuscitation, mean arterial pressure remained markedly below baseline for at least 4 h. The B + H insult triggered a rapid innate immune response, characterized by elevated circulating HMGB1, terminal complement activation, and increased myeloperoxidase levels. Complement deposition (C4d, C5a, and C5b-9) was evident in lung tissue, accompanied by multi-organ histopathological injury, including pronounced inflammatory cell infiltration, hemorrhage, and cellular degeneration, apoptosis, or necrosis. Metabolic disturbances, including acidosis, hyperkalemia, and dilutional anemia, were also observed. Conclusions: Overall, this model reproduced key features of inflammation-driven multi-organ dysfunction syndrome seen in human polytrauma, supporting its utility for studying TH-related immunopathology and therapeutic interventions during prolonged damage control resuscitation. Full article

(This article belongs to the Topic Animal Models of Human Disease 3.0)

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3 pages, 522 KB

Open AccessCorrection

Correction: Arriero-Cabañero et al. Transplantation of Predegenerated Peripheral Nerves after Complete Spinal Cord Transection in Rats: Effect of Neural Precursor Cells and Pharmacological Treatment with the Sulfoglycolipid Tol-51. Cells 2024, 13, 1324

by Alejandro Arriero-Cabañero, Elisa García-Vences, Stephanie Sánchez-Torres, Sergio Aristizabal-Hernandez, Concepción García-Rama, Enrique Pérez-Rizo, Alfonso Fernández-Mayoralas, Israel Grijalva, Vinnitsa Buzoianu-Anguiano, Ernesto Doncel-Pérez and Jörg Mey

Cells 2026, 15(3), 249; https://doi.org/10.3390/cells15030249 - 28 Jan 2026

Abstract

In the original publication [...] Full article

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31 pages, 1755 KB

Open AccessReview

Exercise Protects Skeletal Muscle Fibers from Age-Related Dysfunctional Remodeling of Mitochondrial Network and Sarcotubular System

by Feliciano Protasi, Matteo Serano, Alice Brasile and Laura Pietrangelo

Cells 2026, 15(3), 248; https://doi.org/10.3390/cells15030248 - 27 Jan 2026

Abstract

In skeletal muscles fibers, cellular respiration, excitation–contraction (EC) coupling (the mechanism that translates action potentials in Ca²⁺ release), and store-operated Ca²⁺ entry (SOCE, a mechanism that allows recovery of external Ca²⁺ during fatigue) take place in organelles specifically dedicated to [...] Read more.

In skeletal muscles fibers, cellular respiration, excitation–contraction (EC) coupling (the mechanism that translates action potentials in Ca²⁺ release), and store-operated Ca²⁺ entry (SOCE, a mechanism that allows recovery of external Ca²⁺ during fatigue) take place in organelles specifically dedicated to each function: (a) aerobic ATP production in mitochondria; (b) EC coupling in intracellular junctions formed by association between transverse tubules (TTs) and sarcoplasmic reticulum (SR) named triads; (c) SOCE in Ca²⁺ entry units (CEUs), SR-TT junctions that are in continuity with membranes of triads, but that contain a different molecular machinery (see Graphical Abstract). In the past 20 years, we have studied skeletal muscle fibers by collecting biopsies from humans and isolating muscles from animal models (mouse, rat, rabbit) under different conditions of muscle inactivity (sedentary aging, denervation, immobilization by casting) and after exercise, either after voluntary training in humans (running, biking, etc.) or in mice kept in wheel cages or after running protocols on a treadmill. In all these studies, we have assessed the ultrastructure of the mitochondrial network and of the sarcotubular system (i.e., SR plus TTs) by electron microscopy (EM) and then collected functional data correlating (i) the changes occurring with aging and inactivity with a loss-of-function, and (ii) the structural improvement/rescue after exercise with a gain-of-function. The picture that emerged from this long journey points to the importance of the internal architecture of muscle fibers for their capability to function properly. Indeed, we discovered how the intracellular organization of the mitochondrial network and of the membrane systems involved in controlling intracellular calcium concentration (i[Ca²⁺]) is finely controlled and remodeled by inactivity and exercise. In this manuscript, we give an integrated picture of changes caused by inactivity and exercise and how they may affect muscle function. Full article

(This article belongs to the Special Issue Skeletal Muscle: Structure, Physiology and Diseases)

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22 pages, 1632 KB

Open AccessReview

From Dish to Trial: Building Translational Models of ALS

by Ilias Salamotas, Sotiria Stavropoulou De Lorenzo, Aggeliki Stachtiari, Apostolos Taxiarchis, Magda Tsolaki, Iliana Michailidou and Elisavet Preza

Cells 2026, 15(3), 247; https://doi.org/10.3390/cells15030247 - 27 Jan 2026

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, marked by progressive degeneration of upper and lower motor neurons. Clinically, genetically, and pathologically heterogeneous, ALS poses a major challenge for disease modeling and therapeutic translation. Over the past two decades, induced [...] Read more.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, marked by progressive degeneration of upper and lower motor neurons. Clinically, genetically, and pathologically heterogeneous, ALS poses a major challenge for disease modeling and therapeutic translation. Over the past two decades, induced pluripotent stem cells (iPSCs) have reshaped our understanding of ALS pathogenesis and emerged as a promising translational platform for therapy development. ALS modeling has further expanded with the advent of three-dimensional systems, including ALS-on-chip platforms and organoid models, which better capture cell–cell interactions and tissue-level phenotypes. Despite these advances, effective disease-modifying therapies remain elusive. Recent clinical trial setbacks highlight the need for improved trial design alongside robust, translational iPSC models that can better predict therapeutic response. Nonetheless, the outlook is promising as large iPSC patient cohorts, quantitative phenotyping combined with genetically informed patient stratification, and reverse translational research are beginning to close the gap between in vitro discovery and clinical testing. In this review, we summarize the major advances in iPSC technology and highlight key iPSC-based studies of sporadic ALS. We further discuss emerging examples of iPSC-informed therapeutic strategies and outline the challenges associated with translating iPSC-derived mechanistic insights and pharmacological findings into successful clinical therapies. Full article

(This article belongs to the Section Cellular Neuroscience)

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14 pages, 36585 KB

Open AccessArticle

Integrated Multi-Omics and Spatial Transcriptomics Identify FBLL1 as a Malignant Transformation Driver in Hepatocellular Carcinoma

by Junye Xie, Shujun Guo, Yujie Xiao, Yibo Zhang, An Hong and Xiaojia Chen

Cells 2026, 15(3), 246; https://doi.org/10.3390/cells15030246 - 27 Jan 2026

Abstract

Background: Hepatocellular carcinoma (HCC) is characterized by marked intratumoral heterogeneity and poor clinical outcomes. Dysregulated ribosome biogenesis has emerged as a fundamental hallmark of tumor initiation and progression; however, the specific molecular drivers linking this machinery to HCC pathogenesis remain largely undefined. [...] Read more.

Background: Hepatocellular carcinoma (HCC) is characterized by marked intratumoral heterogeneity and poor clinical outcomes. Dysregulated ribosome biogenesis has emerged as a fundamental hallmark of tumor initiation and progression; however, the specific molecular drivers linking this machinery to HCC pathogenesis remain largely undefined. Methods: By integrating multi-omics data from the TCGA and ICGC cohorts, FBLL1 was identified as a key prognostic candidate gene. Its cellular and spatial distribution was analyzed using single-cell RNA sequencing and spatial transcriptomics. Its biological functions in vitro and in vivo were validated through functional experiments, including lentivirus-mediated ectopic expression and siRNA-mediated gene knockdown. Finally, its molecular mechanism was elucidated through transcriptomic analysis and Western blotting. Results: FBLL1 was significantly upregulated in HCC and correlated with poor patient survival. Spatial and single-cell analyses showed that FBLL1 expression was preferentially enriched in malignant hepatocytes within the tumor region. Functionally, knockdown FBLL1 could inhibit the proliferation and clonogenic capacity of HCC cells, while overexpression FBLL1 in non-tumorigenic hepatocytes could promote the tumorigenic phenotype in xenograft models. Transcriptomic analysis indicated that FBLL1 overexpression was associated with the synergistic upregulation of c-Myc and multiple EGFR ligands, as well as decreased expression of hepatocyte functional markers. Consistently, modulation of FBLL1 expression affected the activity of the EGFR–MAPK signaling pathway. Conclusions: Our study identifies FBLL1 as a previously unrecognized regulator associated with malignant state transition in HCC. Rather than acting as a direct regulator of core signaling components, FBLL1 is associated with ligand-dependent activation of the EGFR–MAPK pathway in conjunction with c-Myc upregulation. These findings indicate that FBLL1 represents a promising therapeutic target for disrupting oncogenic signaling programs in liver cancer. Full article

(This article belongs to the Special Issue How Does Gene Regulation Affect Cancer Development?)

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24 pages, 2490 KB

Open AccessArticle

Mining Differentially Expressed Genes in the Marine Free-Living Flatworm Macrostomum lignano Under Aneuploidy-Driven Ploidy Changes

by Kira S. Zadesenets, Nikita I. Ershov, Natalya P. Bondar, Konstantin E. Orishchenko and Nikolay B. Rubtsov

Cells 2026, 15(3), 245; https://doi.org/10.3390/cells15030245 - 27 Jan 2026

Abstract

Whole-genome duplication (WGD) is a powerful evolutionary force, yet the mechanisms by which neopolyploids achieve transcriptomic stability and phenotypic success remain poorly understood. This study investigated the phenotypic and transcriptomic consequences of ploidy changes in the flatworm Macrostomum lignano, a “successful” neopolyploid [...] Read more.

Whole-genome duplication (WGD) is a powerful evolutionary force, yet the mechanisms by which neopolyploids achieve transcriptomic stability and phenotypic success remain poorly understood. This study investigated the phenotypic and transcriptomic consequences of ploidy changes in the flatworm Macrostomum lignano, a “successful” neopolyploid model. We exploited two established sublines derived from the inbred DV1 line: the euploid DV1_8 (hidden tetraploid, SSL₁L₂) and the aneuploid DV1_10 (hidden hexaploid, SSL₁L₁L₂L₂). By integrating whole-genome sequencing (WGS)-informed normalization with RNA-seq analysis, we differentiated true regulatory shifts from gene-dosage effects. We revealed that while most genes scale linearly with ploidy, 1308 genes exhibited a nonlinear aneuploidy-induced transcriptional response. The remarkable trans-acting effects were observed across subgenome S encoded by disomic small chromosomes. Differentially expressed genes (DEGs) were enriched in pathways essential for homeostasis and growth: mTOR signaling, ubiquitin-mediated proteolysis, and the Hippo/Wnt pathways. Phenotypes of the DV1_10 worms exhibited increased body size, enhanced cell proliferation, and higher viability in comparison to the DV1_8 worms (60.25% vs. 21.5%). These findings suggest that M. lignano possesses mechanisms for dosage compensation to mitigate the deleterious effects of aneuploidy. Ultimately, this study demonstrates how genomic plasticity and rewiring of the transcriptome may facilitate the evolutionary success of animal neopolyploids. Full article

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39 pages, 5125 KB

Open AccessArticle

Orange-Derived Extracellular Vesicles: Characterization and Therapeutic Applications in Normal and Diabetic Wound Healing in In Vivo Models

by Chiara Gai, Margherita Alba Carlotta Pomatto, Federica Negro, Lucia Massari, Maria Chiara Deregibus, Massimo Cedrino, Cristina Grange, Alessandro Burello, Joanna Kopecka, Ivan Molineris, Anel Ordabayeva, Alessandro Damin, Federica Antico, Chiara Riganti, Vito Fanelli, Natasa Zarovni and Giovanni Camussi

Cells 2026, 15(3), 244; https://doi.org/10.3390/cells15030244 - 27 Jan 2026

Abstract

Extracellular vesicles (EVs) of human origin show promise for regenerative medicine and wound healing. However, they have limitations regarding scalability, variability, safety, and costs. Plant-derived EVs may represent a valid alternative. This study investigated the regenerative potential of EVs extracted from orange juice [...] Read more.

Extracellular vesicles (EVs) of human origin show promise for regenerative medicine and wound healing. However, they have limitations regarding scalability, variability, safety, and costs. Plant-derived EVs may represent a valid alternative. This study investigated the regenerative potential of EVs extracted from orange juice (oEVs). oEVs obtained by standard ultracentrifugation were compared with oEVs purified by tangential flow filtration (TFF), a scalable technique suitable for large-scale and regulatory-compliant manufacturing. Comparisons included size, morphology, pH, Zeta potential, protein and RNA content, Raman spectroscopy, and proteomic, metabolomic, and RNA sequencing. The regenerative potential of oEVs was tested in vitro, with cell migration, endothelial tube formation, and proliferation assays performed. Antioxidant ability was tested on endothelial cells stressed by hyperglycemia or pro-inflammatory cytokine cocktails. Next, oEVs were formulated with different hydrogels and tested at different doses on skin ulcers on healthy and diabetic mice. TFF oEVs showed the same physio-chemical characteristics and a comparable molecular content as those isolated by ultracentrifugation, confirming the path to scalability. In vitro oEVs promoted cell migration, formation of capillary-like structures, cell proliferation, and strong antioxidant activity. Moreover, oEVs effectively accelerated in vivo wound closure in healthy and diabetic mice. Thus, oEVs may provide a useful and cost-effective ingredient for improved and effective wound treatment strategies. Full article

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22 pages, 2428 KB

Open AccessReview

Post-Translational Modifications in HIV Infection: Novel Antiretroviral Strategies

by Yidong Sun, Siyi Yang, Youxi Ao and Wei Yu

Cells 2026, 15(3), 243; https://doi.org/10.3390/cells15030243 - 27 Jan 2026

Abstract

Human immunodeficiency virus (HIV) infection remains a major global health burden. Untreated HIV infection leads to CD4⁺ T-cell depletion and severe immune dysfunction, resulting in opportunistic infections, neoplastic changes, and death. Highly active antiretroviral therapy (HAART) is currently the standard treatment for [...] Read more.

Human immunodeficiency virus (HIV) infection remains a major global health burden. Untreated HIV infection leads to CD4⁺ T-cell depletion and severe immune dysfunction, resulting in opportunistic infections, neoplastic changes, and death. Highly active antiretroviral therapy (HAART) is currently the standard treatment for HIV infection, but it cannot eliminate latent reservoirs. Post-translational modifications (PTMs) regulate protein trafficking, function, and degradation, and their in-depth investigation plays a crucial role in identifying novel biomarkers and therapeutic targets. PTMs exert a central regulatory role in HIV infection by both enhancing host restriction factors and contributing to latent infection. This dual role offers novel insights into potential therapeutic targets for activating latent viruses to make them visible to the immune system. This review highlights numerous PTMs associated with HIV infection, including acetylation, phosphorylation, palmitoylation, etc., and assesses their potential for curing HIV infection. Full article

(This article belongs to the Section Cellular Metabolism)

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17 pages, 4848 KB

Open AccessArticle

Effects of Bovine Milk-Derived Extracellular Vesicles on a 3D Intestinal Stromal Compartment

by Georgia Pennarossa, Sharon Arcuri, Madhusha Prasadani, Fulvio Gandolfi, Alireza Fazeli and Tiziana A. L. Brevini

Cells 2026, 15(3), 242; https://doi.org/10.3390/cells15030242 - 27 Jan 2026

Abstract

Milk is an essential component of the diet. Among its diverse molecular constituents, it contains nanoscale entities, known as extracellular vesicles (EVs), which play a pivotal role in intercellular communication. In particular, milk-derived EVs (MEVs) influence intestinal homeostasis by mitigating inflammatory responses, modulating [...] Read more.

Milk is an essential component of the diet. Among its diverse molecular constituents, it contains nanoscale entities, known as extracellular vesicles (EVs), which play a pivotal role in intercellular communication. In particular, milk-derived EVs (MEVs) influence intestinal homeostasis by mitigating inflammatory responses, modulating gut microbiota composition, and contributing to epithelial integrity preservation and restoration. Currently, there are no information regarding their impact on intestinal connective tissue. Here, we investigate bovine MEV effects on the porcine gut stromal compartment, exposing intestinal decellularized bio-scaffolds repopulated with primary intestinal stromal fibroblasts, to different MEV concentrations (10⁶, 10⁸, and 10¹⁰ particles/mL). We observed a dose-dependent effect of MEVs on stromal fibroblast proliferation rate at concentrations higher than 10⁶ particles/mL. In addition, when MEVs were used to pre-condition the decellularized intestinal bio-scaffolds prior to cell repopulation, fibroblast growth was further boosted. Overall, these findings suggest that MEVs may play a significant role in promoting tissue remodeling and repair. This activity appears particularly relevant for enhancing intestinal homeostasis and resilience, as stromal fibroblasts contribute to the maintenance of gut integrity, barrier function, and immune balance. Moreover, the data here presented suggests the possibility of using MEVs to develop serum-free, chemically defined culture media for the generation of advanced three-dimensional (3D) models and intestinal artificial organs. Full article

(This article belongs to the Section Tissues and Organs)

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14 pages, 930 KB

Open AccessReview

Big Tau: Structure, Evolutionary Divergence, and Emerging Roles in Cytoskeletal Dynamics and Tauopathies

by Itzhak Fischer and Peter W. Baas

Cells 2026, 15(3), 241; https://doi.org/10.3390/cells15030241 - 27 Jan 2026

Abstract

Tau proteins are microtubule-associated proteins that regulate axonal structure, dynamics, and transport, and their dysregulation underlies several neurodegenerative diseases. The MAPT gene produces multiple tau isoforms through alternative splicing, including the high-molecular-weight isoform known as Big tau, which contains an insert of the [...] Read more.

Tau proteins are microtubule-associated proteins that regulate axonal structure, dynamics, and transport, and their dysregulation underlies several neurodegenerative diseases. The MAPT gene produces multiple tau isoforms through alternative splicing, including the high-molecular-weight isoform known as Big tau, which contains an insert of the large 4a exon of approximately 250 amino acids. Big tau is predominantly expressed in neurons of the peripheral nervous system (PNS), cranial motor nuclei, and select neurons of the central nervous system (CNS) such as the cerebellum and brainstem. Developmental expression studies indicate a switch from low-molecular-weight isoforms of tau to Big tau during axonal maturation, suggesting that Big tau optimizes cytoskeletal dynamics to accommodate long axonal projections. Comparative sequence and biophysical analyses show that the exon-4a insert is highly acidic, intrinsically disordered, and evolutionarily conserved in its length but not its primary sequence, implying a structural role. Emerging modeling and in vitro assays suggest that the extended projection domain provided by the exon-4a insert spatially and electrostatically shields the aggregation-prone PHF6 and PHF6* motifs in tau’s microtubule-binding domain, thereby reducing β-sheet driven aggregation. This mechanism may explain why tauopathies that involve aggregation of tau have little effect on the PNS and specific regions of the CNS such as the cerebellum, where Big tau predominates. Transcriptomic and proteomic data further suggest that alternative Big tau variants, including 4a-L, are expressed in certain cancerous tissues, indicating broader roles in cytoskeletal remodeling beyond neurons. Despite its putative anti-aggregation properties, the physiological regulation, interaction partners, and in vivo mechanisms of Big tau remain poorly defined. This review summarizes what is known about Big tau and what is missing toward a better understanding of how expansion via inclusion of exon 4a modifies tau’s structural and functional properties. Our purpose is to inspire future studies that could lead to novel therapeutic strategies to mitigate tau aggregation in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Recent Advances in the Study of Tau Protein)

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Cells

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