Cells最新文献

{"title":"Patient-Derived iPSC Modeling Reveals Dysregulation of the Mucin-Type O-Glycan Biosynthesis-Related Transcriptional Program in <i>TBX6</i>-Associated Congenital Scoliosis.","authors":"Jing Hao, Zhengye Zhao, Shuang Li, Di Liu, Guozhuang Li, Lin Wang, Jingyi Xie, Zhifa Zheng, Jianguo Zhang, Zhihong Wu, Nan Wu, Lina Zhao","doi":"10.3390/cells15191785","DOIUrl":"10.3390/cells15191785","url":null,"abstract":"<p><p>TBX6-associated congenital scoliosis (TACS) is a genetic subtype of congenital scoliosis caused by reduced <i>TBX6</i> gene dosage, most commonly through compound inheritance of a rare loss-of-function allele and a hypomorphic T-C-A haplotype. However, the mechanisms linking TBX6 dysfunction to impaired human skeletal development remain unclear. Here, we established a patient-derived induced pluripotent stem cell (iPSC) model of TACS and recapitulated key stages of axial skeletal development through stepwise differentiation into paraxial mesoderm, nascent somites, sclerotome, and subsequently osteogenic and chondrogenic lineages. TACS-derived cells showed impaired differentiation, with reduced mineralized matrix deposition and diminished cartilage matrix formation. Bulk transcriptomic profiling revealed marked alterations in both lineages. Notably, mu-cin-type O-glycan biosynthesis was consistently enriched among downregulated genes in osteogenic and chondrogenic cells and was also significantly represented among genes commonly downregulated across both lineages. qRT-PCR further confirmed reduced expression of <i>GALNT3</i>, <i>GALNT5</i>, <i>GALNT7</i>, <i>GALNT10</i>, <i>GCNT1</i>, and <i>ST6GALNAC2</i>, which participate in distinct steps of mucin-type O-glycan biosynthesis. Consistent with these transcriptional alterations, Tn-antigen staining showed reduced Tn-associated O-GalNAc signals in TACS-derived osteogenic and chondrogenic cells. In silico promoter analysis identified candidate sequences matching the TBX6-binding motif within the upstream regions of these genes, providing potential regulatory regions for future experimental investigation. Collectively, these results establish a human iPSC model for TACS and identify coordinated dysregulation of a mucin-type O-glycan biosynthesis-related transcriptional program, accompanied by reduced Tn-associated O-GalNAc signals, as molecular features associated with impaired osteochondral differentiation in this model. These findings should be interpreted within the context of a single family-based iPSC model, and validation in additional TACS lines and isogenic TBX6-corrected models will be required.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ion Channels in Cardiac Non-Excitable Cells: From Single-Cell Atlases to Disease.","authors":"Weixuan Chen, Ashlyn A Fitzgerald, Brett Bardallis, Anu Priya Bharathi Rajan, Pengfei Liang","doi":"10.3390/cells15191790","DOIUrl":"10.3390/cells15191790","url":null,"abstract":"<p><p>Cardiovascular disease is shaped not only by cardiomyocyte excitability but also by electrophysiological and membrane-signaling programs in cardiac fibroblasts, endothelial cells, mural cells, immune cells, and adipocytes. Recent single-cell RNA sequencing, spatial transcriptomic, and disease-atlas studies have revealed broad expression of ion-channel transcripts across these non-excitable cardiac cell populations. However, transcript detection alone does not establish functional channel activity, cell-state specificity, or therapeutic relevance. This narrative Review therefore focuses on mechanistically supported channel-cell-disease axes rather than providing an exhaustive catalogue of ion channels detected in cardiac non-myocytes. We synthesize evidence for mechanosensitive channels, transient receptor potential channels, calcium-entry pathways, acid-sensing channels, and potassium, sodium, and chloride channels, as well as connexin hemichannels and pannexin channels. We emphasize studies in which omics-based channel nomination is supported by functional validation through electrophysiology, Ca²⁺ imaging, mechanostimulation, pharmacological intervention, or cell-selective genetic perturbation. Particular attention is given to mechanisms linking mechanical stress, Ca²⁺ entry, membrane potential, cell-volume regulation, ATP release, immune activation, vascular tone, fibrosis, and metabolic dysfunction. We also identify key evidence gaps where expression-based observations require direct functional testing in human tissues and disease-relevant cardiac models. By distinguishing atlas-level association from causal channel function, this Review provides a framework for prioritizing non-myocyte ion-channel mechanisms as therapeutic targets in cardiovascular diseases.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Listening in Reverse: A Case for Retrograde Signaling During Auditory Inner Hair Cell Ribbon Synapse Maturation.","authors":"Roos A Voorn, Louisa S Kuenkel, Jan F Ahrend, Christian Vogl","doi":"10.3390/cells15191779","DOIUrl":"10.3390/cells15191779","url":null,"abstract":"<p><p>Cochlear inner hair cells (IHCs) conduct rapid, sustained, and temporally precise transmission of acoustic information onto spiral ganglion neurons (SGNs). For this purpose, IHCs utilize highly specialized sensory synapses. During development, these so-called 'ribbon' synapses and their postsynaptic counterparts undergo extensive structural and functional refinement-a process driven by pre-sensory spontaneous activity. The underlying molecular mechanisms remain incompletely understood to date. Interestingly, little is known about the involvement of retrograde feedback provided by postsynaptic SGN terminals to transsynaptically instruct ribbon morphology and presynaptic active zone organization. This review therefore aims to shed light on this phenomenon and assess a potential role of retrograde signaling during IHC ribbon synapse maturation. We first summarize the main mechanisms established for conventional CNS synapses before discussing the current evidence regarding these pathways at IHC-SGN synapses. In particular, we focus on the gasotransmitter nitric oxide, lipid-derived endocannabinoid signaling, and cell adhesion molecules as the most promising candidate pathways. In summary, we propose that differential retrograde signaling may contribute to IHC synaptogenesis, SGN subtype diversification as well as the pruning of afferent contacts during development and might even play an extended functional role in auditory ribbon synapse regulation after hearing onset.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Localization and Trafficking Behavior of SPPL2A During Mouse Spermiogenesis.","authors":"Cheng Zheng, Wei Li, Shahnaz Parveen, Anuradha Yadav, Kristina Bennett, Jie Xu, Jifeng Zhang, Ling Zhang, Christopher V Kelly, Zhibing Zhang","doi":"10.3390/cells15191773","DOIUrl":"10.3390/cells15191773","url":null,"abstract":"<p><p>Signal peptide peptidase-like 2A (SPPL2A) is an intramembrane protease identified as a binding partner of intraflagellar transport protein 27 (IFT27), suggesting a potential role in sperm flagellum development. However, the localization and trafficking of SPPL2A during spermiogenesis remain unknown. Here, we generated an endogenous SPPL2A-mCherry knock-in mouse model using CRISPR/Cas9 to visualize SPPL2A in living male germ cells. Expression of the fusion protein was confirmed by Western blotting, and fertility, spermatogenesis, sperm morphology, and motility were evaluated. Live-cell fluorescence imaging, immunofluorescence, and single-particle tracking (SPT) were used to characterize SPPL2A localization and trafficking. Homozygous knock-in mice exhibited normal fertility, spermatogenesis, and sperm parameters, indicating that the mCherry fusion did not disrupt SPPL2A function. SPPL2A-mCherry was detected as punctate structures in developing germ cells and elongating sperm tails. Its localization changed dynamically during spermiogenesis and was closely associated with developing tail microtubules. Live-cell SPT demonstrated bidirectional movement of SPPL2A-containing particles within developing sperm tails. Mean-squared displacement analysis indicated predominantly confined diffusion with a confinement length scale of 153 ± 15 nm, while particle trajectories showed a slight bias away from the cell body. Particle mobility progressively decreased during sperm maturation, with highly mobile puncta in early spermatids becoming largely immobile in mature sperm. These findings establish an endogenous SPPL2A fluorescent knock-in mouse model and show that SPPL2A-containing particles exhibit intracellular movement within developing sperm tails during spermiogenesis. This model provides a valuable platform for investigating protein transport during sperm flagellum assembly.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in Core Temperature Following Administration of FC5, a Blood-Brain Carrier Fused with Neurotensin in Mice, Rats and Non-Human Primates.","authors":"Alvaro Yogi, Etienne Lessard, Eric Brunette, Christie E Delaney, Arsalan S Haqqani, Anna Robotham, Wael Alata, Maria J Moreno, Danica B Stanimirovic","doi":"10.3390/cells15191770","DOIUrl":"10.3390/cells15191770","url":null,"abstract":"<p><p>Development of therapies and pharmacological management of central nervous system diseases is significantly hampered by the presence of the highly selective blood-brain barrier (BBB). Receptor-mediated transcytosis (RMT) has proven to be a robust mechanism for delivering a wide variety of therapeutic modalities across the BBB. The present study describes the use of a neurotensin-based pharmacodynamic model to evaluate the brain penetrating capacity of FC5, a well-characterized RMT shuttle. Here we produce fusion molecules of FC5 with human Fc and neurotensin and show that intact but not C-terminally clipped neurotensin proteins containing either FC5 (FC5Fc-neurotensin) or a non-BBB-crossing control (A20.1Fc-neurotensin) retain the ability to activate neurotensin receptor type 1. In in vivo studies, intravenous administration of FC5Fc-neurotensin, but not neurotensin alone or A20.1Fc-neurotensin, induced a drop in the core body temperature in both rats and mice. We further extended these findings to non-human primates, demonstrating the ability of FC5 to cross the BBB in this species. Collectively, our results further support the potential of FC5 in delivering payloads across the BBB. The neurotensin model of hypothermia is also validated as a pharmacodynamic approach for assessing brain delivery, albeit with some necessary considerations into the molecular characterization of fusion constructs before in vivo evaluation.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Enteric Glial and Mast Cell Characteristics Distinguish Microscopic Colitis Subtypes Relative to Healthy and Disease Controls, with Treatment-Associated Reductions in Glial Reactivity and Mast Cell Degranulation in Collagenous Colitis.","authors":"Julie Beaudeau, Celia Escudero-Hernández, Vittorio Abruzzese, Georgios Katinios, Gustav Orell, Nawroz Barazanji, Susanna Walter, Henrik Hjortswang, Vytautas Kiudelis, Juozas Kupčinskas, Andreas Münch, Åsa V Keita","doi":"10.3390/cells15191778","DOIUrl":"10.3390/cells15191778","url":null,"abstract":"<p><p>Microscopic colitis (MC) is an inflammatory bowel disease characterized by chronic watery diarrhea. Although barrier dysfunction and immune activation are implicated, underlying mechanisms remain unclear. The aim of this study was to characterize enteric glial cells (EGC) and mast cell distribution across MC subtypes, assess treatment effects, and explore EGC-related gene expression and barrier markers. Colonic biopsies from patients with active collagenous colitis (aCC), budesonide-refractory CC (rCC), and active lymphocytic colitis (LC) were compared to irritable bowel syndrome (IBS), ulcerative colitis (UC), and healthy controls (HC). A subset of CC patients was studied during active disease (aCC) and in clinical remission due to budesonide treatment (tCC). Immunofluorescence quantified EGC positive for glial fibrillary acidic protein (EGC^GFAP+) and S100 calcium-binding protein B (EGC^S100β+), mast cell tryptase, and tight junction proteins. RNA-sequencing assessed EGC-related gene expression. Results showed that EGC^GFAP+ were highest in rCC and decreased following budesonide treatment in aCC, whereas EGC^S100β+ were highest in aCC, remained unchanged following treatment, resembled IBS, and were reduced compared with UC. Mast cell numbers were higher in aCC than in HC and rCC but remained unchanged following treatment, while mast cell degranulation decreased after treatment. Tight junction proteins were unchanged. RNA-sequencing indicated differential regulation of EGC-related genes. In conclusion, MC shows subtype-specific alterations involving EGC and mast cells, suggesting distinct glial states and differential treatment responsiveness. Our findings support the presence of distinct neuroimmune alterations in CC and LC and highlight EGC as potential contributors to MC pathophysiology.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paracrine Signals from the Tumor Microenvironment Modulate Stem Cell Collagen Interaction and Remodeling, Indicating Early Functional Changes.","authors":"Lora Topalova, Tanya Stoyanova, Nadia García-Parra, José Luis Gómez Ribelles, Svetla Todinova, George Altankov","doi":"10.3390/cells15191775","DOIUrl":"10.3390/cells15191775","url":null,"abstract":"<p><p>The tumor microenvironment (TME) is shaped by dynamic interactions between malignant cells and stromal components, with mesenchymal stem cells (MSCs) contributing to extracellular matrix (ECM) remodeling. Here, we examined how secretomes from two hematological cancer cell lines, RPMI-8226 (multiple myeloma) and HG-3 (B-cell leukemia), influence early functional responses of human adipose-derived MSCs (AD-MSCs) and their interaction with and reorganization of collagen. Cancer-conditioned media accelerated MSC proliferation (~2-fold faster doubling time) and increased SA-β-galactosidase activity (~3-4-fold above control). Upon adhesion to collagen, treated MSCs displayed distinct morphologies and reduced cell spreading (~2100 μm² vs. ~2500 μm² in controls), accompanied by altered collagen organization. To quantify collagen remodeling, we introduced the collagen removal index (CRI), expressing reorganized collagen area relative to cell spreading area. CRI revealed higher remodeling efficiency in HG-3-treated MSCs than in RPMI-8226-treated and control cells, indicating enhanced collagen-interacting capacity. Secretome exposure also modulated cytokine secretion, with increased bFGF under both conditions and IL-6 upregulation specifically following HG-3 exposure. After secretome withdrawal, most functional alterations, including senescence-associated changes, motility, and elevated bFGF, persisted. Notably, IL-6 upregulation and increased CRI emerged in RPMI-8226-exposed MSCs after withdrawal, suggesting a delayed response. Together, these findings reveal early, partially persistent functional shifts in MSC behavior and collagen remodeling that may represent an early stromal response with potential relevance to tumor progression.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acquired Chemoresistance in Colorectal Cancer: Therapy-Induced Signalling Adaptation, Cellular Plasticity and Mechanism-Guided Therapeutic Strategies.","authors":"Dorota Bartusik-Aebisher, Izabella Wilk, Blassan P George, David Aebisher","doi":"10.3390/cells15191776","DOIUrl":"10.3390/cells15191776","url":null,"abstract":"<p><p>The effectiveness of chemotherapy in colorectal cancer (CRC) is significantly reduced by acquired chemoresistance to 5-fluorouracil (5-FU), oxaliplatin and irinotecan. This structured narrative review synthesises mechanistic, preclinical, translational and clinical evidence underlying resistance to these agents. Distinct drug-specific molecular mechanisms can underlie acquired chemoresistance, whereas shared adaptive survival processes support treatment persistence and may, in some settings, contribute to the emergence of stable acquired resistance. 5-FU resistance is associated with factors such as altered thymidylate synthase activity, drug catabolism, nucleotide metabolism and apoptosis avoidance, whereas resistance to oxaliplatin involves enhanced deoxyribonucleic acid (DNA) repair, detoxification, reduced platinum accumulation and metabolic adaptation. Irinotecan resistance can involve reduced <i>TOP1</i> expression or <i>TOP1</i> mutations, altered SN-38 metabolism, increased drug efflux and enhanced tolerance of replication-associated stress. Alongside these drug-proximal mechanisms, drug-tolerant persister states, stem-like programmes, epithelial-mesenchymal plasticity and multidrug-efflux mechanisms can support treatment survival and tumour repopulation. Evidence linking chemoresistance with Wnt/β-catenin, Notch and Hippo/Yes-associated protein 1 (YAP1) signalling is predominantly preclinical and varies according to treatment context, with stronger direct pathway-specific evidence for 5-FU and oxaliplatin than for irinotecan. This distinction allows direct drug-specific associations to be differentiated from broader roles in adaptive survival, cellular plasticity and tumour repopulation after treatment. Cancer-associated fibroblasts, immune and cytokine signalling, extracellular vesicles, hypoxia and treatment-induced remodelling of the tumour microenvironment can all further influence tumour heterogeneity and non-cell-autonomous resistance. Residual disease, resistant cellular states and therapeutically relevant molecular dependencies may be detected or characterised using circulating tumour DNA, pathway-associated biomarkers, patient-derived organoids and emerging resistance-profiling technologies. These findings show that interactions between drug-specific molecular escape mechanisms, adaptive cellular states and the tumour microenvironment contribute to heterogeneous patterns of treatment survival and acquired chemoresistance. The development of molecularly targeted and mechanism-guided strategies for overcoming resistance in CRC may be supported by defining these mechanisms and their associated biomarkers.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.","authors":"Gabriel Burdman, Marco Hanna, Adriana Yndart Arias, Arti Vashist, Madepalli K Lakshmana","doi":"10.3390/cells15191768","DOIUrl":"10.3390/cells15191768","url":null,"abstract":"<p><p>Neurological disorders are the leading cause of overall disease and disability worldwide, affecting more than 3.4 billion people globally and over 180 million Americans. Yet there are no curative treatments available for any of the cardinal neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and Huntington's disease (HD). Many compounds that demonstrate excellent activity in preclinical models fail in clinical trials. The most compelling reason for this failure is attributed to inherent limitations of rodent models that fail to replicate complex human biology. The transformation of patient-derived somatic cells into induced pluripotent stem cells (iPSCs) that can become functional human neurons is an emerging technology that is expected to revolutionize medical treatments and personal medicine. Here, we review the available evidence for the efficacy of iPSC-derived neurons, organoids, assembloids and organ-on-chip in models of AD, PD, ALS-FTD and HD. We focus on how these human-relevant iPSC-derived brain cells are crucial for understanding neurological disease pathogenesis and accelerating drug discovery. We also discuss the current limitations of this technology and how alternative models such as induced neurons (iNs) are generated by directly reprogramming fibroblasts that preserve age-associated epigenetic signatures and may serve as better models for neurological disorders.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct OA:PA Ratios Generate Discrete Hepatocellular Phenotypes in HepG2 Cells.","authors":"Hangyeon Jeong, Yesol Han, Jiyeong Park, Hanbyul Noh, Eunyoung Moon, Yanghoon Huh","doi":"10.3390/cells15191774","DOIUrl":"10.3390/cells15191774","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by hepatic steatosis, metabolic stress, and inflammation. Although free fatty acid (FFA)-based in vitro models are widely used, how OA:PA ratios shape hepatocellular phenotypes remains incompletely characterized. HepG2 cells were treated with oleic acid (OA), palmitic acid (PA), or four OA:PA mixtures (O1P1, O2P1, O3P2, O1P2) for 24 or 48 h. OA and OA:PA mixtures were evaluated at 500 μM total FFA (O2P1: 333.3 μM OA + 166.7 μM PA; O3P2: 300 μM OA + 200 μM PA), whereas PA alone was evaluated at 200 μM. Cell viability, lipid accumulation, ultrastructure, oxidative response, secreted cytokines, and molecular responses were evaluated. Distinct OA:PA ratios generated discrete hepatocellular states rather than a linear steatosis-to-lipotoxicity continuum. O3P2 produced a steatosis-dominant phenotype with pronounced lipid accumulation and relatively limited stress signaling. In contrast, O2P1 combined substantial lipid accumulation with elevated DCF fluorescence, AMP-activated protein kinase (AMPK) phosphorylation, nuclear factor kappa B (NF-κB)-associated inflammatory signaling, and interleukin-8 (IL-8) secretion, representing a pronounced stress-responsive phenotype with selected MASH-relevant features. Selected responses were also evaluated in SNU-449 cells, revealing cell-line-specific patterns. Collectively, these findings support a phenotype-oriented framework for OA:PA ratio selection in hepatocyte-based in vitro MASH modeling.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}