Cells最新文献

{"title":"Role of Kindlin-2-Expressing Extracellular Vesicles in the Invasiveness of Triple Negative Breast Cancer Tumor Cells.","authors":"Neelum Aziz Yousafzai, Mark F Santos, Yeaji Kim, Nofar Avihen Schahaf, Kim Zielke, Lucia Languino, Khalid Sossey-Alaoui, Aurelio Lorico","doi":"10.3390/cells14131034","DOIUrl":"10.3390/cells14131034","url":null,"abstract":"<p><p>Metastatic breast cancer (BC) is a major cause of cancer-related deaths among women. Its progression is influenced by extracellular vesicles (EVs) released by BC cells, which modulate distant tissue environments to promote metastasis. We previously identified the oncogenic protein Kindlin-2 (K2) as a key driver of BC metastasis, including its role in the nucleus in regulating cell senescence. Here, we investigated whether K2-containing EVs facilitate both autologous (cancer-to-cancer) and heterologous (cancer-to-stroma) communication to promote metastasis. We found that 10-15% of EVs from metastatic BC cells contained K2, while this subpopulation was nearly absent in the EVs from K2-knockout (KO) cells, indicating selective packaging. These EVs transferred K2 to recipient K2-KO cells, where they accumulated in the nucleus. Using a 3D tumorsphere assay, we showed that K2+ EVs enhanced cancer cell invasiveness. Moreover, K2+ EVs activated fibroblasts into a cancer-associated phenotype, increasing α-SMA and FAP expression. Conditioned media from these activated fibroblasts further boosted cancer cell invasion. These results show that EV-associated K2 is actively transferred to recipient cells and regulates metastasis through nuclear signaling, suggesting K2+ EVs are critical mediators of BC progression and potential targets for therapy.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 13","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12248540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607601","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":"Duchenne Muscular Dystrophy Patient iPSCs-Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation.","authors":"Urs Kindler, Lampros Mavrommatis, Franziska Käppler, Dalya Gebrehiwet Hiluf, Stefanie Heilmann-Heimbach, Katrin Marcus, Thomas Günther Pomorski, Matthias Vorgerd, Beate Brand-Saberi, Holm Zaehres","doi":"10.3390/cells14131033","DOIUrl":"10.3390/cells14131033","url":null,"abstract":"<p><strong>Background: </strong>Duchenne muscular dystrophy (DMD), which affects 1 in 3500 to 5000 newborn boys worldwide, is characterized by progressive skeletal muscle weakness and degeneration. The reduced muscle regeneration capacity presented by patients is associated with increased fibrosis. Satellite cells (SCs) are skeletal muscle stem cells that play an important role in adult muscle maintenance and regeneration. The absence or mutation of dystrophin in DMD is hypothesized to impair SC asymmetric division, leading to cell cycle arrest.</p><p><strong>Methods: </strong>To overcome the limited availability of biopsies from DMD patients, we used our 3D skeletal muscle organoid (SMO) system, which delivers a stable population of myogenic progenitors (MPs) in dormant, activated, and committed stages, to perform SMO cultures using three DMD patient-derived iPSC lines.</p><p><strong>Results: </strong>The results of scRNA-seq analysis of three DMD SMO cultures versus two healthy, non-isogenic, SMO cultures indicate reduced MP populations with constant activation and differentiation, trending toward embryonic and immature myotubes. Mapping our data onto the human myogenic reference atlas, together with primary SC scRNA-seq data, indicated a more immature developmental stage of DMD organoid-derived MPs. DMD fibro-adipogenic progenitors (FAPs) appear to be activated in SMOs.</p><p><strong>Conclusions: </strong>Our organoid system provides a promising model for studying muscular dystrophies in vitro, especially in the case of early developmental onset, and a methodology for overcoming the bottleneck of limited patient material for skeletal muscle disease modeling.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 13","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12249143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607549","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":"Structural and Functional Characterization of N-Glycanase-1 Pathogenic Variants.","authors":"Antje Banning, Lukas Hoeren, Isis Atallah, Ralph Orczyk, David Jacquier, Diana Ballhausen, Ritva Tikkanen","doi":"10.3390/cells14131036","DOIUrl":"10.3390/cells14131036","url":null,"abstract":"<p><p>NGLY1 deficiency is a congenital disorder of deglycosylation, caused by pathogenic variants of the <i>NGLY1</i> gene. It manifests as global developmental delay, hypo- or alacrima, hypotonia, and a primarily hyperkinetic movement disorder. The NGLY1 enzyme is involved in deglycosylation of misfolded N-glycosylated proteins before their proteasomal degradation and in the activation of transcription factors that control the expression of proteasomal subunits. Here, we have characterized the pathogenic NGLY1 variants found in three Swiss NGLY deficiency patients, as well as the most common pathogenic NGLY1 variant, Arg401*, found in about 20% of patients. Our functional and structural assessments of these variants show that they cause a profound reduction in NGLY1 activity, severely reduced expression of NGLY1 protein, and misprocessing of the transcription factor NFE2L1. Furthermore, transcription of proteasomal subunits and NGLY1 mRNA splicing are impaired by some of these variants. Our in silico structural analysis shows that the Arg390Gln substitution results in destabilization of NGLY1 structure due to a loss of an ionic interaction network of Arg390 and potentially impairment of protein-protein interactions. Our results provide important information on the functional and structural effects of pathogenic NGLY1 variants and pave the way for structure-based development of personalized treatment options.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 13","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12248763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607606","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":"GIGYF2: A Multifunctional Regulator at the Crossroads of Gene Expression, mRNA Surveillance, and Human Disease.","authors":"Chen-Shuo Zhao, Shu-Han Liu, Zheng-Yang Li, Jia-Yue Chen, Xiang-Yang Xiong","doi":"10.3390/cells14131032","DOIUrl":"10.3390/cells14131032","url":null,"abstract":"<p><p>GIGYF2 (Grb10-interacting GYF protein 2) functions as a versatile adaptor protein that regulates gene expression at various levels. At the transcriptional level, GIGYF2 facilitates VCP/p97-mediated extraction of ubiquitylated Rpb1 from stalled RNA polymerase II complexes during DNA damage response. In mRNA surveillance, GIGYF2 participates in ribosome collision-induced quality control, nonsense-mediated decay, no-go decay, and non-stop decay pathways. Furthermore, GIGYF2 interacts with key factors including 4EHP, TTP, CCR4-NOT, DDX6, ZNF598, and TNRC6A to mediate translational repression and mRNA degradation. Additionally, dysregulation of GIGYF2 has been implicated in various pathological conditions, including metabolic diseases, vascular aging, viral infections, and neurodegenerative disorders. This review summarizes the structural and functional characteristics of GIGYF2, highlighting its importance in transcriptional regulation, mRNA surveillance, translational inhibition, and mRNA degradation, while also elucidating its potential as a therapeutic target for disease treatment.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 13","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12249416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607476","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":"MK2 Inhibition as a Novel Treatment for Fibrosis in Primary Sclerosing Cholangitis via an IL-22-Dependent Mechanism.","authors":"Cody S Howe, Ellen J Beswick","doi":"10.3390/cells14131031","DOIUrl":"10.3390/cells14131031","url":null,"abstract":"<p><p>Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by bile duct inflammation and fibrosis, leading to cirrhosis and liver failure. Current therapies are limited to symptom management, with no approved treatments targeting fibrosis. We have identified the MAP kinase-activated protein kinase 2 (MK2) pathway as a potential therapeutic target for treating PSC due to its role in promoting inflammatory cytokine production and activation of fibroblasts. Thus, MDR2 knockout mice were treated therapeutically with MK2 inhibitors, which led to significantly reduced hepatic inflammation and fibrosis. Liver enzymes, collagen 1A1, and fibronectin were decreased in serum with MK2 inhibitor treatment. Furthermore, the production of IL-6, TNFα, CXCL5, collagen 1A1, and fibronectin was decreased in liver tissues and liver stellate cells, whereas the production of IL-10, G-CSF, and IL-22 was increased. MDR2KO mice treated with IL-22 also showed improvements in inflammation and fibrosis, along with increased IL-10 and G-CSF production. Taken together, we identified both a direct mechanism of MK2 regulation of fibrotic factors and an indirect cytokine-mediated mechanism whereby the levels of IL-22, IL-10, and G-CSF were increased with MK2 inhibition and contributed to decreased levels of fibrotic factors. These data suggest that the MK2 pathway is a promising treatment target for PSC.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 13","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12248995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607493","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":"Kynurenic Acid Synthesis from D-Kynurenine in the Cerebellum: A Distinct Role of D-Amino Acid Oxidase.","authors":"Verónica Pérez de la Cruz, Korrapati V Sathyasaikumar, Xiao-Dan Wang, Tonali Blanco Ayala, Sarah Beggiato, Dinora F González Esquivel, Benjamin Pineda, Robert Schwarcz","doi":"10.3390/cells14131030","DOIUrl":"10.3390/cells14131030","url":null,"abstract":"<p><p>The enzymatic formation of kynurenic acid (KYNA), a neuromodulator metabolite of the kynurenine pathway (KP) of tryptophan metabolism, in the mammalian brain is widely attributed to kynurenine aminotransferase II (KATII). However, an alternative biosynthetic route, involving the conversion of D-kynurenine (D-KYN) to KYNA by D-amino acid oxidase (D-AAO), may play a role as well. In the present study, we first confirmed that purified D-AAO efficiently converted D-KYN-but not L-KYN-to KYNA. We then examined KYNA formation from D-KYN (100 µM) in vitro, using tissue homogenates from several human brain regions. KYNA was generated in all areas, with D-AAO-specific production being most effective by far in the cerebellum. Next tested in homogenates from rat cerebellum, KYNA neosynthesis was significantly reduced by D-AAO inhibition, whereas KATII inhibition had no effect. Finally, KYNA production was assessed by in vivo microdialysis in rat cerebellum. Local D-KYN perfusion, alone and in combination with inhibitors of D-AAO (kojic acid) or aminotransferases (AOAA), caused a substantive increase in extracellular KYNA levels. This effect was attenuated dose-dependently by micromolar concentrations of kojic acid, whereas co-perfusion of AOAA (1 mM) was ineffective. Together, our findings indicate that D-AAO should be considered a major contributor to KYNA production in the cerebellum, highlighting region-specific qualitative differences in cerebral KYNA metabolism.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 13","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12249069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607566","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":"Yoda1 Inhibits TGFβ-Induced Cardiac Fibroblast Activation via a BRD4-Dependent Pathway.","authors":"Perwez Alam, Sara M Stiens, Hunter J Bowles, Hieu Bui, Douglas K Bowles","doi":"10.3390/cells14131028","DOIUrl":"10.3390/cells14131028","url":null,"abstract":"<p><p>Fibrosis represents a pivotal pathological process in numerous diseases, characterized by excessive deposition of extracellular matrix (ECM) that disrupts normal tissue architecture and function. In the heart, cardiac fibrosis significantly impairs both structural integrity and functional capacity, contributing to the progression of heart failure. Central to this process are cardiac fibroblasts (CFs), which, upon activation, differentiate into contractile myofibroblasts, driving pathological ECM accumulation. Transforming growth factor-beta (TGFβ) is a well-established regulator of fibroblast activation; however, the precise molecular mechanisms, particularly the involvement of ion channels, remain poorly understood. Emerging evidence highlights the regulatory role of ion channels, including calcium-activated potassium (K_Ca) channels, in fibroblast activation. This study elucidates the role of ion channels and investigates the mechanism by which Yoda1, an agonist of the mechanosensitive ion channel Piezo1, modulates TGFβ-induced fibroblast activation. Using NIH/3T3 fibroblasts, we demonstrated that TGFβ-induced activation is regulated by tetraethylammonium (TEA)-sensitive potassium channels, but not by specific K⁺ channel subtypes such as BK, SK, or IK channels. Intriguingly, Yoda1 was found to inhibit TGFβ-induced fibroblast activation through a Piezo1-independent mechanism. Transcriptomic analysis revealed that Yoda1 modulates fibroblast activation by altering gene expression pathways associated with fibrotic processes. Bromodomain-containing protein 4 (BRD4) was identified as a critical mediator of Yoda1's effects, as pharmacological inhibition of BRD4 with JQ1 or ZL0454 suppressed TGFβ-induced expression of the fibroblast activation marker Periostin (Postn). Conversely, BRD4 overexpression attenuated the inhibitory effects of Yoda1 in both mouse and rat CFs. These results provide novel insights into the pharmacological modulation of TGFβ-induced cardiac fibroblast activation and highlight promising therapeutic targets for the treatment of fibrosis-related cardiac pathologies.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 13","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12249368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607571","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":"Correction: Ferraresi et al. Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy. <i>Cells</i> 2021, <i>10</i>, 3213.","authors":"Alessandra Ferraresi, Andrea Esposito, Carlo Girone, Letizia Vallino, Amreen Salwa, Ian Ghezzi, Suyanee Thongchot, Chiara Vidoni, Danny N Dhanasekaran, Ciro Isidoro","doi":"10.3390/cells14131020","DOIUrl":"10.3390/cells14131020","url":null,"abstract":"<p><p>In the original publication [...].</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 13","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12248942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607543","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":"Macrophage EP4 Deficiency Drives Atherosclerosis Progression via CD36-Mediated Lipid Uptake and M1 Polarization.","authors":"Xinyu Tang, Qian Chen, Manli Guo, Ying Wen, Cuiping Jia, Yun Bu, Ting Wang, Yuan Zhang, Waiho Tang","doi":"10.3390/cells14131021","DOIUrl":"10.3390/cells14131021","url":null,"abstract":"<p><p>Atherosclerosis is a chronic inflammatory disease and a major pathological basis of numerous cardiovascular conditions, with a high global mortality rate. Macrophages play a pivotal role in its pathogenesis through phenotypic switching and foam cell formation. Prostaglandin E2 receptor subtype 4 (EP4) highly expressed on the macrophage surface, is involved in various pathophysiological processes, such as inflammation and lipid metabolism. However, the role of macrophage EP4 in the progression of atherosclerosis remains unclear. To determine whether macrophage EP4 affects the progression of atherosclerosis by regulating foam cell formation and macrophage polarization. Myeloid-specific EP4 knockout mice with an ApoE-deficient background were fed a Western diet for 16 weeks. Our results showed that EP4 expression was significantly downregulated during atherosclerosis. EP4 deficiency was found to exacerbate atherosclerotic plaque formation and destabilizes plaques. In vitro studies further demonstrated that loss of EP4 in myeloid cells promoted foam cell formation and M1 macrophage polarization. Both transcriptomic and proteomic analysis showed that EP4 may regulate these processes by regulating CD36 expression in macrophage, which was further confirmed by Western blot and qPCR. In summary, deficiency of EP4 receptor in macrophages enhance foam cell formation and M1 polarization by upregulating CD36 expression, thereby accelerating the progression of atherosclerosis.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 13","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12249252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607490","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":"Hyperalgesia in the Psychological Stress-Induced Fibromyalgia Model Shows Sexual Dimorphism Mediated by LPA₁ and LPA₃.","authors":"Hiroshi Ueda, Hiroyuki Neyama, Naoki Dozono, Junken Aoki, Jerold Chun","doi":"10.3390/cells14131022","DOIUrl":"10.3390/cells14131022","url":null,"abstract":"<p><p>Since the initial report indicating that LPA₁ signaling plays a key role in initiating nerve injury-induced neuropathic pain (NeuP), subsequent studies using knockout mice and LPA_1/3 antagonists have demonstrated that LPA₁ and LPA₃ signaling impact NeuP and fibromyalgia (FM) models. In the present study, we identified hyperalgesia sexual dimorphism involving LPA_1/3 signaling in the intermittent psychological stress induced-related FM-like model called intermittent psychological stress (IPS)-induced generalized pain (IPGP) model where the hyperalgesia in IPGP mice was abolished in LPA₁- and LPA₃-knock-out mice. Pharmacological intervention by intraperitoneal (i.p.) treatments with the LPA_1/3 antagonist Ki16425 consistently prevented hyperalgesia. However, intracerebroventricular treatments with Ki16425 abolished hyperalgesia in male, but not female, mice. Notably, intrathecal treatments of Ki16425 did not prevent hyperalgesia. Further studies revealed that splenocytes derived from female IPGP mice could initiate hyperalgesia via adoptive transfer in naïve mice, and this effect was abolished when donor mice were pre-treated with Ki16425 (i.p.). Thus, these studies identify male-specific LPA_1/3-mediated mechanisms in the brain underlying IPGP, as well as distinct LPA-LPA_1/3-mediated peripheral immune mechanisms.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 13","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12248790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607559","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}