Frontiers in Cell and Developmental Biology最新文献

{"title":"The 3' region of the ZPA regulatory sequence (ZRS) is required for activity and contains a critical E-box.","authors":"Kathryn F Ball, Stephen Manu, Abbie K Underhill, Jeanyoung Kim, Jessica C Britton, Sarah R Rudd, Madison M Malone, Japhet Amoah, Allen Cooper, Charmaine Pira, Kerby C Oberg","doi":"10.3389/fcell.2025.1569573","DOIUrl":"10.3389/fcell.2025.1569573","url":null,"abstract":"<p><strong>Background: </strong>During development, Hand2 and Hoxd13 transcription factors (TFs) regulate Sonic hedgehog (Shh) expression in the zone of polarizing activity (ZPA) in the distal posterior limb mesoderm. The ZPA regulatory sequence (ZRS) is a conserved, limb-specific enhancer that controls Shh expression. The ZRS can be divided into 5', central, and 3' subdomains, each with an E-box site that can bind basic helix-loop-helix (bHLH) TFs like Hand2. In addition, two Hoxd13 sites are present in the 5' and central subdomains. Hand2 purportedly binds the ZRS through the central E-box, and both Hand2 and Hoxd13 have been shown to activate the ZRS <i>in vitro</i>. We hypothesized that the central E-box was required for activity, while the other E-boxes and Hoxd13 sites localize ZRS activity to the distal posterior limb mesoderm.</p><p><strong>Methods: </strong>To identify the functional role of each subdomain, we generated three ZRS fragments (5', central, and 3') and combined fragment constructs to test subdomain collective contributions. Additionally, we disrupted the five binding sites, alone or in concert, using site-directed mutagenesis. All ZRS constructs were cloned into a GFP reporter and evaluated in an <i>in vivo</i> chicken limb bioassay. We validated our findings using select ZRS constructs in transgenic mice.</p><p><strong>Results: </strong>We found that the 3' fragment was necessary for ZRS activity, while the 5' and central fragments had no activity alone or when combined. However, combining the 3' fragment with the 5' fragment restored robust activity. Further, mutation of all five binding sites markedly reduced ZRS activity. Reinstating each of the Hoxd13 sites restored focal activity, while restoring the 5' and central E-boxes had little effect. However, the 3' E-box proved sufficient for robust activity even in the absence of the other four binding sites.</p><p><strong>Conclusion: </strong>Our data indicate that the ZRS 3', not the central, subdomain is necessary for activity and contains the 3' E-box that Hand2 likely uses to induce Shh expression, while the 5' and central E-boxes appear to be inhibitory. Our data also suggest that the Hoxd13 binding sites promote localized activity within the ZPA.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1569573"},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648914","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":"Cancer research and the mainstream of biology.","authors":"Toivo Maimets","doi":"10.3389/fcell.2025.1623849","DOIUrl":"10.3389/fcell.2025.1623849","url":null,"abstract":"<p><p>John Cairns, a British molecular biologist, has pointed out that biology and cancer research have always developed together, and cancer theories have followed \"whatever branch of biology happens at the time to be fashionable and exciting\". Indeed, following the long historical development of biological thought confirms this observation. However, tumour theories have never been merely a \"fellow runner\" to more modern biology theories. Cancer is an exceptionally large medical and economic problem, and the practical results of cancer research are carefully followed and critically analysed by the community. If the expected results do not arrive and the scientific data do not fit into the old theory, then the theory must be corrected. In other words, tumour theories not only derive from the prevailing biological worldview, but they also influence and, if necessary, actively change it. That is exactly what we are witnessing today-the ruling reductionist Somatic Mutations Theory (SMT) does not explain many new experimental findings and extensive research over the last 50 years has not brought major breakthroughs in cancer treatment. This century brings back the attention to developmental biology (embryology) in connection with the epigenetic revolution in biology, and the causes of tumours are searched for in the disorders of differentiation of cells/tissues and communication between them in the organism.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1623849"},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649006","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":"Overexpression of GDF15 protects kidneys from ischemia reperfusion injury and affects circular RNA expression.","authors":"Cuilin Zhu, Qing Liu, Yale Su, Yixin Zhang, Aanal Patel, Adam Greasley, Jifu Jiang, Douglas Quan, Weiping Min, Kexiang Liu, Xiufen Zheng","doi":"10.3389/fcell.2025.1577625","DOIUrl":"10.3389/fcell.2025.1577625","url":null,"abstract":"<p><strong>Background: </strong>Renal failure and dysfunction remain one of the most significant morbidities impacting patient's life. Effective treatments still lack in the context of an increasing number of patients with renal failure. This study aims to investigate the impact of growth differentiation factor 15 (GDF15) in treating renal dysfunction and to explore its therapeutic potential.</p><p><strong>Methods: </strong>Renal injury was induced with a murine ischemia reperfusion injury (IRI) model. Mice overexpressing GDF15 (GDF15 transgenic (GDF15TG) mice, GDF15 knock out (GDF15 KO) mice and wild type (WT) mice all underwent IRI to test the effects of GDF15 on renal injury. Renal function and histopathological changes were measured 24 h after reperfusion. Cell apoptosis was detected by TUNEL and tissue inflammation was detected by myeloperoxidase (MPO) activity. qRT-PCR was conducted to determine the expression of genes and circular RNAs.</p><p><strong>Results: </strong>Overexpression of GDF15 reduced mortality of mice with lethal renal IRI whereas GDF15 deficiency increased the mortality. GDF15TG mice had better renal function with the lower levels of blood creatinine and blood urea nitrogen (BUN). Over-expression of GDF15 reduced kidney pathological changes, cell apoptosis, neutrophil infiltration and mortality. Over-expression of GDF15 also decreased the expression of apoptotic genes (high mobility group 1, HMGA1 and Bax), inflammatory genes IL-1β, IL-6, tumor necrosis factor (TNF-α), chemokine 1 (CK1), and senescent gene p21 whereas increases Bcl-XL, Importin 11 and CRIM1. IRI upregulated circular RNA Smad3 and reduced circular RNA Hipk3 and circular RNA Crim1, which was offset by GDF15.</p><p><strong>Conclusion: </strong>Over-expression of GDF15 protects renal function and prevents renal failure, highlighting its potential in treating renal failure.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1577625"},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648911","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":"Editorial: Electric stimulation in the eye and brain: advancements and applications.","authors":"Daisy Y Shu, Yukari Nakano, Kin-Sang Cho, Anton Lennikov","doi":"10.3389/fcell.2025.1643111","DOIUrl":"10.3389/fcell.2025.1643111","url":null,"abstract":"","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1643111"},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649009","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":"Circulating tumor DNA in cholangiocarcinoma: current clinical applications and future perspectives.","authors":"Yi Wang, Yike Li, Zhong Liang, Yuqiao Zhang, Tong Li, Chenjun Tian, Jinyu Zhao, Boru Jin, Jie Cao, Yanyan Lin","doi":"10.3389/fcell.2025.1616064","DOIUrl":"10.3389/fcell.2025.1616064","url":null,"abstract":"<p><p>Cholangiocarcinoma is a highly heterogeneous malignant tumor, including intrahepatic cholangiocarcinoma, hepatoportal cholangiocarcinoma and distal cholangiocarcinoma. Its incidence is increasing worldwide and currently accounts for approximately 15% of all primary liver cancers and 3% of all gastrointestinal malignancies. There is a lack of early diagnostic methods for cholangiocarcinoma, and the overall treatment effect is poor, with a 5-year survival rate of less than 25%. New biomarkers are urgently needed in clinical practice to improve the current diagnosis and treatment status. Circulating tumor DNA (ctDNA) is DNA fragments released by tumor cells, which can show tumor-specific gene mutations (such as IDH1/2, FGFR2 fusion) and epigenetic modifications (such as abnormal methylation). With the rapid development of tumor liquid biopsy technology, ctDNA has been gradually applied in solid tumors such as lung cancer and colorectal cancer due to its high sensitivity and dynamic monitoring capabilities. This review systematically introduces ctDNA technology and its progress in early screening, early diagnosis, treatment response, and prognosis monitoring of cholangiocarcinoma. In addition, this review also summarizes the challenges and limitations of current ctDNA technology and analyzes future hot research directions.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1616064"},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649007","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":"Hippo/YAP signaling's multifaceted crosstalk in cancer.","authors":"Jie Zhang, Haipeng Wu, Xinxin Ren, Zhuoshi Chen, Siyu Ye, Shuchang Chen, Jie Fang, Qirou Wu, Tiejun Zhao","doi":"10.3389/fcell.2025.1595362","DOIUrl":"10.3389/fcell.2025.1595362","url":null,"abstract":"<p><p>The Hippo/yes-associated protein (YAP) signaling is an evolutionarily conserved regulator in organ size control, which plays pivotal roles in cell proliferation, differentiation, apoptosis, and tissue regeneration. In cancer, dysregulation of Hippo/YAP signaling is typically recognized as one of the crucial drivers in tumorigenesis. However, beyond its canonical transcriptional targets, Hippo/YAP signaling engages in extensive crosstalk with multiple pathways to form an intricate regulatory network, thereby giving rise to its content-dependent influence on tumor initiation, progression and metastasis. This review focuses on the molecular mechanisms underlying the interplay between Hippo/YAP and pivotal signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), wingless-type (Wnt)/β-catenin signaling pathway, transforming growth factor-beta (TGF-β), Hedgehog, Notch and other signaling pathways, as well as their implications in cancer biology. Ultimately, exploiting these mechanisms may represent promising therapeutic strategies for cancer.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1595362"},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648910","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":"POU5F1 bridges Hedgehog signaling and epithelial remodeling in COPD.","authors":"Laure M G Petit, Randa Belgacemi, Pauline Mulette, Audrey Brisebarre, Lynda Saber Cherif, Maëva A Devilliers, Sarah Hatoum, Julien Ancel, Gonzague Delepine, Anne Durlach, Myriam Polette, Gaëtan Deslée, Jeanne-Marie Perotin, Valérian Dormoy","doi":"10.3389/fcell.2025.1566251","DOIUrl":"10.3389/fcell.2025.1566251","url":null,"abstract":"<p><p>Airway epithelium remodeling is a hallmark of chronic obstructive pulmonary disease (COPD) pathogenesis. Hedgehog signaling is activated during airway epithelial repair to warrant proliferation and during cell differentiation to establish a fully functional epithelium with optimal mucociliary clearance. Consequently, it was found to be altered in COPD patients. Using transcriptomic analysis on air-liquid interface airway epithelial cells during differentiation upon Hedgehog pathway inhibition, we highlighted potential regulators of COPD-associated epithelial remodeling. Furthermore, the alteration of POU5F1 (OCT3/4) was validated in COPD airway epithelial cells and lung tissues. Although further investigations are required, these findings uncovered essential clues tethering respiratory epithelial cell plasticity and Hedgehog signaling.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1566251"},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648912","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":"CKAP4 and PLOD2 as novel prognostic biomarkers in hepatocellular carcinoma: a proteomics-driven risk stratification model.","authors":"Qiulong Lu, Zhao Cao, Yueting Xiong, Junqiang Huang, Huan Zeng, Zhijian Chen, You Shu, Yahan Tan, Xiaoling Long, Xiaohui Liu, Hong Shu","doi":"10.3389/fcell.2025.1577161","DOIUrl":"10.3389/fcell.2025.1577161","url":null,"abstract":"<p><strong>Background: </strong>The prognosis of patients with hepatocellular carcinoma (HCC) is a research hotspot. This study aimed to identify novel prognostic protein markers for HCC using data-independent acquisition mass spectrometry (DIA-MS) and develop an integrative predictive model to enhance clinical decision-making and patient stratification.</p><p><strong>Methods: </strong>DIA-MS were implemented to identify valuable prognostic HCC biomarkers in 31 patients with different prognoses. A prognostic model was developed and validated using immunohistochemistry (IHC).</p><p><strong>Results: </strong>Cytoskeleton-associated membrane protein 4 (CKAP4) and procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) were identified as key prognostic proteins, with higher expression levels associated with poor prognosis. Immunohistochemical validation confirmed the prognostic value of CKAP4 and PLOD2. A nomogram incorporating AJCC stage and the combination of CKAP4 and PLOD2 demonstrated superior predictive Sability for overall survival (OS) compared to individual indicators. The model predicted an outcome with a concordance index (C-index) of 0.738 (95% CI, 0.698-0.779) and significantly stratified patients into distinct risk groups (<i>P</i> < 0.001).</p><p><strong>Conclusion: </strong>In conclusion, this study identified CKAP4 and PLOD2 as novel prognostic protein markers for HCC. The developed nomogram, integrating these molecular markers with AJCC stage, shows promise in predicting OS and stratifying risk in HCC patients.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1577161"},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649008","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":"Repurposing piroxicam enhances the antineoplastic effects of docetaxel and enzalutamide in prostate cancer cells using 2D and 3D <i>in vitro</i> culture models.","authors":"Amani Yehya, Fatima Ghamlouche, Raed Karami, Sana Hachem, Zahraa Salhab, Yen-Nien Liu, Georges Daoud, Wassim Abou-Kheir","doi":"10.3389/fcell.2025.1551010","DOIUrl":"10.3389/fcell.2025.1551010","url":null,"abstract":"<p><strong>Introduction: </strong>Drug repurposing is gaining consideration in cancer due to the challenges of poor outcomes and resistance associated with the current conventional modalities. Non-steroidal anti-inflammatory drugs (NSAIDs), widely used for treating inflammation, are being explored for their potential efficacy in cancer treatment, including prostate cancer (PCa). This study aims to evaluate the efficacy of Piroxicam (PXM), an NSAID, in enhancing the sensitivity of PCa cells to chemotherapy and hormonal drugs.</p><p><strong>Methods: </strong>Computational analysis was conducted to identify differentially expressed genes between our established murine PCa cell models, PLum-AD (androgen-dependent) and PLum-AI (androgen-independent), to uncover potential therapeutic targets. In two-dimensional (2D) cell culture, cell proliferation, viability, and migration assays were performed on PLum-AD and PLum-AI cells treated with PXM alone or in combination with docetaxel (Doc) or enzalutamide (Enz). Additionally, the impact of these treatments on stem-like progenitor cells was assessed using three-dimensional (3D)-Matrigel™-based sphere-forming and organoid formation assays.</p><p><strong>Results: </strong>Transcriptomic analysis revealed that inflammatory pathways are enriched during PCa progression, making them viable targets for NSAID-based interventions. Single treatment of PXM demonstrated significant anti-cancer effects on PLum-AD and PLum-AI cells, evidenced by reduced cell proliferation, viability, migration, sphere growth, and organoid growth.</p><p><strong>Discussion: </strong>Importantly, PXM treatment in combination with Doc or Enz resulted in more pronounced antineoplastic effects compared to single-drug exposure. Our work suggests PXM as a potential adjunctive therapy to enhance the efficacy of conventional treatments in PCa patients.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1551010"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642233","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":"Chromosomal quality control in hPSCs: A practical guide to SNP array analysis with GenomeStudio.","authors":"Josephine Haake, Laura Steenpass","doi":"10.3389/fcell.2025.1599923","DOIUrl":"10.3389/fcell.2025.1599923","url":null,"abstract":"<p><p>Human pluripotent stem cells (hPSCs) are important tools in preclinical research and disease modeling. Valid results can only be obtained using thoroughly quality-controlled hPSCs, which includes ensuring chromosomal stability. Chromosomal aberrations, which frequently arise during reprogramming, gene editing, or maintenance cultivation, can compromise the utility of these cells in research and therapeutic applications. Although traditional G-banding remains a valuable genome-wide analysis method, its limited resolution necessitates complementary approaches. SNP array analysis offers a high-resolution alternative, providing a more detailed genomic overview. We present a practical and user-friendly guide for detecting chromosomal aberrations using Illumina's GenomeStudio, offering an easy-to-follow protocol to simplify quality control workflows for researchers with minimal bioinformatics expertise. Although SNP array analysis for hPSC quality control is not novel, this step-by-step guide highlights critical quality control metrics, thresholds, and values, streamlining the process to make it more accessible and efficient for broader adoption. In 32 hPSCs, we identified chromosomal aberrations in nine, including the frequently reported gain of 20q11.21-a common anomaly in hPSC cultures. Examples from our routine practices underscore the importance of monitoring chromosomal integrity. This guide serves as a practical resource for standardizing and enhancing quality control processes, ensuring the genomic stability of hPSCs for research and clinical applications.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1599923"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642231","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}