Cell Proliferation最新文献

Regenerating Locus Coeruleus-Norepinephrine (LC-NE) Function: A Novel Approach for Neurodegenerative Diseases.

IF 5.9 1区生物学

Cell Proliferation Pub Date : 2025-01-28 DOI: 10.1111/cpr.13807

Yana Yang, Yunlong Tao

{"title":"Regenerating Locus Coeruleus-Norepinephrine (LC-NE) Function: A Novel Approach for Neurodegenerative Diseases.","authors":"Yana Yang, Yunlong Tao","doi":"10.1111/cpr.13807","DOIUrl":"https://doi.org/10.1111/cpr.13807","url":null,"abstract":"Pathological changes in the locus coeruleus-norepinephrine (LC-NE) neurons, the major source of norepinephrine (NE, also known as noradrenaline) in the brain, are evident during the early stages of neurodegenerative diseases (ND). Research on both human and animal models have highlighted the therapeutic potential of targeting the LC-NE system to mitigate the progression of ND and alleviate associated psychiatric symptoms. However, the early and widespread degeneration of the LC-NE system presents a significant challenge for direct intervention in ND. Recent advances in regenerative cell therapy offer promising new strategies for ND treatment. The regeneration of LC-NE from pluripotent stem cells (PSCs) could significantly broaden the scope of LC-NE-based therapies for ND. In this review, we delve into the fundamental background and physiological functions of LC-NE. Additionally, we systematically examine the evidence and role of the LC-NE system in the neuropathology of ND and psychiatric diseases over recent years. Notably, we focus on the significance of PSCs-derived LC-NE and its potential impact on ND therapy. A deeper understanding and further investigation into the regeneration of LC-NE function could pave the way for practical and effective treatments for ND.","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e13807"},"PeriodicalIF":5.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DNA Damage Repair in Glioblastoma: A Novel Approach to Combat Drug Resistance.

IF 5.9 1区生物学

Cell Proliferation Pub Date : 2025-01-27 DOI: 10.1111/cpr.13815

Ludovica Gaiaschi, Claudio Casali, Andrea Stabile, Sharon D'Amico, Mauro Ravera, Elisabetta Gabano, Andrea Galluzzo, Cristina Favaron, Federica Gola, Fabrizio De Luca, Serena Pellegatta, Maria Grazia Bottone

{"title":"DNA Damage Repair in Glioblastoma: A Novel Approach to Combat Drug Resistance.","authors":"Ludovica Gaiaschi, Claudio Casali, Andrea Stabile, Sharon D'Amico, Mauro Ravera, Elisabetta Gabano, Andrea Galluzzo, Cristina Favaron, Federica Gola, Fabrizio De Luca, Serena Pellegatta, Maria Grazia Bottone","doi":"10.1111/cpr.13815","DOIUrl":"https://doi.org/10.1111/cpr.13815","url":null,"abstract":"Due to the lack of effective therapeutic approach, glioblastoma (GBM) remains one of the most malignant brain tumour. By in vitro investigations on primary GBM stem cells, we highlighted one of the underlying mechanisms of drug resistance to alkylating agents, the DNA damage responses. Here, flow cytometric analysis and viability and repopulation assays were used to assess the long-term cytotoxic effect induced by the administration of a fourth-generation platinum prodrug, the (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato) platinum(IV) named Pt(IV)Ac-POA, in comparison to the most widely used Cisplatin. The immunofluorescence studies revealed changing pathways involved in the DNA damage response mechanisms in response to the two chemotherapies, suggesting in particular the role of Poly (ADP-Ribose) polymerases in the onset of resistance to Cisplatin-induced cytotoxicity. Thus, this research provides a proof of concept for how the use of a prodrug which allows the co-administration of Cisplatin and an Histone DeACetylase inhibitors, could suppress DNA repair mechanisms, suggesting a novel effective approach in GBM treatment.","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e13815"},"PeriodicalIF":5.9,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The S-Phase Arrest of Host Cells Caused by an Alpha-Herpesvirus Genome Replication Facilitates Viral Recruitment of RNA Polymerase II to Transcribe Viral Genes.

IF 5.9 1区生物学

Cell Proliferation Pub Date : 2025-01-27 DOI: 10.1111/cpr.13811

Qiqi Yang, Ying Wu, Mingshu Wang, Shun Chen, Renyong Jia, Qiao Yang, Dekang Zhu, Mafeng Liu, Xinxin Zhao, Shaqiu Zhang, Juan Huang, Xumin Ou, Di Sun, Bin Tian, Yu He, Zhen Wu, Anchun Cheng

{"title":"The S-Phase Arrest of Host Cells Caused by an Alpha-Herpesvirus Genome Replication Facilitates Viral Recruitment of RNA Polymerase II to Transcribe Viral Genes.","authors":"Qiqi Yang, Ying Wu, Mingshu Wang, Shun Chen, Renyong Jia, Qiao Yang, Dekang Zhu, Mafeng Liu, Xinxin Zhao, Shaqiu Zhang, Juan Huang, Xumin Ou, Di Sun, Bin Tian, Yu He, Zhen Wu, Anchun Cheng","doi":"10.1111/cpr.13811","DOIUrl":"https://doi.org/10.1111/cpr.13811","url":null,"abstract":"Herpesviruses rely on host RNA polymerae II (RNA Pol II) for their mRNA transcription, yet the mechanisms of which has been poorly defined, while certain herpesviruses can enhance viral gene transcription by altering the RNA Pol II location, modulating its phosphorylation, or directly interacting with RNA Pol II. However, the influence of herpesviruses on RNA Pol II transcription extends beyond these direct effects. Here, we present a novel mechanism by which the host cell cycle regulates viral gene transcription via RNA Pol II during infection by Anatid Herpesvirus 1 (AnHV-1), an avian alpha-herpesvirus. The results demonstrated that the formation of viral replication compartments (vRCs) and the subsequent recruitment of RNA pol II are positively correlated with AnHV-1 DNA synthesis. As viral DNA replication progresses, host cells are arrested in the S phase, which not only halts host gene transcription but also facilitates viral transcription. This cell cycle arrest in the S phase promotes viral DNA (vDNA) synthesis and vRC formation, which further enhances the preferential recruitment of RNA Pol II to viral promoters, enabling efficient viral gene transcription. We propose that this S phase arrest and the hijacking of RNA Pol II represent a novel mechanism by which AnHV-1 enhances viral transcription, offering a unique survival strategy compared to the known strategy in herpesviruses. These findings expand our understanding of herpesvirus-host interactions and highlight potential targets for antiviral strategies.","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e13811"},"PeriodicalIF":5.9,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Airway Basal Stem Cells Inflammatory Alterations in COVID-19 and Mitigation by Mesenchymal Stem Cells.

IF 5.9 1区生物学

Cell Proliferation Pub Date : 2025-01-26 DOI: 10.1111/cpr.13812

Sheng Du, Jing Jin, Chunli Tang, Zhuquan Su, Lulin Wang, Xinyuan Chen, Mengni Zhang, Yiping Zhu, Jiaojiao Wang, Chunrong Ju, Xinyu Song, Shiyue Li

{"title":"Airway Basal Stem Cells Inflammatory Alterations in COVID-19 and Mitigation by Mesenchymal Stem Cells.","authors":"Sheng Du, Jing Jin, Chunli Tang, Zhuquan Su, Lulin Wang, Xinyuan Chen, Mengni Zhang, Yiping Zhu, Jiaojiao Wang, Chunrong Ju, Xinyu Song, Shiyue Li","doi":"10.1111/cpr.13812","DOIUrl":"https://doi.org/10.1111/cpr.13812","url":null,"abstract":"SARS-CoV-2 infection and the resultant COVID-19 pneumonia cause significant damage to the airway and lung epithelium. This damage manifests as mucus hypersecretion, pulmonary inflammation and fibrosis, which often lead to long-term complications collectively referred to as long COVID or post-acute sequelae of COVID-19 (PASC). The airway epithelium, as the first line of defence against respiratory pathogens, depends on airway basal stem cells (BSCs) for regeneration. Alterations in BSCs are associated with impaired epithelial repair and may contribute to the respiratory complications observed in PASC. Given the critical role of BSCs in maintaining epithelial integrity, understanding their alterations in COVID-19 is essential for developing effective therapeutic strategies. This study investigates the intrinsic properties of BSCs derived from COVID-19 patients and evaluates the modulatory effects of mesenchymal stem cells (MSCs). Through a combination of functional assessments and transcriptomic profiling, we identified key phenotypic and molecular deviations in COVID-19 patient-derived BSCs, including goblet cell hyperplasia, inflammation and fibrosis, which may underlie their contribution to PASC. Notably, MSC co-culture significantly mitigated these adverse effects, potentially through modulation of the interferon signalling pathway. This is the first study to isolate BSCs from COVID-19 patients in the Chinese population and establish a COVID-19 BSC-based xenograft model. Our findings reveal critical insights into the role of BSCs in epithelial repair and their inflammatory alterations in COVID-19 pathology, with potential relevance to PASC and virus-induced respiratory sequelae. Additionally, our study highlights MSC-based therapies as a promising strategy to address respiratory sequelae and persistent symptoms.","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e13812"},"PeriodicalIF":5.9,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Interaction Between Vasculogenic Mimicry and the Immune System: Mechanistic Insights and Dual Exploration in Cancer Therapy.

IF 5.9 1区生物学

Cell Proliferation Pub Date : 2025-01-26 DOI: 10.1111/cpr.13814

Shutong Liu, Mei Kang, Yuqing Ren, Yuyuan Zhang, Yuhao Ba, Jinhai Deng, Peng Luo, Quan Cheng, Hui Xu, Siyuan Weng, Anning Zuo, Xinwei Han, Zaoqu Liu, Teng Pan, Li Gao

{"title":"The Interaction Between Vasculogenic Mimicry and the Immune System: Mechanistic Insights and Dual Exploration in Cancer Therapy.","authors":"Shutong Liu, Mei Kang, Yuqing Ren, Yuyuan Zhang, Yuhao Ba, Jinhai Deng, Peng Luo, Quan Cheng, Hui Xu, Siyuan Weng, Anning Zuo, Xinwei Han, Zaoqu Liu, Teng Pan, Li Gao","doi":"10.1111/cpr.13814","DOIUrl":"https://doi.org/10.1111/cpr.13814","url":null,"abstract":"Vasculogenic mimicry (VM) represents a novel form of angiogenesis discovered in numerous malignant tumours in recent years. Unlike traditional angiogenesis, VM facilitates tumour blood supply independently of endothelial cells by enabling tumour cells to form functional vascular networks. This phenomenon, where tumour cells replace endothelial cells to form tubular structures, plays a pivotal role in tumour growth and metastasis. Tumour progression is influenced by a variety of factors, including immune components. The immune system serves as a critical defence mechanism by identifying and eliminating abnormal entities, such as tumour cells. This inevitably reminds us of the intricate connection between the immune system and VM. Indeed, in recent years, some studies have shown that immune responses and related immune cells play different regulatory roles in the formation of VM. Therefore, this review provides a comprehensive discussion on the mechanisms underlying VM formation, its interplay with the immune system, and the potential of leveraging immunotherapy to target VM.","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e13814"},"PeriodicalIF":5.9,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tetrahedral Framework Nucleic Acid Relieves Sepsis-Induced Intestinal Injury by Regulating M2 Macrophages.

IF 5.9 1区生物学

Cell Proliferation Pub Date : 2025-01-22 DOI: 10.1111/cpr.13803

Tingting Tan, Jiajie Li, Wensi Fan, Kangni Shang, Chujun Yang, Xiaohao Liu, Shihui Zhu, Tong Liu, Junjie Wang, Yingchuan Li, Yunfeng Lin

{"title":"Tetrahedral Framework Nucleic Acid Relieves Sepsis-Induced Intestinal Injury by Regulating M2 Macrophages.","authors":"Tingting Tan, Jiajie Li, Wensi Fan, Kangni Shang, Chujun Yang, Xiaohao Liu, Shihui Zhu, Tong Liu, Junjie Wang, Yingchuan Li, Yunfeng Lin","doi":"10.1111/cpr.13803","DOIUrl":"https://doi.org/10.1111/cpr.13803","url":null,"abstract":"This study aimed to clarify the role and mechanism of tetrahedral framework nucleic acids (tFNAs) in regulating M2 macrophages to reduce intestinal injury. An intestinal injury model was established by intraperitoneal injection of lipopolysaccharides (LPS) in mice to explore the alleviating effects of tFNAs on intestinal injury. Inflammatory factors were detected by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). The intestinal barrier and permeability were assessed using western blotting and immunohistochemistry. Macrophages in the gut were localised and quantified using immunofluorescence. Western blotting was used to investigate the role and mechanism of tFNAs in regulating macrophages and alleviating inflammation in the injured intestines. These results show that tFNAs attenuated sepsis-induced intestinal injury. tFNAs can also promote the intestinal barrier reconstruction and reduce intestinal permeability. In vivo, tFNAs accelerated the aggregation of M2 macrophages at an early stage of injury and reduced the number of M1 macrophages in the intestine. In addition, tFNAs enhanced the clearance ability of intestinal macrophages. They activated the signalling and transcription activating factor 1(STAT1) and cytokine signalling inhibitory factor 1/3 (SOCS1/3) pathways by increasing the expression of the phagocytic receptor Mertk. These findings indicated that tFNAs can alleviate sepsis-induced intestinal injury by regulating M2 macrophages, providing a new option for treating intestinal injury.","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e13803"},"PeriodicalIF":5.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ovarian Endometrioma Disrupts Oocyte-Cumulus Communication and Mitochondrial Function, With Melatonin Mitigating the Effects. 卵巢子宫内膜瘤破坏卵丘-卵丘通讯和线粒体功能，褪黑激素可减轻影响。

IF 5.9 1区生物学

Cell Proliferation Pub Date : 2025-01-21 DOI: 10.1111/cpr.13800

Lei Ge, Yali Yang, Yuqing Gao, Tianxia Xiao, Wakam Chang, Hefei Wang, Zhonglin Xiao, Jie Chen, Mengxia Li, Ming Yu, Ping Jin, Jian V Zhang

{"title":"Ovarian Endometrioma Disrupts Oocyte-Cumulus Communication and Mitochondrial Function, With Melatonin Mitigating the Effects.","authors":"Lei Ge, Yali Yang, Yuqing Gao, Tianxia Xiao, Wakam Chang, Hefei Wang, Zhonglin Xiao, Jie Chen, Mengxia Li, Ming Yu, Ping Jin, Jian V Zhang","doi":"10.1111/cpr.13800","DOIUrl":"https://doi.org/10.1111/cpr.13800","url":null,"abstract":"Ovarian endometrioma (OEM), a particularly severe form of endometriosis, is an oestrogen-dependent condition often associated with pain and infertility. The mechanisms by which OEM impairs fertility, particularly through its direct impact on oocyte-cumulus cell (CC) communication and related pathways, remain poorly understood. This study investigates the impact of OEM on oocyte-CC communication and explores melatonin's therapeutic potential. We used a mouse model of OEM and employed ovarian transcriptome and gene set enrichment analyses to identify disrupted gene pathways, alongside phalloidin staining for cytoskeletal analysis, gap junction coupling analysis for intercellular communication, and mitochondrial function assessments for cellular metabolism. Our results showed that OEM significantly impairs steroidogenesis and cumulus cell function, leading to increased apoptosis, disrupted transzonal projections (TZPs), and impaired antioxidant transfer to oocytes. This culminates in oxidative stress, mitochondrial dysfunction, and compromised ATP production. OEM oocytes also exhibited severe abnormalities, including DNA damage, maturation defects, spindle assembly disruptions, and increased aneuploidy. This study identifies disrupted TZPs as a key pathological feature in OEM and highlights melatonin's potential to restore intercellular communication, mitigate oxidative damage, and improve reproductive outcomes.","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e13800"},"PeriodicalIF":5.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MUSTN1 Interaction With SMPX Regulates Muscle Development and Regeneration. MUSTN1与SMPX的相互作用调节肌肉发育和再生。

IF 5.9 1区生物学

Cell Proliferation Pub Date : 2025-01-19 DOI: 10.1111/cpr.13809

Yu Fu, Xin Hao, Peng Shang, Jingru Nie, Yangzom Chamba, Bo Zhang, Hao Zhang

{"title":"MUSTN1 Interaction With SMPX Regulates Muscle Development and Regeneration.","authors":"Yu Fu, Xin Hao, Peng Shang, Jingru Nie, Yangzom Chamba, Bo Zhang, Hao Zhang","doi":"10.1111/cpr.13809","DOIUrl":"https://doi.org/10.1111/cpr.13809","url":null,"abstract":"Pigs are important agricultural animals whose growth rate and meat production performance are related to muscle development. Musculoskeletal embryonic nuclear protein 1 (MUSTN1) participates in various biological processes, including myogenesis and growth in animals, but the physiological functions and mechanisms of porcine MUSTN1 on muscle development are unclear; thus, we aimed to elucidate them. We found that MUSTN1 was highly expressed in the muscles of fast-growing pigs. Functionally, MUSTN1 promoted myoblast proliferation and differentiation. MUSTN1 knockout mice exhibited reduced muscle mass and fibre cross-sectional area, decreased exercise endurance, and delayed muscle regeneration. Small muscle protein X-linked (SMPX) was identified as an interacting protein of MUSTN1, and its promotion of myogenic differentiation depended on MUSTN1. Furthermore, MUSTN1 stabilised SMPX and maintained myofiber morphology. This study suggests that MUSTN1 is a critical regulator in the control of muscle development and regeneration and is a potential target for animal genetic improvement and the treatment of human muscle disease.","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e13809"},"PeriodicalIF":5.9,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genome-Wide Screening in Haploid Stem Cells Reveals Synthetic Lethality Targeting MLH1 and TP53 Deficient Tumours. 单倍体干细胞全基因组筛选揭示针对MLH1和TP53缺陷肿瘤的合成致死性

IF 5.9 1区生物学

Cell Proliferation Pub Date : 2025-01-15 DOI: 10.1111/cpr.13788

Rivki Cashman, Guy Haim-Abadi, Elyad Lezmi, Hagit Philip, Jonathan Nissenbaum, Ruth Viner-Breuer, Chen Kozulin, Tamar Golan-Lev, Aseel Gadban, Shiri Spinner-Potesky, Ofra Yanuka, Oded Kopper, Nissim Benvenisty

{"title":"Genome-Wide Screening in Haploid Stem Cells Reveals Synthetic Lethality Targeting MLH1 and TP53 Deficient Tumours.","authors":"Rivki Cashman, Guy Haim-Abadi, Elyad Lezmi, Hagit Philip, Jonathan Nissenbaum, Ruth Viner-Breuer, Chen Kozulin, Tamar Golan-Lev, Aseel Gadban, Shiri Spinner-Potesky, Ofra Yanuka, Oded Kopper, Nissim Benvenisty","doi":"10.1111/cpr.13788","DOIUrl":"https://doi.org/10.1111/cpr.13788","url":null,"abstract":"Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death, whereas each of them separately does not. Synthetic lethality can be a useful tool in personalised oncology. MLH1 is a cancer-related gene that has a central role in DNA mismatch-repair and TP53 is the most frequently mutated gene in cancer. To identify genetic events that can lead to tumour death once either MLH1 or TP53 is mutated, a genome-wide genetic screening was performed. Thus, mutations in all protein-coding genes were introduced into haploid human embryonic stem cells (hESCs) with and without loss-of-function mutations in the MLH1 or TP53 genes. These experiments uncovered a list of putative hits with EXO1, NR5A2, and PLK2 genes for MLH1, and MYH10 gene for TP53 emerging as the most promising candidates. Synthetic lethal interactions of these genes were validated genetically or chemically using small molecules that inhibit these genes. The specific effects of SR1848, which inhibits NR5A2, ON1231320 or BI2536, which inhibits PLK2, and blebbistatin, which inhibits MYH10, were further validated in cancer cell lines. Finally, animal studies with CCL xenografts showed the selective effect of the small molecule BI2536 on MLH1-null tumours and of blebbistatin on TP53-mutated tumours. Thus, demonstrating their potential for personalised medicine, and the robustness of genetic screening in haploid hESCs in the context of cancer therapeutics.","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e13788"},"PeriodicalIF":5.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Single-cell multi-omics deciphers hepatocyte dedifferentiation and illuminates maintenance strategies. 单细胞多组学解释肝细胞去分化和阐明维持策略。

IF 5.9 1区生物学

Cell Proliferation Pub Date : 2025-01-14 DOI: 10.1111/cpr.13772

Jie Hao, Zhenyi Wang, Jilong Ren, Shenghao Cao, Zhongchen Xie, Jinghuan Yang, Jiachen Li, Weizhe Ding, Jie Li, Zhiqiang Han, Ye Yuan, Tang Hai, Sheng Ding, Michael Q Zhang, Minglei Shi

{"title":"Single-cell multi-omics deciphers hepatocyte dedifferentiation and illuminates maintenance strategies.","authors":"Jie Hao, Zhenyi Wang, Jilong Ren, Shenghao Cao, Zhongchen Xie, Jinghuan Yang, Jiachen Li, Weizhe Ding, Jie Li, Zhiqiang Han, Ye Yuan, Tang Hai, Sheng Ding, Michael Q Zhang, Minglei Shi","doi":"10.1111/cpr.13772","DOIUrl":"https://doi.org/10.1111/cpr.13772","url":null,"abstract":"Due to the similarity to human hepatocytes, porcine hepatocytes play an important role in hepatic research and drug evaluation. However, once hepatocytes were cultured in vitro, it was often prone to dedifferentiate, resulting in the loss of their characteristic features and normal functions, which impede their application in liver transplantation and hepatotoxic drugs evaluation. Up to now, this process has yet to be thoroughly investigated from the single-cell resolution and multi-omics perspective. In this study, we utilized 10× multiome technology to dissect the heterogeneity of porcine hepatocytes at different time points (Days 0, 1, 3, 5 and 7) during dedifferentiation. We comprehensively investigated cell heterogeneity, cellular dynamics, signalling pathways, potential gene targets, enhancer-driven gene regulatory networks, cell-cell communications of these cells and the conservation of mechanisms across species. We found that a series of critical signalling pathways driven by ERK, PI3K, Src and TGF-β were activated during this process, especially in the early stage of dedifferentiation. Based on these discoveries, we constructed a chemical combination targeting these pathways, which effectively inhibited the dedifferentiation of porcine hepatocytes in vitro. To validate the effectiveness of this combination, we transplanted such treated hepatocytes into FRGN mice, and the results demonstrated that these cells could effectively repopulate the liver and improve the survival of mice.","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e13772"},"PeriodicalIF":5.9,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0