Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells","authors":"Kentaro Tominaga ,&nbsp;Daniel O. Kechele ,&nbsp;J. Guillermo Sanchez ,&nbsp;Simon Vales ,&nbsp;Ingrid Jurickova ,&nbsp;Lizza Roman ,&nbsp;Akihiro Asai ,&nbsp;Jacob R. Enriquez ,&nbsp;Heather A. McCauley ,&nbsp;Keishi Kishimoto ,&nbsp;Kentaro Iwasawa ,&nbsp;Akaljot Singh ,&nbsp;Yuko Horio ,&nbsp;Jorge O. Múnera ,&nbsp;Takanori Takebe ,&nbsp;Aaron M. Zorn ,&nbsp;Michael A. Helmrath ,&nbsp;Lee A. Denson ,&nbsp;James M. Wells","doi":"10.1016/j.jcmgh.2024.101444","DOIUrl":"10.1016/j.jcmgh.2024.101444","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Organs of the gastrointestinal tract contain tissue-resident immune cells that function during tissue development, homeostasis, and disease. However, most published human organoid model systems lack resident immune cells, thus limiting their potential as disease avatars. For example, human intestinal organoids (HIOs) derived from pluripotent stem cells contain epithelial and various mesenchymal cell types but lack immune cells. In this study, we aimed to develop an HIO model with functional tissue-resident macrophages.</div></div><div><h3>Methods</h3><div>HIOs and macrophages were generated separately through the directed differentiation of human pluripotent stem cells and combined in vitro. Following 2 weeks of coculture, the organoids were used for transcriptional profiling, functional analysis of macrophages, or transplanted into immunocompromised mice and matured in vivo for an additional 10–12 weeks.</div></div><div><h3>Results</h3><div>Macrophages were incorporated into developing HIOs and persisted for 2 weeks in vitro HIOs and for at least 12 weeks in HIOs in vivo. These cocultured macrophages had a transcriptional signature that resembled those in the human fetal intestine, indicating that they were acquiring the features of tissue-resident macrophages. HIO macrophages could phagocytose bacteria and produced inflammatory cytokines in response to proinflammatory signals, such as lipopolysaccharide, which could be reversed with interleukin-10.</div></div><div><h3>Conclusions</h3><div>We generated an HIO system containing functional tissue-resident macrophages for an extended period. This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 4","pages":"Article 101444"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mouse Models for Pancreatic Ductal Adenocarcinoma are Affected by the cre-driver Used to Promote KRASG12D Activation","authors":"Fatemeh Mousavi ,&nbsp;Joyce Thompson ,&nbsp;Justine Lau ,&nbsp;Nur Renollet ,&nbsp;Mickenzie B. Martin ,&nbsp;Jake McGue ,&nbsp;Oneeb Hassan ,&nbsp;Timothy Frankel ,&nbsp;Parisa Shooshtari ,&nbsp;Christopher L. Pin ,&nbsp;Filip Bednar","doi":"10.1016/j.jcmgh.2024.101428","DOIUrl":"10.1016/j.jcmgh.2024.101428","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The fundamental biology of pancreatic ductal adenocarcinoma has been greatly impacted by the characterization of genetically engineered mouse models that allow temporal and spatial activation of oncogenic KRAS (KRAS^G12D). One of the most commonly used models involves targeted insertion of a <em>cre</em>-recombinase into the <em>Ptf1a</em> gene. However, this approach disrupts the <em>Ptf1a</em> gene, resulting in haploinsufficiency that likely affects sensitivity to oncogenic KRAS (KRAS^G12D). This study aims to determine if <em>Ptf1a</em> haploinsufficiency affected the acinar cell response to KRAS^G12D before and after induction of pancreatic injury.</div></div><div><h3>Methods</h3><div>We performed morphological and molecular analysis of 3 genetically engineered mouse models that express a tamoxifen-inducible <em>cre</em>-recombinase to activate <em>Kras</em>^{<em>G12D</em>} in acinar cells of the pancreas. The cre-recombinase was targeted to the acinar-specific transcription factor genes, <em>Ptf1a</em> or <em>Mist1/Bhlha15</em>, or expressed within a BAC-derived <em>Elastase</em> transgene. Histological and RNA-seq analyses were used to delineate differences between the models.</div></div><div><h3>Results</h3><div>Up to 2 months after tamoxifen induction of KRAS^G12D, morphological changes were negligible. However, induction of pancreatic injury by cerulein resulted in widespread PanIN lesions in <em>Ptf1a</em>^{<em>creERT</em>} pancreata within 7 days and maintained for at least 5 weeks post-injury, which was not seen in the models with 2 functional <em>Ptf1a</em> alleles. RNA-sequencing analysis prior to injury induction suggested <em>Ptf1a</em>^{<em>creERT</em>} and <em>Mist1</em>^{<em>creERT</em>} mice have unique profiles of gene expression that predict a differential response to injury. Multiplex analysis of pancreatic tissue confirmed different inflammatory responses between the models.</div></div><div><h3>Conclusions</h3><div>These findings suggest <em>Ptf1a</em> haploinsufficiency in <em>Ptf1a</em>^{<em>creERT</em>} mouse models promotes KRAS^G12D priming of genes for promotion of pancreatic ductal adenocarcinoma.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 4","pages":"Article 101428"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytomegalovirus Worsens Necrotizing Enterocolitis Severity in Mice via Increased Toll-Like Receptor 4 Signaling","authors":"Daniel Scheese,&nbsp;Peng Lu,&nbsp;Hannah Moore,&nbsp;Koichi Tsuboi,&nbsp;Cody Tragesser,&nbsp;Johannes Duess,&nbsp;Zachariah Raouf,&nbsp;Maame F. Sampah,&nbsp;Daphne Klerk,&nbsp;Mahmoud El Baassiri,&nbsp;Hee-seong Jang,&nbsp;Sierra Williams-McLeod,&nbsp;Asuka Ishiyama,&nbsp;Steve N. Steinway,&nbsp;Sanxia Wang,&nbsp;Menghan Wang,&nbsp;Thomas Prindle Jr.,&nbsp;William B. Fulton,&nbsp;Chhinder P. Sodhi,&nbsp;David J. Hackam","doi":"10.1016/j.jcmgh.2025.101473","DOIUrl":"10.1016/j.jcmgh.2025.101473","url":null,"abstract":"<div><h3>Background and Aims</h3><div>Necrotizing enterocolitis (NEC) is a life-threatening condition in premature infants, marked by acute intestinal necrosis. NEC develops in part after activation of the lipopolysaccharide receptor toll-like receptor 4 (TLR4) by intestinal microbes in the intestinal epithelium. Previous authors have shown an increased risk of NEC in human infants after cytomegalovirus (CMV) infection, which can affect mitochondrial function. We now seek to explore the impact and the mechanisms of CMV infection on NEC severity and its relationship with TLR4 signaling and mitochondria function.</div></div><div><h3>Methods</h3><div>NEC was induced in newborn mice with and without CMV infection. RNA sequencing and gene set enrichment analysis were performed to identify effects on inflammatory and metabolic pathways. The role of TLR4 signaling and mitochondrial function were investigated in wild-type and <em>Tlr4</em>-deficient mice. The adenosine receptor agonist 5'-N-ethylcarboxamido adenosine was tested for its ability to reduce CMV-induced effects on NEC severity.</div></div><div><h3>Results</h3><div>CMV infection significantly increased NEC severity in wild-type mice. Mechanistically, CMV infection triggered proinflammatory pathways, disrupted cellular metabolism, and upregulated <em>Tlr4</em> expression, leading to mitochondrial dysfunction and nuclear factor-kB translocation. These effects were notably absent in Tlr4-deficient mice. 5'-N-ethylcarboxamido adenosine treatment reversed CMV-induced NEC severity by reducing mitochondrial dysfunction and TLR4-driven nuclear factor-kB activation.</div></div><div><h3>Conclusions</h3><div>CMV infection worsens NEC severity in mice by amplifying TLR4 signaling, inflammation, and mitochondrial dysfunction. Targeting CMV and its influence on TLR4 may offer novel therapeutic approaches for NEC.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 6","pages":"Article 101473"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Attenuating ABHD17 Isoforms Augments the S-acylation and Function of NOD2 and a Subset of Crohn’s Disease-associated NOD2 Variants","authors":"Charneal L. Dixon ,&nbsp;Noah R. Martin ,&nbsp;Micah J. Niphakis ,&nbsp;Benjamin F. Cravatt ,&nbsp;Gregory D. Fairn","doi":"10.1016/j.jcmgh.2025.101491","DOIUrl":"10.1016/j.jcmgh.2025.101491","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>NOD2 is an intracellular innate immune receptor that detects bacterial peptidoglycan fragments. Although nominally soluble, some NOD2 is associated with the plasma membrane and endosomal compartments for microbial surveillance. This membrane targeting is achieved through post-translational <em>S</em>-acylation of NOD2 by the protein acyltransferase ZDHHC5. Membrane attachment is necessary to initiate a signaling cascade in response to cytosolic peptidoglycan fragments. Ultimately, this signaling results in the production of antimicrobial peptides and proinflammatory cytokines. In most cases, <em>S</em>-acylation is a reversible post-translational modification with removal of the fatty acyl chain catalyzed by one of several acyl protein thioesterases. Deacylation of NOD2 by such an enzyme will displace it from the plasma membrane and endosomes, thus preventing signaling.</div></div><div><h3>Methods</h3><div>To identify the enzymes responsible for NOD2 deacylation, we used engineered cell lines with RNA interference and small-molecule inhibitors. These approaches were combined with confocal microscopy, acyl-resin-assisted capture, immunoblotting, and cytokine multiplex assays.</div></div><div><h3>Results</h3><div>We identified <em>α</em>/<em>β</em>-hydrolase domain-containing protein 17 isoforms (ABHD17A, ABHD17B, and ABHD17C) as the acyl protein thioesterases responsible for NOD2 deacylation. Inhibiting ABHD17 increased the plasma membrane localization of wild-type NOD2 and a subset of poorly acylated Crohn’s disease-associated variants. This enhanced NOD2 activity, increasing NF-κB activation and pro-inflammatory cytokine production in epithelial cells.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that ABHD17 isoforms are negative regulators of NOD2. The results also suggest that targeting ABHD17 isoforms could restore functionality to specific Crohn’s disease-associated NOD2 variants, offering a potential therapeutic strategy.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 6","pages":"Article 101491"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover","authors":"","doi":"10.1016/S2352-345X(25)00047-5","DOIUrl":"10.1016/S2352-345X(25)00047-5","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101506"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143825761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aquaporin-7 Deficiency Attenuates Liver Fibrosis by Inhibiting the Activation and Proliferation of Hepatic Stellate Cells","authors":"Junqi Zhang ,&nbsp;Yijun Ma ,&nbsp;Yu Wang ,&nbsp;Chi Zhang ,&nbsp;Peng Chen ,&nbsp;Qing Ye ,&nbsp;Yueyue Lei ,&nbsp;Yanghao Li ,&nbsp;Bo Zhang ,&nbsp;Tonghui Ma","doi":"10.1016/j.jcmgh.2024.101449","DOIUrl":"10.1016/j.jcmgh.2024.101449","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Aquaporin-7 (Aqp7) is an aquaglyceroporin that provides transmembrane gateway of water, glycerol, and hydrogen peroxide (H₂O₂). Analysis of the Gene Expression Omnibus (GEO) database revealed upregulation of hepatic AQP7 expression in liver fibrosis patients. This study aimed to elucidate the role of Aqp7 in the pathogenesis of liver fibrosis.</div></div><div><h3>Methods</h3><div>The GEO database analysis and TGF_β -induced human hepatic stellate cell (HSC) line LX-2 cells were used to study the relevance of AQP7 to human liver fibrosis. Bile duct ligation-induced and carbon tetrachloride-induced liver fibrosis models were employed to investigate the role of Aqp7 in liver fibrosis formation in conventional and HSC-specific Aqp7 knockout mice. Primary mouse HSCs were isolated to explore the role of Aqp7-mediated glycerol and H₂O₂ transport in HSC activation and proliferation.</div></div><div><h3>Results</h3><div>AQP7 mRNA and protein levels are remarkably upregulated in TGF_β-induced LX-2, as well as in primary mouse HSCs isolated from liver fibrosis models induced by bile duct ligation and peritoneal injection of carbon tetrachloride. Liver fibrosis formation was significantly alleviated in both conventional and HSC-specific Aqp7 knockout mice compared with their respective wild-type littermates, as evidenced by significantly decreased deposition of fibrous extracellular matrix. Aqp7 deletion resulted in the accumulation of intracellular glycerol, an increase in triglyceride content, the retention of intracellular lipid droplets, and dilatory activation of HSCs. Moreover, Aqp7 deficiency led to elevated intracellular H₂O₂ levels during activation, which impaired autophagy, proliferation, and survival of HSCs by disrupting relevant cell signaling pathways. Virus-mediated replacement with glycerol- or H₂O₂-transporting aquaporins Aqp3 or Aqp8, but not the strictly water-selective channel Aqp4, effectively rescued the impaired activation and proliferation in primary cultured Aqp7^-/- HSCs.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that Aqp7 plays a crucial role in the activation of HSCs and the formation of liver fibrosis by regulating triglyceride catabolism and maintaining reactive oxygen species homeostasis in HSCs.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101449"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paneth Cells: Dispensable yet Irreplaceable for the Intestinal Stem Cell Niche","authors":"Michaela Quintero ,&nbsp;Linda C. Samuelson","doi":"10.1016/j.jcmgh.2024.101443","DOIUrl":"10.1016/j.jcmgh.2024.101443","url":null,"abstract":"<div><div>Intestinal stem cells replenish the epithelium throughout life by continuously generating intestinal epithelial cell types, including absorptive enterocytes, and secretory goblet, endocrine, and Paneth cells. This process is orchestrated by a symphony of niche factors required to maintain intestinal stem cells and to direct their proliferation and differentiation. Among the various mature intestinal epithelial cell types, Paneth cells are unique in their location in the stem cell zone, directly adjacent to intestinal stem cells. Although Paneth cells were first described as an epithelial cell component of the innate immune system due to their expression of anti-microbial peptides, they have been proposed to be niche cells due to their close proximity to intestinal stem cells and expression of niche factors. However, function as a niche cell has been debated since mice lacking Paneth cells retain functional stem cells that continue to replenish the intestinal epithelium. In this review, we summarize the intestinal stem cell niche, including the Notch, Wnt, growth factor, mechanical, and metabolic niche, and discuss how Paneth cells might contribute to these various components. We also present a nuanced view of the Paneth cell as a niche cell. Although not required, Paneth cells enhance stem cell function, particularly during intestinal development and regeneration. Furthermore, we suggest that Paneth cell loss induces intestinal stem cell remodeling to adjust their niche demands.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 4","pages":"Article 101443"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wall of Resilience: How the Intestinal Epithelium Prevents Inflammatory Onslaught in the Gut","authors":"Eva Liebing ,&nbsp;Susanne M. Krug ,&nbsp;Markus F. Neurath ,&nbsp;Britta Siegmund ,&nbsp;Christoph Becker","doi":"10.1016/j.jcmgh.2024.101423","DOIUrl":"10.1016/j.jcmgh.2024.101423","url":null,"abstract":"<div><div>The intestinal epithelium forms the boundary between the intestinal immune system in the lamina propria and the outside world, the intestinal lumen, which contains a diverse array of microbial and environmental antigens. Composed of specialized cells, this epithelial monolayer has an exceptional turnover rate. Differentiated epithelial cells are released into the intestinal lumen within a few days, at the villus tip, a process that requires strict regulation. Dysfunction of the epithelial barrier increases the intestinal permeability and paves the way for luminal antigens to pass into the intestinal serosa. Stem cells at the bottom of Lieberkühn crypts provide a constant supply of mature epithelial cells. Differentiated intestinal epithelial cells exhibit a diverse array of mechanisms that enable communication with surrounding cells, fortification against microorganisms, and orchestration of nutrient absorption and hormonal balance. Furthermore, tight junctions regulate paracellular permeability properties, and their disruption can lead to an impairment of the intestinal barrier, allowing inflammation to develop or further progress. Intestinal epithelial cells provide a communication platform through which they maintain homeostasis with a spectrum of entities including immune cells, neuronal cells, and connective tissue cells. This homeostasis can be disrupted in disease, such as inflammatory bowel disease. Patients suffering from inflammatory bowel disease show an impaired gut barrier, dysregulated cellular communication, and aberrant proliferation and demise of cells. This review summarizes the individual cellular and molecular mechanisms pivotal for upholding the integrity of the intestinal epithelial barrier and shows how these can be disrupted in diseases, such as inflammatory bowel disease.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101423"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142513556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKMζ: A Brain Kinase Driving Metabolic Reprogramming and Myofibroblastic Differentiation","authors":"Aveline Filliol","doi":"10.1016/j.jcmgh.2024.101437","DOIUrl":"10.1016/j.jcmgh.2024.101437","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101437"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sorafenib Promotes Treg Cell Differentiation To Compromise Its Efficacy via VEGFR/AKT/Foxo1 Signaling in Hepatocellular Carcinoma","authors":"Yingying Shen ,&nbsp;Hanliang Wang ,&nbsp;Zeyu Ma ,&nbsp;Minyan Hao ,&nbsp;Shuowang Wang ,&nbsp;Junwei Li ,&nbsp;Yue Fang ,&nbsp;Lei Yu ,&nbsp;Yingying Huang ,&nbsp;Changrong Wang ,&nbsp;Jingjing Xiang ,&nbsp;Zhijian Cai ,&nbsp;Jianli Wang ,&nbsp;Hongchuan Jin ,&nbsp;Jia Zhou ,&nbsp;Jufeng Guo ,&nbsp;Pingting Ying ,&nbsp;Xian Wang","doi":"10.1016/j.jcmgh.2024.101454","DOIUrl":"10.1016/j.jcmgh.2024.101454","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Sora is the first-line drug for advanced hepatocellular carcinoma (HCC). However, acquired resistance to Sora treatment largely hinders its therapeutic efficacy, and the mechanisms underlying Sora resistance remain poorly understood. Here, we revealed a new mechanism by which Sora promotes the differentiation of regulatory T (Treg) cells to suppress the immune response in the HCC tumor microenvironment (TME) and induce Sora resistance.</div></div><div><h3>Methods</h3><div>Human liver tissues were obtained from HCC patients. Female C57BL/6J, OT-II, and <em>Foxp3</em>^<em>GFP</em> mice were also used. Flow cytometry was used to analyze immune cells in TME. Flow cytometry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay were performed to evaluate Treg cell differentiation. Immunoblotting was conducted to identify relevant proteins. Mouse and human tumor tissues were evaluated via multiplex immunofluorescence staining. Sora-treated HCC tissues and Sora-treated Treg cells were subjected to RNA sequencing analysis. Tumor models were generated and treated with Sora, Sora combined with an anti-CD25 antibody, or Sora combined with the Foxo1 inhibitor AS1842856.</div></div><div><h3>Results</h3><div>First, we found through bioinformatic analysis that Sora suppresses the immune response in HCC. Furthermore, Sora increased the Treg cell population to promote the formation of an immunosuppressive TME in HCC. In vitro, Sora promoted Treg cell differentiation and increased the immunosuppressive activity of Treg cells. Activating VEGF and AKT abolished the effect of Sora on Treg cell differentiation, whereas inhibiting Foxo1 compromised Sora-induced Treg cell differentiation, indicating that the induction of Treg cells by Sora is dependent on the VEGFR/AKT/Foxo1 pathway. Finally, Treg inactivation by an anti-CD25 antibody or the Foxo1 inhibitor AS1842856 in combination with Sora showed greater efficacy in the treatment of HCC.</div></div><div><h3>Conclusions</h3><div>Sora induced Treg cell differentiation by inhibiting VEGFR/AKT signaling and activating Foxo1, thus suppressing the immune response and reducing Sora efficacy. Treg inactivation might be a promising strategy to alleviate the immunosuppressive TME and overcome Sora resistance.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101454"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}