Pub Date : 2025-01-01DOI: 10.1016/j.jcmgh.2024.101419
Meng Xu, Diego F. Calvisi, Xin Chen
{"title":"Splicing, Signaling, and Survival: The Role of RBM39 in Cholangiocarcinoma Progression","authors":"Meng Xu, Diego F. Calvisi, Xin Chen","doi":"10.1016/j.jcmgh.2024.101419","DOIUrl":"10.1016/j.jcmgh.2024.101419","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 1","pages":"Article 101419"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570578","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}
Pub Date : 2025-01-01DOI: 10.1016/S2352-345X(25)00008-6
{"title":"Cover","authors":"","doi":"10.1016/S2352-345X(25)00008-6","DOIUrl":"10.1016/S2352-345X(25)00008-6","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101467"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403268","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jcmgh.2024.101430
Jia Ming Nickolas Teo, Guang Sheng Ling
{"title":"Sphingosine Kinase 1 – A Therapeutic Opportunity for Alleviating Liver Fibrosis?","authors":"Jia Ming Nickolas Teo, Guang Sheng Ling","doi":"10.1016/j.jcmgh.2024.101430","DOIUrl":"10.1016/j.jcmgh.2024.101430","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101430"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793096","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jcmgh.2024.101425
Atehkeng Zinkeng , F. Lloyd Taylor , Samuel H. Cheong , Heyu Song , Juanita L. Merchant
The onset of colorectal cancer (CRC) in patients younger than 50 continues to rapidly increase. This study highlights the epidemiologic changes, risk factors, clinical characteristics, and molecular profiles prevalent in early onset CRC patients, and identifies key areas for future research. It has been noted that only a small fraction of early onset CRC cases is attributed to known hereditary mutations and fit the canonical pathway of late-onset colorectal cancer development. To highlight this, we review the genetic and epigenetic modifications specific to early onset CRC. We also discuss the synergetic effect of single-nucleotide polymorphisms and environmental factors on the early onset of CRC. Additionally, we discuss the potential of noninvasive biomarker assays to enhance early detection, screening, diagnosis, and prognostic outcome predictions.
{"title":"Early Onset Colorectal Cancer: Molecular Underpinnings Accelerating Occurrence","authors":"Atehkeng Zinkeng , F. Lloyd Taylor , Samuel H. Cheong , Heyu Song , Juanita L. Merchant","doi":"10.1016/j.jcmgh.2024.101425","DOIUrl":"10.1016/j.jcmgh.2024.101425","url":null,"abstract":"<div><div>The onset of colorectal cancer (CRC) in patients younger than 50 continues to rapidly increase. This study highlights the epidemiologic changes, risk factors, clinical characteristics, and molecular profiles prevalent in early onset CRC patients, and identifies key areas for future research. It has been noted that only a small fraction of early onset CRC cases is attributed to known hereditary mutations and fit the canonical pathway of late-onset colorectal cancer development. To highlight this, we review the genetic and epigenetic modifications specific to early onset CRC. We also discuss the synergetic effect of single-nucleotide polymorphisms and environmental factors on the early onset of CRC. Additionally, we discuss the potential of noninvasive biomarker assays to enhance early detection, screening, diagnosis, and prognostic outcome predictions.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101425"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607582","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jcmgh.2024.101434
Kodisundaram Paulrasu , Ravindran Caspa Gokulan , Wael El-Rifai , Zhibin Chen , Jianwen Que , Timothy C. Wang , Olivier G. Boutaud , Karoline Briegel , Sergey I. Dikalov , Monica T. Garcia-Buitrago , Alexander I. Zaika
Background & aims
Gastroesophageal reflux disease (GERD) is a common digestive disorder that is characterized by esophageal tissue damage produced by exposure of the esophageal lining to the gastric refluxate. GERD can raise the risk of multiple serious complications including esophageal tumors. At the molecular levels, GERD-affected tissues are characterized by strong oxidative stress and the formation of reactive isolevuglandins (isoLGs). These products of lipid peroxidation rapidly interact with cellular proteins forming protein adducts. Here, we investigated the interrelationship between isoLG adduction and aggregation of cellular proteins.
Methods
Protein misfolding and aggregation were analyzed using multiple protein misfolding and aggregation assays. Pathologic consequences of protein adduction and aggregation were studied using human and murine esophageal tissues. Surgical model of esophageal reflux injury and L2-IL1β transgenic mice were used to investigate the mechanisms of protein misfolding and aggregation.
Results
Our studies demonstrate that gastroesophageal reflux causes protein misfolding and aggregation that is associated with severity of GERD. Dysregulation of proteostasis induces ferroptotic cell death and is mediated by modification of cellular proteins with reactive isoLGs that can be prevented by isoLG scavengers.
Conclusions
GERD causes dysregulation of cellular proteostasis, accumulation of isoLG protein adducts, misfolded, and aggregated proteins that promote ferroptotic cell death. Taken together, this study suggests that GERD has similarities to other known pathologic conditions that are characterized by protein misfolding and aggregation.
背景和目的：胃食管反流病（GERD）是一种常见的消化系统疾病，其特征是食管内膜暴露于胃反流物而导致食管组织损伤。反流可增加包括食管肿瘤在内的多种严重并发症的风险。在分子水平上，受gerd影响的组织表现为强烈的氧化应激和反应性异重素（isolg）的形成。这些脂质过氧化的产物迅速与细胞蛋白相互作用，形成蛋白质加合物。在这里，我们研究了isoLG内聚和细胞蛋白聚集之间的相互关系。方法：采用多种蛋白质错误折叠和聚集试验分析蛋白质错误折叠和聚集。用人和鼠食管组织研究了蛋白质内聚和聚集的病理后果。采用食管反流损伤手术模型和l2 - il - 1β转基因小鼠研究其蛋白错误折叠和聚集的机制。结果：我们的研究表明，胃食管反流导致蛋白质错误折叠和聚集，这与胃食管反流的严重程度有关。蛋白质平衡失调可诱导铁致细胞死亡，并通过反应性isoLG修饰细胞蛋白介导，而这种修饰可被isoLG清除剂阻止。结论：胃食管反流导致细胞蛋白平衡失调，isoLG蛋白加合物的积累，错误折叠和聚集的蛋白促进了铁致细胞死亡。综上所述，本研究表明GERD与其他已知的以蛋白质错误折叠和聚集为特征的病理状况相似。
{"title":"Chronic Gastroesophageal Reflux Dysregulates Proteostasis in Esophageal Epithelial Cells","authors":"Kodisundaram Paulrasu , Ravindran Caspa Gokulan , Wael El-Rifai , Zhibin Chen , Jianwen Que , Timothy C. Wang , Olivier G. Boutaud , Karoline Briegel , Sergey I. Dikalov , Monica T. Garcia-Buitrago , Alexander I. Zaika","doi":"10.1016/j.jcmgh.2024.101434","DOIUrl":"10.1016/j.jcmgh.2024.101434","url":null,"abstract":"<div><h3>Background & aims</h3><div>Gastroesophageal reflux disease (GERD) is a common digestive disorder that is characterized by esophageal tissue damage produced by exposure of the esophageal lining to the gastric refluxate. GERD can raise the risk of multiple serious complications including esophageal tumors. At the molecular levels, GERD-affected tissues are characterized by strong oxidative stress and the formation of reactive isolevuglandins (isoLGs). These products of lipid peroxidation rapidly interact with cellular proteins forming protein adducts. Here, we investigated the interrelationship between isoLG adduction and aggregation of cellular proteins.</div></div><div><h3>Methods</h3><div>Protein misfolding and aggregation were analyzed using multiple protein misfolding and aggregation assays. Pathologic consequences of protein adduction and aggregation were studied using human and murine esophageal tissues. Surgical model of esophageal reflux injury and L2-IL1β transgenic mice were used to investigate the mechanisms of protein misfolding and aggregation.</div></div><div><h3>Results</h3><div>Our studies demonstrate that gastroesophageal reflux causes protein misfolding and aggregation that is associated with severity of GERD. Dysregulation of proteostasis induces ferroptotic cell death and is mediated by modification of cellular proteins with reactive isoLGs that can be prevented by isoLG scavengers.</div></div><div><h3>Conclusions</h3><div>GERD causes dysregulation of cellular proteostasis, accumulation of isoLG protein adducts, misfolded, and aggregated proteins that promote ferroptotic cell death. Taken together, this study suggests that GERD has similarities to other known pathologic conditions that are characterized by protein misfolding and aggregation.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101434"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788019","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jcmgh.2024.101441
Kim E. Barrett
{"title":"New Molecular Player In Colitis and Colitis-Associated Cancer","authors":"Kim E. Barrett","doi":"10.1016/j.jcmgh.2024.101441","DOIUrl":"10.1016/j.jcmgh.2024.101441","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101441"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886517","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jcmgh.2024.101445
David H. Wang
{"title":"Dysregulated Proteostasis-induced Ferroptosis in Gastroesophageal Reflux Disease: Hero or Villain?","authors":"David H. Wang","doi":"10.1016/j.jcmgh.2024.101445","DOIUrl":"10.1016/j.jcmgh.2024.101445","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101445"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907896","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jcmgh.2024.101444
Kentaro Tominaga , Daniel O. Kechele , J. Guillermo Sanchez , Simon Vales , Ingrid Jurickova , Lizza Roman , Akihiro Asai , Jacob R. Enriquez , Heather A. McCauley , Keishi Kishimoto , Kentaro Iwasawa , Akaljot Singh , Yuko Horio , Jorge O. Múnera , Takanori Takebe , Aaron M. Zorn , Michael A. Helmrath , Lee A. Denson , James M. Wells
Background & Aims
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.
Methods
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.
Results
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.
Conclusions
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.
{"title":"Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells","authors":"Kentaro Tominaga , Daniel O. Kechele , J. Guillermo Sanchez , Simon Vales , Ingrid Jurickova , Lizza Roman , Akihiro Asai , Jacob R. Enriquez , Heather A. McCauley , Keishi Kishimoto , Kentaro Iwasawa , Akaljot Singh , Yuko Horio , Jorge O. Múnera , Takanori Takebe , Aaron M. Zorn , Michael A. Helmrath , Lee A. Denson , James M. Wells","doi":"10.1016/j.jcmgh.2024.101444","DOIUrl":"10.1016/j.jcmgh.2024.101444","url":null,"abstract":"<div><h3>Background & 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}
Pub Date : 2025-01-01DOI: 10.1016/j.jcmgh.2024.101411
Chao Gao , Shiguan Wang , Xiaoyu Xie , Pierluigi Ramadori , Xinying Li , Xiaoyu Liu , Xue Ding , Jinyuan Liang , Bowen Xu , Yawei Feng , Xueying Tan , Haoran Wang , Yan Zhang , Haiyan Zhang , Tingguo Zhang , Ping Mi , Shiyang Li , Cuijuan Zhang , Detian Yuan , Mathias Heikenwalder , Peng Zhang
Background & Aims
The immunological mechanisms underpinning the pathogenesis of alcoholic-associated liver disease (ALD) remain incompletely elucidated. This study aims to explore the transcriptomic profiles of hepatic immune cells in ALD compared with healthy individuals and those with metabolic dysfunction-associated steatotic liver disease (MASLD).
Methods
We utilized single-cell RNA sequencing to analyze liver samples from healthy subjects and patients with MASLD and ALD, focusing on the immune cell landscapes within the liver. Key alterations in immune cell subsets were further validated using liver biopsy samples from additional patient cohorts.
Results
We observed a significant accumulation of CD4+ T cells in livers of patients with ALD, surpassing the prevalence of CD8+ T cells, in contrast to patients with MASLD and healthy counterparts, whereas natural killer (NK) cells and γδT cells exhibited reduced intrahepatic infiltration. In-depth transcriptional and developmental trajectory analyses unveiled that a distinct CD4+ subset characterized by granzyme K (GZMK) expression, displaying a tissue-resident signature and terminal effector state, prominently enriched among CD4+ T cells infiltrating the livers of patients with ALD. Subsequent examination of an independent ALD patient cohort corroborated the substantial enrichment of GZMK+CD4+ T lymphocytes, primarily within liver fibrotic zones, suggesting their potential involvement in disease progression. Additionally, we noted shifts in myeloid populations, with expanded APOE+ macrophage and FCGR3B+ monocyte subsets in ALD samples relative to MASLD and healthy tissues.
Conclusions
In summary, this study unravels the intricate cellular diversity within hepatic immune cell populations, highlighting the pivotal immune pathogenic role of the GZMK+CD4+ T lymphocyte subset in ALD pathogenesis.
背景与目的：酒精相关性肝病（ALD）发病机制的免疫学机制仍未完全阐明。本研究旨在探索与健康人和代谢功能障碍相关性脂肪性肝病（MASLD）患者相比，ALD患者肝脏免疫细胞的转录组特征：我们利用单细胞 RNA 测序技术分析了健康人、MASLD 和 ALD 患者的肝脏样本，重点研究了肝脏内的免疫细胞景观。利用其他患者队列的肝活检样本进一步验证了免疫细胞亚群的关键改变：结果：我们观察到 ALD 患者肝脏中 CD4+ T 细胞明显增多，超过了 CD8+ T 细胞的数量，这与 MASLD 和健康患者形成了鲜明对比，而自然杀伤（NK）细胞和 γδT 细胞的肝内浸润则有所减少。深入的转录和发育轨迹分析揭示了一种以颗粒酶K（GZMK）表达为特征的独特CD4+亚群，该亚群显示出组织驻留特征和终末效应状态，在ALD患者肝脏浸润的CD4+T细胞中明显富集。随后对一个独立的 ALD 患者队列进行的检查证实了 GZMK+CD4+ T 淋巴细胞的大量富集，主要是在肝纤维化区，这表明它们可能参与了疾病的进展。此外，我们还注意到髓系细胞群的变化，ALD样本中的APOE+巨噬细胞和FCGR3B+单核细胞亚群相对于MASLD和健康组织有所扩大：总之，本研究揭示了肝脏免疫细胞群中错综复杂的细胞多样性，突出了GZMK+CD4+ T淋巴细胞亚群在ALD发病机制中的关键免疫致病作用。
{"title":"Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4+ T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver Diseases","authors":"Chao Gao , Shiguan Wang , Xiaoyu Xie , Pierluigi Ramadori , Xinying Li , Xiaoyu Liu , Xue Ding , Jinyuan Liang , Bowen Xu , Yawei Feng , Xueying Tan , Haoran Wang , Yan Zhang , Haiyan Zhang , Tingguo Zhang , Ping Mi , Shiyang Li , Cuijuan Zhang , Detian Yuan , Mathias Heikenwalder , Peng Zhang","doi":"10.1016/j.jcmgh.2024.101411","DOIUrl":"10.1016/j.jcmgh.2024.101411","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The immunological mechanisms underpinning the pathogenesis of alcoholic-associated liver disease (ALD) remain incompletely elucidated. This study aims to explore the transcriptomic profiles of hepatic immune cells in ALD compared with healthy individuals and those with metabolic dysfunction-associated steatotic liver disease (MASLD).</div></div><div><h3>Methods</h3><div>We utilized single-cell RNA sequencing to analyze liver samples from healthy subjects and patients with MASLD and ALD, focusing on the immune cell landscapes within the liver. Key alterations in immune cell subsets were further validated using liver biopsy samples from additional patient cohorts.</div></div><div><h3>Results</h3><div>We observed a significant accumulation of CD4<sup>+</sup> T cells in livers of patients with ALD, surpassing the prevalence of CD8<sup>+</sup> T cells, in contrast to patients with MASLD and healthy counterparts, whereas natural killer (NK) cells and γδT cells exhibited reduced intrahepatic infiltration. In-depth transcriptional and developmental trajectory analyses unveiled that a distinct CD4<sup>+</sup> subset characterized by granzyme K (GZMK) expression, displaying a tissue-resident signature and terminal effector state, prominently enriched among CD4<sup>+</sup> T cells infiltrating the livers of patients with ALD. Subsequent examination of an independent ALD patient cohort corroborated the substantial enrichment of GZMK<sup>+</sup>CD4<sup>+</sup> T lymphocytes, primarily within liver fibrotic zones, suggesting their potential involvement in disease progression. Additionally, we noted shifts in myeloid populations, with expanded APOE<sup>+</sup> macrophage and FCGR3B<sup>+</sup> monocyte subsets in ALD samples relative to MASLD and healthy tissues.</div></div><div><h3>Conclusions</h3><div>In summary, this study unravels the intricate cellular diversity within hepatic immune cell populations, highlighting the pivotal immune pathogenic role of the GZMK<sup>+</sup>CD4<sup>+</sup> T lymphocyte subset in ALD pathogenesis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101411"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333076","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jcmgh.2024.101424
Callie E. Scull , Yawen Hu , Scott Jennings, Guoshun Wang
Background & Aims
Cystic fibrosis (CF) is an autosomal recessive genetic disorder, affecting multiple organ systems. CF intestinal disease develops early, manifesting as intestinal bacterial overgrowth/dysbiosis, neutrophilic inflammation, and obstruction. As unresolvable infection and inflammation reflect host immune deficiency, we sought to determine if the CF-affected immune system plays any significant role in CF intestinal disease pathogenesis.
Methods
CF and sibling wild-type (WT) mice underwent reciprocal bone marrow transplantation. After immune reconstitution, their mortality, intestinal transit, fecal inflammatory markers, and mucosal immune cell composition were assessed. Moreover, reciprocal neutrophil transfusion was conducted to determine if neutrophil function affects intestinal movement. Furthermore, expression of induced nitric oxide synthase (iNOS) and production of nitric oxide (NO) in CF and WT neutrophils were compared. Lastly, specific iNOS inhibitor 1400W was tested to prevent CF intestinal obstruction.
Results
Immune restoration in CF mice reversed the intestinal neutrophilic inflammation, improved the intestinal dysmotility, and rescued the mice from mortality. Transfusion of WT neutrophils into CF mice ameliorated the retarded bowel movement. CF neutrophils expressed significantly more iNOS and produced significantly more NO. Pharmaceutical blocking of iNOS significantly improved intestinal transit and survival of CF mice.
Conclusions
CF immune defect plays a critical role in CF intestinal disease development. Activation of iNOS in inflammatory cells produces excessive NO, slows the bowel movement, and facilitates intestinal paralysis and obstruction in CF. Thus, normalization of the CF immune system may offer a novel therapy to treat CF intestinal disease.
{"title":"Normalization of Cystic Fibrosis Immune System Reverses Intestinal Neutrophilic Inflammation and Significantly Improves the Survival of Cystic Fibrosis Mice","authors":"Callie E. Scull , Yawen Hu , Scott Jennings, Guoshun Wang","doi":"10.1016/j.jcmgh.2024.101424","DOIUrl":"10.1016/j.jcmgh.2024.101424","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Cystic fibrosis (CF) is an autosomal recessive genetic disorder, affecting multiple organ systems. CF intestinal disease develops early, manifesting as intestinal bacterial overgrowth/dysbiosis, neutrophilic inflammation, and obstruction. As unresolvable infection and inflammation reflect host immune deficiency, we sought to determine if the CF-affected immune system plays any significant role in CF intestinal disease pathogenesis.</div></div><div><h3>Methods</h3><div>CF and sibling wild-type (WT) mice underwent reciprocal bone marrow transplantation. After immune reconstitution, their mortality, intestinal transit, fecal inflammatory markers, and mucosal immune cell composition were assessed. Moreover, reciprocal neutrophil transfusion was conducted to determine if neutrophil function affects intestinal movement. Furthermore, expression of induced nitric oxide synthase (iNOS) and production of nitric oxide (NO) in CF and WT neutrophils were compared. Lastly, specific iNOS inhibitor 1400W was tested to prevent CF intestinal obstruction.</div></div><div><h3>Results</h3><div>Immune restoration in CF mice reversed the intestinal neutrophilic inflammation, improved the intestinal dysmotility, and rescued the mice from mortality. Transfusion of WT neutrophils into CF mice ameliorated the retarded bowel movement. CF neutrophils expressed significantly more iNOS and produced significantly more NO. Pharmaceutical blocking of iNOS significantly improved intestinal transit and survival of CF mice.</div></div><div><h3>Conclusions</h3><div>CF immune defect plays a critical role in CF intestinal disease development. Activation of iNOS in inflammatory cells produces excessive NO, slows the bowel movement, and facilitates intestinal paralysis and obstruction in CF. Thus, normalization of the CF immune system may offer a novel therapy to treat CF intestinal disease.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101424"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607586","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号