Hepatology Communications最新文献

{"title":"Mannose reduces fructose metabolism and reverses MASH in human liver slices and murine models in vivo.","authors":"John G Hong, Joshaya Trotman, Yvette Carbajal, Poulomi Dey, Mariel Glass, Victoria Sclar, Isaac L Alter, Peng Zhang, Liheng Wang, Li Chen, Mathieu Petitjean, Dipankar Bhattacharya, Shuang Wang, Scott L Friedman, Charles DeRossi, Jaime Chu","doi":"10.1097/HC9.0000000000000671","DOIUrl":"10.1097/HC9.0000000000000671","url":null,"abstract":"<p><strong>Background: </strong>Fibrosis drives liver-related mortality in metabolic dysfunction-associated steatohepatitis (MASH), yet we have limited medical therapies to target MASH-fibrosis progression. Here we report that mannose, a simple sugar, attenuates MASH steatosis and fibrosis in 2 robust murine models and human liver slices.</p><p><strong>Methods: </strong>The well-validated fat-and-tumor MASH murine model for liver steatosis and fibrosis was employed. Mannose was supplied in the drinking water at the start (\"Prevention\" group) or at week 6 of the 12-week MASH regimen (\"Therapy\" group). The in vivo antifibrotic effects of mannose supplementation were tested in a second model of carbon tetrachloride (CCl4)-induced liver fibrosis. A quantitative and automated digital pathology approach was used to comprehensively assess steatosis and fibrosis phenotypes. Mannose was also tested in vitro in human and primary mouse hepatocytes conditioned with free fatty acids alone or with fructose, and human precision-cut liver slices from patients with end-stage MASH cirrhosis.</p><p><strong>Results: </strong>Oral mannose supplementation improved liver fibrosis in vivo in both fat-and-tumor MASH and CCl4 mouse models, as well as in human precision-cut liver slice MASH samples. Mannose also reduced liver steatosis in fat-and-tumor MASH mice, and in human and mouse hepatocytes in vitro. Ketohexokinase, the main enzyme in fructolysis, was decreased with mannose in whole mouse liver, cultured hepatocytes, and human precision-cut liver slices. Removal of fructose or overexpression of ketohexokinase each abrogated the antisteatotic effects of mannose.</p><p><strong>Conclusions: </strong>This study identifies mannose as a novel therapeutic candidate for MASH that mitigates steatosis by dampening hepatocyte ketohexokinase expression and exerts independent antifibrotic effects in 2 mouse models and human liver tissue slices.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperbilirubinemia at hospitalization predicts nosocomial infection in decompensated cirrhosis: Data from ATTIRE trial.","authors":"Harriett Fuller, Thais H Tittanegro, Alexander A Maini, Louise China, Freya Rhodes, Natalia Becares Salles, Subhankar Mukhopadhyay, Bernadette Moore, Alastair O'Brien","doi":"10.1097/HC9.0000000000000648","DOIUrl":"10.1097/HC9.0000000000000648","url":null,"abstract":"<p><strong>Background: </strong>To identify clinical characteristics and serological biomarkers that predicted subsequent nosocomial infection in ATTIRE trial patients.</p><p><strong>Methods: </strong>We identified 360 patients at hospitalization without infection and not prescribed antibiotics and compared clinical characteristics between those who subsequently developed a nosocomial infection and not. In a 68-patient subcohort, we compared plasma biomarkers of bacterial translocation, infection, and inflammation at hospitalization between those who developed a nosocomial infection and not. In a 56-patient subcohort, we investigated plasma lipidomic profiles in those who did and did not develop nosocomial infection using Lipotype Shotgun platform analysis and multivariate statistical techniques. To further investigate lipid pathways, we compared outcomes in patients taking statins or not at hospitalization.</p><p><strong>Results: </strong>Serum bilirubin >188 µmol/L at hospitalization predicted subsequent nosocomial infection in univariate and multivariate analyses, with 80% specificity. The most common nosocomial infections were respiratory tract (29%) and those developing infection had significantly greater 28 and 90-day mortality than those not (p=9.34E-05 and 0.014). Serological biomarkers of bacterial translocation, infection, and inflammation did not predict subsequent infection. Partial least squares discriminatory analyses identified cholesterol esters (CEs) (CE.18.1.2, CE.18.1.0, and CE.16.0.0) as important predictors of infection but provided only a small improvement in predictive ability over bilirubin alone. RNA-sequencing analyses suggest this is mediated by a downregulation of the cellular cholesterol esterification enzyme sterol O-acyltransferase 1. Statin use was not associated with nosocomial infection prevention.</p><p><strong>Conclusions: </strong>In ATTIRE, elevated serum bilirubin at hospitalization was the only clinical characteristic that predicted subsequent development of nosocomial infection. Considering the rising incidence of antimicrobial resistance, these data could be used to limit antibiotic prophylaxis or aid trial design for investigating use in high-risk patients.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EBV enhances immunotherapy sensitivity in intrahepatic cholangiocarcinoma through cGAS-STING pathway activation.","authors":"Lingli Huang, Qian Zhong, Silan Huang, Kejia Yang, Yuchen Cai, Guifang Guo","doi":"10.1097/HC9.0000000000000674","DOIUrl":"10.1097/HC9.0000000000000674","url":null,"abstract":"<p><strong>Background: </strong>The absence of representative Epstein-Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) cell lines has limited our understanding of the molecular and immunological characteristics of this cancer subtype.</p><p><strong>Methods: </strong>We reviewed patients with metastatic cholangiocarcinoma at Sun Yat-sen University Cancer Center from January 2015 to August 2023. Among them, 22 patients with EBVaICC and 66 patients with non-EBVaICC who received anti-PD1 treatment were included. Additionally, 2 EBV-positive ICC cell lines, RBE-EBV and HuH28-EBV, were developed through cell-to-cell infection. Stable EBV infection and responsiveness to viral reactivation were confirmed. Transcriptomic and bioinformatics analyses were performed, and in vitro experiments examined the immune effects of EBV-positive ICC. Key immune-related genes and cytokines were validated by reverse transcription quantitative polymerase chain reaction and ELISA in cell lines and patient plasma samples.</p><p><strong>Results: </strong>In this study, we found that patients with EBVaICC showed enhanced immune responses and improved overall and progression-free survival compared to patients with non-EBVaICC. We first successfully established and validated 2 EBV-positive ICC cell lines (RBE-EBV and HuH28-EBV). These cell lines were confirmed for stable EBV infection and displayed responsiveness to viral reactivation, making them suitable for future studies. Transcriptomic analyses and in vitro studies revealed that EBV activated the cGAS-STING pathway, resulting in MHC-I upregulation and CXCL10 secretion in ICC cells, which collectively enhanced CD8+ T cell chemotaxis and cytotoxicity. Furthermore, ELISA analysis showed higher plasma levels of CXCL10 and IFN-γ in patients with EBVaICC, suggesting a potential role for EBV in enhancing immunotherapy sensitivity in this subtype.</p><p><strong>Conclusions: </strong>The established EBV-positive ICC cell lines revealed enhanced immunogenicity driven by cGAS-STING pathway activation, providing valuable models for future research and insights into the mechanisms of improved immunotherapy sensitivity in EBVaICC.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amphisome plays a role in HBV production and release through the endosomal and autophagic pathways.","authors":"Jia Li, Thekla Kemper, Ruth Broering, Yong Lin, Xueyu Wang, Mengji Lu","doi":"10.1097/HC9.0000000000000654","DOIUrl":"10.1097/HC9.0000000000000654","url":null,"abstract":"<p><strong>Background: </strong>Autophagic and endosomal pathways coordinately contribute to HBV virions and subviral particles (SVPs) production. To date, limited evidence supports that HBV and exosomes have a common pathway for their biogenesis and secretion. The final steps of HBV production and release have not yet been well studied.</p><p><strong>Methods: </strong>We examined the production and release of HBV virions and SVPs by using GW4869 (N,N'-Bis[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-3,3'-pht hal amide dihydrochloride), a small molecule inhibiting ceramide-mediated inward membrane budding. Neutral sphingomyelinase, the target of GW4869, and RAB27A and -B,  2 small GTPases involved in exosome release control, were silenced using gene silencing to confirm the results obtained. Western blot, immunofluorescence staining, and confocal microscopy were applied.</p><p><strong>Results: </strong>GW4869 inhibited HBV virion release, causing their accumulation along with SVPs in hepatocytes. This triggered cellular endoplasmic reticulum stress, leading to protein kinase B-mechanistic target of rapamycin kinase signaling pathway inactivation. GW4869 treatment increased autophagosome formation and impaired autophagic degradation by blocking autophagosome-lysosome fusion. Consequently, HBsAg is increasingly localized to autophagosomes and late endosomes/multivesicular bodies. Silencing neutral sphingomyelinase yielded consistent results. Similarly, RAB27A silencing inhibited HBV virion and SVP secretion, causing their accumulation within hepatoma cells. Notably, GW4869 treatment, as well as RAB27A and -B silencing, increased the presence of LC3+CD63+HBsAg+ complexes.</p><p><strong>Conclusions: </strong>Our results demonstrate the involvement of the autophagosome-late endosome/multivesicular bodies-exosome axis in regulating HBV production and release, highlighting amphisomes as a potential platform for HBV release.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Second harmonic generation microscopy reveals the spatial orientation of glutamine-potentiated liver regeneration after hepatectomy.","authors":"Chih-Chieh Yen, Chia-Sheng Yen, Hung-Wen Tsai, Matthew M Yeh, Tse-Ming Hong, Wen-Lung Wang, I-Ting Liu, Yan-Shen Shan, Chia-Jui Yen","doi":"10.1097/HC9.0000000000000640","DOIUrl":"10.1097/HC9.0000000000000640","url":null,"abstract":"<p><strong>Background: </strong>Glutamine (Gln) is a critical amino acid for energy expenditure. It participates in extracellular matrix (ECM) formation and circulates in the hepatic parenchyma in a spatial-oriented manner. Posthepatectomy liver mass recovery poses a regenerative challenge. However, little is known about the role of Gln in liver regeneration, notably the spatial orientation in the remodeling process. This study aimed to elucidate Gln-potentiated liver regeneration and ECM remodeling after mass loss.</p><p><strong>Methods: </strong>We studied the regenerative process in hepatectomized mice supplemented with Gln. Second harmonic generation/two-photon excitation fluorescence microscopy, an artificial intelligence-assisted structure-based imaging, was used to demonstrate the spatial-oriented process in a hepatic acinus.</p><p><strong>Results: </strong>Gln promotes liver mass regrowth through the cell cycle, Gln metabolism, and adipogenesis pathways after hepatectomy. Ornithine transaminase, one of the upregulated enzymes, showed temporal, spatial, and functional correspondence with the regeneration process. Second harmonic generation/two-photon excitation fluorescence microscopy highlighted transient hepatic steatosis and ECM collagen synthesis, predominantly in the portal tract instead of the central vein area. Structural remodeling was also observed in the portal tract area.</p><p><strong>Conclusions: </strong>Gln promotes liver regeneration through cellular proliferation and metabolic reprogramming after hepatectomy. Using structure-based imaging, we found that Gln potentiated hepatic steatosis and ECM collagen deposition predominantly in the portal tract area. These results highlighted the spatial orientation and mechanistic implications of Gln in liver regeneration.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling enhanced liver regeneration in ALPPS: Integrating multi-omics profiling and in vivo CRISPR in mouse models.","authors":"Yuan Du, YiHan Yang, YiPeng Zhang, FuYang Zhang, JunJun Wu, JunXiang Yin","doi":"10.1097/HC9.0000000000000630","DOIUrl":"10.1097/HC9.0000000000000630","url":null,"abstract":"<p><strong>Background: </strong>Postoperative liver failure due to insufficient liver cell quantity and function remains a major cause of mortality following surgery. Hence, additional investigation and elucidation are required concerning suitable surgeries for promoting in vivo regeneration.</p><p><strong>Methods: </strong>We established the portal vein ligation (PVL) and associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) mouse models to compare their in vivo regeneration capacity. Then, RNA-seq and microRNA-seq were conducted on the livers from both mouse models. Weighted gene co-expression network analysis algorithm was leveraged to identify crucial gene modules. ScRNA-seq analysis was used to understand the distinctions between Signature30high hepatocytes and Signature30low hepatocytes. Moreover, in vivo, validation was performed in fumarylacetoacetate hydrolase knockout mice with gene editing using the CRISPR-cas9 system. A dual luciferase report system was carried out to further identify the regulatory mechanisms.</p><p><strong>Results: </strong>RNA-seq analysis revealed that ALPPS could better promote cell proliferation compared to the sham and portal vein ligation models. Moreover, a Plk1-related 30-gene signature was identified to predict the cell state. ScRNA-seq analysis confirmed that signature30high hepatocytes had stronger proliferative ability than signature30low hepatocytes. Using microRNA-seq analysis, we identified 53 microRNAs that were time-dependently reduced after ALPPS. Finally, miR-30a-3p might be able to regulate the expression of Plk1, contributing to the liver regeneration of ALPPS.</p><p><strong>Conclusions: </strong>ALPPS could successfully promote liver regeneration by activating hepatocytes into a proliferative state. Moreover, a Plk1-related 30-gene signature was identified to predict the cell state of hepatocytes. miR-30a-3p might be able to regulate the expression of Plk1, contributing to the liver regeneration of ALPPS.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pregnancy and liver-related outcomes after alcohol-associated hepatitis: A global multicenter study.","authors":"Katherine M Cooper, Ami K Patel, Sonali Kaluri, Deepika Devuni","doi":"10.1097/HC9.0000000000000663","DOIUrl":"10.1097/HC9.0000000000000663","url":null,"abstract":"<p><strong>Background: </strong>The incidence of alcohol-associated hepatitis (AH) is rising in women of reproductive age. While the adverse effects of alcohol on pregnancy are well documented, there is limited data on pregnancy in women with a history of AH.</p><p><strong>Methods: </strong>This study was completed by using the TriNetX Research Network. The primary objectives were to evaluate the incidence of pregnancy and related complications in pregnancies following an episode of AH (AH pregnancies) compared to pregnancies in healthy patients (control pregnancies). The secondary objective was to assess long-term liver-related complications and mortality in women with AH who experienced a pregnancy compared to no pregnancy. Propensity score matching was used for comparative analyses to balance cohorts by age, race, ethnicity, prior delivery, and obesity status.</p><p><strong>Results: </strong>The incidence of pregnancy was significantly lower in women with AH compared to controls (26 vs. 54 cases per 1000 person-years, p<0.001). AH pregnancies were associated with higher odds of spontaneous abortion (OR 2.0, 95% CI: 1.2 to 3.3, p=0.011), pre-eclampsia (OR 1.9, 95% CI: 1.1 to 3.0, p=0.002), peri-partum hemorrhage (OR 2.7, 95% CI: 1.3 to 5.6, p=0.007) and perinatal psychiatric disorders (OR 3.2, 95% CI: 1.6 to 6.2, p=0.001). The incidence of cirrhosis and hepatic decompensation were similar between women with AH who experienced a pregnancy compared to no pregnancy, but Kaplan Meier analysis revealed a significantly faster time to event in the no-pregnancy group.</p><p><strong>Conclusions: </strong>Pregnancies following AH diagnosis were associated with adverse pregnancy outcomes. Pregnancy after AH does not reduce the overall risk of developing advanced liver disease but may delay disease progression. These findings highlight the importance of tailored reproductive counseling and support for this population.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Learn, adapt, act: A pragmatic approach for intervening on disparities in hepatocellular carcinoma outcomes.","authors":"Tiana Walker, Lauren D Nephew","doi":"10.1097/HC9.0000000000000665","DOIUrl":"10.1097/HC9.0000000000000665","url":null,"abstract":"","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel KEAP1 inhibitor, tiliroside, activates NRF2 to protect against acetaminophen-induced oxidative stress and acute liver injury.","authors":"Fangfang Cai, Kaiqian Zhou, Peipei Wang, Wen Zhang, Lei Liu, Yunwen Yang","doi":"10.1097/HC9.0000000000000658","DOIUrl":"10.1097/HC9.0000000000000658","url":null,"abstract":"<p><strong>Background: </strong>Acetaminophen-induced acute liver injury (AILI) is one of the common causes of abrupt liver failure in numerous nations. Several previous studies revealed that tiliroside, a glycoside flavonoid, exerts neuroprotective and renal protective effects. However, whether it has hepatoprotective effects is not known. The objective of this research is to examine whether tiliroside can protect against AILI.</p><p><strong>Methods: </strong>AILI mouse and cell models were performed to evaluate the protective effects of tiliroside. Molecular docking, cellular thermal shift assay, immunoprecipitation, and RNA-seq were performed to analyze the possible mechanisms of tiliroside.</p><p><strong>Results: </strong>In vivo, tiliroside attenuated AILI in mice significantly, as evidenced by lower ALT and AST levels. Molecular docking, cellular thermal shift assay, and RNA-seq analysis revealed that tiliroside promoted the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the expression of its downstream genes through disruption of the NRF2-KEAP1 protein-protein interaction to inhibit KEAP1-mediated ubiquitination and degradation of NRF2, thereby inhibiting oxidative stress in the livers of AILI mice. Furthermore, hepatocyte-specific knockout of NRF2 greatly attenuated the hepatic-protective effects of tiliroside in mice. In vitro, tiliroside protected against acetaminophen-induced oxidative stress on cultured hepatocytes through activation of NRF2. In addition, NRF2 knockout markedly blunted the protection effects of tiliroside, suggesting that NRF2 mediates the hepatic-protective effects of tiliroside.</p><p><strong>Conclusions: </strong>Our study demonstrated that tiliroside could protect against AILI by activating the KEAP1/NRF2 pathway, which primarily inhibits the processing of oxidative stress and cell death. Our results suggest that tiliroside could serve as a potential agent for the clinical treatment of AILI.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11868432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative single-cell and spatial transcriptome analysis reveals heterogeneity of human liver progenitor cells.","authors":"Chuanjun Liu, Kai Wang, Junpu Mei, Ruizhen Zhao, Juan Shen, Wei Zhang, Liangyu Li, Bhaskar Roy, Xiaodong Fang","doi":"10.1097/HC9.0000000000000662","DOIUrl":"10.1097/HC9.0000000000000662","url":null,"abstract":"<p><strong>Background: </strong>Liver progenitor cells (LPCs) with bipotential differentiation capacities are essential for restoring liver homeostasis and hepatocyte population after damage. However, the low proportion and shared markers with epithelial cells make studying LPC heterogeneity difficult, especially in humans. To address this gap, we explored over 259,400 human liver single cells across 4 conditions (fetal, healthy, cirrhotic, and HCC-affected livers).</p><p><strong>Methods: </strong>Human liver tissue samples were analyzed using spatial transcriptomics sequencing technologies to describe the heterogeneity of LPCs. Liver tissue was characterized by LPC heterogeneity at single-cell resolution by employing cellular modules, differentiation trajectories, and gene co-expression patterns.</p><p><strong>Results: </strong>We annotated and identified 1 LPC cluster, 3 LPC subpopulations, and 4 distinct cellular modules, indicating the heterogeneity within LPC and the diversity between LPCs and epithelial cells. LPCs showed spatial colocalization with cholangiocytes and comprised a small proportion (2.95±1.91%) within the merged epithelial cells and LPC populations, exhibiting marked differences in marker expression patterns compared to those in mice. LPCs exhibited distinct cellular states in functional restoration, activation, proliferation, and cell transition. Additionally, the gene co-expression network of LPCs exhibited 3 unique modules, reflecting the distinct connectivity of genes encoding apolipoproteins and heat shock proteins in the gene co-expression network modules.</p><p><strong>Conclusions: </strong>Our study provides valuable insights into the multifaceted heterogeneity of human LPCs. Future studies focusing on spatial gene expression dynamics will contribute to our understanding of the spatial arrangement of liver regeneration.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11868439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}