Laboratory Investigation最新文献

{"title":"Age and Hypertension Synergize with Dehydration to Cause Renal Frailty in Rats and Predispose Them to Intrinsic Acute Kidney Injury.","authors":"Noelia Díaz-Morales, Sandra M Sancho-Martínez, Eva M Baranda-Alonso, Isabel Fuentes-Calvo, Rebeca S Sidhu-Muñoz, Nuria Martín-Fernández, Francisco J López-Hernández, Carlos Martínez-Salgado","doi":"10.1016/j.labinv.2024.102211","DOIUrl":"https://doi.org/10.1016/j.labinv.2024.102211","url":null,"abstract":"<p><p>Acute kidney frailty (AKF) is a condition of increased susceptibility to acute kidney injury (AKI), an abrupt impairment of renal excretory function potentially leading to severe complications. Prevention of AKI relies on the recognition of risk factors contributing to AKF. At the population level, dehydration constitutes a predisposing factor for AKI. However, renal frailty may be context-specific, with variations among patients in the types of damage and the distinct pathological mechanisms. In this regard, we studied the combined effect of dehydration with other factors on renal homeostasis, such as increasing age and hypertension. AKF status was studied in rats bearing risk factors individually and in combination and was evaluated as the level of AKI induced by a triggering dose of cisplatin, Which is known to be mildly nephrotoxic for young, healthy rats. AKI was assessed through parameters of renal function (including creatinine, urea, creatinine clearance, proteinuria, and fractional excretion of sodium) and histopathology of renal tissue specimens. The hydration status was measured by bioelectric impedance and other techniques. Water deprivation induces a dehydration state characterized by reductions in body weight and urinary flow and increases in haematocrit and plasma and urine osmolality. Bioelectric impedance showed a net loss of body water after water deprivation with no relevant changes in body mass distribution. Dehydration is not sufficient to predispose young control rats to intrinsic AKI. However, combination of dehydration with advanced age or hypertension induces AKF evidenced by a magnified response of renal dysfunction (reduced filtration and tubular function) and tubular necrosis caused by low dose cisplatin treatment. This study highlights the relevance of addressing AKF as a premorbid condition providing prophylactic opportunities and shows that dehydration differentially predisposes to pre-renal and intrinsic AKI.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"102211"},"PeriodicalIF":5.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829284","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":"Downregulation of MHC-I on melanoma cells and decreased CD8+ T-cell infiltration are associated with metastatic spread and resistance to immunotherapy.","authors":"Miriam Mengoni, Felix Oliver Mahlo, Evelyn Gaffal, Thomas Tüting, Andreas Dominik Braun","doi":"10.1016/j.labinv.2024.102209","DOIUrl":"https://doi.org/10.1016/j.labinv.2024.102209","url":null,"abstract":"<p><p>The success of immune checkpoint inhibitors (ICI) for melanoma therapy has catalyzed the introduction of ICI in increasingly early stages of disease. This exposes many patients with lower risk of relapse to the risk of protracted adverse events, highlighting the need for biomarkers guiding the use of ICI. Already many years ago, brisk infiltration of primary melanomas by lymphocytes has been linked to improved patient outcome, but controversial findings due to a high variability in classification systems have been described. CD8+ T-cells have been identified as a primary mediator of antitumor immunity in patients treated with ICI. As CD8+ T-cells require the presentation of antigen via MHC-I on target cells, downregulation and loss of MHC-I has been observed as resistance mechanisms to ICI. Here, we revisit the role of MHC-I expression and CD8+ T-cell infiltration in melanoma evolution using a cohort of advanced primary and matched metastatic melanomas by using an automated immunohistochemistry and digital pathology workflow. Our results show that downregulation of MHC-I expression is a frequent event in advanced primary melanomas that is associated with decreased CD8+ T cell infiltration and early metastatic spread to sentinel lymph nodes. Furthermore, MHC-I downregulation and decreased infiltration with CD8+ T-cells is also associated with resistance to ICI. Our results suggest that analyses of MHC-I expression and CD8+ T-cell infiltration patterns could serve as future biomarkers to guide the decision to treat patients in early stages of melanoma with ICI.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"102209"},"PeriodicalIF":5.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829286","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":"Diagnosis of fibrotic interstitial lung diseases based on the combination of label-free quantitative multiphoton fiber histology and machine learning.","authors":"Wenzhuo Qiu, Qingyang Wang, Ying Zhang, Xiuxue Cao, Ling Zhao, Longhao Cao, Yuxuan Sun, Feili Yang, Yuanyuan Guo, Yuming Sui, Ziyi Chang, Congcong Wang, Lifang Cui, Yun Niu, Pingping Liu, Jie Lin, Shixuan Liu, Jia Guo, Bei Wang, Ruiqi Zhong, Ce Wang, Wei Liu, Dawei Li, Huaping Dai, Sheng Xie, Heping Cheng, Aimin Wang, Dingrong Zhong","doi":"10.1016/j.labinv.2024.102210","DOIUrl":"https://doi.org/10.1016/j.labinv.2024.102210","url":null,"abstract":"<p><p>Interstitial lung disease (ILD), characterized by inflammation and fibrosis, often suffers from low diagnostic accuracy and consistency. Traditional H&E staining primarily reveals cellular inflammation with limited detail on fibrosis. To address these issues, we introduce a pioneering label-free quantitative multiphoton fiber histology (MPFH) technique that delineates the intricate characteristics of collagen and elastin fibers for ILDs diagnosis. We acquired co-located multiphoton and H&E-stained images from a single tissue slice. Multiphoton imaging was performed on the deparaffinized section to obtain fibrotic tissue information, followed by H&E staining to capture cellular information. This approach was tested in a blinded diagnostic trial among 7 pathologists involving 14 relatively normal lung patients and 31 ILD patients (11 idiopathic pulmonary fibrosis (IPF) / usual interstitial pneumonia (UIP), 14 nonspecific interstitial pneumonia (NSIP), and 6 pleuroparenchymal fibroelastosis (PPFE)). A customized algorithm extracted quantitative fiber indicators from multiphoton images. These indicators, combined with clinical and radiological features, were used to develop an automatic multi-class ILDs classifier. Using MPFH, we can acquire high-quality, co-localized images of collagen fibers, elastin fibers, and cells. We found that the type, distribution, and degree of fibrotic proliferation can effectively distinguish between different subtypes. The blind study showed MPFH enhanced diagnostic consistency (kappa values from 0.56 to 0.72) and accuracy (from 73.0% to 82.5%, p=0.0090). The combination of quantitative fiber indicators effectively distinguished between different tissues, with areas under the receiver operating characteristic curves exceeding 0.92. The automatic classifier achieved 93.8% accuracy, closely paralleling the 92.2% accuracy of expert pathologists. The outcomes of our research underscore the transformative potential of MPFH in the field of f-ILD diagnostics. By integrating quantitative analysis of fiber characteristics with advanced machine learning algorithms, MPFH facilitates the automatic and accurate identification of various fibrotic disease subtypes, showcasing a significant leap forward in precision diagnostics.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"102210"},"PeriodicalIF":5.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829285","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":"Beyond the Bubble: A Debate on microRNA Sorting in Extracellular Vesicles.","authors":"Xiao-Man Liu, Marc K Halushka","doi":"10.1016/j.labinv.2024.102206","DOIUrl":"https://doi.org/10.1016/j.labinv.2024.102206","url":null,"abstract":"<p><p>Over the past decade, a scientific field has developed demonstrating microRNAs are actively sorted into extracellular vesicles via specific nucleotide motifs that interact with discrete RNA-binding proteins. These microRNAs are preferentially transported into recipient cells where they can regulate specific cellular pathways. This mechanism could have enormous potential in explaining how cells signal and regulate other cells nearby or at a distance. Tens of studies have built this theme of a regulated transport of microRNAs. However, some concerns exist about this field. Taken together, there are concerns of a lack of a consistent motif, RNA-binding protein, or preferential microRNA involved in this process. Here we provide expert and extensive analysis of the field that makes the cases for and against an active sorting mechanism. We provide potential explanations on why there is a lack of agreement. Most importantly, we provide ideas on how to move this field forward with more rigor and reproducibility. It is hoped that engaging in a scientific debate of the pros and cons of this field, more rigorous experiments can be performed to conclusively demonstrate this biological activity.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"102206"},"PeriodicalIF":5.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794970","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":"NKX3.1 helps distinguish hyalinizing clear cell carcinoma from other clear cell salivary gland neoplasms.","authors":"Airi Sakyo, Eijitsu Ryo, Shogo Nishino, Kenya Kobayashi, Seiichi Yoshimoto, Go Omura, Chihiro Fushimi, Toshihiko Sakai, Azusa Sakai, Kohtaro Eguchi, Hideaki Takahashi, Kazuki Yokoyama, Yoshitaka Honma, Akiko Mori, Hiroko Kato, Toshiyuki Hatano, Akihiko Yoshida, Fumihiko Matsumoto, Yasushi Yatabe, Taisuke Mori","doi":"10.1016/j.labinv.2024.102205","DOIUrl":"https://doi.org/10.1016/j.labinv.2024.102205","url":null,"abstract":"<p><p>Hyalinized clear cell carcinoma (HCCC) is a rare tumor of the minor salivary gland, characterized by pale cytoplasm and EWSR1::ATF1 fusion. Recently, new fusions such as EWSR1::LARP4 and SMARCA2::CREM have also been identified. Histologically, HCCC closely resembles other salivary gland tumors like mucoepidermoid carcinoma and myoepithelial carcinoma, and there are no specific immunohistological markers for its identification. In this study, we investigated potential markers for HCCC based on the characteristics of minor salivary gland acini, from which these tumors may originate. SOX10 is a known marker for serous gland clusters and NKX3.1 for mucus gland clusters. Fluorescence intensity analysis of double staining, objectively evaluated by AI, revealed variations in the positive intensity of cells single positive for NKX3.1 and SOX10, as well as cells positive for both markers, which are commonly observed in normal minor salivary glands. We evaluated NKX3.1 expression by immunohistochemistry in 12 HCCC cases (including 9 EWSR1::ATF1, one EWSR1::LARP4, and one SMARCA2::CREM), 12 myoepithelial carcinoma cases and Tissue micro array (TMA) containing 88 cases of multiple salivary gland tumors using immunohistochemistry. NKX3.1 was expressed in all 12 HCCC cases (100%), with NKX3.1-positive cells ≧90% in four 3 cases, ≧60% one case, ≧30% five 4 cases, and <30% two 4 cases, respectively. SOX10 was negative in 10 cases and weakly positive in 2 cases. This finding mimics the pattern of expression in minor salivary glands and may explain the occurrence of weak NKX3.1 staining and SOX10 positive cases in HCCC. Additionally, in the TMA analysis, NKX3.1 staining was observed in only one HCCC case. These findings indicate that NKX3.1 is a useful marker for distinguishing HCCC from other clear cell salivary gland neoplasms. This study suggests that NKX3.1, along with SOX10 and CK7, can be utilized to improve the accuracy of HCCC diagnosis.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"102205"},"PeriodicalIF":5.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770136","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":"Comprehensive RNA Sequencing Analysis Identifies Network Hub Genes and Biomarkers Differentiating Desmoid-type Fibromatosis From Reactive Fibrosis.","authors":"Eunjin Jeong, Jamin Ku, Ji Min Na, Wonkyung Kim, Chang Ohk Sung, Seok-Hyung Kim","doi":"10.1016/j.labinv.2024.102204","DOIUrl":"10.1016/j.labinv.2024.102204","url":null,"abstract":"<p><p>Desmoid-type fibromatosis (DTF) is a benign but locally aggressive neoplasm characterized by persistent fibroblast activation, unlike reactive fibrosis (RF), where fibroblast activation is transient. Although the Wnt/β-catenin signaling pathway is known to play a role in DTF pathogenesis, the specific genetic drivers contributing to this abnormal fibroblast activation are not fully understood. To identify additional driver genes that underlie the persistent activation of fibroblasts in DTF, we conducted a comparative transcriptome analysis between 29 DTF and 14 RF tissue samples, identifying 4267 differentially expressed genes (DEGs) specific to DTF. These DTF-specific DEGs were significantly associated with pathways involved in embryonic limb morphogenesis and muscle contraction, whereas RF-specific DEGs were linked to immune response and apoptosis. Using weighted gene coexpression network analysis to further elucidate the key regulatory circuits associated with persistent activation of DTF fibroblasts, we identified a highly DTF-specific gene module comprising 120 genes. This module was also significantly enriched in other fibroproliferative conditions showing persistent fibroblast activation, such as keloid disease and idiopathic pulmonary fibrosis. Subsequent analyses identified 7 driver transcription factors (ZNF536, IRX5, TWIST2, NKD2, PAX9, SHOX2, and SALL4) within this DTF-specific module that may contribute to the sustained activation of DTF fibroblasts. We further assessed the utility of 5 key genes from this module (TWIST2, LRRC15, CTHRC1, SHOX2, and SALL4) as potential biomarkers to distinguish DTF from RF using immunohistochemistry. All markers demonstrated excellent diagnostic performance, with TWIST2 showing exceptionally high sensitivity and specificity, surpassing β-catenin, the current standard biomarker for DTF. In conclusion, our study identifies gene modules and driver transcription factors that are highly specific to DTF, offering new insights into the genetic underpinnings of abnormal fibroblast activation in DTF. We also propose novel biomarkers that could improve the diagnostic accuracy and clinical management of DTF.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"102204"},"PeriodicalIF":5.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770130","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":"The molecular landscape of 227 adult granulosa cell tumors of the ovary: Insights into the progression from primary to recurrence.","authors":"Romana Michálková, Adam Šafanda, Nikola Hájková, Jan Hojný, Eva Krkavcová, Michaela Kendall Bártů, Marián Švajdler, Tetiana Shatokhina, Jan Laco, Radoslav Matěj, Gábor Méhes, Jitka Hausnerová, Jozef Škarda, Mária Hácová, Monika Náležinská, Tomáš Zima, Pavel Dundr, Kristýna Němejcová","doi":"10.1016/j.labinv.2024.102201","DOIUrl":"https://doi.org/10.1016/j.labinv.2024.102201","url":null,"abstract":"<p><p>Adult granulosa cell tumors (AGCTs) of the ovary are characterized by their propensity for late recurrences and are primarily managed surgically due to the limited efficacy of systemic treatment. The FOXL2 p.C134W somatic mutation has been identified in ∼95% of AGCT cases, and TERT promoter alterations have been linked to worse overall survival. This study highlights the potential prognostic significance of FOXO1 mutations, suggesting that they may be associated with poorer overall survival and shorter time to recurrence. A total of 183 primary AGCTs and 44 recurrences without corresponding primary tumors were analyzed. The primary AGCTs were categorized into three groups: 77 non-recurrent tumors, 18 tumors which later recurred (including 9 cases with matched primary-recurrence pairs), and 88 tumors with unknown recurrence status. Targeted next-generation sequencing was conducted on 786 cancer-related genes to investigate their genetic profile. The study aimed to identify the molecular alterations associated with AGCT pathogenesis and recurrence rate, comparing primary vs. recurrent tumors, and primary-recurrent vs. primary non-recurrent cases. Our findings confirmed the high prevalence (99%) of the FOXL2 p.C134W mutation in AGCTs. Secondary truncating FOXL2 mutations were observed in 5% of cases. Two cases with typical AGCT morphology were FOXL2 wild-type, harboring mutations in KRAS or KMT2D instead, suggesting alternative genetic pathways. TERT promoter mutations were found in 43% of cases, more frequently in recurrences. Other recurrent mutations detected in the cohort included KMT2D (10%), FOXO1 (7%), CHEK2 (5%), TP53 (3.5%), PIK3CA (3.5%), and AKT1 (3%). Two recurrent, FOXL2-mutated cases also carried DICER1 mutations. One tumor exhibited MSI-High status and a TMB of 19 mut/Mb. Our results indicate the need for further investigation into the role of FOXO1 as a potential prognostic marker in AGCTs.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"102201"},"PeriodicalIF":5.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770094","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":"HECW1-mediated ubiquitination of HIPK2 drives metastasis in gastric cancer through the AKT signaling pathway.","authors":"Jianfeng Yi, Weilong Qu, Xinkun Huang, Guangze Zhang, Hanxu Gao, Jiancheng He, Wanjiang Xue","doi":"10.1016/j.labinv.2024.102202","DOIUrl":"https://doi.org/10.1016/j.labinv.2024.102202","url":null,"abstract":"<p><p>E3 ubiquitin ligases, crucial enzymes in the ubiquitination pathway, significantly influence the development of malignant tumors, including gastric cancer (GC), by regulating the stability of oncogenic and tumor-suppressive proteins. This study employed bioinformatics analysis of public databases alongside various experimental techniques-tissue arrays, qRT-PCR, Western blot, immunofluorescence, and co-immunoprecipitation-to identify and explore the role of HECW1, a pivotal NEDD4 family E3 ubiquitin ligase, in GC progression. Results demonstrated that HECW1 is markedly overexpressed in GC tissues relative to normal gastric tissues, and its elevated expression correlates with poor prognosis in GC patients. In vitro experiments revealed that HECW1 overexpression significantly enhances the metastatic capabilities of GC cells. Mechanistically, HECW1 interacts with HIPK2 to facilitate its ubiquitination and degradation, thereby activating AKT and promoting the expression of downstream epithelial mesenchymal transition related genes. In vivo experiments confirmed HECW1's role in promoting GC cell metastasis, highlighting the HECW1-HIPK2-AKT signaling axis as critical in GC metastasis. These findings not only elucidate a novel metastasis mechanism of GC but also suggest potential molecular targets for developing new therapeutic strategies against GC.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"102202"},"PeriodicalIF":5.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770132","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":"Annotation practices in computational pathology: a European Society of Digital and Integrative Pathology (ESDIP) survey study.","authors":"Diana Montezuma, Sara P Oliveira, Yuri Tolkach, Peter Boor, Alex Haragan, Rita Carvalho, Vincenzo Della Mea, Tim-Rasmus Kiehl, Sabine Leh, Mustafa Yousif, David Ameisen, Mircea-Sebastian Șerbănescu, Norman Zerbe, Vincenzo L'Imperio","doi":"10.1016/j.labinv.2024.102203","DOIUrl":"https://doi.org/10.1016/j.labinv.2024.102203","url":null,"abstract":"<p><p>Integrating digital pathology (DP) and artificial intelligence (AI) algorithms can potentially improve diagnostic practice and precision medicine. Developing reliable, generalizable, and comparable AI algorithms depends on access to meticulously annotated data. However, achieving this requires robust collaboration among pathologists, computer scientists and other researchers to ensure data quality and consistency. The lack of standardization and scalability is a significant challenge when generating annotations and annotated datasets. Recognizing these limitations, the Scientific Committee of the European Society of Digital and Integrative Pathology (ESDIP) performed a comprehensive international survey to understand the current state of annotation practices and identify actionable areas to address critical needs in the annotation process. The analysis and summary of the survey results provide several insights for all stakeholders involved in data preparation and ground-truthing, ultimately contributing to the advancement of AI in computational pathology.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"102203"},"PeriodicalIF":5.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769990","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":"Dysregulated Activation of Hippo-YAP1 Signaling Induces Oxidative Stress and Aberrant Development of Intrahepatic Biliary Cells in Biliary Atresia.","authors":"Hua Xie, Zhongxian Zhu, Jiaqi Tang, Wei Zhu, Mengyan Zhu, Amy Wing Yi Wai, Junzhi Li, Zhongluan Wu, Paul Kwong Hang Tam, Vincent Chi Hang Lui, Weibing Tang","doi":"10.1016/j.labinv.2024.102199","DOIUrl":"10.1016/j.labinv.2024.102199","url":null,"abstract":"<p><p>The canonical Hippo-YAP1 signaling pathway is crucial for liver development and regeneration, but its role in repair and regeneration of intrahepatic bile duct in biliary atresia (BA) remains largely unknown. YAP1 expression in the liver tissues of patients with BA and Rhesus rotavirus-induced experimental BA mouse models were examined using quantitative reverse transcriptase-PCR and double immunofluorescence. Mouse EpCAM-expressing cell-derived liver organoids were generated and treated with Hippo-YAP1 pathway activators (Xmu-mp-1 and TRULI) or an inhibitor (Peptide17). Morphologic, immunofluorescence, RNA-seq, and bioinformatic analyses were performed. Oxidative stress in human intrahepatic biliary epithelial cells transfected with a constitutively active YAP1 (YAPS127A) plasmid was assessed using quantitative reverse transcriptase-PCR and fluorescence-activated cell sorting analysis. PRDX1 expression in BA and experimental BA mouse model livers was examined by double immunofluorescence. The mRNA expression and nuclear localization of YAP1 in EpCAM-expressing bile duct cells were increased in the livers of BA and experimental BA mouse model. Aberrant development of intrahepatic organoids, differential expression of oxidative stress response genes Sod3 and Prdx1, enrichment of oxidative stress, and mitochondrial reactive oxidative stress-associated gene sets were observed in organoids treated with the Hippo-YAP1 activator, whereas organoid development was unaffected by the addition of the Hippo-YAP1 inhibitor. Transfection with constitutively active YAP1 led to the downregulation of PRDX1 and oxidative stress in human intrahepatic biliary epithelial cells. Additionally, reduced PRDX1 expression was also observed in the bile duct of human BA and experimental BA mouse livers. In conclusion, dysregulated activation of Hippo-YAP1 signaling induces oxidative stress and impairs the development of intrahepatic biliary organoids, which indicates therapeutic strategies targeting Hippo-YAP1 signaling may offer the potential to improve biliary repair and regeneration in patients with BA.</p>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":" ","pages":"102199"},"PeriodicalIF":5.1,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695448","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}