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Thurner A, Dalla Torre G, Hartung V, Kickuth R. A biodegradable polymer plug for liver tract embolization after percutaneous or surgical placement of transhepatic biliary drainage tubes: a feasibility study. ROFO-FORTSCHR RONTG 2025. [PMID: 39824210 DOI: 10.1055/a-2509-5189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2025]
Abstract
To evaluate the feasibility of liver tract embolization after transhepatic biliary drainage using a biodegradable polymer plug (IMPEDE-FX, Shape Memorial Medical, Santa Clara, CA, USA).In a retrospective observational study, 15 plug embolizations were performed in 13 patients at risk for tract-related adverse events (AEs). Risk factors included coagulopathy, cirrhosis, central bile duct puncture, previous drain-related bleeding, malignant obstruction, large tract diameter, or multilevel strictures. Clinical and imaging follow-up was performed at 24 hours, 3 months, and 6 months. Primary endpoints were technical and clinical success. Technical success was defined as plug deployment in the intended position. Clinical success was defined as the absence of biliary, infectious, or bleeding AEs. To assess clinically occult bleeding or biliary obstruction, periprocedural hemoglobin, hematocrit, and bilirubin levels were compared. Secondary endpoints were plug migration, plug oversizing, and plug visibility on imaging.The technical success rate was 100%. The clinical success rate was 84.6%. There were no infectious or bleeding AEs. In 2 cases where the persistence of biliary congestion was clinically underestimated prior to drain removal, 2 biliary AEs occurred (2 biliocutaneous fistulas including 1 plug migration within 24 hours; 15.4% SIR grade 3 AEs). The median plug oversizing relative to the diameter of the hepatic tract was substantially lower in unsuccessful cases than in successful cases (27% vs. 86%). The plug was visible on ultrasound and CT. On MRI, no plug-related artifacts occurred.The plug could be an option when a non-permanent, precisely deployable device is desired for tract embolization. Adequate plug-to-tract oversizing and biliary decongestion are essential to achieve durable tract closure. Therefore, the plug seems unsuitable for patients with multilevel strictures where complete drainage of the biliary system is not feasible. · The polymer plug can be precisely delivered within the liver tract.. · Plug-to-tract oversizing and biliary decongestion are essential for durable tract closure.. · The plug appears unsuitable for endoscopically incompletely relievable multilevel biliary strictures.. · Thurner A, Giulia Dalla G, Hartung V et al. A biodegradable polymer plug for liver tract embolization after percutaneous or surgical placement of transhepatic biliary drainage tubes: a feasibility study. Rofo 2025; DOI 10.1055/a-2509-5189.
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Affiliation(s)
- Annette Thurner
- Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, Würzburg, Germany
| | - Giulia Dalla Torre
- Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, Würzburg, Germany
| | - Viktor Hartung
- Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, Würzburg, Germany
| | - Ralph Kickuth
- Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, Würzburg, Germany
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Yan J, Ye Z, Wang X, Zhong D, Wang Z, Yan T, Li T, Yuan Y, Liu Y, Wang Y, Cai X. Recent research progresses of bioengineered biliary stents. Mater Today Bio 2024; 29:101290. [PMID: 39444940 PMCID: PMC11497374 DOI: 10.1016/j.mtbio.2024.101290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/01/2024] [Accepted: 10/03/2024] [Indexed: 10/25/2024] Open
Abstract
Bile duct lesion, including benign (eg. occlusion, cholelithiasis, dilatation, malformation) and malignant (cholangiocarcinoma) diseases, is a frequently encountered challenge in hepatobiliary diseases, which can be repaired by interventional or surgical procedures. A viable cure for bile duct lesions is implantation with biliary stents. Despite the placement achieved by current clinical biliary stents, the creation of functional and readily transplantable biliary stents remains a formidable obstacle. Excellent biocompatibility, stable mechanics, and absorbability are just a few benefits of using bioengineered biliary stents, which can also support and repair damaged bile ducts that drain bile. Additionally, cell sources & organoids derived from the biliary system that are loaded onto scaffolds can encourage bile duct regeneration. Therefore, the implantation of bioengineered biliary stent is considered as an ideal treatment for bile duct lesion, holding a broad potential for clinical applications in future. In this review, we look back on the development of conventional biliary stents, biodegradable biliary stents, and bioengineered biliary stents, highlighting the crucial elements of bioengineered biliary stents in promoting bile duct regeneration. After providing an overview of the various types of cell sources & organoids and fabrication methods utilized for the bioengineering process, we present the in vitro and in vivo applications of bioengineered biliary ducts, along with the latest advances in this exciting field. Finally, we also emphasize the ongoing challenges and future development of bioengineered biliary stents.
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Affiliation(s)
- Jianing Yan
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
| | - Zhichao Ye
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
| | - Xiaofeng Wang
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang Province, China
| | - Danyang Zhong
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
| | - Ziyuan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
| | - Tingting Yan
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
| | - Tianyu Li
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
- Department of Translational Medicine & Clinical Research, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
| | - Yuyang Yuan
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
- Department of Translational Medicine & Clinical Research, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
| | - Yu Liu
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
| | - Yifan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
- Department of Translational Medicine & Clinical Research, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, China
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Chang X, Chi S, Zhang X, Li X, Yu C, Zhou Y, Tang S. Inhibition of Notch3/Hey1 ameliorates peribiliary hypoxia by preventing hypertrophic hepatic arteriopathy in biliary atresia progression. Histochem Cell Biol 2024; 161:461-476. [PMID: 38597939 DOI: 10.1007/s00418-024-02278-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2024] [Indexed: 04/11/2024]
Abstract
Emerging evidence indicates the presence of vascular abnormalities and ischemia in biliary atresia (BA), although specific mechanisms remain undefined. This study examined both human and experimental BA. Structural and hemodynamic features of hepatic arteries were investigated by Doppler ultrasound, indocyanine green angiography, microscopic histology, and invasive arterial pressure measurement. Opal multiplex immunohistochemistry, western blot, and RT-PCR were applied to assess Notch3 expression and the phenotype of hepatic arterial smooth muscle cells (HASMCs). We established animal models of Notch3 inhibition, overexpression, and knockout to evaluate the differences in overall survival, hepatic artery morphology, peribiliary hypoxia, and HASMC phenotype. Hypertrophic hepatic arteriopathy was evidenced by an increased wall-to-lumen ratio and clinically manifested as hepatic arterial hypertension, decreased hepatic artery perfusion, and formation of hepatic subcapsular vascular plexuses (HSVPs). We observed a correlation between overactivation of Notch3 and phenotypic disruption of HASMCs with the exacerbation of peribiliary hypoxia. Notch3 signaling mediated the phenotype alteration of HASMCs, resulting in arterial wall thickening and impaired oxygen supply in the portal microenvironment. Inhibition of Notch3/Hey1 ameliorates portal hypoxia by restoring the balance of contractile/synthetic HASMCs, thereby preventing hypertrophic arteriopathy in BA.
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Affiliation(s)
- Xiaopan Chang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430019, China
| | - Shuiqing Chi
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430019, China
| | - Xi Zhang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430019, China
| | - Xiangyang Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430019, China
| | - Cheng Yu
- Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430019, China
| | - Ying Zhou
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430019, China
| | - Shaotao Tang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430019, China.
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Aksu I, Kiray M, Gencoglu C, Tas A, Acikgoz O. The effects of subtoxic dose of acetaminophen combined with exercise on the liver of rats. Physiol Res 2023; 72:383-392. [PMID: 37449750 PMCID: PMC10668997 DOI: 10.33549/physiolres.935091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 03/31/2023] [Indexed: 08/26/2023] Open
Abstract
Regular physical exercise is beneficial to the body. Acute exercise causes oxidant stress in many tissues including the liver by creating an unbalanced status between oxidant and antioxidant levels. Analgesic drugs are commonly consumed to reduce the pain after exercise. Acetaminophen (APAP), commonly used as an over-the-counter analgesic, can cause hepatotoxicity. The aim of this study was to investigate the effect and underlying mechanisms of APAP at subtoxic dose, which is given after the acute and exhaustive exercise on the rat livers. Male Wistar rats weighing 200-250 g were divided into 6 groups each consisting of 7 rats/group; Control, APAP (250 mg/kg, ip), Acute Exercise (AEx), Acute Exhaustive Exercise (AEEx), Acute Exercise and APAP (AEx+APAP) and Acute Exhaustive Exercise and APAP (AEEx+APAP) groups. Rats were exercised at moderate intensity or exhaustive on the treadmill and then received APAP. Tissue MDA levels were significantly increased in AEEx, AEx+APAP and AEEx+APAP groups compared with the control. There was no significant difference in GSH levels between groups. Tissue Sirtuin1 (Sirt1) levels of APAP, AEx and AEEx groups were significantly less than control. There was no significant difference between groups in VEGF levels. Liver damage score was significantly higher in all groups compared with control group. As a result, this study shows that subtoxic dose of APAP treatment alone or in combination with acute or exhaustive treadmill exercise can cause oxidative liver damage by affecting Sirt1 levels and without affecting VEGF levels.
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Affiliation(s)
- I Aksu
- Department of Physiology, Dokuz Eylul University Medical Faculty, Balcova, Izmir, Republic of Türkiye.
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Kozlov AV, Polikarpov AA, Tarazov PG, Moiseenko AV, Jutkin MV, Shapoval SV, Turlak AS, Granov DA. Intraductal photodynamic therapy and its combination with intra-arterial chemoinfusion in the treatment of inoperable patients with Klatskin tumor. КЛИНИЧЕСКАЯ ПРАКТИКА 2023; 14:84-94. [DOI: 10.17816/clinpract114961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2025] Open
Abstract
Background: A palliative or symptomatic treatment is indicated for 7080% of patients with Klatskins tumor because of the advanced lesion volume and the patients grave condition. Hepatic arterial infusion chemotherapy, chemoembolization, radioembolization are successfully used in the treatment of hepatocellular carcinoma and liver metastases. Aim: to estimate the immediate and long-term results of photodynamic therapy (PDT) and its combination with hepatic arterial infusion in inoperable patients with Klatskin tumors. Methods: Between 2010 and 2021, 83 palliative PDT sessions (from 1 to 8, average 2.4) were performed in 82 patients as a single treatment or in combination with hepatic arterial infusion. In all cases, percutaneous transhepatic biliary drainage was previously performed; no chemotherapy was applied. Two groups of 48 patients were stratified according to the ECOG status (23) and the numbers of PDT sessions (no more than two). The treatment group of the combination therapy consisted of 24 patients (13 male, 11 female) aged 38 to 85 (mean 63) years with the ECOG status of 24 (mean 2.4). This group received PDT with hepatic arterial infusion using a GemCis regimen. On average, 1.4 PDT sessions were performed, the treatment started on the 89th (27225) day after the biliary drainage. The hepatic arterial infusion was performed on the 2d3th day after the PDT. The control group received only PDT and consisted of 24 patients (13 male, 11 female) aged 51 to 83 (66 on average) years, with the ECOG status of 23 (mean 2.6). On average, 1.4 PDT sessions were performed, starting on the 106th (32405) day after the biliary drainage. Results: There were no serious adverse events associated with PDT in both groups. Toxic complications of hepatic arterial infusion were observed in 13 of 24 patients (54%): III grade hematological (54%) and gastrointestinal (69%); all were eliminated with medical therapy. Complications of the percutaneous transhepatic biliary drainage in three patients (hemobilia, n=2, and sepsis, n=1) were estimated as grade III by the CIRSE classification (2017) and successfully treated without surgery. In the combination treatment group, the overall mean survival and median survival were higher than those in the control group: 327.939.8 days (10.9 mo) versus 246.931.2 days (8.2 mo) and 275 days versus 244 days. However, these differences did not reach the statistical significance (p=0.12). Conclusions: PDT is a safe method of a palliative treatment of critically ill patients with Klatskin tumor (ECOG 23). PDT alone has limited clinical efficacy. A combination of PDT and hepatic arterial infusion does not cause serious complications and may increase the survival rates.
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Affiliation(s)
- Alexey V. Kozlov
- Granov Russian Research Center of Radiology and Surgical Technologies
| | | | - Pavel G. Tarazov
- Granov Russian Research Center of Radiology and Surgical Technologies
| | | | - Maksim V. Jutkin
- Granov Russian Research Center of Radiology and Surgical Technologies
| | | | | | - Dmitrii A. Granov
- Granov Russian Research Center of Radiology and Surgical Technologies
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Fickert P, Lin AC, Ritschl H, Hammer N, Denk H. Portal venous branches as an anatomic railroad for a gut-bile duct-axis. J Hepatol 2023:S0168-8278(23)00221-0. [PMID: 37044219 DOI: 10.1016/j.jhep.2023.03.043] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 03/30/2023] [Accepted: 03/31/2023] [Indexed: 04/14/2023]
Affiliation(s)
- Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Medicine.
| | - Alvin C Lin
- Division of Macroscopic and Clinical Anatomy, Gottfried Schatz Research Center
| | - Helmut Ritschl
- Institute of Radiology Technology; FH Joanneum University of Applied Sciences, Graz, Austria
| | - Niels Hammer
- Division of Macroscopic and Clinical Anatomy, Gottfried Schatz Research Center
| | - Helmut Denk
- Department of Pathology; Medical University of Graz, Graz, Austria
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Intra-arterial chemotherapy in the treatment of inoperable patients with Klatskin's tumor: preliminary results. КЛИНИЧЕСКАЯ ПРАКТИКА 2022. [DOI: 10.17816/clinpract109310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2022] Open
Abstract
Aim. To evaluate the safety and efficacy of hepatic arterial infusion (HAI) in patients with Klatskin tumor.
Materials and methods. Between 2010-2021, 14 of 119 patients with inoperable Klatskin tumor were treated with HAI of GEMICS. All patients had obstructive jaundice and received percutaneous transhepatic biliary drainage (PTBD). Chemotherapy was started when serum bilirubin level became normal (average on the 106th day from PTBD). In total, 19 (from 1 to 4 per patient) HAI cycles were performed.
Results. PTBD complications such as cholangitis (n=2) and local peritonitis (n=1) developed in 3 patients (21%) and were successfully treated using minimally invasive techniques. Toxicity of chemotherapy were observed in 8 of 14 patients (57%): I-II degree hematological (43%) and gastrointestinal (50%); all were cured by medical therapy. The overall mean survival was 286 days (9.6 months), median survival 283 days (9.4 months).
Conclusions. Our preliminary results showed that HAI in patients with Klatskin tumor is safe, but has limited effectiveness. The combination of arterial infusion with other methods such as radiotherapy, intra-ductal photodynamic therapy, radiofrequency ablation, target therapy, should be investigated.
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Uemoto Y, Taura K, Nakamura D, Xuefeng L, Nam NH, Kimura Y, Yoshino K, Fuji H, Yoh T, Nishio T, Yamamoto G, Koyama Y, Seo S, Tsuruyama T, Iwaisako K, Uemoto S, Tabata Y, Hatano E. Bile duct regeneration with an artificial bile duct made of gelatin hydrogel non-woven fabrics. Tissue Eng Part A 2022; 28:737-748. [PMID: 35383474 DOI: 10.1089/ten.tea.2021.0209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Although choledochojejunostomy is the standard technique for biliary reconstruction, there are various associated problems that need to be solved such as reflux cholangitis. Interposition with an artificial bile duct (ABD) to replace the resected bile duct maintains a physiological conduit for bile and may solve this problem. This study investigated the usefulness of an ABD made of gelatin hydrogel non-woven fabric (GHNF). GHNF was prepared by the solution blow spinning method. The migration and activity of murine fibroblast L929 cells were examined in GHNF sheets. L929 cells migrated into GHNF sheets, where they proliferated and synthesized collagen, suggesting GHNF is a promising scaffold for bile duct regeneration. ABDs made of GHNF were implanted in place of resected bile duct segments in rats. The rats were sacrificed at 2, 6, and 12 weeks post-implantation. The implantation site was histologically evaluated for bile duct regeneration. At postoperative 2 weeks, migrating cells were observed in the ABD pores. The implanted ABD was mostly degraded and replaced by collagen fibers at 6 weeks. Ki67-positive bile duct epithelial cells appeared within the implanted ABD. These were most abundant within the central part of the ABD after 6 weeks. The percentages of Ki67-positive cells were 31.7%±9.1% in the experimental group and 0.8%±0.6% in the sham operation group at 6 weeks (p<0.05), indicating that mature biliary epithelial cells at the stump proliferated to regenerate the biliary epithelium. Biliary epithelial cells had almost completely covered the bile duct lumen at 12 weeks (epithelialization ratios: 10.4%±6.9% at 2 weeks, 93.1%±5.1% at 6 weeks, 99.2%±1.6% at 12 weeks). The regenerated epithelium was positive for the bile duct epithelium marker cytokeratin 19. Bile duct regeneration was accompanied by angiogenesis, as evidenced by the appearance of CD31-positive vascular structures. Capillaries were induced 2 weeks after implantation. The number of capillaries reached a maximum at 6 weeks and decreased to the same level as that of normal bile ducts at 12 weeks. These results showed that an ABD of GHNF contributed to successful bile duct regeneration in rats by facilitating the cell migration required for extracellular matrix synthesis, angiogenesis, and epithelialization.
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Affiliation(s)
- Yusuke Uemoto
- Kyoto University, 12918, Surgery, Kyoto, Japan.,Kyoto University Institute for Frontier Life and Medical Sciences, 84090, Regeneration Science and Engineering, Kyoto, Kyoto, Japan;
| | | | | | - Li Xuefeng
- Kyoto University, 12918, Surgery, Kyoto, Japan;
| | | | | | - Kenji Yoshino
- Kyoto University, 12918, Surgery, Kyoto, Japan.,Nagahama City Hospital, 37078, Surgery, Nagahama, Shiga, Japan;
| | | | - Tomoaki Yoh
- Kyoto University, 12918, Surgery, Kyoto, Japan;
| | | | | | | | - Satoru Seo
- Kyoto University, 12918, Surgery, Kyoto, Japan;
| | - Tatsuaki Tsuruyama
- Kyoto University Hospital Clinical Bio Resource Center, 593766, Kyoto, Kyoto, Japan;
| | - Keiko Iwaisako
- Doshisha University - Kyotanabe Campus, 358002, Medical Life Systems, Kyotanabe, Kyoto, Japan;
| | - Shinji Uemoto
- Shiga University of Medical Science, 13051, Otsu, Shiga, Japan;
| | - Yasuhiko Tabata
- Kyoto University Institute for Frontier Life and Medical Sciences, 84090, Regeneration Science and Engineering, Kyoto, Kyoto, Japan;
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9
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Dann E, Henderson NC, Teichmann SA, Morgan MD, Marioni JC. Differential abundance testing on single-cell data using k-nearest neighbor graphs. Nat Biotechnol 2022; 40:245-253. [PMID: 34594043 PMCID: PMC7617075 DOI: 10.1038/s41587-021-01033-z] [Citation(s) in RCA: 308] [Impact Index Per Article: 102.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 07/26/2021] [Indexed: 12/13/2022]
Abstract
Current computational workflows for comparative analyses of single-cell datasets typically use discrete clusters as input when testing for differential abundance among experimental conditions. However, clusters do not always provide the appropriate resolution and cannot capture continuous trajectories. Here we present Milo, a scalable statistical framework that performs differential abundance testing by assigning cells to partially overlapping neighborhoods on a k-nearest neighbor graph. Using simulations and single-cell RNA sequencing (scRNA-seq) data, we show that Milo can identify perturbations that are obscured by discretizing cells into clusters, that it maintains false discovery rate control across batch effects and that it outperforms alternative differential abundance testing strategies. Milo identifies the decline of a fate-biased epithelial precursor in the aging mouse thymus and identifies perturbations to multiple lineages in human cirrhotic liver. As Milo is based on a cell-cell similarity structure, it might also be applicable to single-cell data other than scRNA-seq. Milo is provided as an open-source R software package at https://github.com/MarioniLab/miloR .
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Affiliation(s)
- Emma Dann
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
| | - Neil C Henderson
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Sarah A Teichmann
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
- Theory of Condensed Matter Group, The Cavendish Laboratory, University of Cambridge, Cambridge, UK
| | - Michael D Morgan
- European Molecular Biology Laboratory European Bioinformatics Institute, Hinxton, Cambridge, UK.
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
| | - John C Marioni
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
- European Molecular Biology Laboratory European Bioinformatics Institute, Hinxton, Cambridge, UK.
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
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Ramírez-Marín Y, Abad-Contreras DE, Ustarroz-Cano M, Pérez-Gallardo NS, Villafuerte-García L, Puente-Guzmán DM, del Villar-Velasco JL, Rodríguez-López LA, Torres-Villalobos G, Mercado MÁ, Tapia-Jurado J, Martínez-García FD, Harmsen MC, Piña-Barba MC, Giraldo-Gomez DM. Perfusion Decellularization of Extrahepatic Bile Duct Allows Tissue-Engineered Scaffold Generation by Preserving Matrix Architecture and Cytocompatibility. MATERIALS 2021; 14:ma14113099. [PMID: 34198787 PMCID: PMC8201334 DOI: 10.3390/ma14113099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/24/2021] [Accepted: 06/02/2021] [Indexed: 12/19/2022]
Abstract
Reconstruction of bile ducts damaged remains a vexing medical problem. Surgeons have few options when it comes to a long segment reconstruction of the bile duct. Biological scaffolds of decellularized biliary origin may offer an approach to support the replace of bile ducts. Our objective was to obtain an extracellular matrix scaffold derived from porcine extrahepatic bile ducts (dECM-BD) and to analyze its biological and biochemical properties. The efficiency of the tailored perfusion decellularization process was assessed through histology stainings. Results from 4'-6-diamidino-2-phenylindole (DAPI), Hematoxylin and Eosin (H&E) stainings, and deoxyribonucleic acid (DNA) quantification showed proper extracellular matrix (ECM) decellularization with an effectiveness of 98%. Immunohistochemistry results indicate an effective decrease in immunogenic marker as human leukocyte antigens (HLA-A) and Cytokeratin 7 (CK7) proteins. The ECM of the bile duct was preserved according to Masson and Herovici stainings. Data derived from scanning electron microscopy (SEM) and thermogravimetric analysis (TGA) showed the preservation of the dECM-BD hierarchical structures. Cytotoxicity of dECM-BD was null, with cells able to infiltrate the scaffold. In this work, we standardized a decellularization method that allows one to obtain a natural bile duct scaffold with hierarchical ultrastructure preservation and adequate cytocompatibility.
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Affiliation(s)
- Yolik Ramírez-Marín
- Program of Medical Specialization General Surgery, Division of Posgraduate Studies, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Avenida Universidad 3000, Circuito de Posgrados, Unidad de Posgrado Edificio “E” 2° piso, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico;
- National Institute of Medical Sciences and Nutrition of Mexico Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Secc. 16, Tlalpan, Ciudad de México 14080, Mexico; (L.A.R.-L.); (G.T.-V.); (M.Á.M.)
| | - David Eduardo Abad-Contreras
- Laboratory for Biomaterials, Materials Research Institute, National Autonomous University of Mexico (UNAM), Avenida Universidad 3000, Circuito Exterior, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (D.E.A.-C.); (M.C.P.-B.)
| | - Martha Ustarroz-Cano
- Department of Cell and Tissue Biology, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Avenida Universidad 3000, Circuito Interior, Edificio “A” 3° piso, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico;
| | - Norma S. Pérez-Gallardo
- Surgical Training Section, Faculty of Veterinary Medicine and Animal Husbandry, National Autonomous University of Mexico (UNAM), Avenida Universidad 3000, Circuito Exterior, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (N.S.P.-G.); (L.V.-G.); (D.M.P.-G.); (J.L.d.V.-V.)
| | - Lorena Villafuerte-García
- Surgical Training Section, Faculty of Veterinary Medicine and Animal Husbandry, National Autonomous University of Mexico (UNAM), Avenida Universidad 3000, Circuito Exterior, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (N.S.P.-G.); (L.V.-G.); (D.M.P.-G.); (J.L.d.V.-V.)
| | - Dulce Maria Puente-Guzmán
- Surgical Training Section, Faculty of Veterinary Medicine and Animal Husbandry, National Autonomous University of Mexico (UNAM), Avenida Universidad 3000, Circuito Exterior, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (N.S.P.-G.); (L.V.-G.); (D.M.P.-G.); (J.L.d.V.-V.)
| | - Jorge Luna del Villar-Velasco
- Surgical Training Section, Faculty of Veterinary Medicine and Animal Husbandry, National Autonomous University of Mexico (UNAM), Avenida Universidad 3000, Circuito Exterior, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (N.S.P.-G.); (L.V.-G.); (D.M.P.-G.); (J.L.d.V.-V.)
| | - Leonardo Alejandro Rodríguez-López
- National Institute of Medical Sciences and Nutrition of Mexico Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Secc. 16, Tlalpan, Ciudad de México 14080, Mexico; (L.A.R.-L.); (G.T.-V.); (M.Á.M.)
| | - Gonzalo Torres-Villalobos
- National Institute of Medical Sciences and Nutrition of Mexico Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Secc. 16, Tlalpan, Ciudad de México 14080, Mexico; (L.A.R.-L.); (G.T.-V.); (M.Á.M.)
| | - Miguel Ángel Mercado
- National Institute of Medical Sciences and Nutrition of Mexico Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Secc. 16, Tlalpan, Ciudad de México 14080, Mexico; (L.A.R.-L.); (G.T.-V.); (M.Á.M.)
| | - Jesús Tapia-Jurado
- Unit of Advanced Medical Simulation, Division of Posgraduate Studies, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Avenida Universidad 3000, Circuito de Posgrados, Unidad de Posgrado Edificio “B” 2° piso, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico;
| | - Francisco Drusso Martínez-García
- Department of Pathology and Medical Biology, University Medical Center Groningen University of Groningen, Hanzeplein 1, 9713 Groningen, The Netherlands; (F.D.M.-G.); (M.C.H.)
| | - Martin Conrad Harmsen
- Department of Pathology and Medical Biology, University Medical Center Groningen University of Groningen, Hanzeplein 1, 9713 Groningen, The Netherlands; (F.D.M.-G.); (M.C.H.)
| | - M. Cristina Piña-Barba
- Laboratory for Biomaterials, Materials Research Institute, National Autonomous University of Mexico (UNAM), Avenida Universidad 3000, Circuito Exterior, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (D.E.A.-C.); (M.C.P.-B.)
| | - David M. Giraldo-Gomez
- Department of Cell and Tissue Biology, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Avenida Universidad 3000, Circuito Interior, Edificio “A” 3° piso, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico;
- Microscopy Core Facility, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Avenida Universidad 3000, Circuito Interior, Edificio “A” planta baja, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico
- Correspondence:
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Hamada T, Nakamura A, Soyama A, Sakai Y, Miyoshi T, Yamaguchi S, Hidaka M, Hara T, Kugiyama T, Takatsuki M, Kamiya A, Nakayama K, Eguchi S. Bile duct reconstruction using scaffold-free tubular constructs created by Bio-3D printer. Regen Ther 2021; 16:81-89. [PMID: 33732817 PMCID: PMC7921183 DOI: 10.1016/j.reth.2021.02.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/16/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction Biliary strictures after bile duct injury or duct-to-duct biliary reconstruction are serious complications that markedly reduce patients’ quality of life because their treatment involves periodic stent replacements. This study aimed to create a scaffold-free tubular construct as an interposition graft to treat biliary complications. Methods Scaffold-free tubular constructs of allogeneic pig fibroblasts, that is, fibroblast tubes, were created using a Bio-3D Printer and implanted into pigs as interposition grafts for duct-to-duct biliary reconstruction. Results Although the fibroblast tube was weaker than the native bile duct, it was sufficiently strong to enable suturing. The pigs' serum hepatobiliary enzyme levels remained stable during the experimental period. Micro-computed tomography showed no biliary strictures, no biliary leakages, and no intrahepatic bile duct dilations. The tubular structure was retained in all resected specimens, and the fibroblasts persisted at the graft sites. Immunohistochemical analyses revealed angiogenesis in the fibroblast tube and absence of extensions of the biliary epithelium into the fibroblast tube's lumen. Conclusions This study's findings demonstrated successful reconstruction of the extrahepatic bile duct with a scaffold-free tubular construct created from pig fibroblasts using a novel Bio-3D Printer. This construct could provide a novel regenerative treatment for patients with hepatobiliary diseases.
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Key Words
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- Artificial bile duct
- Bio-3D printer
- Cr, creatinine
- DMEM, Dulbecco's Modified Eagle's Medium
- EDTA, trypsin-ethylenediaminetetraacetic acid
- FBS, fetal bovine serum
- IBDI, iatrogenic bile duct injury
- KCL, potassium chloride
- LDLT, living donor liver transplantation
- PBS, phosphate-buffered saline
- QOL, quality of life
- Reconstruction
- Scaffold-free tubular construct
- T-Bil, total bilirubin
- γ-GTP, γ-glutamyl transpeptidase
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Affiliation(s)
- Takashi Hamada
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Anna Nakamura
- Department of Regenerative Medicine and Biomedical Engineering, Faculty of Medicine, Saga University, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Yusuke Sakai
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan.,Department of Chemical Engineering, Faculty of Engineering, Graduate School, Kyushu University, Japan
| | - Takayuki Miyoshi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Shun Yamaguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Takanobu Hara
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Tota Kugiyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Mitsuhisa Takatsuki
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Akihide Kamiya
- Department of Molecular Life Sciences, Tokai University School of Medicine, Japan
| | - Koichi Nakayama
- Department of Regenerative Medicine and Biomedical Engineering, Faculty of Medicine, Saga University, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
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12
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Cell therapy for advanced liver diseases: Repair or rebuild. J Hepatol 2021; 74:185-199. [PMID: 32976865 DOI: 10.1016/j.jhep.2020.09.014] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/18/2020] [Accepted: 09/14/2020] [Indexed: 12/15/2022]
Abstract
Advanced liver disease presents a significant worldwide health and economic burden and accounts for 3.5% of global mortality. When liver disease progresses to organ failure the only effective treatment is liver transplantation, which necessitates lifelong immunosuppression and carries associated risks. Furthermore, the shortage of suitable donor organs means patients may die waiting for a suitable transplant organ. Cell therapies have made their way from animal studies to a small number of early clinical trials. Herein, we review the current state of cell therapies for liver disease and the mechanisms underpinning their actions (to repair liver tissue or rebuild functional parenchyma). We also discuss cellular therapies that are on the clinical horizon and challenges that must be overcome before routine clinical use is a possibility.
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Siddiqui H, Rawal P, Bihari C, Arora N, Kaur S. Vascular Endothelial Growth Factor Promotes Proliferation of Epithelial Cell Adhesion Molecule-Positive Cells in Nonalcoholic Steatohepatitis. J Clin Exp Hepatol 2020; 10:275-283. [PMID: 32655229 PMCID: PMC7335719 DOI: 10.1016/j.jceh.2019.11.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 11/28/2019] [Indexed: 12/12/2022] Open
Abstract
AIM An impaired hepatocyte proliferation during severe liver injury causes the proliferation of hepatic progenitor cells (HPCs), also called as the ductular reaction (DR). In the present study, we studied the role of key angiogenic factors in HPC-mediated DR in nonalcoholic steatohepatitis (NASH). METHODS Liver biopsies from patients with NASH (n = 14) were included in the study. Patients with NASH were divided in two groups, early and late fibrosis (based on fibrosis staging). Biopsies were used to analyze the gene expression by quantitative real-time polymerase chain reaction and immunohistochemical (IHC) staining for two markers of DR, viz, CK19 and epithelial cell adhesion molecule (EpCAM). Cocultures were performed between steatotic human umbilical vein endothelial cells (HUVECs) and LX2 and Huh7 cells. Enzyme-linked immunosorbent assays were performed to measure levels of vascular endothelial growth factor (VEGF) in coculture studies. Next, Huh7 cells were treated with VEGF, and proliferation was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assays. The number of EpCAM-positive cells was analyzed by flow cytometry. RESULTS Of all the angiogenic factors, the gene expression of VEGF and angiopoietin 2 (Ang2) was significantly different between patients with NASH in the early and late fibrosis groups (P < 0.05 for both). Both VEGF and Ang2 also correlated significantly with the IHC scores of CK19 and EpCAM in the study group. In the in vitro studies, VEGF levels were significantly increased when Huh7 cells were cocultured with steatotic HUVECs and LX2 cells. The proliferation and percentage of EpCAM-positive cells was increased when Huh7 cells were treated with VEGF. CONCLUSION Our study indicates an important contribution of VEGF toward the activation of HPC-mediated regeneration and DR in NASH.
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Key Words
- Ang2, angiopoietin 2
- BSA, bovine serum albumin
- CM, conditioned medium
- DMEM, Dulbecco's Modified Eagle medium
- DR, ductular reaction
- ELISA, enzyme-linked immunosorbent assay
- EpCAM, epithelial cell adhesion molecule
- FBS, fetal bovine serum
- H&E, hematoxylin and eosin
- HPC, hepatic progenitor cell
- HSC, hepatic stellate cell
- HUVEC, human umbilical vein endothelial cell
- IHC, immunohistochemical
- MT, Masson trichrome
- NAFLD, nonalcoholic fatty liver disease
- NASH, nonalcoholic steatohepatitis
- PCR, polymerase chain reaction
- VEGF, vascular endothelial growth factor
- angiogenesis
- ductular reaction
- hepatic progenitor cells
- nonalcoholic steatohepatitis
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Affiliation(s)
- Hamda Siddiqui
- Institute of Liver and Biliary Sciences, New Delhi, India,Gautam Buddha University, Greater Noida, Uttar Pradesh, India
| | - Preety Rawal
- Gautam Buddha University, Greater Noida, Uttar Pradesh, India
| | - Chaggan Bihari
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Naveen Arora
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Savneet Kaur
- Institute of Liver and Biliary Sciences, New Delhi, India,Address for correspondence. Dr Savneet Kaur, Institute of liver and biliary sciences, New Delhi, India.
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Abstract
Cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, are highly specialized cells residing in a complex anatomic niche where they participate in bile production and homeostasis. Cholangiocytes are damaged in a variety of human diseases termed cholangiopathies, often causing advanced liver failure. The regulation of cholangiocyte transport properties is increasingly understood, as is their anatomical and functional heterogeneity along the biliary tract. Furthermore, cholangiocytes are pivotal in liver regeneration, especially when hepatocyte regeneration is compromised. The role of cholangiocytes in innate and adaptive immune responses, a critical subject relevant to immune-mediated cholangiopathies, is also emerging. Finally, reactive ductular cells are present in many cholestatic and other liver diseases. In chronic disease states, this repair response contributes to liver inflammation, fibrosis and carcinogenesis and is a subject of intense investigation. This Review highlights advances in cholangiocyte research, especially their role in development and liver regeneration, their functional and biochemical heterogeneity, their activation and involvement in inflammation and fibrosis and their engagement with the immune system. We aim to focus further attention on cholangiocyte pathobiology and the search for new disease-modifying therapies targeting the cholangiopathies.
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15
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Fiorotto R, Amenduni M, Mariotti V, Fabris L, Spirli C, Strazzabosco M. Liver diseases in the dish: iPSC and organoids as a new approach to modeling liver diseases. Biochim Biophys Acta Mol Basis Dis 2018; 1865:920-928. [PMID: 30264693 DOI: 10.1016/j.bbadis.2018.08.038] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 08/10/2018] [Accepted: 08/28/2018] [Indexed: 02/07/2023]
Abstract
Liver diseases negatively impact the quality of life and survival of patients, and often require liver transplantation in cases that progress to organ failure. Understanding the cellular and molecular mechanisms of liver development and pathogenesis has been a challenging task, in part for the lack of adequate cellular models directly relevant to the human diseases. Recent technological advances in the stem cell field have shown the potentiality of induced pluripotent stem cells (iPSC) and liver organoids as the next generation tool to model in vitro liver diseases. Hepatocyte-like cells and cholangiocyte are currently being generated from skin fibroblasts and mononuclear blood cells reprogrammed into iPSC and have been successfully used for disease modeling, drug testing and gene editing, with the hope to be able to find application also in regenerative medicine. Protocols to generate other liver cell types are still under development, but the field is advancing rapidly. On the other end, liver cells can now be isolated from liver specimens (liver explants or liver biopsies) and cultured in specific conditions to form polarized 3D organoids. The purpose of this review is to summarize all these recent technological advances and their potential applications but also to analyze the current issues to be addressed before the technology can reach its full potential.
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Affiliation(s)
- Romina Fiorotto
- Digestive Disease Section, Yale Liver Center, Yale University School of Medicine, New Haven, CT, (USA)
| | - Mariangela Amenduni
- Digestive Disease Section, Yale Liver Center, Yale University School of Medicine, New Haven, CT, (USA)
| | - Valeria Mariotti
- Department of Molecular Medicine, University of Padova School of Medicine, Padova, Italy
| | - Luca Fabris
- Department of Molecular Medicine, University of Padova School of Medicine, Padova, Italy
| | - Carlo Spirli
- Digestive Disease Section, Yale Liver Center, Yale University School of Medicine, New Haven, CT, (USA)
| | - Mario Strazzabosco
- Digestive Disease Section, Yale Liver Center, Yale University School of Medicine, New Haven, CT, (USA).
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Rao HB, Prakash A, Sudhindran S, Venu RP. Biliary strictures complicating living donor liver transplantation: Problems, novel insights and solutions. World J Gastroenterol 2018; 24:2061-2072. [PMID: 29785075 PMCID: PMC5960812 DOI: 10.3748/wjg.v24.i19.2061] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 04/28/2018] [Accepted: 05/11/2018] [Indexed: 02/06/2023] Open
Abstract
Biliary stricture complicating living donor liver transplantation (LDLT) is a relatively common complication, occurring in most transplant centres across the world. Cases of biliary strictures are more common in LDLT than in deceased donor liver transplantation. Endoscopic management is the mainstay for biliary strictures complicating LDLT and includes endoscopic retrograde cholangiography, sphincterotomy and stent placement (with or without balloon dilatation). The efficacy and safety profiles as well as outcomes of endoscopic management of biliary strictures complicating LDLT is an area that needs to be viewed in isolation, owing to its unique set of problems and attending complications; as such, it merits a tailored approach, which is yet to be well established. The diagnostic criteria applied to these strictures are not uniform and are over-reliant on imaging studies showing an anastomotic narrowing. It has to be kept in mind that in the setting of LDLT, a subjective anastomotic narrowing is present in most cases due to a mismatch in ductal diameters. However, whether this narrowing results in a functionally significant narrowing is a question that needs further study. In addition, wide variation in the endotherapy protocols practised in most centres makes it difficult to interpret the results and hampers our understanding of this topic. The outcome definition for endotherapy is also heterogenous and needs to be standardised to allow for comparison of data in this regard and establish a clinical practice guideline. There have been multiple studies in this area in the last 2 years, with novel findings that have provided solutions to some of these issues. This review endeavours to incorporate these new findings into the wider understanding of endotherapy for biliary strictures complicating LDLT, with specific emphasis on diagnosis of strictures in the LDLT setting, endotherapy protocols and outcome definitions. An attempt is made to present the best management options currently available as well as directions for future research in the area.
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Affiliation(s)
- Harshavardhan B Rao
- Department of Gastroenterology, Amrita Institute of Medical Sciences, Amrita University, Kochi 682041, India
| | - Arjun Prakash
- Department of Gastroenterology, Amrita Institute of Medical Sciences, Amrita University, Kochi 682041, India
| | - Surendran Sudhindran
- Department of Transplant and Vascular Surgery, Amrita Institute of Medical Sciences, Amrita University, Kochi 682041, India
| | - Rama P Venu
- Department of Gastroenterology, Amrita Institute of Medical Sciences, Amrita University, Kochi 682041, India
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Park J, Kim S, Kim K. Bone morphogenetic protein-2 associated multiple growth factor delivery for bone tissue regeneration. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2018. [DOI: 10.1007/s40005-017-0382-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Zanus G, Romano M, Finotti M, Dalla Bona E, Sgarabotto D, Bassi D, Mescoli C, Angeli P, Burra P, Gringeri E, Vitale A, D'Amico F, Feltracco P, Cillo U. Liver Retransplantation for Hepatic Abscess Due to Hepatic Artery Thrombosis: A Case Report. Transplant Proc 2017; 49:736-739. [PMID: 28457384 DOI: 10.1016/j.transproceed.2017.02.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatic artery thrombosis (HAT) is a well-recognized complication of liver transplantation (LT). HAT is an important risk factor for infectious, in particular hepatic abscess, which can cause graft loss and increasing morbidity and mortality. CASE REPORT We present a case report of complicated LT in a 52-year-old Caucasian man with primary sclerosing cholangitis. In 2007 the patient was included on the waiting list in Padua for LT. In 2012 the patient underwent percutaneous transhepatic biliary drainage for bile duct stricture, complicated with acute pancreatitis. A diagnostic laparoscopy was performed with choledochotomy and Kehr's T tube drainage. On February 14, 2012, the patient underwent LT with arterial reconstruction and choledochojejunostomy. The postoperative course was complicated with HAT, multiple liver abscesses, and sepsis associated with bacteremia due to Enterococcus faecium despite massive intravenous antibiotic therapy and percutaneous drainages. On November 28, 2012, the patient underwent retransplantation. Four years after transplantation the patient is still in good general condition. CONCLUSION Hepatic abscess formation secondary to HAT following LT is a major complication associated with important morbidity and mortality. In selected cases retransplantation should be considered as our case demonstrates.
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Affiliation(s)
- G Zanus
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy
| | - M Romano
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy.
| | - M Finotti
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy
| | - E Dalla Bona
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy
| | - D Sgarabotto
- Tropical and Infectious Diseases Unit, Padova University Hospital, Padova, Italy
| | - D Bassi
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy
| | - C Mescoli
- Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - P Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - P Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Padova, Italy
| | - E Gringeri
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy
| | - A Vitale
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy
| | - F D'Amico
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy
| | - P Feltracco
- Section of Anaesthesia and Intensive Care Medicine, Department of Medicine, Padua University Hospital, Padua, Italy
| | - U Cillo
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy
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Justin AW, Saeb-Parsy K, Markaki AE, Vallier L, Sampaziotis F. Advances in the generation of bioengineered bile ducts. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1532-1538. [PMID: 29097260 DOI: 10.1016/j.bbadis.2017.10.034] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 10/25/2017] [Accepted: 10/26/2017] [Indexed: 12/17/2022]
Abstract
The generation of bioengineered biliary tissue could contribute to the management of some of the most impactful cholangiopathies associated with liver transplantation, such as biliary atresia or ischemic cholangiopathy. Recent advances in tissue engineering and in vitro cholangiocyte culture have made the achievement of this goal possible. Here we provide an overview of these developments and review the progress towards the generation and transplantation of bioengineered bile ducts. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.
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Affiliation(s)
| | - Kourosh Saeb-Parsy
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Athina E Markaki
- Department of Engineering, University of Cambridge, Cambridge, UK
| | - Ludovic Vallier
- Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge, UK; Wellcome Trust Sanger Institute, Hinxton, UK; Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Fotios Sampaziotis
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge, UK; Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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de Jong IEM, van Leeuwen OB, Lisman T, Gouw ASH, Porte RJ. Repopulating the biliary tree from the peribiliary glands. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1524-1531. [PMID: 28778591 DOI: 10.1016/j.bbadis.2017.07.037] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/21/2017] [Accepted: 07/31/2017] [Indexed: 12/13/2022]
Abstract
The larger ducts of the biliary tree contain numerous tubulo-alveolar adnexal glands that are lined with biliary epithelial cells and connected to the bile duct lumen via small glandular canals. Although these peribiliary glands (PBG) were already described in the 19th century, their exact function and role in the pathophysiology and development of cholangiopathies have not become evident until recently. While secretion of serous and mucinous components into the bile was long considered as the main function of PBG, recent studies have identified PBG as an important source for biliary epithelial cell proliferation and renewal. Activation, dilatation, and proliferation of PBG (or the lack thereof) have been associated with various cholangiopathies. Moreover, PBG have been identified as niches of multipotent stem/progenitor cells with endodermal lineage traits. This has sparked research interest in the role of PBG in the pathogenesis of various cholangiopathies as well as bile duct malignancies. Deeper understanding of the regenerative capacity of the PBG may contribute to the development of novel regenerative therapeutics for previously untreatable hepatobiliary diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Iris E M de Jong
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, The Netherlands; Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Otto B van Leeuwen
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, The Netherlands; Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Ton Lisman
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Annette S H Gouw
- Department of Pathology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, The Netherlands.
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Hall C, Sato K, Wu N, Zhou T, Kyritsi K, Meng F, Glaser S, Alpini G. Regulators of Cholangiocyte Proliferation. Gene Expr 2017; 17:155-171. [PMID: 27412505 PMCID: PMC5494439 DOI: 10.3727/105221616x692568] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cholangiocytes, a small population of cells within the normal liver, have been the focus of a significant amount of research over the past two decades because of their involvement in cholangiopathies such as primary sclerosing cholangitis and primary biliary cholangitis. This article summarizes landmark studies in the field of cholangiocyte physiology and aims to provide an updated review of biliary pathogenesis. The historical approach of rodent extrahepatic bile duct ligation and the relatively recent utilization of transgenic mice have led to significant discoveries in cholangiocyte pathophysiology. Cholangiocyte physiology is a complex system based on heterogeneity within the biliary tree and a number of signaling pathways that serve to regulate bile composition. Studies have expanded the list of neuropeptides, neurotransmitters, and hormones that have been shown to be key regulators of proliferation and biliary damage. The peptide histamine and hormones, such as melatonin and angiotensin, angiotensin, as well as numerous sex hormones, have been implicated in cholangiocyte proliferation during cholestasis. Numerous pathways promote cholangiocyte proliferation during cholestasis, and there is growing evidence to suggest that cholangiocyte proliferation may promote hepatic fibrosis. These pathways may represent significant therapeutic potential for a subset of cholestatic liver diseases that currently lack effective therapies.
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Affiliation(s)
- Chad Hall
- *Research, Central Texas Veterans Health Care System, Temple, TX, USA
- †Baylor Scott & White Digestive Disease Research Center, Temple, TX, USA
- ‡Department of Surgery, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
| | - Keisaku Sato
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
| | - Nan Wu
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
| | - Tianhao Zhou
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
| | | | - Fanyin Meng
- *Research, Central Texas Veterans Health Care System, Temple, TX, USA
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
- ¶Department of Medicine, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
| | - Shannon Glaser
- *Research, Central Texas Veterans Health Care System, Temple, TX, USA
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
- ¶Department of Medicine, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
| | - Gianfranco Alpini
- ‡Department of Surgery, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
- ¶Department of Medicine, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
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23
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Kovalenko YA, Zharikov YO. [Portal cholangiocarcinoma: epidemiology, staging principles and aspects of tumor biology]. Khirurgiia (Mosk) 2017:85-91. [PMID: 29186104 DOI: 10.17116/hirurgia20171185-91] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
| | - Yu O Zharikov
- A.V. Vishnevsky Institute of Surgery, Moscow, Russia
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24
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Joshi N, Kopec AK, Cline-Fedewa H, Luyendyk JP. Lymphocytes contribute to biliary injury and fibrosis in experimental xenobiotic-induced cholestasis. Toxicology 2016; 377:73-80. [PMID: 28049044 DOI: 10.1016/j.tox.2016.12.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 12/20/2016] [Accepted: 12/31/2016] [Indexed: 02/07/2023]
Abstract
The etiology of chronic bile duct injury and fibrosis in patients with autoimmune cholestatic liver diseases is complex, and likely involves immune cells such as lymphocytes. However, most models of biliary fibrosis are not autoimmune in nature. Biliary fibrosis can be induced experimentally by prolonged exposure of mice to the bile duct toxicant alpha-naphthylisothiocyanate (ANIT). We determined whether lymphocytes contributed to ANIT-mediated biliary hyperplasia and fibrosis in mice. Hepatic accumulation of T-lymphocytes and increased serum levels of anti-nuclear-autoantibodies were evident in wild-type mice exposed to ANIT (0.05% ANIT in chow). This occurred alongside bile duct hyperplasia and biliary fibrosis. To assess the role of lymphocytes in ANIT-induced biliary fibrosis, we utilized RAG1-/- mice, which lack T- and B-lymphocytes. ANIT-induced bile duct injury, indicated by increased serum alkaline phosphatase activity, was reduced in ANIT-exposed RAG1-/- mice compared to ANIT-exposed wild-type mice. Despite this reduction in biliary injury, ANIT-induced bile duct hyperplasia was similar in wild-type and RAG1-/- mice. However, hepatic induction of profibrogenic genes including COL1A1, ITGβ6 and TGFβ2 was markedly attenuated in ANIT-exposed RAG1-/- mice compared to ANIT-exposed wild-type mice. Peribiliary collagen deposition was also reduced in ANIT-exposed RAG1-/- mice. The results indicate that lymphocytes exacerbate bile duct injury and fibrosis in ANIT-exposed mice without impacting bile duct hyperplasia.
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Affiliation(s)
- Nikita Joshi
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, USA; Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | - Anna K Kopec
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | - Holly Cline-Fedewa
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA
| | - James P Luyendyk
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, USA; Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA.
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25
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Mancinelli R, Glaser S, Francis H, Carpino G, Franchitto A, Vetuschi A, Sferra R, Pannarale L, Venter J, Meng F, Alpini G, Onori P, Gaudio E. Ischemia reperfusion of the hepatic artery induces the functional damage of large bile ducts by changes in the expression of angiogenic factors. Am J Physiol Gastrointest Liver Physiol 2015; 309:G865-73. [PMID: 26451003 PMCID: PMC4669349 DOI: 10.1152/ajpgi.00015.2015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023]
Abstract
Liver transplantation and cholangiocarcinoma induce biliary dysfunction following ischemia reperfusion (IR). The function of the intrahepatic biliary tree is regulated by both autocrine and paracrine factors. The aim of the study was to demonstrate that IR-induced damage of cholangiocytes is associated with altered expression of biliary angiogenic factors. Normal and bile duct ligation rats underwent 24-h sham or hepatic reperfusion after 30 min of transient occlusion of the hepatic artery (HAIR) or portal vein (PVIR) before collecting liver blocks and cholangiocyte RNA or protein. We evaluated liver histology, biliary apoptosis, proliferation and expression of VEGF-A/C, VEGFR-2/3, Ang-1/2, and Tie-1/2 in liver sections and isolated small and large cholangiocytes. Normal rat intrahepatic cholangiocyte cultures (NRICC) were maintained under standard conditions in normoxic or under a hypoxic atmosphere for 4 h and then transferred to normal conditions for selected times. Subsequently, we measured changes in biliary proliferation and apoptosis and the expression of VEGF-A/C and VEGFR-2/3. In vivo, HAIR (but not PVIR) induced damage of large bile ducts and decreased proliferation and secretin-stimulated cAMP levels. HAIR-induced damage of large bile ducts was associated with increased expression of VEGF-A/C, VEGFR-2/3, Ang-1/2, and Tie-1/2. In vitro, under hypoxic conditions, there was increased apoptosis and reduced proliferation of NRICC concomitant with enhanced expression of VEGF-A/C and VEGFR-2/3. The functional damage of large bile ducts by HAIR and hypoxia is associated with increased expression of angiogenic factors in small cholangiocytes, presumably due to a compensatory mechanism in response to biliary damage.
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Affiliation(s)
- Romina Mancinelli
- 1Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
| | - Shannon Glaser
- 2Research, Central Texas Veterans Health Care System, Temple, Texas; ,3Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
| | - Heather Francis
- 2Research, Central Texas Veterans Health Care System, Temple, Texas; ,3Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
| | - Guido Carpino
- 1Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
| | - Antonio Franchitto
- 1Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy; ,6Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy
| | - Antonella Vetuschi
- 5Department of Biotechnological and Applied Clinical Sciences, University of L′Aquila, L′Aquila, Italy;
| | - Roberta Sferra
- 5Department of Biotechnological and Applied Clinical Sciences, University of L′Aquila, L′Aquila, Italy;
| | - Luigi Pannarale
- 1Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
| | - Julie Venter
- 4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
| | - Fanyin Meng
- 2Research, Central Texas Veterans Health Care System, Temple, Texas; ,3Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
| | - Gianfranco Alpini
- 2Research, Central Texas Veterans Health Care System, Temple, Texas; ,3Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
| | - Eugenio Gaudio
- 1Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
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26
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Spirli C, Villani A, Mariotti V, Fabris L, Fiorotto R, Strazzabosco M. Posttranslational regulation of polycystin-2 protein expression as a novel mechanism of cholangiocyte reaction and repair from biliary damage. Hepatology 2015; 62:1828-39. [PMID: 26313562 PMCID: PMC4681612 DOI: 10.1002/hep.28138] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 08/12/2015] [Indexed: 12/12/2022]
Abstract
UNLABELLED Polycystin-2 (PC2 or TRPPC2), a member of the transient receptor potential channel family, is a nonselective calcium channel. Mutations in PC2 are associated with polycystic liver diseases. PC2-defective cholangiocytes show increased production of cyclic adenosine monophosphate, protein kinase A-dependent activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, hypoxia-inducible factor 1α (HIF-1α)-mediated vascular endothelial growth factor (VEGF) production, and stimulation of cyst growth and progression. Activation of the ERK/HIF-1α/VEGF pathway in cholangiocytes plays a key role during repair from biliary damage. We hypothesized that PC2 levels are modulated during biliary damage/repair, resulting in activation of the ERK/HIF-1α/VEGF pathway. PC2 protein expression, but not its gene expression, was significantly reduced in mouse livers with biliary damage (Mdr2(-/-) knockout, bile duct ligation, 3,5-diethoxycarbonyl-1,4-dihydrocollidine treatment). Treatment of cholangiocytes with proinflammatory cytokines, nitric oxide donors, and endoplasmic reticulum stressors increased ERK1/2 phosphorylation, HIF-1α transcriptional activity, secretion of VEGF, and VEGF receptor type 2 phosphorylation and down-regulated PC2 protein expression without affecting PC2 gene expression. Expression of homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein and NEK, ubiquitin-like proteins that promote proteosomal PC2 degradation, was increased. Pretreatment with the proteasome inhibitor MG-132 restored the expression of PC2 in cells treated with cytokines but not in cells treated with nitric oxide donors or with endoplasmic reticulum stressors. In these conditions, PC2 degradation was instead inhibited by interfering with the autophagy pathway. Treatment of 3,5-diethoxycarbonyl-1,4-dihydrocollidine mice and of Mdr2(-/-) mice with the proteasome inhibitor bortezomib restored PC2 expression and significantly reduced the ductular reaction, fibrosis, and phosphorylated ERK1/2. CONCLUSION In response to biliary damage, PC2 expression is modulated posttranslationally by the proteasome or the autophagy pathway, and PC2 down-regulation is associated with activation of ERK1/2 and an increase of HIF-1α-mediated VEGF secretion; treatments able to restore PC2 expression and to reduce ductular reaction and fibrosis may represent a new therapeutic approach in biliary diseases.
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Affiliation(s)
- Carlo Spirli
- Section of Digestive Diseases, Yale University, New Haven, Connecticut, USA
| | - Ambra Villani
- Section of Digestive Diseases, Yale University, New Haven, Connecticut, USA
| | - Valeria Mariotti
- Section of Digestive Diseases, Yale University, New Haven, Connecticut, USA,Department of Surgery and Interdisciplinary Medicine, University of Milan-Bicocca, Milan, Italy
| | - Luca Fabris
- Section of Digestive Diseases, Yale University, New Haven, Connecticut, USA,Department of Molecular Medicine, University of Padova, Italy
| | - Romina Fiorotto
- Section of Digestive Diseases, Yale University, New Haven, Connecticut, USA
| | - Mario Strazzabosco
- Section of Digestive Diseases, Yale University, New Haven, Connecticut, USA,Department of Surgery and Interdisciplinary Medicine, University of Milan-Bicocca, Milan, Italy
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27
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Du Z, Dong S, Lin P, Chen S, Wu S, Zhang S, Liu H, He Q, Zhuang W, Zhang C. Warm ischemia may damage peribiliary vascular plexus during DCD liver transplantation. Int J Clin Exp Med 2015; 8:758-763. [PMID: 25785054 PMCID: PMC4358509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 12/01/2014] [Indexed: 06/04/2023]
Abstract
Biliary complications cause significant morbidity and mortality in liver transplantation. Warm ischemia can induce biliary duct injury. This study aimed to investigate the effects of warm ischemia on the peribiliary vascular plexus in rat liver transplantation. A total of 102 Sprague-Dawley rats were divided into three groups: sham-operation group, non-ischemic group, and ischemic group. Liver transplantation was performed in both the non-ischemic group and the ischemic group. The animals were sacrificed on day 1, 3, 7, and 14 to collect the blood and liver samples. Serum levels of bile duct obstruction, viz, alkaline phosphatase and gamma-glutamyl transpeptidase, as well as direct and indirect bilirubin were measured. Liver biopsy samples were examined with hematoxylin-eosin staining and transmission electron microscopy. The levels of enzymes and bilirubin were significantly higher in the ischemic group than the non-ischemic group and sham-operated animals (P<0.05), with return to normal levels in the ischemic group after two weeks. Morphological examination showed microthrombi and endothelial damage in the bile ducts and the peribiliary vascular plexus of the ischemic group. Warm ischemia/reperfusion injury can damage the endothelium of the peribiliary vascular plexus, which might compromise the bile duct microcirculation and lead to ischemic cholangiopathy after liver transplantation.
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Affiliation(s)
- Zhenshuang Du
- Department of General Surgery, PLA 180 HospitalQuanzhou 362000, China
| | - Shaoliang Dong
- Department of General Surgery, PLA 180 HospitalQuanzhou 362000, China
| | - Pingdong Lin
- Department of General Surgery, PLA 180 HospitalQuanzhou 362000, China
| | - Shulan Chen
- Department of General Surgery, PLA 180 HospitalQuanzhou 362000, China
| | - Shanshan Wu
- Department of General Surgery, PLA 180 HospitalQuanzhou 362000, China
| | - Shaobo Zhang
- Department of General Surgery, PLA 180 HospitalQuanzhou 362000, China
| | - Hongyu Liu
- Department of General Surgery, PLA 180 HospitalQuanzhou 362000, China
| | - Qian He
- Department of General Surgery, PLA 180 HospitalQuanzhou 362000, China
| | | | - Chenghua Zhang
- Department of General Surgery, PLA 180 HospitalQuanzhou 362000, China
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28
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Cadis AS, Velasquez CD, Brauer M, Hoak B. Intraoperative management of a carbon dioxide embolus in the setting of laparoscopic cholecystectomy for a patient with primary biliary cirrhosis: A case report. Int J Surg Case Rep 2014; 5:833-5. [PMID: 25462045 PMCID: PMC4245685 DOI: 10.1016/j.ijscr.2014.09.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Revised: 09/01/2014] [Accepted: 09/03/2014] [Indexed: 11/20/2022] Open
Abstract
We discuss appropriate detection and management of a carbon dioxide embolus. We review the pathologic hepatic changes in patients with primary biliary cirrhosis. We postulate that cirrhosis may increase the risk of a carbon dioxide embolus. We share an understanding that more invasive monitoring may be helpful, but ultimately hypervigilance from the anesthesia team is the number one safeguard. INTRODUCTION Carbon dioxide (CO2) embolism is a rare complication of laparoscopic cholecystectomy of which both surgeons and anesthesiologists must be aware. This paper presents a case of a CO2 embolus that occurred in a patient with primary biliary cirrhosis (PBC) and discusses the possible correlation between these two events. PRESENTATION OF CASE Our patient with PBC presented with symptomatic biliary dyskinesia and was determined to be a good candidate for laparoscopic cholecystectomy. During this routine surgery a CO2 embolus entered through the altered hepatic parenchyma and progressed to the heart leading to acute hemodynamic collapse. Rapid detection and management aided in the subsequent dissolution of the embolus and recovery of the patient. DISCUSSION In patients with PBC, pathological changes that have taken place in the liver may increase the risk of CO2 embolism. Hepatic alterations that have been previously described include increased angiogenesis and vasodilation. Prior to the operation, the most appropriate method of monitoring should be determined for patients with known liver disease. CONCLUSION Both the surgical and anesthesia team must keep in mind the potential for CO2 embolism during laparoscopic surgery. It is imperative that the medical staff be aware of the risks, signs, and subsequent management so this rare, but potentially fatal event can be managed appropriately.
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Affiliation(s)
- Amy Susan Cadis
- Texas A&M Health Science Center, College of Medicine, 8447 State HW 47, Bryan, TX 77807, United States.
| | - Chelsea Diane Velasquez
- Texas A&M Health Science Center, College of Medicine, 8447 State HW 47, Bryan, TX 77807, United States.
| | - Mark Brauer
- Department of Anesthesiology, Texas A&M Health Science Center, College of Medicine, 8447 State HW 47, Bryan, TX 77807, United States.
| | - Bruce Hoak
- General Surgery, Texas A&M Health Science Center, College of Medicine, 8447 State HW 47, Bryan, TX 77807, United States.
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29
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Walter TJ, Cast AE, Huppert KA, Huppert SS. Epithelial VEGF signaling is required in the mouse liver for proper sinusoid endothelial cell identity and hepatocyte zonation in vivo. Am J Physiol Gastrointest Liver Physiol 2014; 306:G849-62. [PMID: 24650547 PMCID: PMC4024728 DOI: 10.1152/ajpgi.00426.2013] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Vascular endothelial growth factor (VEGF) is crucial for vascular development in several organs. However, the specific contribution of epithelial-VEGF signaling in the liver has not been tested. We used a mouse model to specifically delete Vegf from the liver epithelial lineages during midgestational development and assessed the cell identities and architectures of epithelial and endothelial tissues. We find that without epithelial-derived VEGF, the zonal endothelial and hepatocyte cell identities are altered. We also find decreased portal vein and hepatic artery branching coincident with an increase in hepatic hypoxia postnatally. Together, these data indicate that VEGF secreted from the hepatic epithelium is required for normal differentiation of cells and establishment of three-dimensional vascular branching and zonal architectures in both epithelial and endothelial hepatic tissues.
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Affiliation(s)
- Teagan J. Walter
- 1Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; and ,2Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Ashley E. Cast
- 2Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Kari A. Huppert
- 2Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Stacey S. Huppert
- 2Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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Spirli C, Strazzabosco M. Vascular endothelial growth factors in progenitor cells mediated liver repair. Hepatobiliary Surg Nutr 2014; 2:65-7. [PMID: 24570918 DOI: 10.3978/j.issn.2304-3881.2012.12.05] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 12/20/2012] [Indexed: 01/14/2023]
Affiliation(s)
- Carlo Spirli
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Mario Strazzabosco
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, USA; ; Department of Clinical Medicine, University of Milano-Bicocca, Milan, Italy
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