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Yadav P, Singh SK, Rajput S, Allawadhi P, Khurana A, Weiskirchen R, Navik U. Therapeutic potential of stem cells in regeneration of liver in chronic liver diseases: Current perspectives and future challenges. Pharmacol Ther 2024; 253:108563. [PMID: 38013053 DOI: 10.1016/j.pharmthera.2023.108563] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/04/2023] [Accepted: 11/15/2023] [Indexed: 11/29/2023]
Abstract
The deposition of extracellular matrix and hyperplasia of connective tissue characterizes chronic liver disease called hepatic fibrosis. Progression of hepatic fibrosis may lead to hepatocellular carcinoma. At this stage, only liver transplantation is a viable option. However, the number of possible liver donors is less than the number of patients needing transplantation. Consequently, alternative cell therapies based on non-stem cells (e.g., fibroblasts, chondrocytes, keratinocytes, and hepatocytes) therapy may be able to postpone hepatic disease, but they are often ineffective. Thus, novel stem cell-based therapeutics might be potentially important cutting-edge approaches for treating liver diseases and reducing patient' suffering. Several signaling pathways provide targets for stem cell interventions. These include pathways such as TGF-β, STAT3/BCL-2, NADPH oxidase, Raf/MEK/ERK, Notch, and Wnt/β-catenin. Moreover, mesenchymal stem cells (MSCs) stimulate interleukin (IL)-10, which inhibits T-cells and converts M1 macrophages into M2 macrophages, producing an anti-inflammatory environment. Furthermore, it inhibits the action of CD4+ and CD8+ T cells and reduces the activity of TNF-α and interferon cytokines by enhancing IL-4 synthesis. Consequently, the immunomodulatory and anti-inflammatory capabilities of MSCs make them an attractive therapeutic approach. Importantly, MSCs can inhibit the activation of hepatic stellate cells, causing their apoptosis and subsequent promotion of hepatocyte proliferation, thereby replacing dead hepatocytes and reducing liver fibrosis. This review discusses the multidimensional therapeutic role of stem cells as cell-based therapeutics in liver fibrosis.
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Affiliation(s)
- Poonam Yadav
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab 151401, India
| | - Sumeet Kumar Singh
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab 151401, India
| | - Sonu Rajput
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab 151401, India
| | - Prince Allawadhi
- Department of Pharmacy, Vaish Institute of Pharmaceutical Education and Research (VIPER), Pandit Bhagwat Dayal Sharma University of Health Sciences (Pt. B. D. S. UHS), Rohtak, Haryana 124001, India
| | - Amit Khurana
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab 151401, India; Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074 Aachen, Germany.
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074 Aachen, Germany.
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab 151401, India; Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074 Aachen, Germany.
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Wang Y, Zhou C, Fu Y, Zhang L, Liu S, Cai L, Jiang Z, Xu X, Feng L, Gao Y. Establishment of acute liver failure model in Tibetan miniature pig and verified by dual plasma molecular adsorption system. Int J Artif Organs 2023; 46:141-152. [PMID: 36600401 DOI: 10.1177/03913988221145501] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Acute liver failure (ALF) is a severe liver disease with high morbidity and mortality rates. Animal models are important for research on ALF. This study aimed to establish a reproducible, Tibetan miniature pig model of D-galactosamine-induced ALF and verify it using a dual plasma molecular adsorption system (DPMAS). METHODS Tibet miniature pigs were randomly divided into four groups (A, B, C, D) after catheterization. D-galactosamine (D-gal) at 0.45, 0.40, 0.35, and 0.35 g/kg body weight, respectively, was injected through the catheter. Group D was treated with DPMAS 48 h after D-gal administration. Vital signs and blood index values were recorded every 12 h after D-gal administration. H&E, TUNEL, Ki67, and Masson staining tests were performed. RESULTS After D-gal administration, Tibetan miniature pigs developed different degrees of debilitation, loss of appetite, and jaundice. Survival times of groups A, B, C, and D were 39.7 ± 5.9, 53.0 ± 12.5,61.3 ± 8.1, and 61 ± 7 h, respectively. Blood levels of ALT, AST, TBIL, ammonia, PT, and inflammation factors significantly increased compared with baseline levels in the different groups (Ps < 0.05). Pathological results revealed a clear liver cell necrosis positive correlation with D-gal dose. However, DPMAS did not increase the survival time in ALF, ammonia, or liver cell necrosis. CONCLUSION We successfully established a reproducible Tibetan miniature pig model of d-galactosamine-induced ALF, and we believe that a dosage of 0.35 g/kg is optimal.
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Affiliation(s)
- Yi Wang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chenjie Zhou
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yu Fu
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Linya Zhang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shusong Liu
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lei Cai
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zesheng Jiang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoping Xu
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lei Feng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, Guangdong, China
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Kalhori D, Zakeri N, Azarpira N, Fanian M, Solati-Hashjin M. Chitosan-Coated-Alginate encapsulation of HepG2 cells for enhanced cellular functions. JOURNAL OF MACROMOLECULAR SCIENCE PART A-PURE AND APPLIED CHEMISTRY 2023. [DOI: 10.1080/10601325.2022.2162414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Dianoosh Kalhori
- BioFabrication Lab (BFL), Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Nima Zakeri
- BioFabrication Lab (BFL), Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Fanian
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehran Solati-Hashjin
- BioFabrication Lab (BFL), Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
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Tuerxun K, He J, Ibrahim I, Yusupu Z, Yasheng A, Xu Q, Tang R, Aikebaier A, Wu Y, Tuerdi M, Nijiati M, Zou X, Xu T. Bioartificial livers: a review of their design and manufacture. Biofabrication 2022; 14. [PMID: 35545058 DOI: 10.1088/1758-5090/ac6e86] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 05/11/2022] [Indexed: 11/11/2022]
Abstract
Acute liver failure (ALF) is a rapidly progressive disease with high morbidity and mortality rates. Liver transplantation and artificial liver support systems, such as artificial livers (ALs) and bioartificial livers (BALs), are the two major therapies for ALF. Compared to ALs, BALs are composed of functional hepatocytes that provide essential liver functions, including detoxification, metabolite synthesis, and biotransformation. Furthermore, BALs can potentially provide effective support as a form of bridging therapy to liver transplantation or spontaneous recovery for patients with ALF. In this review, we systematically discussed the currently available state-of-the-art designs and manufacturing processes for BAL support systems. Specifically, we classified the cell sources and bioreactors that are applied in BALs, highlighted the advanced technologies of hepatocyte culturing and bioreactor fabrication, and discussed the current challenges and future trends in developing next generation BALs for large scale clinical applications.
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Affiliation(s)
- Kahaer Tuerxun
- Department of hepatobiliary and pancreatic surgery, First People's Hospital of Kashi, 120th, Yingbin Road, Kashi, Xinjiang, 844000, CHINA
| | - Jianyu He
- Department of Mechanical Engineering, Tsinghua University, 30 Shuangqing Road, Haidian District, Beijing, Beijing, 100084, CHINA
| | - Irxat Ibrahim
- Department of hepatobiliary and pancreatic surgery, First People's Hospital of Kashi, 120th, Yingbin Road, Kashi, Xinjiang, China, Kashi, Xinjiang, 844000, CHINA
| | - Zainuer Yusupu
- Department of Ultrasound, First People's Hospital of Kashi, 120th, Yingbin Road, Kashi, Xinjiang, China, Kashi, Xinjiang, 844000, CHINA
| | - Abudoukeyimu Yasheng
- Department of hepatobiliary and pancreatic surgery, First People's Hospital of Kashi, 120th, Yingbin Road, Kashi, Xinjiang, 844000, CHINA
| | - Qilin Xu
- Department of hepatobiliary and pancreatic surgery, First People's Hospital of Kashi, 120th, Yingbin Road, Kashi, Xinjiang, 844000, CHINA
| | - Ronghua Tang
- Department of hepatobiliary and pancreatic surgery, First People's Hospital of Kashi, 120th, Yingbin Road, Kashi, Xinjiang, 844000, CHINA
| | - Aizemaiti Aikebaier
- Department of hepatobiliary and pancreatic surgery, First People's Hospital of Kashi, 120th, Yingbin Road, Kashi, Xinjiang, 844000, CHINA
| | - Yuanquan Wu
- Department of hepatobiliary and pancreatic surgery, First People's Hospital of Kashi, 120th, Yingbin Road, Kashi, Xinjiang, China, Kashi, Xinjiang, 844000, CHINA
| | - Maimaitituerxun Tuerdi
- Department of hepatobiliary and pancreatic surgery, First People's Hospital of Kashi, 120th, Yingbin Road, Kashi, Xinjiang, China, Kashi, Xinjiang, 844000, CHINA
| | - Mayidili Nijiati
- Medical imaging center, First People's Hospital of Kashi, 120th, Yingbin Road, Kashi, Xinjiang, China, Kashi, Xinjiang, 844000, CHINA
| | - Xiaoguang Zou
- Hospital Organ, First People's Hospital of Kashi, 120th, Yingbin Road, Kashi, Xinjiang, 844000, CHINA
| | - Tao Xu
- Tsinghua University, 30 Shuangqing Road, Haidian District, Beijing, 100084, CHINA
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Feng L, Wang Y, Liu S, He G, Cai L, Qin J, Xu X, Jiang Z, Zhou C, Gao Y. In vitro safety and efficacy evaluation of a novel hybrid bioartificial liver system with simulated liver failure serum. Int J Artif Organs 2022; 45:523-532. [PMID: 35416082 DOI: 10.1177/03913988221091286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Acute liver failure (ALF), which can potentially be treated with an artificial liver, is a fatal condition. The purpose of this study was to evaluate the safety and effectiveness of a novel hybrid bioartificial liver system (NHBLS) using simulated liver failure serum in vitro. METHODS The bioreactor in experimental group was cultivated with primary porcine hepatocytes, whereas in control group was not. Next, the simulated liver failure serum was treated using the NHBLS for 10 h. Changes in albumin (ALB), total bilirubin (TBIL), ammonia (Amm), total bile acid (TBA), creatinine (Cr), and blood urea nitrogen (BUN) were measured before treatment (0 h) and every 2 h during treatment. In addition, changes in NHBLS pressures, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lidocaine metabolism were also recorded. RESULTS The NHBLS worked steadily without unexpected occurrences during the treatment. Blood culture showed no bacterial growth after 7 days, and the endotoxin level was less than 0.5 EU. The TBIL, TBA, Cr, and BUN levels in both groups were markedly lower than those at 0 h (p < 0.05). The Amm level in experimental group was significantly lower than that in control group (p < 0.05). NHBLS pressures were also stable, and the hepatocytes in the bioreactor functioned well. CONCLUSIONS The preparation method for the simulated liver failure serum was optimized successfully, and the safety and effectiveness of the NHBLS in vitro were verified. Furthermore, the NHBLS significantly reduced the levels of Amm which can lead to hepatic encephalopathy.
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Affiliation(s)
- Lei Feng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Yi Wang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Shusong Liu
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Guolin He
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Lei Cai
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Jiasheng Qin
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Xiaoping Xu
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Zesheng Jiang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Chenjie Zhou
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, P.R. China
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Lu J, Zhu D, Li L. Evaluation of hydromechanical and functional properties of diversion-type microcapsule-suspension bioreactor for bioartificial liver. Int J Artif Organs 2022; 45:309-321. [PMID: 35034506 DOI: 10.1177/03913988211066502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
AIM To evaluate the performance of a diversion-type microcapsulesuspension fluidized bed bioreactor and a choanoid fluidized bed bioreactor as bioartificial liver support systems. MATERIALS AND METHODS We evaluated the performance between the modified fluidized bed bioreactor based on diversion-type microcapsule suspension (DMFBB) and choanoid fluidized bed bioreactor (CFBB). The fluidization performance, fluidized height, bed expansion, and the mechanical stability and strength of microcapsule were determined. The viability, synthetic, metabolism, and apoptosis of microcapsulated HepLi5 cells were evaluated. Finally, samples were collected for measurement of alanine aminotransferase, total bilirubin, direct bilirubin, and albumin concentrations. RESULTS Uniform fluidization was established in both DMFBB and CFBB. The bed expansion, shear force, retention rate, swelling rate, and breakage rate of microcapsules differed significantly between two bioreactors over 3 days. The viability of microencapsulated HepLi5 cells and the activities of cytochrome P450 1A2 and 3A4 increased on each day in DMFBB compared to the control. The albumin and urea concentrations in the DMFBB displayed obvious improvements compared to the control. Caspase3/7 activities in the DMFBB decreased compared to those in the CFBB. At 24 h, the alanine aminotransferase concentration in the DMFBB declined significantly compared to the control. The total and direct bilirubin concentrations within plasma perfusion were decreased and albumin was increased in the DMFBB at 24 h than in the CFBB. CONCLUSION The DMFBB shows a promising alternative bioreactor for use in bioartificial liver support systems for application of clinical practice.
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Affiliation(s)
- Juan Lu
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
| | - Danhua Zhu
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
| | - Lanjuan Li
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
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Zhang Y, Lu J, Li Z, Zhu D, Yu X, Li L. Enhanced cellular functions of hepatocytes in the hyaluronate-alginate-chitosan microcapsules. Int J Artif Organs 2020; 44:340-349. [PMID: 32969286 DOI: 10.1177/0391398820959345] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The study aimed to develop a biocompatible microcapsule for hepatocytes and create a bio-mimic microenvironment for maintaining hepatic-specific functions of hepatocytes in vitro. The work is proposed for the bioartificial liver system in the treatment of liver failure. In this study, microcapsules were prepared with hyaluronate (HA)/sodium alginate (SA) as an inner core and an outer chitosan (CS) shell via one-step spraying method. C3A cells were encapsulated in microcapsules to examine the biocompatibility of HA-SA-CS microcapsules. MTT and fluorescence microscopy indicated that C3A cells had high viability in the HA-SA-CS microcapsules. The liver-specific functions, such as urea and albumin synthesis, and CYP1A2 and CYP3A4 activities from encapsulated cells were increased in the HA-SA-CS microcapsules compared to the SA-CS microcapsules. The gene expressions of CYP450 related genes were also increased by HA on day 3. The study suggests that HA-SA-CS microcapsules have good biocompatibility and can maintain a favorable environment for hepatocytes. This approach has improved the preservation of liver cells' metabolic functions and could be a candidate for the bioartificial liver system.
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Affiliation(s)
- Yanhong Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zuhong Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaopeng Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Liu W, Zhang M, Xiao Y, Ye Z, Zhou Y, Lang M, Tan WS. Fabrication and in vitro evaluation of a packed-bed bioreactor based on galactosylated poly(ethylene terephthalate) microfibrous scaffolds. Biochem Eng J 2020. [DOI: 10.1016/j.bej.2020.107565] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Zhang S, Yang Y, Fan L, Zhang F, Li L. The clinical application of mesenchymal stem cells in liver disease: the current situation and potential future. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:565. [PMID: 32775366 PMCID: PMC7347776 DOI: 10.21037/atm.2020.03.218] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver disease is a major health issue which present poor clinical treatment performance. Cirrhosis and liver failure are common clinical manifestations of liver diseases. Liver transplantation is recognized as the ultimate and most efficient therapy to the end stage of liver disease. But it was limited by the shortage of honor organs and high cost. Nowadays, stem cell therapy gained more and more attention due to its attractive efficacy in treating liver disease especially in cirrhosis during the clinical trials. Mesenchymal stem cell (MSC) can be differentiated into hepatocytes, promote liver regeneration, inhibit liver fibrosis and induce liver apoptosis, particularly via paracrine mechanisms. This review will highlight recent clinical applications of MSC, providing the available evidence and discussing some unsolved questions in treating liver disease.
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Affiliation(s)
- Sainan Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Linxiao Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Fen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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Hou YT, Hsu CC. Development of a 3D porous chitosan/gelatin liver scaffold for a bioartificial liver device. J Biosci Bioeng 2020; 129:741-748. [PMID: 32014416 DOI: 10.1016/j.jbiosc.2019.12.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 12/07/2019] [Accepted: 12/29/2019] [Indexed: 12/28/2022]
Abstract
Functional artificial livers (FALs), with embedded hepatocytes that perform the functions of a normal liver, have been developed during the past decades. It is important to note that the liver scaffold, which is a biologically functional core of bioartificial livers, plays a vital role in the bio-cartridge within a bioartificial liver. In this study, a three-dimensional (3D) liver scaffold for in vitro cultures was fabricated by freeze-drying a chitosan/gelatin (CG) solution. A CG scaffold has advantages such as (i) inexpensive and easy-to-make; (ii) easy to fabricate with varying compressive modulus by changing the concentration of glutaraldehyde; (iii) non-cytotoxicity; and (iv) porous structure is similar to extracellular matrix (ECM), thus facilitating hepatocyte adhesion and proliferation. The results revealed that the compressive modulus and maintainability of a CG scaffold was correlated to the increase in glutaraldehyde. Furthermore, hepatocyte viability and hepatic functions showed the best performances with a 0.61% glutaraldehyde-CG scaffold. This CG scaffold not only had higher hepatocyte biocompatibility and mechanical strength, but also maintained hepatic functions and viability in vitro cultures; especially, the mechanical properties of 0.61% glutaraldehyde-CG scaffold were very similar to those in normal liver. The CG scaffold as a liver scaffold may have high potential for further bioartificial liver design in the near future.
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Affiliation(s)
- Yung-Te Hou
- Department of Biomechatronics Engineering, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 106, Taiwan, ROC.
| | - Chao-Chun Hsu
- Department of Biomechatronics Engineering, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 106, Taiwan, ROC
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Mirdamadi ES, Kalhori D, Zakeri N, Azarpira N, Solati-Hashjin M. Liver Tissue Engineering as an Emerging Alternative for Liver Disease Treatment. TISSUE ENGINEERING PART B-REVIEWS 2020; 26:145-163. [PMID: 31797731 DOI: 10.1089/ten.teb.2019.0233] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Chronic liver diseases affect thousands of lives throughout the world every year. The shortage of liver donors for transplantation has been the main driving force to employ alternative methods such as liver tissue engineering (LTE) in fabricating a three-dimensional transplantable liver tissue or enhancing cell delivery techniques alleviating the need for liver donors. LTE consists of three components, cells, ECM (extracellular matrix), and signaling molecules, which we discuss the first and second. The three most common cell sources used in LTE are human and animal primary hepatocytes, and stem cells for different applications. Two major categories of ECM are used to mimic the microenvironment of these cells, named scaffolds and microbeads. Scaffolds have been made by numerous methods with a wide range of synthetic and natural biomaterials. Cell encapsulation has also been utilized by many polymeric biomaterials. To investigate their functions, many properties have been discussed in the literature, such as biochemical, geometrical, and mechanical properties, in both of these categories. Overall, LTE shows excellent potential in assisting hepatic disorders. However, some challenges exist that prevent the practical use of it clinically, making LTE an ongoing research subject in the scientific society.
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Affiliation(s)
- Elnaz Sadat Mirdamadi
- BioFabrication Lab (BFL), Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Dianoosh Kalhori
- BioFabrication Lab (BFL), Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Nima Zakeri
- BioFabrication Lab (BFL), Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehran Solati-Hashjin
- BioFabrication Lab (BFL), Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
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Cen PP, Fan LX, Wang J, Chen JJ, Li LJ. Therapeutic potential of menstrual blood stem cells in treating acute liver failure. World J Gastroenterol 2019; 25:6190-6204. [PMID: 31745380 PMCID: PMC6848012 DOI: 10.3748/wjg.v25.i41.6190] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/11/2019] [Accepted: 10/17/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute liver failure (ALF) is a significant and complex hepatic insult that may rapidly progress to life-threatening conditions. Recently, menstrual blood stem cells (MenSCs) have been identified as a group of easily accessible mesenchymal stem cells with the advantages of non-invasive acquisition, low immunogenicity, a greater capacity of self-renewal and multi-lineage differentiation, making them promising candidates for stem cell-based therapy to revolutionize the treatment strategies for liver failure. AIM To investigate the therapeutic potential of MenSCs for treating ALF in pigs and to dynamically trace the biodistribution of transplanted cells. METHODS MenSCs were labeled in vitro with PKH26, a lipophilic fluorescent dye. The treatment group received immediate transplantation of PKH26-labelled MenSCs (2.5 × 106/kg) via the portal vein after D-galactosamine injection, and the control group underwent sham operation. The survival time, liver function, and hepatic pathological changes were compared between the two groups. Three major organs (liver, lungs and spleen) were extracted from animals and imaged directly with the In vivo Imaging System (IVIS) at the predetermined time points. The regions of interest were drawn to quantify the cell uptake in different organs. RESULTS The labelling procedure did not affect the morphology, viability or multipotential differentiation of MenSCs. Biochemical analysis showed that the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and prothrombin time (PT) measured at selected time points 24 h after transplantation were significantly decreased in the treatment group (P < 0.05). The survival time of ALF animals was prolonged in the treatment group compared with the control group (75.75 ± 5.11 h vs 53.75 ± 2.37 h, log rank, P < 0.001). The liver pathological tissue in the MenSC treatment group showed obviously increased numbers of remaining hepatocytes and a comparatively slight necrotic degree and area. In addition, the IVIS imaging revealed that PKH26-positive MenSCs were clearly retained in the liver initially and then diffused through the systemic circulation. Interestingly, the signal intensity in the liver increased obviously at 36 h, which corresponded to the biochemical result that liver function deteriorated most rapidly at 24 - 36 h. CONCLUSION Our study demonstrates the therapeutic efficacy and homing ability of transplanted MenSCs in a large animal model of ALF and suggests that MenSC transplantation could be a promising strategy for treating ALF.
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Affiliation(s)
- Pan-Pan Cen
- Department of Infectious Diseases, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, China
| | - Lin-Xiao Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jie Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jia-Jia Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Lan-Juan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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He YT, Qi YN, Zhang BQ, Li JB, Bao J. Bioartificial liver support systems for acute liver failure: A systematic review and meta-analysis of the clinical and preclinical literature. World J Gastroenterol 2019; 25:3634-3648. [PMID: 31367162 PMCID: PMC6658398 DOI: 10.3748/wjg.v25.i27.3634] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/03/2019] [Accepted: 05/31/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute liver failure (ALF) has a high mortality varying from 80% to 85% with rapid progress in multi-organ system failure. Bioartificial liver (BAL) support systems have the potential to provide temporary support to bridge patients with ALF to liver transplantation or spontaneous recovery. In the past decades, several BAL support systems have been conducted in clinical trials. More recently, concerns have been raised on the renovation of high-quality cell sources and configuration of BAL support systems to provide more benefits to ALF models in preclinical experiments. AIM To investigate the characteristics of studies about BAL support systems for ALF, and to evaluate their effects on mortality. METHODS Eligible clinical trials and preclinical experiments on large animals were identified on Cochrane Library, PubMed, and EMbase up to March 6, 2019. Two reviewers independently extracted the necessary information, including key BAL indicators, survival and indicating outcomes, and adverse events during treatment. Descriptive analysis was used to identify the characteristics of the included studies, and a meta-analysis including only randomized controlled trial (RCT) studies was done to calculate the overall effect of BAL on mortality among humans and large animals, respectively. RESULTS Of the 30 selected studies, 18 were clinical trials and 12 were preclinical experiments. The meta-analysis result suggested that BAL might reduce mortality in ALF in large animals, probably due to the recent improvement of BAL, including the type, cell source, cell mass, and bioreactor, but seemed ineffective for humans [BAL vs control: relative risk (95% confidence interval), 0.27 (0.12-0.62) for animals and 0.72 (0.48-1.08) for humans]. Liver and renal functions, hematologic and coagulative parameters, encephalopathy index, and neurological indicators seemed to improve after BAL, with neither meaningful adverse events nor porcine endogenous retrovirus infection. CONCLUSION BAL may reduce the mortality of ALF by bridging the gap between preclinical experiments and clinical trials. Clinical trials using improved BAL must be designed scientifically and conducted in the future to provide evidence for transformation.
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Affiliation(s)
- Yu-Ting He
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ya-Na Qi
- Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Bing-Qi Zhang
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jian-Bo Li
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ji Bao
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Zhang Y, Li L. State of the art—Artificial liver in China. Artif Organs 2019; 43:336-341. [DOI: 10.1111/aor.13448] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 02/21/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Yimin Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases the First Affiliated Hospital, College of Medicine, Zhejiang University Hangzhou China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases the First Affiliated Hospital, College of Medicine, Zhejiang University Hangzhou China
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Liu W, Hu D, Gu C, Zhou Y, Tan WS. Fabrication and in vitro evaluation of a packed-bed bioreactor based on an optimum two-stage culture strategy. J Biosci Bioeng 2018; 127:506-514. [PMID: 30322683 DOI: 10.1016/j.jbiosc.2018.09.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 09/11/2018] [Accepted: 09/13/2018] [Indexed: 12/14/2022]
Abstract
A packed-bed (PB) bioreactor for bioartificial liver (BAL) was fabricated based on an optimum two-stage culture strategy and evaluated in vitro in this research. Human induced hepatocytes (hiHeps) were first expanded using Cytodex 3 microcarriers and the choice of microcarrier concentration and fetal bovine serum (FBS) content was optimized. Then, the cells expanded under the optimum expansion condition were perfused into a perfusion system containing Fibra-Cel (FC) disks to fabricate a PB bioreactor. Operating parameters including flow rate and seeding density for perfusion culture were optimized, respectively. Results indicated that during suspension culture, rapid cell proliferation and favorable amino acid metabolism were achieved at 3 mg/mL microcarriers combined with 1% FBS. While for the perfusion culture, the most effective flow rate and seeding density were 2 mL/min and 1 × 106 cells/mL, respectively. Under this optimum perfusion condition, hiHeps showed good proliferation ability, high viability, homogeneous distribution, high metabolism activities and efficient albumin secretion as well as high liver-specific genes expression. Therefore, the two-stage culture strategy based on operating parameters optimization provides a new method for the development of PB bioreactors.
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Affiliation(s)
- Wei Liu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
| | - Dan Hu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
| | - Ce Gu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
| | - Yan Zhou
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China.
| | - Wen-Song Tan
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
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Abstract
This method is used to prepare microencapsulation of hepatocytes. The key steps in the protocol are (a) isolation of porcine hepatocytes, followed by (b) production of hepatocytes encapsulation, and (c) evaluation of encapsulations and hepatocytes. This method of collecting porcine hepatocytes was first used in 2003 (Maruyama et al. Cell Transplant 12:593-598, 2003). Cell encapsulation technology was first introduced by Chang (Science 146:524-525, 1964) and later by Lim and Sun in 1980 (Science 210:908-910, 1980). Since then, it has been well adopted in tissue engineering and controlled delivery of biological therapeutics such as bioartificial liver.
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Zhang J, Zhao X, Liang L, Li J, Demirci U, Wang S. A decade of progress in liver regenerative medicine. Biomaterials 2017; 157:161-176. [PMID: 29274550 DOI: 10.1016/j.biomaterials.2017.11.027] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 11/05/2017] [Accepted: 11/21/2017] [Indexed: 12/15/2022]
Abstract
Liver diseases can be caused by viral infection, metabolic disorder, alcohol consumption, carcinoma or injury, chronically progressing to end-stage liver disease or rapidly resulting in acute liver failure. In either situation, liver transplantation is most often sought for life saving, which is, however, significantly limited by severe shortage of organ donors. Until now, tremendous multi-disciplinary efforts have been dedicated to liver regenerative medicine, aiming at providing transplantable cells, microtissues, or bioengineered whole liver via tissue engineering, or maintaining partial liver functions via extracorporeal support. In both directions, new compatible biomaterials, stem cell sources, and bioengineering approaches have fast-forwarded liver regenerative medicine towards potential clinical applications. Another important progress in this field is the development of liver-on-a-chip technologies, which enable tissue engineering, disease modeling, and drug testing under biomimetic extracellular conditions. In this review, we aim to highlight the last decade's progress in liver regenerative medicine from liver tissue engineering, bioartificial liver devices (BAL), to liver-on-a-chip platforms, and then to present challenges ahead for further advancement.
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Affiliation(s)
- Jingwei Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, 310003, China; Institute for Translational Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310029, China
| | - Xin Zhao
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China
| | - Liguo Liang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, 310003, China; Institute for Translational Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310029, China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, 310003, China.
| | - Utkan Demirci
- Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford University, School of Medicine, Palo Alto, CA 94304, USA; Department of Electrical Engineering (By courtesy), Stanford University, Stanford, CA 94305, USA.
| | - ShuQi Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, 310003, China; Institute for Translational Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310029, China; Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford University, School of Medicine, Palo Alto, CA 94304, USA.
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Feng L, Cai L, He GL, Weng J, Li Y, Pan MX, Jiang ZS, Peng Q, Gao Y. Novel D-galactosamine-induced cynomolgus monkey model of acute liver failure. World J Gastroenterol 2017; 23:7572-7583. [PMID: 29204057 PMCID: PMC5698250 DOI: 10.3748/wjg.v23.i42.7572] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/17/2017] [Accepted: 10/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To establish a simplified, reproducible D-galactosamine-induced cynomolgus monkey model of acute liver failure having an appropriate treatment window.
METHODS Sixteen cynomolgus monkeys were randomly divided into four groups (A, B, C and D) after intracranial pressure (ICP) sensor implantation. D-galactosamine at 0.3, 0.25, 0.20 + 0.05 (24 h interval), and 0.20 g/kg body weight, respectively, was injected via the small saphenous vein. Vital signs, ICP, biochemical indices, and inflammatory factors were recorded at 0, 12, 24, 36, 48, 72, 96, and 120 h after D-galactosamine administration. Progression of clinical manifestations, survival times, and results of H&E staining, TUNEL, and Masson staining were recorded.
RESULTS Cynomolgus monkeys developed different degrees of debilitation, loss of appetite, and jaundice after D-galactosamine administration. Survival times of groups A, B, and C were 56 ± 8.7 h, 95 ± 5.5 h, and 99 ± 2.2 h, respectively, and in group D all monkeys survived the 144-h observation period except for one, which died at 136 h. Blood levels of ALT, AST, CK, LDH, TBiL, Cr, BUN, and ammonia, prothrombin time, ICP, endotoxin, and inflammatory markers [(tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6)] significantly increased compared with baseline values in different groups (P < 0.05). Pathological results showed obvious liver cell necrosis that was positively correlated with the dose of D-galactosamine.
CONCLUSION We successfully established a simplified, reproducible D-galactosamine-induced cynomolgus monkey model of acute liver failure, and the single or divided dosage of 0.25 g/kg is optimal for creating this model.
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Affiliation(s)
- Lei Feng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Lei Cai
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Guo-Lin He
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Jun Weng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Yang Li
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Ming-Xin Pan
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Ze-Sheng Jiang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Qing Peng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510282, Guangdong Province, China
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Chen E, Lu J, Chen D, Zhu D, Wang Y, Zhang Y, Zhou N, Wang J, Li J, Li L. Dynamic changes of plasma metabolites in pigs with GalN-induced acute liver failure using GC-MS and UPLC-MS. Biomed Pharmacother 2017; 93:480-489. [PMID: 28668767 DOI: 10.1016/j.biopha.2017.06.049] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 06/08/2017] [Accepted: 06/19/2017] [Indexed: 12/22/2022] Open
Abstract
Metabolomics facilitates investigation of the mechanisms of disease and screening for biomarkers. Here, a gas chromatography-mass spectrometry (GC-MS) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)-based metabolomics approach was employed to identify plasma biomarkers of acute liver failure (ALF) in pigs. Blood was collected from pigs at 12h intervals during ALF. Hepatic injury was quantified by determining liver function and histopathology. Based on a multivariate data matrix and pattern recognition, two upregulated metabolites, namely, amino acids and conjugated bile acids, and two downregulated metabolites, lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs), were identified. All of these metabolites showed a strong relationship with the extent of liver injury. Amino acids were biomarkers of the severity of liver impairment, conjugated bile acids were predictive of early stage liver damage, and LPCs and PCs were related to the prognosis of liver injury. In conclusion, our results demonstrated the occurrence of marked metabolic disturbances during ALF and that integrated metabolomics analysis facilitates identification of biomarkers of disease.
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Affiliation(s)
- Ermei Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Deying Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yini Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yimin Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Ning Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jie Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jianzhou Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
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Zhang X, Lu J, He B, Tang L, Liu X, Zhu D, Cao H, Wang Y, Li L. A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro. Int J Mol Med 2017; 39:101-112. [PMID: 27959388 PMCID: PMC5179183 DOI: 10.3892/ijmm.2016.2825] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Accepted: 12/05/2016] [Indexed: 01/01/2023] Open
Abstract
Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotra-nsformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two‑dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases.
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Affiliation(s)
- Xiaoqian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University
| | - Bin He
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang 310003, P.R. China
| | - Lingling Tang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University
| | - Xiaoli Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University
| | - Hongcui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University
| | - Yingjie Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University
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Mahou R, Passemard S, Carvello M, Petrelli A, Noverraz F, Gerber-Lemaire S, Wandrey C. Contribution of polymeric materials to progress in xenotransplantation of microencapsulated cells: a review. Xenotransplantation 2016; 23:179-201. [PMID: 27250036 DOI: 10.1111/xen.12240] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 05/09/2016] [Indexed: 12/13/2022]
Abstract
Cell microencapsulation and subsequent transplantation of the microencapsulated cells require multidisciplinary approaches. Physical, chemical, biological, engineering, and medical expertise has to be combined. Several natural and synthetic polymeric materials and different technologies have been reported for the preparation of hydrogels, which are suitable to protect cells by microencapsulation. However, owing to the frequent lack of adequate characterization of the hydrogels and their components as well as incomplete description of the technology, many results of in vitro and in vivo studies appear contradictory or cannot reliably be reproduced. This review addresses the state of the art in cell microencapsulation with special focus on microencapsulated cells intended for xenotransplantation cell therapies. The choice of materials, the design and fabrication of the microspheres, as well as the conditions to be met during the cell microencapsulation process, are summarized and discussed prior to presenting research results of in vitro and in vivo studies. Overall, this review will serve to sensitize medically educated specialists for materials and technological aspects of cell microencapsulation.
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Affiliation(s)
- Redouan Mahou
- Interfaculty Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Solène Passemard
- Interfaculty Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Michele Carvello
- Department of Surgery, San Raffaele Scientific Institute, Milan, Italy
| | | | - François Noverraz
- Interfaculty Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Sandrine Gerber-Lemaire
- Interfaculty Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Christine Wandrey
- Interfaculty Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Zhou P, Shao L, Zhao L, Lv G, Pan X, Zhang A, Li J, Zhou N, Chen D, Li L. Efficacy of Fluidized Bed Bioartificial Liver in Treating Fulminant Hepatic Failure in Pigs: A Metabolomics Study. Sci Rep 2016; 6:26070. [PMID: 27194381 PMCID: PMC4872127 DOI: 10.1038/srep26070] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 04/26/2016] [Indexed: 12/13/2022] Open
Abstract
Bioartificial livers may act as a promising therapy for fulminant hepatic failure (FHF) with better accessibility and less injury compared to orthotopic liver transplantation. This study aims to evaluate the efficacy and safety of a fluidized bed bioartificial liver (FBBAL) and to explore its therapeutic mechanisms based on metabolomics. FHF was induced by D-galactosamine. Eighteen hours later, pigs were treated with an FBBAL containing encapsulated primary porcine hepatocytes (B group), with a sham FBBAL (containing cell-free capsules, S group) or with only intensive care (C group) for 6 h. Serum samples were assayed using ultra-performance liquid chromatography-mass spectrometry. The difference in survival time (51.6 ± 7.9 h vs. 49.3 ± 6.6 h) and serum metabolome was negligible between the S and C groups, whereas FBBAL treatment significantly prolonged survival time (70.4 ± 11.5h, P < 0.01) and perturbed the serum metabolome, resulting in a marked decrease in phosphatidylcholines, lysophosphatidylcholines, sphingomyelinase, and fatty acids and an increase in conjugated bile acids. The FBBAL exhibits some liver functions and may exert its therapeutic effect by altering the serum metabolome of FHF pigs. Moreover, alginate-chitosan capsules have less influence on serum metabolites. Nevertheless, the alterations were not universally beneficial, revealing that much should be done to improve the FBBAL.
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Affiliation(s)
- Pengcheng Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
- Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Li Shao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Lifu Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Guoliang Lv
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Xiaoping Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Anye Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Jianzhou Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Ning Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Deying Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
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Lu J, Zhang X, Li J, Yu L, Chen E, Zhu D, Zhang Y, Li L. A New Fluidized Bed Bioreactor Based on Diversion-Type Microcapsule Suspension for Bioartificial Liver Systems. PLoS One 2016; 11:e0147376. [PMID: 26840840 PMCID: PMC4739599 DOI: 10.1371/journal.pone.0147376] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 01/04/2016] [Indexed: 12/25/2022] Open
Abstract
A fluidized bed bioreactor containing encapsulated hepatocytes may be a valuable alternative to a hollow fiber bioreactor for achieving the improved mass transfer and scale-up potential necessary for clinical use. However, a conventional fluidized bed bioreactor (FBB) operating under high perfusion velocity is incapable of providing the desired performance due to the resulting damage to cell-containing microcapsules and large void volume. In this study, we developed a novel diversion-type microcapsule-suspension fluidized bed bioreactor (DMFBB). The void volume in the bioreactor and stability of alginate/chitosan microcapsules were investigated under different flow rates. Cell viability, synthesis and metabolism functions, and expression of metabolizing enzymes at transcriptional levels in an encapsulated hepatocyte line (C3A cells) were determined. The void volume was significantly less in the novel bioreactor than in the conventional FBB. In addition, the microcapsules were less damaged in the DMFBB during the fluidization process as reflected by the results for microcapsule retention rates, swelling, and breakage. Encapsulated C3A cells exhibited greater viability and CYP1A2 and CYP3A4 activity in the DMFBB than in the FBB, although the increases in albumin and urea synthesis were less prominent. The transcription levels of several CYP450-related genes and an albumin-related gene were dramatically greater in cells in the DMFBB than in those in the FBB. Taken together, our results suggest that the DMFBB is a promising alternative for the design of a bioartificial liver system based on a fluidized bed bioreactor with encapsulated hepatocytes for treating patients with acute hepatic failure or other severe liver diseases.
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Affiliation(s)
- Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoqian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianzhou Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liang Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ermei Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yimin Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - LanJuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- * E-mail:
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Deng F, Chen L, Zhang Y, Zhao S, Wang Y, Li N, Li S, Guo X, Ma X. Development of a bioreactor based on magnetically stabilized fluidized bed for bioartificial liver. Bioprocess Biosyst Eng 2015; 38:2369-77. [PMID: 26391509 DOI: 10.1007/s00449-015-1472-x] [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: 04/17/2015] [Accepted: 09/07/2015] [Indexed: 12/12/2022]
Abstract
Bioartificial liver (BAL) based on microcapsules has been proposed as a potential treatment for acute liver failure. The bioreactors used in such BAL are usually expected to achieve sufficient flow rate and minimized void volume for effective application. Due to the superiorities in bed pressure drop and operation velocity, magnetically stabilized fluidized beds (MSFBs) show the potential to serve as ideal microcapsule-based bioreactors. In the present study, we attempted to develop a microcapsule-based MSFB bioreactor for bioartificial liver device. Compared to conventional-fluidized bed bioreactors, the bioreactor presented here increased perfusion velocity and decreased void volume significantly. Meanwhile, the mechanical stability as well as the immunoisolation property of magnetite microcapsules were well maintained during the fluidization. Besides, the magnetite microcapsules were found no toxicity to cell survival. Therefore, our study might provide a novel approach for the design of microcapsule-based bioartificial liver bioreactors.
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Affiliation(s)
- Fei Deng
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Li Chen
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Ying Zhang
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.
| | - Shan Zhao
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Yu Wang
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Na Li
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Shen Li
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Xin Guo
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China
| | - Xiaojun Ma
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.
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26
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Zhou N, Li J, Zhang Y, Lu J, Chen E, Du W, Wang J, Pan X, Zhu D, Yang Y, Chen Y, Cao H, Li L. Efficacy of coupled low-volume plasma exchange with plasma filtration adsorption in treating pigs with acute liver failure: A randomised study. J Hepatol 2015; 63:378-387. [PMID: 25814048 DOI: 10.1016/j.jhep.2015.03.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 03/13/2015] [Accepted: 03/14/2015] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS Extracorporeal blood purification systems for supportive therapy of liver failure are widely used. We developed a novel blood purification system, named Li's artificial liver system (Li-ALS), which couples low-volume plasma exchange (low-volume PE) with plasma filtration adsorption (PFA). This study aims to evaluate the efficacy of our novel system in pigs with acute liver failure (ALF). METHODS Thirty-two pigs were infused with D-galactosamine (1.3g/kg) to induce ALF. All animals were equally and randomly divided into four groups: the ALF control group received intensive care, the PFA group underwent five hour plasma recycling filtration and adsorption purification, the low-volume PE group received one hour low-volume PE, and the Li-ALS group underwent one hour low-volume PE, followed by five hour PFA. Intervention was initiated 36hours after drug administration. The efficacy of each treatment was assessed by survival time and improvement in hematological, biochemical, and immunohistological parameters. RESULTS Pigs in the Li-ALS group survived longer than those in the other groups (p<0.001, ALF control: 60±2h; PFA group: 74±2h; low-volume PE group: 75±2h; and Li-ALS group: 90±3h). Liver enzyme, bilirubin, bile acid and blood ammonia levels were decreased significantly after Li-ALS treatment, and increases in inflammatory cytokines were ameliorated. A higher hepatocyte regeneration index was also observed in the Li-ALS group. CONCLUSION Our novel Li-ALS could expedite liver regeneration and improve survival time; hence, it could be promising for treating ALF.
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Affiliation(s)
- Ning Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China
| | - Jianzhou Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China
| | - Yimin Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China
| | - Ermei Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China
| | - Weibo Du
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China
| | - Jie Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China
| | - Xiaoping Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China
| | - Ying Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China
| | - Yu Chen
- Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China
| | - Hongcui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China.
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27
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Yang Y, Liu XX. Pharmaceutical care for patients with anti-tuberculosis drug induced liver injury. Shijie Huaren Xiaohua Zazhi 2015; 23:3060-3068. [DOI: 10.11569/wcjd.v23.i19.3060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Drug induced liver injury is one of the most important and serious adverse effects of anti-tuberculosis drugs. The clinical features of anti-tuberculosis drug induced liver injury (ATLI) ranges from asymptomatic alanine aminotransferase (ALT) elevations to acute hepatitis symptoms, and the mortality cases associated with liver failure are not rare. ATLI diminishes the effectiveness of anti-tuberculosis treatment, as they may cause non-adherence, and further leads to treatment interruption, recurrence or the emergence of drug resistance. The aim of this paper is to discuss the clinical features, mechanisms, risk factors and treatment principles for ATLI. In addition, the reasonable adjustment of anti-tuberculosis treatment and implementation of pharmaceutical care are also reviewed so as to provide thoughts on the prevention, diagnosis and timely intervention of ATLI.
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28
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Sullivan DC, Repper JP, Frock AW, McFetridge PS, Petersen BE. Current Translational Challenges for Tissue Engineering: 3D Culture, Nanotechnology, and Decellularized Matrices. CURRENT PATHOBIOLOGY REPORTS 2015. [DOI: 10.1007/s40139-015-0066-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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29
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Chen L, Zhang Y, Li S, Wang X, Li N, Wang Y, Guo X, Zhao S, Yu W, Sun G, Liu Y, Ma X. Effect of plasma components on the stability and permeability of microcapsule. J Biomed Mater Res A 2013; 102:2408-16. [PMID: 23946210 DOI: 10.1002/jbm.a.34907] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 07/11/2013] [Accepted: 08/05/2013] [Indexed: 01/05/2023]
Abstract
Immobilization of hepatocytes in microcapsules has been a potentially alternative methodology for bioartificial livers (BALs). Moreover, the stability and permeability are the key parameters of these microcapsules. However, these alginate-based microcapsules are unstable if the surrounding medium disrupts the ionic interactions between alginate and the polycation. As hundreds of components are included in human plasma, the stability and permeability in plasma of microcapsules need to be sufficiently investigated. In the present study, the stability of three kinds of alginate-based microcapsules was evaluated when they were immersed in plasma. Our results showed that stability of alginate-α-poly (L-lysine)-alginate (α-APA) microcapsules was well maintained, better than those of alginate-ε-poly (L-lysine)-alginate (ε-APA) and alginate-chitosan-alginate (ACA) microcapsules. Also, factors affecting the stability of microcapsules in plasma were analyzed and it showed that heparin was the key factor that affected the stability of α-APA microcapsules, whereas heparin and low molecular electrolytes such as HCO3(-) and H2 PO4(-)/HPO4(2-) were the factors to ε-APA and ACA microcapsules. In addition, the permeability evaluation showed no decrease in permeability of microcapsules after incubation in plasma. Our study might provide a foundation for the selection and modification of materials for microcapsule-based BAL devices.
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Affiliation(s)
- Li Chen
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China; University of the Chinese Academy of Sciences, Beijing, 100049, China
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30
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Lin CC, Wang CC, Hung KC, Chen CL, Yong CC, Young TH, Kobayash E. Study of porcine hepatocyte-entrapped bioartificial liver in surgery-induced fulminant hepatic failure rabbits. Biochem Eng J 2013. [DOI: 10.1016/j.bej.2013.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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31
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Yang Y, Li J, Pan X, Zhou P, Yu X, Cao H, Wang Y, Li L. Co-culture with mesenchymal stem cells enhances metabolic functions of liver cells in bioartificial liver system. Biotechnol Bioeng 2013; 110:958-968. [PMID: 23055347 DOI: 10.1002/bit.24752] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2012] [Revised: 09/14/2012] [Accepted: 10/01/2012] [Indexed: 01/06/2023]
Abstract
Bioartificial liver provides a combination of three-dimensional support, matrix interactions, and extracellular cues to create a bio-mimic microenvironment for maintaining hepatic-specific functions of liver cells in vitro. However, its transformal and metabolic functions are not yet satisfactory for clinic application. In this study, hepatoma-derived C3A cells were co-cultured with human placental mesenchymal stem cells (hPMSC) in microspheres placed in a fluidized bioreactor. The secretion of albumin and urea, the expression of metabolizing enzymes at both transcriptional and translational levels and the drug metabolism functions of co-cultured C3A cells were determined. With the three-dimensional culture system, when C3A cells were co-cultured with hPMSCs in separate microspheres, the secretion of albumin and activity of CYP1A2 were significantly improved although the enhancement of urea synthesis and CYP3A4 activity was less prominent. Combining co-culture system with fluidization significantly increased the secretion of urea and the activities of CYP1A2, CYP3A4 but not the albumin synthesis. Interestingly, the levels of phospho-PKA (Thr 197), phospho-PKC, phospho-ERK1/2 (Thr 202/Tyr 204) and CaMKII were all found to decrease in co-cultured C3A cells, implicating suppressed signaling pathways in those cells. Taken together, our results suggest that co-culturing of liver cells with hPMSC cells in three-dimensional fluidized bioreactor significantly improved the preservation of liver cells' metabolic functions which may greatly enhance the efficacy of bioartificial liver treatment.
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Affiliation(s)
- Ying Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Acarregui A, Murua A, Pedraz JL, Orive G, Hernández RM. A Perspective on Bioactive Cell Microencapsulation. BioDrugs 2012; 26:283-301. [DOI: 10.1007/bf03261887] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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33
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Tran NM, Dufresne M, Duverlie G, Castelain S, Défarge C, Paullier P, Legallais C. An appropriate selection of a 3D alginate culture model for hepatic Huh-7 cell line encapsulation intended for viral studies. Tissue Eng Part A 2012; 19:103-13. [PMID: 22889091 DOI: 10.1089/ten.tea.2012.0139] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Three-dimensional (3D) culture systems have been introduced to provide cells with a biomimetic environment that is similar to in vivo conditions. Among the polymeric molecules available, sodium-alginate (Na-alg) salt is a material that is currently employed in different areas of drug delivery and tissue engineering, because it offers biocompatibility and optimal chemical properties, and its gelation with calcium chloride provides calcium-alginate (Ca-alg) scaffolds with mechanical stability and relative permeability. In this work, four different preparations of Ca-alg beads with varying Na-alg viscosity and concentration were used for a human hepatoma cell line (Huh-7) encapsulation. The effects of Ca-alg bead preparation on structural cell organization, liver-specific functions, and the expression of specific receptors implicated in hepatotropic virus permissivity were evaluated. Hepatic cells were cultured in 500 μm diameter Ca-alg beads for 7 days under dynamic conditions. For all culture systems, cell viability reached almost 100% at day 7. Cell proliferation was concomitantly followed by hepatocyte organization in aggregates, which adopted two different morphologies (spheroid aggregates or multicellular channel-like structures), depending on Ca-alg bead preparation. These cellular organizations established a real 3D hepatocyte architecture with cell polarity, cell junctions, and abundant bile canaliculi possessing microvillus-lined channels. The functionality of these 3D cultures was confirmed by the production of albumin and the exhibition of CYP1A activity over culture time, which were variable, according to Ca-alg bead condition. The expression of specific receptors of hepatitis C virus by Huh-7 cells suggests encouraging data for the further development of a new viral culture system in Ca-alg beads. In summary, this 3D hepatic cell culture represents a promising physiologically relevant system for further in vitro studies and demonstrates that an adequate encapsulation condition can be selected for each target application in liver tissue engineering, specifically in viral studies.
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Affiliation(s)
- Nhu Mai Tran
- Biomechanics and Bioengineering, Unité Mixte de Recherche CNRS 7338, University of Technology of Compiègne, Compiègne, France
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Li J, Zhang L, Xin J, Jiang L, Li J, Zhang T, Jin L, Li J, Zhou P, Hao S, Cao H, Li L. Immediate intraportal transplantation of human bone marrow mesenchymal stem cells prevents death from fulminant hepatic failure in pigs. Hepatology 2012; 56:1044-1052. [PMID: 22422600 DOI: 10.1002/hep.25722] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Accepted: 02/29/2012] [Indexed: 12/15/2022]
Abstract
UNLABELLED The effectiveness of human bone marrow mesenchymal stem cell (hBMSC) transplantation to treat acute and chronic liver injury has been demonstrated in animal models and in a few nonrandomized clinical trials. However, no studies have investigated hBMSC transplantation in the treatment of fulminant hepatic failure (FHF), especially in large animal (pig) models. The aim of this study was to demonstrate the safety, effectiveness, and underlying mechanism of hBMSC transplantation for treating FHF in pigs through the intraportal route. Human BMSCs (3 × 10(7) ) were transplanted into pigs with FHF via the intraportal route or peripheral vein immediately after D-galactosamine injection, and a sham group underwent intraportal transplantation (IPT) without cells (IPT, peripheral vein transplantation [PVT], and control groups, respectively, n = 15 per group). All of the animals in the PVT and control groups died of FHF within 96 hours. In contrast, 13 of 15 animals in the IPT group achieved long-term survival (>6 months). Immunohistochemistry demonstrated that transplanted hBMSC-derived hepatocytes in surviving animals were widely distributed in the hepatic lobules and the liver parenchyma from weeks 2 to 10. Thirty percent of the hepatocytes were hBMSC-derived. However, the number of transplanted cells decreased significantly at week 15. Only a few single cells were scattered in the regenerated liver lobules at week 20, and the liver tissues exhibited a nearly normal structure. CONCLUSION Immediate IPT of hBMSCs is a safe and effective treatment for FHF. The transplanted hBMSCs may quickly participate in liver regeneration via proliferation and transdifferentiation into hepatocytes during the initial stage of FHF. This method can possibly be used in future clinical therapy.
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Affiliation(s)
- Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Zhang S, Liu T, Chen L, Ren M, Zhang B, Wang Z, Wang Y. Bifunctional polyethersulfone hollow fiber with a porous, single-layer skin for use as a bioartificial liver bioreactor. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2012; 23:2001-2011. [PMID: 22584823 DOI: 10.1007/s10856-012-4673-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2012] [Accepted: 05/02/2012] [Indexed: 05/31/2023]
Abstract
A bioartificial liver bioreactor requires a bifunctional hollow fiber that is hemocompatible on one side and cytocompatible on the other side. In this study, we developed a single-layer skin polyethersulfone (PES) hollow fiber with smooth inner surface and rough/porous outer surface for an artificial liver bioreactor. The hemocompatibility of the inner surface was evaluated by hemolysis, complement activation and clotting time. The cytocompatibility of the outer surface with HepG2 cells was examined by morphology, proliferation and liver-specific functions. The inner surface of the PES hollow fiber exhibited lower hemolysis and complement activation than cellulose acetate (CA) hollow fiber and a prolonged blood coagulation time. HepG2 cells readily adhered to the outer surfaces of the PES hollow fibers, and proliferated to form multicellular aggregates with time. Furthermore, HepG2 cells cultured on the outer surface of the PES hollow fiber exhibited higher proliferation ability and liver-specific functions than those grown on the CA hollow fiber. These results suggest that the single-layer skin PES hollow fiber is a bifunctional hollow fiber with good hemocompatibility on the inner side and cytocompatibility on the outer side. Thus, porous and single-layer skin PES hollow fibers may have potential as materials for an artificial liver bioreactor.
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Affiliation(s)
- Shichang Zhang
- Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
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Li J, Xin J, Hao S, Zhang L, Jiang L, Chen D, Xie Q, Xu W, Cao H, Li L. Return of the metabolic trajectory to the original area after human bone marrow mesenchymal stem cell transplantation for the treatment of fulminant hepatic failure. J Proteome Res 2012; 11:3414-3422. [PMID: 22582960 DOI: 10.1021/pr3002639] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Our recent study first demonstrated that human bone marrow mesenchymal stem cell (hBMSC) transplantation could prevent death from fulminant hepatic failure (FHF) in pigs. To further clarify the metabolic mechanism of hBMSC transplantation in FHF, the plasma collected from FHF pigs that received transplantation of hBMSCs was examined using metabolic analysis to identify the key molecular markers that regulate recovery. The results showed that obvious metabolic disturbance occurred during FHF, whereas the hBMSC transplantation group showed less severe liver injury. The metabolic trajectory returns to its original state at week 3 following the hBMSC transplantation. In total, the concentration of 26 metabolites, including conjugated bile acids, phosphatidylcholines, lysophosphatidylcholines, fatty acids, amino acid and sphingomyelin, are significantly different between the FHF group and the hBMSC transplantation group. Moreover, the time course of changes in the metabolites corresponded with that of the biochemical and histological analyses. Real-time PCR further confirmed that the gene expression of phospholipase A1, lecithin-cholesterol acyltransferase and lysophosphatidylcholine acyltransferase 1 decreased significantly, whereas that of phospholipase A2 remained stable, which explains the decrease of the phosphatidylcholines and lysophosphatidylcholines. These novel results have revealed a metabolic mechanism for the hBMSC transplantation in FHF, which could lead to the future development of treatment strategies for stem cell therapies.
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Affiliation(s)
- Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University , 79 Qingchun Rd., Hangzhou 310003, China
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