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1
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Wu JJ, Huang Y, Gao HN, Sheng GP. A successful case report of menstrual blood derived-mesenchymal stem cell-based therapy for Wilson's disease. Hepatobiliary Pancreat Dis Int 2025; 24:352-354. [PMID: 37978031 DOI: 10.1016/j.hbpd.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 10/30/2023] [Indexed: 11/19/2023]
Affiliation(s)
- Jia-Jun Wu
- Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310022, China
| | - Yong Huang
- Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310022, China
| | - Hai-Nv Gao
- Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310022, China
| | - Guo-Ping Sheng
- Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310022, China.
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2
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Hu C, Wang L. Advances in the treatment of liver injury based on mesenchymal stem cell-derived exosomes. Stem Cell Res Ther 2024; 15:474. [PMID: 39696473 DOI: 10.1186/s13287-024-04087-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have shown a great potential role in treating liver injury. MSCs can promote liver regeneration by differentiating into hepatocytes, and can also secrete exosomes to participate in the repair of liver injury. Increasing evidence has shown that mesenchymal stem cell-derived exosomes (MSC-EXOs) play an important role in treating liver injury. In this review, the biogenesis and function of exosomes and the characteristics of MSC-EXOs were analyzed based on recent research results. MSC-EXOs are significant in liver injuries such as liver fibrosis, liver failure, hepatocellular carcinoma, oxidative stress, and lipid steatosis, and participate in the process of liver regeneration.
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Affiliation(s)
- Changlong Hu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China.
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3
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Mahmoudi A, Meidany P, Almahmeed W, Jamialahmadi T, Sahebkar A. Stem Cell Therapy as a Potential Treatment of Non-Alcoholic Steatohepatitis-Related End-Stage Liver Disease: A Narrative Review. CURRENT STEM CELL REPORTS 2024; 10:85-107. [DOI: 10.1007/s40778-024-00241-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2024] [Indexed: 01/04/2025]
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4
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Manskikh VN. Organ Frame Elements or Free Intercellular Gel-Like Matrix as Necessary Conditions for Building Organ Structures during Regeneration. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:269-278. [PMID: 38622095 DOI: 10.1134/s000629792402007x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/02/2023] [Accepted: 11/15/2023] [Indexed: 04/17/2024]
Abstract
Over the past decades, an unimaginably large number of attempts have been made to restore the structure of mammalian organs after injury by introducing stem cells into them. However, this procedure does not lead to full recovery. At the same time, it is known that complete regeneration (restitution without fibrosis) is possible in organs with proliferating parenchymal cells. An analysis of such models allows to conclude that the most important condition for the repair of histological structures of an organ (in the presence of stem cells) is preservation of the collagen frame structures in it, which serve as "guide rails" for proliferating and differentiating cells. An alternative condition for complete reconstruction of organ structures is the presence of a free "morphogenetic space" containing a gel-like matrix of the embryonic-type connective tissue, which exists during embryonal development of organs in mammals or during complete regeneration in amphibians. Approaches aimed at preserving frame structures or creating a "morphogenetic space" could radically improve the results of organ regeneration using both local and exogenous stem cells.
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Affiliation(s)
- Vasily N Manskikh
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
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5
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Zhang H, Chen Q, Hu D, Lai J, Yan M, Wu Z, Yang Z, Zheng S, Liu W, Zhang L, Bai L. Manipulating HGF signaling reshapes the cirrhotic liver niche and fills a therapeutic gap in regeneration mediated by transplanted stem cells. Exp Cell Res 2024; 434:113867. [PMID: 38043723 DOI: 10.1016/j.yexcr.2023.113867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 11/22/2023] [Accepted: 11/27/2023] [Indexed: 12/05/2023]
Abstract
Long-term stem cell survival in the cirrhotic liver niche to maintain therapeutic efficacy has not been achieved. In a well-defined diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis animal model, we previously showed that liver-resident stem/progenitor cells (MLpvNG2+ cells) or immune cells have improved survival in the fibrotic liver environment but died via apoptosis in the cirrhotic liver environment, and increased levels of hepatocyte growth factor (HGF) mediated this cell death. We tested the hypothesis that inhibiting HGF signaling during the cirrhotic phase could keep the cells alive. We used adeno-associated virus (AAV) vectors designed to silence the c-Met (HGF-only receptor) gene or a neutralizing antibody (anti-cMet-Ab) to block the c-Met protein in the DEN-induced liver cirrhosis mouse model transplanted with MLpvNG2+ cells between weeks 6 and 7 after DEN administration, which is the junction of liver fibrosis and cirrhosis at the site where most intrahepatic stem cells move toward apoptosis. After 4 weeks of treatment, the transplanted MLpvNG2+ cells survived better in c-Met-deficient mice than in wild-type mice, and cell activity was similar to that of the mice that received MLpvNG2+ cells at 5 weeks after DEN administration (liver fibrosis phase when most of these cells proliferated). Mechanistically, a lack of c-Met signaling remodeled the cirrhotic environment, which favored transplanted MLpvNG2+ cell expansion to differentiation into mature hepatocytes and initiate endogenous regeneration by promoting mature host hepatocyte generation and mediating functional improvements. Therapeutically, c-Met-mediated regeneration can be mimicked by anti-cMet-Ab to interfere functions, which is a potential drug for cell-based treatment of liver fibrosis/cirrhosis.
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Affiliation(s)
- Hongyu Zhang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Quanyu Chen
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Deyu Hu
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China; Bioengineering College, Chongqing University, No. 175 Gaotan, ShapingBa Distract, Chongqing 400044, China
| | - Jiejuan Lai
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Min Yan
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China; Department of Specific Medicine, the First Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Zhifang Wu
- Department of Specific Medicine, the First Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Zhiqing Yang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Shuguo Zheng
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Wei Liu
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Leida Zhang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China
| | - Lianhua Bai
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, China; Bioengineering College, Chongqing University, No. 175 Gaotan, ShapingBa Distract, Chongqing 400044, China; Department of Specific Medicine, the First Hospital of Shanxi Medical University, Taiyuan, 030000, China.
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6
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Wang J, Li Q, Li W, Méndez-Sánchez N, Liu X, Qi X. Stem Cell Therapy for Liver Diseases: Current Perspectives. FRONT BIOSCI-LANDMRK 2023; 28:359. [PMID: 38179765 DOI: 10.31083/j.fbl2812359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 10/03/2023] [Accepted: 10/17/2023] [Indexed: 01/06/2024]
Abstract
Stem cell therapy offers a promising avenue for advanced liver disease cases as an alternative to liver transplantation. Clinical studies are underway to explore the potential of stem cells from various sources in treating different liver diseases. However, due to the variability among current studies, further validation is needed to ensure the safety and effectiveness of stem cell therapy. To establish a strong foundation for optimal stem cell therapy applications, selection of suitable stem cell sources, standardization of transplantation protocols, and patient criteria are vital. This review comprehensively examines existing literature on stem cell sources, transplantation methods, and patient selection. Additionally, we discuss novel strategies, including stem cell preconditioning, cell-free therapy, genetic modification of stem cells, and the use of liver organoids, addressing the limitations of current stem cell therapies. Nevertheless, these innovative approaches require further validation.
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Affiliation(s)
- Jing Wang
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Qun Li
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Wenbo Li
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation and Faculty of Medicine, National Autonomous University of Mexico, 14050 Mexico City, Mexico
| | - Xiaofeng Liu
- Department of Gastroenterology, The 960th Hospital of the PLA, 250000 Jinan, Shandong, China
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), 110840 Shenyang, Liaoning, China
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7
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Lu X, Guo H, Wei X, Lu D, Shu W, Song Y, Qiu N, Xu X. Current Status and Prospect of Delivery Vehicle Based on Mesenchymal Stem Cell-Derived Exosomes in Liver Diseases. Int J Nanomedicine 2023; 18:2873-2890. [PMID: 37283714 PMCID: PMC10239634 DOI: 10.2147/ijn.s404925] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 05/10/2023] [Indexed: 06/08/2023] Open
Abstract
With the improvement of the average life expectancy and increasing incidence of obesity, the burden of liver disease is increasing. Liver disease is a serious threat to human health. Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, liver transplantation still faces unavoidable difficulties. Mesenchymal stem cells (MSCs) can be used as an alternative therapy for liver disease, especially liver cirrhosis, liver failure, and liver transplantation complications. However, MSCs may have potential tumorigenic effects. Exosomes derived from MSCs (MSC-Exos), as the important intercellular communication mode of MSCs, contain various proteins, nucleic acids, and DNA. MSC-Exos can be used as a delivery system to treat liver diseases through immune regulation, apoptosis inhibition, regeneration promotion, drug delivery, and other ways. Good histocompatibility and material exchangeability make MSC-Exos a new treatment for liver diseases. This review summarizes the latest research on MSC-Exos as delivery vehicles in different liver diseases, including liver injury, liver failure, liver fibrosis, hepatocellular carcinoma (HCC), and ischemia and reperfusion injury. In addition, we discuss the advantages, disadvantages, and clinical application prospects of MSC-Exos-based delivery vectors in the treatment of liver diseases.
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Affiliation(s)
- Xinfeng Lu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Haijun Guo
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Xuyong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Di Lu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Wenzhi Shu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
| | - Yisu Song
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
| | - Nasha Qiu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Xiao Xu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
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8
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Shafritz DA, Ebrahimkhani MR, Oertel M. Therapeutic Cell Repopulation of the Liver: From Fetal Rat Cells to Synthetic Human Tissues. Cells 2023; 12:529. [PMID: 36831196 PMCID: PMC9954009 DOI: 10.3390/cells12040529] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 02/10/2023] Open
Abstract
Progenitor cells isolated from the fetal liver can provide a unique cell source to generate new healthy tissue mass. Almost 20 years ago, it was demonstrated that rat fetal liver cells repopulate the normal host liver environment via a mechanism akin to cell competition. Activin A, which is produced by hepatocytes, was identified as an important player during cell competition. Because of reduced activin receptor expression, highly proliferative fetal liver stem/progenitor cells are resistant to activin A and therefore exhibit a growth advantage compared to hepatocytes. As a result, transplanted fetal liver cells are capable of repopulating normal livers. Important for cell-based therapies, hepatic stem/progenitor cells containing repopulation potential can be separated from fetal hematopoietic cells using the cell surface marker δ-like 1 (Dlk-1). In livers with advanced fibrosis, fetal epithelial stem/progenitor cells differentiate into functional hepatic cells and out-compete injured endogenous hepatocytes, which cause anti-fibrotic effects. Although fetal liver cells efficiently repopulate the liver, they will likely not be used for human cell transplantation. Thus, utilizing the underlying mechanism of repopulation and developed methods to produce similar growth-advantaged cells in vitro, e.g., human induced pluripotent stem cells (iPSCs), this approach has great potential for developing novel cell-based therapies in patients with liver disease. The present review gives a brief overview of the classic cell transplantation models and various cell sources studied as donor cell candidates. The advantages of fetal liver-derived stem/progenitor cells are discussed, as well as the mechanism of liver repopulation. Moreover, this article reviews the potential of in vitro developed synthetic human fetal livers from iPSCs and their therapeutic benefits.
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Affiliation(s)
- David A. Shafritz
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Mo R. Ebrahimkhani
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Michael Oertel
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
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9
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Ali S, Haque N, Azhar Z, Saeinasab M, Sefat F. Regenerative Medicine of Liver: Promises, Advances and Challenges. Biomimetics (Basel) 2021; 6:biomimetics6040062. [PMID: 34698078 PMCID: PMC8544204 DOI: 10.3390/biomimetics6040062] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 10/06/2021] [Accepted: 10/14/2021] [Indexed: 12/16/2022] Open
Abstract
Liver tissue engineering is a rapidly developing field which combines the novel use of liver cells, appropriate biochemical factors, and engineering principles, in order to replace or regenerate damaged liver tissue or the organ. The aim of this review paper is to critically investigate different possible methods to tackle issues related with liver diseases/disorders mainly using regenerative medicine. In this work the various regenerative treatment options are discussed, for improving the prognosis of chronic liver disorders. By reviewing existing literature, it is apparent that the current popular treatment option is liver transplantation, although the breakthroughs of stem cell-based therapy and bioartificial liver technology make them a promising alternative.
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Affiliation(s)
- Saiful Ali
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD7 1DP, UK; (S.A.); (N.H.); (Z.A.)
| | - Nasira Haque
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD7 1DP, UK; (S.A.); (N.H.); (Z.A.)
| | - Zohya Azhar
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD7 1DP, UK; (S.A.); (N.H.); (Z.A.)
| | - Morvarid Saeinasab
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran;
| | - Farshid Sefat
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD7 1DP, UK; (S.A.); (N.H.); (Z.A.)
- Interdisciplinary Research Centre in Polymer Science & Technology (Polymer IRC), University of Bradford, Bradford BD7 1DP, UK
- Correspondence: ; Tel.: +44-(0)-1274-233679 or +44-(0)-781-381-7460
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10
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Artificial cells for the treatment of liver diseases. Acta Biomater 2021; 130:98-114. [PMID: 34126265 DOI: 10.1016/j.actbio.2021.06.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/06/2021] [Accepted: 06/03/2021] [Indexed: 12/13/2022]
Abstract
Liver diseases have become an increasing health burden and account for over 2 million deaths every year globally. Standard therapies including liver transplant and cell therapy offer a promising treatment for liver diseases, but they also suffer limitations such as adverse immune reactions and lack of long-term efficacy. Artificial cells that mimic certain functions of a living cell have emerged as a new strategy to overcome some of the challenges that liver cell therapy faces at present. Artificial cells have demonstrated advantages in long-term storage, targeting capability, and tuneable features. This article provides an overview of the recent progress in developing artificial cells and their potential applications in liver disease treatment. First, the design of artificial cells and their biomimicking functions are summarized. Then, systems that mimic cell surface properties are introduced with two concepts highlighted: cell membrane-coated artificial cells and synthetic lipid-based artificial cells. Next, cell microencapsulation strategy is summarized and discussed. Finally, challenges and future perspectives of artificial cells are outlined. STATEMENT OF SIGNIFICANCE: Liver diseases have become an increasing health burden. Standard therapies including liver transplant and cell therapy offer a promising treatment for liver diseases, but they have limitations such as adverse immune reactions and lack of long-term efficacy. Artificial cells that mimic certain functions of a living cell have emerged as a new strategy to overcome some of the challenges that liver cell therapy faces at present. This article provides an overview of the recent progress in developing artificial cells and their potential applications in liver disease treatment, including the design of artificial cells and their biomimicking functions, two systems that mimic cell surface properties (cell membrane-coated artificial cells and synthetic lipid-based artificial cells), and cell microencapsulation strategy. We also outline the challenges and future perspectives of artificial cells.
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11
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Cell Therapy and Bioengineering in Experimental Liver Regenerative Medicine: In Vivo Injury Models and Grafting Strategies. CURRENT TRANSPLANTATION REPORTS 2021. [DOI: 10.1007/s40472-021-00325-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Abstract
Purpose of Review
To describe experimental liver injury models used in regenerative medicine, cell therapy strategies to repopulate damaged livers and the efficacy of liver bioengineering.
Recent Findings
Several animal models have been developed to study different liver conditions. Multiple strategies and modified protocols of cell delivery have been also reported. Furthermore, using bioengineered liver scaffolds has shown promising results that could help in generating a highly functional cell delivery system and/or a whole transplantable liver.
Summary
To optimize the most effective strategies for liver cell therapy, further studies are required to compare among the performed strategies in the literature and/or innovate a novel modifying technique to overcome the potential limitations. Coating of cells with polymers, decellularized scaffolds, or microbeads could be the most appropriate solution to improve cellular efficacy. Besides, overcoming the problems of liver bioengineering may offer a radical treatment for end-stage liver diseases.
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12
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Wei S, Tang J, Cai X. Founder cells for hepatocytes during liver regeneration: from identification to application. Cell Mol Life Sci 2020; 77:2887-2898. [PMID: 32060582 PMCID: PMC11105049 DOI: 10.1007/s00018-020-03457-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 01/02/2020] [Accepted: 01/10/2020] [Indexed: 12/12/2022]
Abstract
Liver regeneration (LR) capacity in vertebrates developed through natural selection over a hundred million years of evolution. To maintain homeostasis or recover from various injuries, liver cells must regenerate; this process includes the renewal of parenchymal and nonparenchymal cells as well as the formation of liver structures. The cellular origin of newly grown tissue is one of the critical questions in this area and has been a subject of prolonged debate. The regenerative tissue may derive from either hepatocyte self-duplication or liver stem/progenitor cells (LSPCs). Recently, hepatocyte subpopulations and cholangiocytes were also described as important founder cells. The niche that triggers the proliferation of hepatocytes and the differentiation of LSPCs has been extensively studied. Meanwhile, in vitro culture systems for liver founder cells and organoids have been developed rapidly for mechanistic studies and potential therapeutic purposes. This review summarizes the cellular sources and niches that give rise to renewed hepatocytes during LR, and it also describes in vitro culture studies of those founder cells for future applications, as well as current reports for stem cell-based therapies for liver diseases.
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Affiliation(s)
- Saisai Wei
- Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
| | - Jiacheng Tang
- Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
| | - Xiujun Cai
- Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
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13
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Hara H, Sano K, Ishikawa H, Ohkoshi S. Differentiation of Dental Pulp-Derived MSCs into Hepatocyte-Like Cells and Their Therapeutic Use for Chemical Liver Injuries of Rats. J HARD TISSUE BIOL 2020; 29:215-222. [DOI: 10.2485/jhtb.29.215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Hajime Hara
- Department of Internal Medicine, School of Life Dentistry at Niigata, The Nippon Dental University
| | - Kimito Sano
- Department of Dental Anesthesiology, School of Life Dentistry at Niigata, The Nippon Dental University
| | - Hiroshi Ishikawa
- Laboratory of Clinical Regenerative Medicine, Faculty of Medicine, University of Tsukuba
| | - Shogo Ohkoshi
- Department of Internal Medicine, School of Life Dentistry at Niigata, The Nippon Dental University
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14
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Chen B, Pang L, Cao H, Wu D, Wang Y, Tao Y, Wang M, Chen E. Autologous stem cell transplantation for patients with viral hepatitis-induced liver cirrhosis: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2019; 31:1283-1291. [PMID: 31206409 DOI: 10.1097/meg.0000000000001455] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Recently, stem cells have been used in the treatment of viral hepatitis-induced liver cirrhosis (LC), and stem cell therapy is showing potential therapeutic effects on liver function improvement. The consensus on effects and safety of stem cell therapy has not been reached, thus it is essential for us to conduct a systematic review and meat-analysis to investigate the efficacy and safety of stem cell therapy for viral hepatitis-induced LC. MATERIALS AND METHODS Medline, Embase, SinoMed and Cochrane Library databases were searched with appropriate keywords through 5 August 2018. We included eight trials involving 467 patients. The pooled weight mean difference (WMD) and 95% confidence interval (CI) were calculated using a fixed or random effects model. Quality assessment and publication bias were also performed. The selected studies were considered for meta-analysis using RevMan V5.3. RESULTS Compared with traditional therapy group, autologous stem cell transplantation increased the level of albumin (WMD: 2.47, 95% CI: 1.05-3.90, P < 0.001), but decreased the level of total bilirubin (WMD: -2.26, 95% CI: -3.61 to -0.90, P = 0.001), alanine aminotransferase (WMD: -9.16, 95% CI: -16.47 to -1.85, P = 0.01) and prothrombin time (WMD: -3.02, 95% CI: -4.83 to -1.22, P = 0.001). Clinical symptoms such as edema, fatigue, anorexia and abdominal distention were alleviated. Model for End-Stage Liver Disease and Child-Pugh scores were decreased after stem cell therapy. Whereas, there was no statistically significant difference between two groups regarding aspartate aminotransferase, prothrombin time activity, ascites and pleural fluid. No procedure-related complications were found. CONCLUSION Autologous stem cell transplantation might have beneficial effects on patients with viral hepatitis-induced LC and is relatively safe for these patients. Further high-quality randomized controlled trials are needed.
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Affiliation(s)
- Bin Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University
| | - Long Pang
- West China School of Medicine, Sichuan University, Chengdu, People's Republic of China
| | - Hongxin Cao
- West China School of Medicine, Sichuan University, Chengdu, People's Republic of China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital of Sichuan University
| | - Yonghong Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University
| | - Yachao Tao
- Center of Infectious Diseases, West China Hospital of Sichuan University
| | - Menglan Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University
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Kitade M, Kaji K, Nishimura N, Seki K, Nakanishi K, Tsuji Y, Sato S, Saikawa S, Takaya H, Kawaratani H, Namisaki T, Moriya K, Mitoro A, Yoshiji H. Blocking development of liver fibrosis augments hepatic progenitor cell-derived liver regeneration in a mouse chronic liver injury model. Hepatol Res 2019; 49:1034-1045. [PMID: 30989766 DOI: 10.1111/hepr.13351] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 04/08/2019] [Accepted: 04/10/2019] [Indexed: 02/08/2023]
Abstract
AIM The roles of hepatic progenitor cells (HPCs) in regeneration of a diseased liver are unclear. Hepatic stellate cells (HSCs) contribute to liver fibrosis but are also a component of the HPC niche. Hepatic progenitor cells expand along with HSC activation and liver fibrosis. However, little is known about the interplay of liver fibrosis and HPC-mediated liver regeneration. This study aimed to investigate HSCs and HPCs in liver regeneration. METHODS Liver injury in mice was induced with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, and HPC expansion and fibrosis were assessed. An angiotensin II type 1 receptor blocker (ARB) was administered to assess its effect on fibrosis and regeneration. RESULTS Treatment with ARB attenuated fibrosis and expansion of α-smooth muscle actin-positive activated HSCs as indicated by increased liver weight and Ki-67-positive hepatocytes. Immunohistochemical staining suggested that HPC differentiation was shifted toward hepatocytes (HCs) when ARB treatment decreased HPC encapsulation by HSCs and extracellular matrix. Conditioned medium produced by culturing the human HSC LX-2 line strongly augmented differentiation to biliary epithelial cells (BECs) but inhibited that to HCs. Activated HSCs expressed Jagged1, a NOTCH ligand, which plays a central role in differentiation of HPCs toward BECs. CONCLUSIONS Hepatic stellate cells, the HPC niche cells, control differentiation of HPCs, directing them toward BECs rather than HCs in a diseased liver model. Antifibrosis treatment with an ARB preferentially redirects HPC differentiation toward HCs by blocking the NOTCH pathway in the HPC niche, resulting in more efficient HPC-mediated liver regeneration.
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Affiliation(s)
- Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Norihisa Nishimura
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Kenichiro Seki
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Keisuke Nakanishi
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Yuki Tsuji
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Soichiro Saikawa
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
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Yovchev MI, Lee EJ, Rodriguez‐Silva W, Locker J, Oertel M. Biliary Obstruction Promotes Multilineage Differentiation of Hepatic Stem Cells. Hepatol Commun 2019; 3:1137-1150. [PMID: 31388633 PMCID: PMC6672331 DOI: 10.1002/hep4.1367] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 04/23/2019] [Indexed: 12/17/2022] Open
Abstract
Because of their high regenerative potential, stem cells are an ideal resource for development of therapies that replace injured tissue mass and restore function in patients with end-stage liver diseases. Using a rat model of bile duct ligation (BDL) and biliary fibrosis, we investigated cell engraftment, liver repopulation, and ectopic tissue formation after intrasplenic transplantation of epithelial stem/progenitor cells. Fetal liver cells were infused into the spleens of Fisher 344 rats with progressing biliary fibrosis induced by common BDL or rats without BDL. Cell delivery was well tolerated. After migration to the liver, donor-derived stem/progenitor cells engrafted, differentiated into hepatocytes and cholangiocytes, and formed large cell clusters at 2 months in BDL rats but not controls. Substantial numbers of donor cells were also detected at the splenic injection site where they generated hepatic and nonhepatic tissue. Transplanted cells differentiated into phenotypes other than hepato/cholangiocytic cells only in rats that underwent BDL. Quantitative reverse-transcription polymerase chain reaction analyses demonstrated marked up-regulation of tissue-specific genes of nonhepatic endodermal lineages (e.g., caudal type homeobox 2 [Cdx2], pancreatic and duodenal homeobox 1 [Pdx1], keratin 13 [CK-13]), confirmed by immunohistochemistry. Conclusion: BDL and its induced fibrosis promote liver repopulation by ectopically transplanted fetal liver-derived cells. These cell fractions contain multipotent stem cells that colonize the spleen of BDL rats and differentiate into multiple gastrointestinal tissues, including liver, pancreas, intestine, and esophagus. The splenic microenvironment, therefore, represents an ideal niche to assess the differentiation of these stem cells, while BDL provides a stimulus that induces their differentiation.
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Affiliation(s)
- Mladen I. Yovchev
- Department of Pathology, Division of Experimental PathologyUniversity of PittsburghPittsburghPA
| | - Edward J. Lee
- Department of Pathology, Division of Experimental PathologyUniversity of PittsburghPittsburghPA
| | | | - Joseph Locker
- Department of Pathology, Division of Experimental PathologyUniversity of PittsburghPittsburghPA
- Pittsburgh Liver Research CenterUniversity of PittsburghPittsburghPA
| | - Michael Oertel
- Department of Pathology, Division of Experimental PathologyUniversity of PittsburghPittsburghPA
- Pittsburgh Liver Research CenterUniversity of PittsburghPittsburghPA
- McGowan Institute for Regenerative MedicineUniversity of PittsburghPittsburghPA
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17
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Jones RE, Foster DS, Hu MS, Longaker MT. Wound healing and fibrosis: current stem cell therapies. Transfusion 2019; 59:884-892. [PMID: 30737822 DOI: 10.1111/trf.14836] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 02/01/2018] [Indexed: 12/20/2022]
Abstract
Scarring is a result of the wound healing response and causes tissue dysfunction after injury. This process is readily evident in the skin, but also occurs internally across organ systems in the form of fibrosis. Stem cells are crucial to the innate tissue healing response and, as such, present a possible modality to therapeutically promote regenerative healing while minimizing scaring. In this review, the cellular basis of scaring and fibrosis is examined. Current stem cell therapies under exploration for skin wound healing and internal organ fibrosis are discussed. While most therapeutic approaches rely on the direct application of progenitor-type cells to injured tissue to promote healing, novel strategies to manipulate the scarring response are also presented. As our understanding of developmental and stem cell biology continues to increase, therapies to encourage regeneration of healthy functional tissue after damage secondary to injury or disease will continue to expand.
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Affiliation(s)
- Ruth Ellen Jones
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, California
| | - Deshka S Foster
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, California
| | - Michael S Hu
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, California
| | - Michael T Longaker
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, California
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18
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Itaba N, Kono Y, Watanabe K, Yokobata T, Oka H, Osaki M, Kakuta H, Morimoto M, Shiota G. Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets. Sci Rep 2019; 9:6841. [PMID: 31048740 PMCID: PMC6497888 DOI: 10.1038/s41598-019-43298-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 04/17/2019] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis viral infection, alcoholic intoxication, and obesity cause liver fibrosis, which progresses to decompensated liver cirrhosis, a disease for which medical demands cannot be met. Since there are currently no approved anti-fibrotic therapies for established liver fibrosis, the development of novel modalities is required to improve patient prognosis. In this study, we clarified the anti-fibrotic effects of cell sheets produced from human bone marrow-derived mesenchymal stem cells (MSCs) incubated on a temperature-sensitive culture dish with the chemical compound IC-2. Orthotopic transplantation of IC-2-engineered MSC sheets (IC-2 sheets) remarkably reduced liver fibrosis induced by chronic CCl4 administration. Further, the marked production of fibrolytic enzymes such as matrix metalloproteinase (MMP)-1 and MMP-14, as well as thioredoxin, which suppresses hepatic stellate cell activation, was observed in IC-2 sheets. Moreover, the anti-fibrotic effect of IC-2 sheets was much better than that of MSC sheets. Finally, knockdown experiments revealed that MMP-14 was primarily responsible for the reduction of liver fibrosis. Here, we show that IC-2 sheets could be a promising therapeutic option for established liver fibrosis.
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Affiliation(s)
- Noriko Itaba
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Yohei Kono
- KanonCure Inc., 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Kaori Watanabe
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Tsuyoshi Yokobata
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Hiroyuki Oka
- Research Initiative Center, Tottori University, 4-101 Koyama, Tottori, 680-8550, Japan
| | - Mitsuhiko Osaki
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Hiroki Kakuta
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-naka, Kita-ku, Okayama, 700-8530, Japan
| | - Minoru Morimoto
- Research Initiative Center, Tottori University, 4-101 Koyama, Tottori, 680-8550, Japan
| | - Goshi Shiota
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.
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19
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Itaba N, Noda I, Oka H, Kono Y, Okinaka K, Yokobata T, Okazaki S, Morimoto M, Shiota G. Hepatic cell sheets engineered from human mesenchymal stem cells with a single small molecule compound IC-2 ameliorate acute liver injury in mice. Regen Ther 2018; 9:45-57. [PMID: 30525075 PMCID: PMC6222293 DOI: 10.1016/j.reth.2018.07.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 06/22/2018] [Accepted: 07/02/2018] [Indexed: 01/31/2023] Open
Abstract
INTRODUCTION We previously reported that transplantation of hepatic cell sheets from human bone marrow-derived mesenchymal stem cells (BM-MSCs) with hexachlorophene, a Wnt/β-catenin signaling inhibitor, ameliorated acute liver injury. In a further previous report, we identified IC-2, a newly synthesized derivative of the Wnt/β-catenin signaling inhibitor ICG-001, as a potent inducer of hepatic differentiation of BM-MSCs. METHODS We manufactured hepatic cell sheets by engineering from human BM-MSCs using the single small molecule IC-2. The therapeutic potential of IC-2-induced hepatic cell sheets was assessed by transplantation of IC-2- and hexachlorophene-treated hepatic cell sheets using a mouse model of acute liver injury. RESULTS Significant improvement of liver injury was elicited by the IC-2-treated hepatic cell sheets. The expression of complement C3 was enhanced by IC-2, followed by prominent hepatocyte proliferation stimulated through the activation of NF-κB and its downstream molecule STAT-3. Indeed, IC-2 also enhanced the expression of amphiregulin, resulting in the activation of the EGFR pathway and further stimulation of hepatocyte proliferation. As another important therapeutic mechanism, we revealed prominent reduction of oxidative stress mediated through upregulation of the thioredoxin (TRX) system by IC-2-treated hepatic cell sheets. The effects mediated by IC-2-treated sheets were superior compared with those mediated by hexachlorophene-treated sheets. CONCLUSION The single compound IC-2 induced hepatic cell sheets that possess potent regeneration capacity and ameliorate acute liver injury.
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Key Words
- 8-OHdG, 8-hydroxydeoxyguanosine
- A1AT, α1-antitrypsin
- ALT, alanine aminotransferase
- APOE, apolipoprotein E
- AREG, amphiregulin
- AST, aspartate aminotransferase
- Acute liver failure
- BM-MSCs, bone marrow-derived mesenchymal stem cells
- C3, complement C3
- C4A, complement C4A
- C5aR, complement C5a receptor
- CBP, CREB-binding protein
- CCl4, carbon tetrachloride
- CP, ceruloplasmin
- ChREBP, Carbohydrate-responsive element-binding protein
- ChoREs, carbohydrate response elements
- DMSO, dimethyl sulfoxide
- EGFR, epidermal growth factor receptor
- ERK, extracellular signal-regulated kinase
- GPX, glutathione peroxidase
- GR, Glutathione reductase
- GRX, glutaredoxin
- GSH, glutathione
- HB-EGF, heparin binding-epidermal growth factor-like growth factor
- HGFR, hepatocyte growth factor receptor
- Hepatic cell sheets
- IL-1ra, interleukin-1 receptor antagonist
- IL-6, interleukin-6
- LXR, liver X receptor
- Liver regeneration
- MDA, malondialdehyde
- Mesenchymal stem cells
- NF-κB, nuclear factor-kappa B
- PCNA, proliferating cell nuclear antigen
- PRX, peroxiredoxin
- RBP4, retinol binding protein 4
- SOD, superoxide dismutase
- STAT-3, Signal Tranducer and Activator of Transcription 3
- TF, transferrin
- TGFα, transforming growth factor alpha
- TNFα, tumor necrosis factor alpha
- TRX, thioredoxin
- TRXR, thioredoxin reductase
- Wnt/β-catenin signal inhibitor
- hGAPDH, human glyceraldehyde 3-phosphate dehydrogenase
- mActb, mouse actin, beta
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Affiliation(s)
- Noriko Itaba
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
| | - Ikuya Noda
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
| | - Hiroyuki Oka
- Research Initiative Center, Tottori University, 4-101 Koyama, Tottori 680-8550, Japan
| | - Yohei Kono
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
| | - Kaori Okinaka
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
| | - Tsuyoshi Yokobata
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
| | - Shizuma Okazaki
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
| | - Minoru Morimoto
- Research Initiative Center, Tottori University, 4-101 Koyama, Tottori 680-8550, Japan
| | - Goshi Shiota
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan
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Ohkoshi S, Hirono H, Nakahara T, Ishikawa H. Dental pulp cell bank as a possible future source of individual hepatocytes. World J Hepatol 2018; 10:702-707. [PMID: 30386463 PMCID: PMC6206155 DOI: 10.4254/wjh.v10.i10.702] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/30/2018] [Accepted: 07/10/2018] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) as a source for regenerative medicine are now the subject of much clinical attention. There are high expectations due to their safety, low tumorigenic risk, and low ethical concerns. MSC therapy has been approved for acute graft-versus host diseases since 2015. Tooth-derived MSCs are known to have a great potential in their proliferation and differentiation capacities, even when compared with bone-marrow-derived MSCs. In particular, stem cells from human exfoliated deciduous teeth (SHEDs) are the best candidates for personal cell banking (dental pulp cell bank), because they can be obtained less invasively in the natural process of individual growth. SHEDs are known to differentiate into hepatocytes. There have been several studies showing the effectiveness of SHEDs on the treatment of liver failure in animal models. They may exert their effects either by repopulation of cells in injured liver or by paracrine mechanisms due to their immune-regulatory functions. Moreover, it may be possible to use each individuals' dental pulp cells as a future source of tailor-made differentiated hepatocytes in the context of a bioartificial liver or liver-on-a-chip to screen for drug toxicity.
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Affiliation(s)
- Shogo Ohkoshi
- Department of Internal Medicine, School of Life Dentistry at Niigata, the Nippon Dental University, Niigata 951-8580, Japan.
| | - Haruka Hirono
- Department of Internal Medicine, School of Life Dentistry at Niigata, the Nippon Dental University, Niigata 951-8580, Japan
| | - Taka Nakahara
- Department of Developmental and Regenerative Dentistry, School of Life Dentistry at Tokyo, the Nippon Dental University, Chiyoda-ku 102-8159, Japan
| | - Hiroshi Ishikawa
- Laboratory of Clinical Regenerative Medicine, Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Laboratory of Advanced Research D #326, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
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Wang MF, Li YB, Gao XJ, Zhang HY, Lin S, Zhu YY. Efficacy and safety of autologous stem cell transplantation for decompensated liver cirrhosis: A retrospective cohort study. World J Stem Cells 2018; 10:138-145. [PMID: 30397424 PMCID: PMC6212545 DOI: 10.4252/wjsc.v10.i10.138] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 07/29/2018] [Accepted: 08/26/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the long-term efficacy and safety of autologous stem cell transplantation (SCT) for decompensated liver cirrhosis. METHODS Consecutive patients with decompensated liver cirrhosis were included and assigned into the SCT group and non-transplantation (non-SCT) group according to whether they received SCT treatment. Patients were followed up for ten years. The long-term survival rate and incidence of hepatocellular carcinoma (HCC) were compared between groups. RESULTS A total of 159 patients were enrolled, including 27 cases in the SCT group and 132 cases in the non-SCT group. The baseline characteristics were significantly different between the two groups. Propensity score matching (PSM) was used to match SCT and non-SCT patients. After PSM, 92 subjects were enrolled in the final analysis, including 23 cases in the SCT group and 69 cases in the non-SCT group. The overall mortality was 73.9% and 55.1%, and the median survival period was 48 and 64 mo, respectively. However, no significant difference was found in the long-term survival rate between the two groups (P > 0.05). In addition, the incidence of HCC was higher in the SCT group than in the non-SCT group (47.8% vs 21.7%, P < 0.05). After adjusting for other covariates, SCT (OR = 3.065, 95%CI: 1.378-6.814) and age (OR = 1.061, 95%CI: 1.021-1.102) were independently correlated with the development of HCC in this decompensated liver cirrhosis cohort. CONCLUSION Autologous SCT may fail to improve the long-term efficacy and increase the incidence of HCC for decompensated liver cirrhosis. Close monitoring of HCC is strongly recommended in patients undergoing autologous SCT.
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Affiliation(s)
- Ming-Fang Wang
- Liver Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, China
| | - You-Bing Li
- Liver Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, China
| | - Xiao-Juan Gao
- Fujian Provincial Governmental Hospital, Fuzhou 350001, Fujian Province, China
| | - Hao-Yang Zhang
- School of Biological Sciences, the University of Hong Kong, Hong Kong, China
| | - Su Lin
- Liver Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, China
| | - Yue-Yong Zhu
- Liver Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, China.
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22
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Liau LL, Makpol S, Azurah AGN, Chua KH. Human adipose-derived mesenchymal stem cells promote recovery of injured HepG2 cell line and show sign of early hepatogenic differentiation. Cytotechnology 2018; 70:1221-1233. [PMID: 29549558 PMCID: PMC6081923 DOI: 10.1007/s10616-018-0214-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 03/08/2018] [Indexed: 12/27/2022] Open
Abstract
Currently, orthotopic liver transplantation is the gold standard therapy for liver failure. However, it is limited by the insufficient organ donor and risk of immune rejection. Stem cell therapy is a promising alternative treatment for liver failure. One of the most ideal sources of stem cells for regenerative medicine is adipose-derived stem cells (ADSCs). In this study, primary ADSCs seeded on cell culture insert were indirectly co-cultured with injured HepG2 to elucidate the role of ADSCs in promoting the recovery of injured HepG2 in non-contact manner. HepG2 recovery was determined by the surface area covered by cells and growth factor concentration was measured to identify the factors involved in regeneration. Besides, HepG2 were collected for q-PCR analysis of injury, hepatocyte functional and regenerative markers expression. For the ADSCs, expression of hepatogenic differentiation genes was analyzed. Results showed that non-contact co-culture with ADSCs helped the recovery of injured HepG2. ELISA quantification revealed that ADSCs secreted higher amount of HGF and VEGF to help the recovery of injured HepG2. Furthermore, HepG2 co-cultured with ADSCs expressed significantly lower injury markers as well as significantly higher regenerative and functional markers compared to the control HepG2. ADSCs co-cultured with injured HepG2 expressed significantly higher hepatic related genes compared to the control ADSCs. In conclusion, ADSCs promote recovery of injured HepG2 via secretion of HGF and VEGF. In addition, co-cultured ADSCs showed early sign of hepatogenic differentiation in response to the factors released or secreted by the injured HepG2.
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Affiliation(s)
- Ling Ling Liau
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
| | - Suzana Makpol
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
| | - Abdul Ghani Nur Azurah
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia
| | - Kien Hui Chua
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Kuala Lumpur, Malaysia.
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Du C, Jiang M, Wei X, Qin J, Xu H, Wang Y, Zhang Y, Zhou D, Xue H, Zheng S, Zeng W. Transplantation of human matrix metalloproteinase-1 gene-modified bone marrow-derived mesenchymal stem cell attenuates CCL4-induced liver fibrosis in rats. Int J Mol Med 2018; 41:3175-3184. [PMID: 29512750 PMCID: PMC5881841 DOI: 10.3892/ijmm.2018.3516] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 02/12/2018] [Indexed: 12/18/2022] Open
Abstract
It has been reported that bone marrow-derived mesenchymal stem cells (BMSCs) alleviated liver fibrosis. We investigated whether BMSCs transfected with human matrix metalloproteinase 1 (BMSCs/MMP1) would improve their therapeutic effect in liver fibrosis induced by carbon tetrachloride (CCl4) in rats. BMSCs were transfected with an adenovirus carrying enhanced green fluorescence protein (GFP) and human MMP1 gene. BMSCs or BMSCs/MMP1 were directly injected into fibrotic rats via the tail vein. GFP-labeled cells appeared in the fibrotic liver after BMSC transplantation. The expression of BMSCs/MMP1 elevated levels of MMP1 in vitro. Although BMSC administration reduced liver fibrosis, transplantation of BMSCs/MMP1 enhanced the reduction of liver fibrosis to a higher level. Treatment with BMSCs/MMP1 not only decreased collagen content but also suppressed activation of hepatic stellate cells (HSCs) in fibrotic liver, which led to subsequent improvement of both liver injury and fibrosis. Treatment with BMSCs/MMP1 resulted in an improved therapeutic effect compared with BMSCs alone, which is probably because of the sustainably expressed MMP1 level in the liver. BMSCs/MMP1 transplantation not only improved biochemical parameters but also attenuated progression of liver fibrosis, suggesting that BMSCs may be a potential cell source in preventing liver fibrosis and MMP1 gene may enhance the anti-fibrotic effect of BMSCs.
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Affiliation(s)
- Chao Du
- Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
| | - Mingde Jiang
- Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
| | - Xiaolong Wei
- Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
| | - Jianpin Qin
- Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
| | - Hui Xu
- Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
| | - Yunxia Wang
- Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
| | - Yong Zhang
- Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
| | - Dejiang Zhou
- Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
| | - Hongli Xue
- Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
| | - Shumei Zheng
- Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
| | - Weizheng Zeng
- Department of Gastroenterology and Hepatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
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Babaei A, Katoonizadeh A, Ranjbar A, Naderi M, Ahmadbeigi N. Directly injected native bone-marrow stem cells cannot incorporate into acetaminophen-induced liver injury. Biologicals 2018; 52:55-58. [PMID: 29317122 DOI: 10.1016/j.biologicals.2017.12.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Revised: 12/26/2017] [Accepted: 12/29/2017] [Indexed: 01/09/2023] Open
Abstract
The paucity of liver donation highlights the use of cell-based strategies for end-stage liver failure. We recently showed that bone marrow-derived aggregates (BMDAs) can completely restore the hematopoietic system in gamma-irradiated mice. These aggregates are stem and progenitor cells in the bone marrow (BM), composed of both hematopoietic and non-hematopoietic lineages. Furthermore, reports showed that resident BM cells migrate to the liver and integrate themselves into the tissue in small numbers. Hence, we hypothesized that direct delivery of BMDAs to the damaged liver might enhance the integration of BM cells in the liver because of its stemness property, intact BM architecture, the physical proximity of these niche-like structures to the damaged sites and the existence of liver paracrine factors. To this aim, we made an acute liver model by intraperitoneal injection of acetaminophen. Then, GFP-expressing BMDAs were intrahepatically injected. Despite the detection of GFP-expressing cells five days after intrahepatic injection, these cells were not detectable at days 15 and 60, indicating that the puzzle of BM cell integration in the liver still has more missing pieces other than stemness, physical proximity, and paracrine factors. Actually, it seems that even intact BM structures need further signals to be qualified for integration.
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Affiliation(s)
- Azadeh Babaei
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azam Katoonizadeh
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azam Ranjbar
- SABZ Biomedicals Science-based Company, Tehran, Iran
| | - Mahmood Naderi
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Naser Ahmadbeigi
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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25
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Zhang JB, Wang XQ, Lu GL, Huang HS, Xu SY. Adipose-derived mesenchymal stem cells therapy for acute kidney injury induced by ischemia-reperfusion in a rat model. Clin Exp Pharmacol Physiol 2017; 44:1232-1240. [PMID: 28688148 DOI: 10.1111/1440-1681.12811] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 06/10/2017] [Accepted: 06/14/2017] [Indexed: 12/28/2022]
Abstract
Acute kidney injury (AKI) represents a group of complicated syndromes with a high mortality rate. The administration of adipose-derived mesenchymal stem cells (ADMSCs) has been tested as a possible treatment method for AKI. The long-term evaluation of AKI induced by ischemia/reperfusion (IR) and the probable renal protection of ADMSCs are limited. In this study we have established a rat AKI model induced by IR and investigated the possible protective effects of ADMSCs. Adult Sprague-Dawley (SD) rats were divided into three groups (n = 6/each group). The MOCK group was as the normal control. Rats in the IR-AKI and IR-AKI+ADMSCs groups were subjected to IR injury by clamping both renal pedicles for 40 minutes. Rats in the MOCK and IR-AKI groups were injected with PBS via the tail vein as negative treatment controls. Rats in the IR-AKI+ADMSCs group received ADMSCs therapy (2 × 106 cells were injected into the rats via the tail vein). We found that ADMSC transplantation restored the pathologic morphology induced by IR-AKI to normal compared with the MOCK group, suggesting the reparative function of ADMSCs in kidney tissues. Compared with IR-induced AKI alone, ADMSC treatment significantly decreased the number of apoptotic cells, the level of total urinary protein and serum creatinine, the expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β, IFN-γ, TNF-α, IFN-γ, and TGF-β), and the inflammation-associated proteins (HGF and SDF1), but increased the expression of the anti-inflammatory cytokine, IL-10, and the anti-apoptotic regulator, Bcl-2. Our data have indicated that ADMSC transplantation may protect against IR-induced AKI by anti-apoptotic and anti-inflammatory effects.
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Affiliation(s)
- Jian-Bo Zhang
- Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, China.,Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiao-Qiao Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Guo-Lin Lu
- Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Huan-Sen Huang
- Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shi-Yuan Xu
- Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
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26
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Emerging advancements in liver regeneration and organogenesis as tools for liver replacement. Curr Opin Organ Transplant 2017; 21:581-587. [PMID: 27755169 DOI: 10.1097/mot.0000000000000365] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Although the liver possesses a unique, innate ability to regenerate through mass compensation, transplantation remains the only therapy when damage outpaces regeneration, or liver metabolic capacity is irreversibly impacted. Recent insight from developmental biology has greatly influenced the advancement of alternative options to transplantation in these settings. RECENT FINDINGS Factors known to direct liver cell specification, expansion, and differentiation have been used to generate hepatocyte-like cells from stem and somatic cells for developing cell therapies. Additionally, interactions between hepatic epithelial and nonepithelial cells key to establishing hepatic architecture have been used in tissue engineering approaches to advance self-organizing hepatic organoids and bioartificial liver devices. Simultaneously, recent clinically applicable advances in human hepatocyte transplantation and promotion of innate hepatic regeneration have been limited. SUMMARY Although mature hepatocytes have the potential to bridge to, or replace whole organ transplantation, limits in the ability to obtain healthy cells, stabilize in-vitro expansion, cryopreserve, and alleviate rejection, still exist. Alternative sources for generating hepatocytes hold promise for cell therapy and tissue engineering. These may allow generation of autologous or universal donor cells that eliminate the need for immunosuppression; however, limits exist regarding hepatocyte maturity and efficacy at liver repopulation, as well as applicability to human chronic liver disease.
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Abstract
Liver regeneration is a fascinating and complex process with many medical implications. An important component of this regenerative process is the hepatic progenitor cell (HPC). These appealing cells are able to participate in the renewal of hepatocytes and cholangiocytes when the normal homeostatic regeneration is exhausted. Moreover, the HPC niche is of vital importance toward the activation, differentiation, and proliferation of the HPC. This niche provides a rich microenvironment for the regulation of the HPC, thanks to the intercellular secretion of molecules. New findings indicate that the regenerative possibilities in the liver could provide a diverse basis for therapeutic targets.
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Affiliation(s)
- Matthias Van Haele
- Liver Research Unit, Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Minderbroederstraat 12, 3000 Leuven, Belgium
| | - Tania Roskams
- Liver Research Unit, Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Minderbroederstraat 12, 3000 Leuven, Belgium.
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28
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Lee KS, Santagostino SF, Li D, Ramjit A, Serrano K, Ginsberg MD, Ding BS, Rafii S, Madoff DC. Catheter-directed Intraportal Delivery of Endothelial Cell Therapy for Liver Regeneration: A Feasibility Study in a Large-Animal Model of Cirrhosis. Radiology 2017; 285:114-123. [PMID: 28498793 DOI: 10.1148/radiol.2017162617] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Purpose To demonstrate the feasibility of imaging-guided catheter-directed delivery of endothelial cell therapy in a porcine model of cirrhosis for liver regeneration. Materials and Methods After approval from the institutional animal care and use committee, autologous liver endothelial cells were grown from core hepatic specimens from swine. Cirrhosis was induced in swine by means of transcatheter infusion of ethanol and iodized oil into the hepatic artery. Three weeks after induction of cirrhosis, the swine were randomly assigned to receive autologous cell therapy (endothelial cells, n = 4) or control treatment (phosphate-buffered saline, n = 4) by means of imaging-guided transhepatic intraportal catheterization. Fluorescence-activated cell sorting analysis was performed on biopsy samples 1 hour after therapy. Three weeks after intraportal delivery of endothelial cells, the swine were euthanized and the explanted liver underwent quantitative pathologic examination. Statistical analysis was performed with an unpaired t test by using unequal variance. Results Liver endothelial cells were successfully isolated, cultured, and expanded from eight 20-mm, 18-gauge hepatic core samples to 50 × 106 autologous cells per pig. Intraportal delivery of endothelial cell therapy or saline was technically successful in all eight swine, with no complications. Endothelial cells were present in the liver for a minimum of 1 hour after intraportal infusion. Swine treated with endothelial cell therapy showed mean levels of surrogate markers of hepatobiliary injury that were consistent with decreases in hepatic fibrosis and biliary ductal damage relative to the control animals, although statistical significance was not met in this pilot study: The mean percentage of positive pixels at Masson trichrome staining was 7.28% vs 5.57%, respectively (P = .20), the mean proliferation index with cytokeratin wide-spectrum was 2.55 vs 1.13 (P = .06), and the mean proliferation index with Ki67 was 7.08 vs 4.96 (P = .14). Conclusion The results confirm the feasibility of imaging-guided catheter-directed endothelial cell therapy with an intraportal technique for the treatment of cirrhosis in a porcine model. A trend toward decreased liver fibrosis with endothelial cell therapy was observed. Larger animal studies and human studies are necessary to confirm significance. © RSNA, 2017.
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Affiliation(s)
- Kyungmouk Steve Lee
- From the Department of Radiology (K.S.L., D.L., A.R., K.S., D.C.M.), Laboratory of Comparative Pathology (S.F.S.), and Department of Genetic Medicine (B.S.D., S.R.), Weill Cornell Medicine, 525 E 68th St, Payson Pavilion 5, New York, NY 10065; and Angiocrine Bioscience, San Diego, Calif (M.D.G.)
| | - Sara F Santagostino
- From the Department of Radiology (K.S.L., D.L., A.R., K.S., D.C.M.), Laboratory of Comparative Pathology (S.F.S.), and Department of Genetic Medicine (B.S.D., S.R.), Weill Cornell Medicine, 525 E 68th St, Payson Pavilion 5, New York, NY 10065; and Angiocrine Bioscience, San Diego, Calif (M.D.G.)
| | - David Li
- From the Department of Radiology (K.S.L., D.L., A.R., K.S., D.C.M.), Laboratory of Comparative Pathology (S.F.S.), and Department of Genetic Medicine (B.S.D., S.R.), Weill Cornell Medicine, 525 E 68th St, Payson Pavilion 5, New York, NY 10065; and Angiocrine Bioscience, San Diego, Calif (M.D.G.)
| | - Amit Ramjit
- From the Department of Radiology (K.S.L., D.L., A.R., K.S., D.C.M.), Laboratory of Comparative Pathology (S.F.S.), and Department of Genetic Medicine (B.S.D., S.R.), Weill Cornell Medicine, 525 E 68th St, Payson Pavilion 5, New York, NY 10065; and Angiocrine Bioscience, San Diego, Calif (M.D.G.)
| | - Kenneth Serrano
- From the Department of Radiology (K.S.L., D.L., A.R., K.S., D.C.M.), Laboratory of Comparative Pathology (S.F.S.), and Department of Genetic Medicine (B.S.D., S.R.), Weill Cornell Medicine, 525 E 68th St, Payson Pavilion 5, New York, NY 10065; and Angiocrine Bioscience, San Diego, Calif (M.D.G.)
| | - Michael D Ginsberg
- From the Department of Radiology (K.S.L., D.L., A.R., K.S., D.C.M.), Laboratory of Comparative Pathology (S.F.S.), and Department of Genetic Medicine (B.S.D., S.R.), Weill Cornell Medicine, 525 E 68th St, Payson Pavilion 5, New York, NY 10065; and Angiocrine Bioscience, San Diego, Calif (M.D.G.)
| | - Bi-Sen Ding
- From the Department of Radiology (K.S.L., D.L., A.R., K.S., D.C.M.), Laboratory of Comparative Pathology (S.F.S.), and Department of Genetic Medicine (B.S.D., S.R.), Weill Cornell Medicine, 525 E 68th St, Payson Pavilion 5, New York, NY 10065; and Angiocrine Bioscience, San Diego, Calif (M.D.G.)
| | - Shahin Rafii
- From the Department of Radiology (K.S.L., D.L., A.R., K.S., D.C.M.), Laboratory of Comparative Pathology (S.F.S.), and Department of Genetic Medicine (B.S.D., S.R.), Weill Cornell Medicine, 525 E 68th St, Payson Pavilion 5, New York, NY 10065; and Angiocrine Bioscience, San Diego, Calif (M.D.G.)
| | - David C Madoff
- From the Department of Radiology (K.S.L., D.L., A.R., K.S., D.C.M.), Laboratory of Comparative Pathology (S.F.S.), and Department of Genetic Medicine (B.S.D., S.R.), Weill Cornell Medicine, 525 E 68th St, Payson Pavilion 5, New York, NY 10065; and Angiocrine Bioscience, San Diego, Calif (M.D.G.)
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Pham DH, Zhang C, Yin C. Using zebrafish to model liver diseases-Where do we stand? CURRENT PATHOBIOLOGY REPORTS 2017; 5:207-221. [PMID: 29098121 DOI: 10.1007/s40139-017-0141-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Purpose of Review The liver is the largest internal organ and performs both exocrine and endocrine function that is necessary for survival. Liver failure is among the leading causes of death and represents a major global health burden. Liver transplantation is the only effective treatment for end-stage liver diseases. Animal models advance our understanding of liver disease etiology and hold promise for the development of alternative therapies. Zebrafish has become an increasingly popular system for modeling liver diseases and complements the rodent models. Recent Findings The zebrafish liver contains main cell types that are found in mammalian liver and exhibits similar pathogenic responses to environmental insults and genetic mutations. Zebrafish have been used to model neonatal cholestasis, cholangiopathies, such as polycystic liver disease, alcoholic liver disease, and non-alcoholic fatty liver disease. It also provides a unique opportunity to study the plasticity of liver parenchymal cells during regeneration. Summary In this review, we summarize the recent work of building zebrafish models of liver diseases. We highlight how these studies have brought new knowledge of disease mechanisms. We also discuss the advantages and challenges of using zebrafish to model liver diseases.
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Affiliation(s)
- Duc-Hung Pham
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA
| | - Changwen Zhang
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA
| | - Chunyue Yin
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA.,Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA
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30
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Ezquer F, Bahamonde J, Huang YL, Ezquer M. Administration of multipotent mesenchymal stromal cells restores liver regeneration and improves liver function in obese mice with hepatic steatosis after partial hepatectomy. Stem Cell Res Ther 2017; 8:20. [PMID: 28129776 PMCID: PMC5273822 DOI: 10.1186/s13287-016-0469-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 11/11/2016] [Accepted: 12/31/2016] [Indexed: 02/06/2023] Open
Abstract
Background The liver has the remarkable capacity to regenerate in order to compensate for lost or damaged hepatic tissue. However, pre-existing pathological abnormalities, such as hepatic steatosis (HS), inhibits the endogenous regenerative process, becoming an obstacle for liver surgery and living donor transplantation. Recent evidence indicates that multipotent mesenchymal stromal cells (MSCs) administration can improve hepatic function and increase the potential for liver regeneration in patients with liver damage. Since HS is the most common form of chronic hepatic illness, in this study we evaluated the role of MSCs in liver regeneration in an animal model of severe HS with impaired liver regeneration. Methods C57BL/6 mice were fed with a regular diet (normal mice) or with a high-fat diet (obese mice) to induce HS. After 30 weeks of diet exposure, 70% hepatectomy (Hpx) was performed and normal and obese mice were divided into two groups that received 5 × 105 MSCs or vehicle via the tail vein immediately after Hpx. Results We confirmed a significant inhibition of hepatic regeneration when liver steatosis was present, while the hepatic regenerative response was promoted by infusion of MSCs. Specifically, MSC administration improved the hepatocyte proliferative response, PCNA-labeling index, DNA synthesis, liver function, and also reduced the number of apoptotic hepatocytes. These effects may be associated to the paracrine secretion of trophic factors by MSCs and the hepatic upregulation of key cytokines and growth factors relevant for cell proliferation, which ultimately improves the survival rate of the mice. Conclusions MSCs represent a promising therapeutic strategy to improve liver regeneration in patients with HS as well as for increasing the number of donor organs available for transplantation. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0469-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fernando Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile
| | - Javiera Bahamonde
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile.,Departamento de Fomento de la Producción Animal, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Av. Santa Rosa 11735, La Pintana, Santiago, Chile
| | - Ya-Lin Huang
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile
| | - Marcelo Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile.
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31
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Balmayor ER, Geiger JP, Koch C, Aneja MK, van Griensven M, Rudolph C, Plank C. Modified mRNA for BMP-2 in Combination with Biomaterials Serves as a Transcript-Activated Matrix for Effectively Inducing Osteogenic Pathways in Stem Cells. Stem Cells Dev 2017; 26:25-34. [DOI: 10.1089/scd.2016.0171] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Affiliation(s)
- Elizabeth R. Balmayor
- Experimental Trauma Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Ethris GmbH, Planegg, Germany
| | | | | | | | - Martijn van Griensven
- Experimental Trauma Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | | | - Christian Plank
- Ethris GmbH, Planegg, Germany
- Institute of Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
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32
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Bukovsky A. Involvement of blood mononuclear cells in the infertility, age-associated diseases and cancer treatment. World J Stem Cells 2016; 8:399-427. [PMID: 28074124 PMCID: PMC5183987 DOI: 10.4252/wjsc.v8.i12.399] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Revised: 08/19/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023] Open
Abstract
Blood mononuclear cells consist of T cells and monocyte derived cells. Beside immunity, the blood mononuclear cells belong to the complex tissue control system (TCS), where they exhibit morphostatic function by stimulating proliferation of tissue stem cells followed by cellular differentiation, that is stopped after attaining the proper functional stage, which differs among various tissue types. Therefore, the term immune and morphostatic system (IMS) should be implied. The TCS-mediated morphostasis also consists of vascular pericytes controlled by autonomic innervation, which is regulating the quantity of distinct tissues in vivo. Lack of proper differentiation of tissue cells by TCS causes either tissue underdevelopment, e.g., muscular dystrophy, or degenerative functional failures, e.g., type 1 diabetes and age-associated diseases. With the gradual IMS regression after 35 years of age the gonadal infertility develops, followed by a growing incidence of age-associated diseases and cancers. Without restoring an altered TCS function in a degenerative disease, the implantation of tissue-specific stem cells alone by regenerative medicine can not be successful. Transfused young blood could temporarily restore fertility to enable parenthood. The young blood could also temporarily alleviate aging diseases, and this can be extended by substances inducing IMS regeneration, like the honey bee propolis. The local and/or systemic use of honey bee propolis stopped hair and teeth loss, regressed varicose veins, improved altered hearing, and lowered high blood pressure and sugar levels. Complete regression of stage IV ovarian cancer with liver metastases after a simple elaborated immunotherapy is also reported.
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Affiliation(s)
- Antonin Bukovsky
- Antonin Bukovsky, Laboratory of Reproductive Biology BIOCEV, Institute of Biotechnology Czech Academy of Sciences, 25250 Vestec, Czech Republic
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33
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Naranjo JD, Scarritt ME, Huleihel L, Ravindra A, Torres CM, Badylak SF. Regenerative Medicine: lessons from Mother Nature. Regen Med 2016; 11:767-775. [PMID: 27885899 DOI: 10.2217/rme-2016-0111] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Regenerative medicine strategies for the restoration of functional tissue have evolved from the concept of ex vivo creation of engineered tissue toward the broader concept of in vivo induction of functional tissue reconstruction. Multidisciplinary approaches are being investigated to achieve this goal using evolutionarily conserved principles of stem cell biology, developmental biology and immunology, current methods of engineering and medicine. This evolution from ex vivo tissue engineering to the manipulation of fundamental in vivo tenets of development and regeneration has the potential to capitalize upon the incredibly complex and only partially understood ability of cells to adapt, proliferate, self-organize and differentiate into functional tissue.
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Affiliation(s)
- Juan Diego Naranjo
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA.,Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Michelle E Scarritt
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA.,Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Luai Huleihel
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA.,Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Anjani Ravindra
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA.,Division of Pediatric Pulmonary Medicine, Allergy & Immunology, Children's Hospital of UPMC, Pittsburgh, PA 15224, USA
| | - Crisanto M Torres
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA.,Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Stephen F Badylak
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA.,Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.,Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Fagoonee S, Famulari ES, Silengo L, Camussi G, Altruda F. Prospects for Adult Stem Cells in the Treatment of Liver Diseases. Stem Cells Dev 2016; 25:1471-1482. [PMID: 27503633 DOI: 10.1089/scd.2016.0144] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocytes constitute the main bulk of the liver and perform several essential functions. After injury, the hepatocytes have a remarkable capacity to regenerate and restore functionality. However, in some cases, the endogenous hepatocytes cannot replicate or restore the function, and liver transplantation, which is not exempt of complications, is required. Stem cells offer in theory the possibility of generating unlimited supply of hepatocytes in vitro due to their capacity to self-renew and differentiate when given the right cues. Stem cells isolated from an array of tissues have been investigated for their capacity to differentiate into hepatocyte-like cells in vitro and are employed in rescue experiments in vivo. Adult stem cells have gained in attractiveness over embryonic stem cells for liver cell therapy due to their origin, multipotentiality, and the possibility of autologous transplantation. This review deals with the promise and limitations of adult stem cells in clinically restoring liver functionality.
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Affiliation(s)
- Sharmila Fagoonee
- 1 Institute of Biostructure and Bioimaging , CNR, Turin, Italy
- 2 Molecular Biotechnology Center, University of Turin , Turin, Italy
- 3 Department of Molecular Biotechnology and Health Sciences, University of Turin , Turin, Italy
| | - Elvira Smeralda Famulari
- 2 Molecular Biotechnology Center, University of Turin , Turin, Italy
- 3 Department of Molecular Biotechnology and Health Sciences, University of Turin , Turin, Italy
| | - Lorenzo Silengo
- 2 Molecular Biotechnology Center, University of Turin , Turin, Italy
- 3 Department of Molecular Biotechnology and Health Sciences, University of Turin , Turin, Italy
| | - Giovanni Camussi
- 2 Molecular Biotechnology Center, University of Turin , Turin, Italy
- 4 Department of Medical Sciences, University of Torino , Torino, Italy
| | - Fiorella Altruda
- 2 Molecular Biotechnology Center, University of Turin , Turin, Italy
- 3 Department of Molecular Biotechnology and Health Sciences, University of Turin , Turin, Italy
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