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Zhang W, Cui Y, Lu M, Xu M, Li Y, Song H, Luo Y, Song J, Yang Y, Wang X, Liao L, Wang Y, Reid L, He Z. Hormonally and chemically defined expansion conditions for organoids of biliary tree Stem Cells. Bioact Mater 2024; 41:672-695. [PMID: 39309110 PMCID: PMC11415613 DOI: 10.1016/j.bioactmat.2024.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 07/25/2024] [Accepted: 08/13/2024] [Indexed: 09/25/2024] Open
Abstract
Wholly defined ex vivo expansion conditions for biliary tree stem cell (BTSC) organoids were established, consisting of a defined proliferative medium (DPM) used in combination with soft hyaluronan hydrogels. The DPM consisted of commercially available Kubota's Medium (KM), to which a set of small molecules, particular paracrine signals, and heparan sulfate (HS) were added. The small molecules used were DNA methyltransferase inhibitor (RG108), TGF- β Type I receptor inhibitor (A83-01), adenylate cyclase activator (Forskolin), and L-type Ca2+ channel agonist (Bay K8644). A key paracrine signal proved to be R-spondin 1 (RSPO1), a secreted protein that activates Wnts. Soluble hyaluronans, 0.05 % sodium hyaluronate, were used with DPM to expand monolayer cultures. Expansion of organoids was achieved by using DPM in combination with embedding organoids in Matrigel that was replaced with a defined thiol-hyaluronan triggered with PEGDA to form a hydrogel with a rheology [G*] of less than 100 Pa. The combination is called the BTSC-Expansion-Glycogel-System (BEX-gel system) for expanding BTSCs as a monolayer or as organoids. The BTSC organoids were expanded more than 3000-fold ex vivo in the BEX-gel system within 70 days while maintaining phenotypic traits indicative of stem/progenitors. Stem-cell-patch grafting of expanded BTSC organoids was performed on the livers of Fah-/- mice with tyrosinemia and resulted in the rescue of the mice and restoration of their normal liver functions. The BEX-gel system for BTSC organoid expansion provides a strategy to generate sufficient numbers of organoids for the therapeutic treatments of liver diseases.
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Affiliation(s)
- Wencheng Zhang
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Yangyang Cui
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Postgraduate Training Base of Shanghai East Hospital, Jinzhou Medical University, Jinzhou, Liaoning, 121001, China
| | - Mengqi Lu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Postgraduate Training Base of Shanghai East Hospital, Jinzhou Medical University, Jinzhou, Liaoning, 121001, China
| | - Mingyang Xu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Yuting Li
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Haimeng Song
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Yi Luo
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Jinjia Song
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Yong Yang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Xicheng Wang
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Lijun Liao
- Department of Anesthesiology and Pain Management, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China
| | - Yunfang Wang
- Hepatobiliary and Pancreatic Center, Medical Research Center, Beijing Tsinghua Changgung Hospital, Beijing, 102218, China
| | - Lola Reid
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, United States
| | - Zhiying He
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
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Chavan C, Ray S, Kumar CM. Stem cell therapy approaches for non-malignant diseases & non-haematological diseases in India: A systematic review. Indian J Med Res 2024; 160:411-427. [PMID: 39737504 DOI: 10.25259/ijmr_2141_23] [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: 11/07/2023] [Accepted: 10/01/2024] [Indexed: 01/01/2025] Open
Abstract
Background & objectives Our study aims to provide the diversity of stem cell use for non-malignant, non-haematological diseases in India through the lens of clinical trials. Methods A PRISMA approach was used to evaluate the safety and efficacy of stem cell use for the period 2001-2021 in India. The outcomes were measured using each disease category, types of stem cells, the origin of stem cells, safety, and efficacy. Results Of the 9206 studies screened, 61 studies that were relevant to stem cell use for non-malignant diseases were included for analysis. Autologous stem cells (75%) were used predominantly compared to allogenic stem cells (18.33%), followed by mixed type (6.67%). Use of bone marrow-derived stem cells (51%) was dominant, followed by melanocytes (19%), adipose (7%), haematopoietic (12%), and (11%) other types of stem cells. The study revealed 37 randomized clinical trial studies conducted in the government research hospital compared to the non-government. Interpretation & conclusions Maintaining the gold standard for stem cell therapy requires randomized clinical trials with large sample sizes, control groups, failures, adverse effects, etc. It is important to have a monitoring and regulation system in stem cell clinical research activities with enough preclinical data and repeated exchanges between the bench and the bedside.
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Affiliation(s)
- Chandrashekhar Chavan
- Department of Inclusive Health, CSIR-National Institute of Science Communication and Policy Research, New Delhi, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
| | - Suman Ray
- Department of Inclusive Health, CSIR-National Institute of Science Communication and Policy Research, New Delhi, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
| | - Chandra Mohan Kumar
- Department of Pediatrics, All India Institute of Medical Sciences, Patna, India
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Tripura C, Gunda S, Vishwakarma SK, Thatipalli AR, Jose J, Jerald MK, Khan AA, Pande G. Long-term and non-invasive in vivo tracking of DiD dye-labeled human hepatic progenitors in chronic liver disease models. World J Hepatol 2022; 14:1884-1898. [PMID: 36340748 PMCID: PMC9627437 DOI: 10.4254/wjh.v14.i10.1884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/02/2022] [Accepted: 10/02/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic liver diseases (CLD) are the major public health burden due to the continuous increasing rate of global morbidity and mortality. The inherent limitations of organ transplantation have led to the development of stem cell-based therapy as a supportive and promising therapeutic option. However, identifying the fate of transplanted cells in vivo represents a crucial obstacle. AIM To evaluate the potential applicability of DiD dye as a cell labeling agent for long-term, and non-invasive in vivo tracking of transplanted cells in the liver. METHODS Magnetically sorted, epithelial cell adhesion molecule positive (1 × 106 cells/mL) fetal hepatic progenitor cells were labeled with DiD dye and transplanted into the livers of CLD-severe combined immunodeficiency (SCID) mice. Near-infrared (NIR) imaging was performed for in vivo tracking of the DiD-labeled transplanted cells along with colocalization of hepatic markers for up to 80 d. The existence of human cells within mouse livers was identified using Alu polymerase chain reaction and sequencing. RESULTS NIR fluorescence imaging of CLD-SCID mice showed a positive fluorescence signal of DiD at days 7, 15, 30, 45, 60, and 80 post-transplantation. Furthermore, positive staining of cytokeratin, c-Met, and albumin colocalizing with DiD fluorescence clearly demonstrated that the fluorescent signal of hepatic markers emerged from the DiD-labeled transplanted cells. Recovery of liver function was also observed with serum levels of glutamic-oxaloacetic transaminase, glutamate-pyruvate transaminase, and bilirubin. The detection of human-specific Alu sequence from the transplanted mouse livers provided evidence for the survival of transplanted cells at day 80. CONCLUSION DiD-labeling is promising for long-term and non-invasive in vivo cell tracking, and understanding the regenerative mechanisms incurred by the transplanted cells.
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Affiliation(s)
- Chaturvedula Tripura
- Cell and Stem Cell Biology, CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, Telangana, India.
| | - Srinivas Gunda
- Cell and Stem Cell Biology, CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, Telangana, India
| | - Sandeep Kumar Vishwakarma
- Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Avinash Raj Thatipalli
- Cell and Stem Cell Biology, CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, Telangana, India
| | - Jedy Jose
- Cell and Stem Cell Biology, CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, Telangana, India
| | - Mahesh Kumar Jerald
- Cell and Stem Cell Biology, CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, Telangana, India
| | - Aleem Ahmed Khan
- Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Gopal Pande
- Cell and Stem Cell Biology, CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, Telangana, India
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Petrosyan A, Montali F, Peloso A, Citro A, Byers LN, La Pointe C, Suleiman M, Marchetti A, Mcneill EP, Speer AL, Ng WH, Ren X, Bussolati B, Perin L, Di Nardo P, Cardinale V, Duisit J, Monetti AR, Savino JR, Asthana A, Orlando G. Regenerative medicine technologies applied to transplant medicine. An update. Front Bioeng Biotechnol 2022; 10:1015628. [PMID: 36263358 PMCID: PMC9576214 DOI: 10.3389/fbioe.2022.1015628] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
Regenerative medicine (RM) is changing how we think and practice transplant medicine. In regenerative medicine, the aim is to develop and employ methods to regenerate, restore or replace damaged/diseased tissues or organs. Regenerative medicine investigates using tools such as novel technologies or techniques, extracellular vesicles, cell-based therapies, and tissue-engineered constructs to design effective patient-specific treatments. This review illustrates current advancements in regenerative medicine that may pertain to transplant medicine. We highlight progress made and various tools designed and employed specifically for each tissue or organ, such as the kidney, heart, liver, lung, vasculature, gastrointestinal tract, and pancreas. By combing both fields of transplant and regenerative medicine, we can harbor a successful collaboration that would be beneficial and efficacious for the repair and design of de novo engineered whole organs for transplantations.
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Affiliation(s)
- Astgik Petrosyan
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles, Los Angeles, CA, United States
| | - Filippo Montali
- Department of General Surgery, di Vaio Hospital, Fidenza, Italy
| | - Andrea Peloso
- Visceral Surgery Division, University Hospitals of Geneva, Geneva, Switzerland
| | - Antonio Citro
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Lori N. Byers
- Wake Forest School of Medicine, Winston Salem, NC, United States
| | | | - Mara Suleiman
- Wake Forest School of Medicine, Winston Salem, NC, United States
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Alice Marchetti
- Wake Forest School of Medicine, Winston Salem, NC, United States
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Eoin P. Mcneill
- Department of Pediatric Surgery, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, United States
| | - Allison L Speer
- Department of Pediatric Surgery, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, United States
| | - Wai Hoe Ng
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States
| | - Xi Ren
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Laura Perin
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles, Los Angeles, CA, United States
| | - Paolo Di Nardo
- Centro Interdipartimentale per la Medicina Rigenerativa (CIMER), Università Degli Studi di Roma Tor Vergata, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Jerome Duisit
- Department of Plastic, Reconstructive and Aesthetic Surgery, CHU Rennes, University of Rennes I, Rennes, France
| | | | | | - Amish Asthana
- Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Giuseppe Orlando
- Wake Forest School of Medicine, Winston Salem, NC, United States
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Du Y, Zhang W, Qiu H, Xiao C, Shi J, Reid LM, He Z. Mouse Models of Liver Parenchyma Injuries and Regeneration. Front Cell Dev Biol 2022; 10:903740. [PMID: 35721478 PMCID: PMC9198899 DOI: 10.3389/fcell.2022.903740] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/11/2022] [Indexed: 12/11/2022] Open
Abstract
Mice have genetic and physiological similarities with humans and a well-characterized genetic background that is easy to manipulate. Murine models have become the most favored, robust mammalian systems for experimental analyses of biological processes and disease conditions due to their low cost, rapid reproduction, a wealth of mouse strains with defined genetic conditions (both native ones as well as ones established experimentally), and high reproducibility with respect to that which can be done in experimental studies. In this review, we focus on murine models for liver, an organ with renown regenerative capacity and the organ most central to systemic, complex metabolic and physiological functions for mammalian hosts. Establishment of murine models has been achieved for all aspects of studies of normal liver, liver diseases, liver injuries, and regenerative repair mechanisms. We summarize key information on current mouse systems that partially model facets of clinical scenarios, particularly those associated with drug-induced acute or chronic liver injuries, dietary related, non-alcoholic liver disease (NAFLD), hepatitis virus infectious chronic liver diseases, and autoimmune hepatitis (AIH). In addition, we also include mouse models that are suitable for studying liver cancers (e.g., hepatocellular carcinomas), the aging process (senescence, apoptosis), and various types of liver injuries and regenerative processes associated with them.
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Affiliation(s)
- Yuan Du
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wencheng Zhang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
| | - Hua Qiu
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Canjun Xiao
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
| | - Jun Shi
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
| | - Lola M. Reid
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, United States
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
| | - Zhiying He
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
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Fagoonee S, Shukla SP, Dhasmana A, Birbrair A, Haque S, Pellicano R. Routes of Stem Cell Administration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022:63-82. [PMID: 35389198 DOI: 10.1007/5584_2022_710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Stem cells are very promising for the treatment of a plethora of human diseases. Numerous clinical studies have been conducted to assess the safety and efficacy of various stem cell types. Factors that ensure successful therapeutic outcomes in patients are cell-based parameters such as source, viability, and number, as well as frequency and timing of intervention and disease stage. Stem cell administration routes should be appropriately chosen as these can affect homing and engraftment of the cells and hence reduce therapeutic effects, or compromise safety, resulting in serious adverse events. In this chapter, we will describe the use of stem cells in organ repair and regeneration, in particular, the liver and the available routes of cell delivery in the clinic for end-stage liver diseases. Factors affecting homing and engraftment of stem cells for each administration route will be discussed.
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Affiliation(s)
- Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, National Research Council (CNR), Molecular Biotechnology Center, Turin, Italy.
| | - Shiv Poojan Shukla
- Department of Dermatology & Cutaneous Biology, Sydney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Anupam Dhasmana
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA
- Department of Biosciences and Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, India
| | - Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Bursa Uludağ University Faculty of Medicine, Nilüfer, Bursa, Turkey
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Sukowati CHC, Tiribelli C. Adult Stem Cell Therapy as Regenerative Medicine for End-Stage Liver Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022:57-72. [DOI: 10.1007/5584_2022_719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Al Reza H, Okabe R, Takebe T. Organoid transplant approaches for the liver. Transpl Int 2021; 34:2031-2045. [PMID: 34614263 PMCID: PMC8602742 DOI: 10.1111/tri.14128] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/13/2021] [Accepted: 08/30/2021] [Indexed: 12/12/2022]
Abstract
Organoid technology is a state-of-the-art cell culture tool that has revolutionized study of development, regeneration, and diseases. Human liver organoids (HLOs) are now derived from either adult stem/progenitors or pluripotent stem cells (PSCs), emulating cellular diversity and structural symphony akin to the human liver. With the rapid rise in decompensated liver disease conditions only treated by liver transplant therapy, HLOs represent an alternate source for transplantation to address the ongoing shortage of grafts. Although ongoing advancements in bioengineering technology have moved the organoid transplant approach to the next level, sustained survival of the transplanted tissue still eludes us toward functional organ replacement. Herein, we review the development of HLOs and discuss promises and challenges on organoid transplant approaches.
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Affiliation(s)
- Hasan Al Reza
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA
- Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA
| | - Ryo Okabe
- Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takanori Takebe
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA
- Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA
- Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan
- Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Communication Design Center, Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Japan
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Abstract
Aim of the study CD326 has been used as a single marker to enrich for hepatic stem cell populations in the liver. However, bile duct epithelium is also positive for CD326, which impedes the selection of pure hepatic stem cell populations. Some markers have been proposed to be co-expressed by hepatic stem cells but these have not been systematically compared. Therefore, we determined the percentages and compared the characteristics of human liver cells expressing potential stem cell surface markers. Material and methods We analyzed CD326 expression in human liver tissues from fetal, neonatal, pediatric, and adult stages using immunohistochemistry. In flow cytometry, we quantified fetal liver cells for their co-expression of CD326 with CD56, CD117, CD44, CD90, CD49f, LGR5 and SSEA4. We analyzed the various fractions for their quantitative expression of genes typically associated with progenitors and hepatic lineages. Results 12.5% of cells were positive for CD326; of these, 63.5% co-expressed CD44. The lowest co-expression percentages were for SSEA4 (2.1%) and LGR5 (0.7%). Fractions revealed distinct gene expression patterns. Of all combinations, cells that co-expressed surface CD326 and SSEA4 demonstrated the highest gene expression for the proliferation marker MKi67 and hepatic markers DLK1, AFP and ALB, and were the only fraction negative for the biliary epithelial marker KRT19. Histology of adult and fetal liver showed cells positive for CD326 and SSEA4 but negative for CK19. Conclusions CD326-positive cells represent a heterogeneous population, which in combination with SSEA4 potentially distinguishes bile duct epithelium from hepatic stem cells. These findings can help to further classify human hepatic progenitor stages.
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Laurent A, Hirt-Burri N, Scaletta C, Michetti M, de Buys Roessingh AS, Raffoul W, Applegate LA. Holistic Approach of Swiss Fetal Progenitor Cell Banking: Optimizing Safe and Sustainable Substrates for Regenerative Medicine and Biotechnology. Front Bioeng Biotechnol 2020; 8:557758. [PMID: 33195124 PMCID: PMC7644790 DOI: 10.3389/fbioe.2020.557758] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 08/21/2020] [Indexed: 12/17/2022] Open
Abstract
Safety, quality, and regulatory-driven iterative optimization of therapeutic cell source selection has constituted the core developmental bedrock for primary fetal progenitor cell (FPC) therapy in Switzerland throughout three decades. Customized Fetal Transplantation Programs were pragmatically devised as straightforward workflows for tissue procurement, traceability maximization, safety, consistency, and robustness of cultured progeny cellular materials. Whole-cell bioprocessing standardization has provided plethoric insights into the adequate conjugation of modern biotechnological advances with current restraining legislative, ethical, and regulatory frameworks. Pioneer translational advances in cutaneous and musculoskeletal regenerative medicine continuously demonstrate the therapeutic potential of FPCs. Extensive technical and clinical hindsight was gathered by managing pediatric burns and geriatric ulcers in Switzerland. Concomitant industrial transposition of dermal FPC banking, following good manufacturing practices, demonstrated the extensive potential of their therapeutic value. Furthermore, in extenso, exponential revalorization of Swiss FPC technology may be achieved via the renewal of integrative model frameworks. Consideration of both longitudinal and transversal aspects of simultaneous fetal tissue differential processing allows for a better understanding of the quasi-infinite expansion potential within multi-tiered primary FPC banking. Multiple fetal tissues (e.g., skin, cartilage, tendon, muscle, bone, lung) may be simultaneously harvested and processed for adherent cell cultures, establishing a unique model for sustainable therapeutic cellular material supply chains. Here, we integrated fundamental, preclinical, clinical, and industrial developments embodying the scientific advances supported by Swiss FPC banking and we focused on advances made to date for FPCs that may be derived from a single organ donation. A renewed model of single organ donation bioprocessing is proposed, achieving sustained standards and potential production of billions of affordable and efficient therapeutic doses. Thereby, the aim is to validate the core therapeutic value proposition, to increase awareness and use of standardized protocols for translational regenerative medicine, potentially impacting millions of patients suffering from cutaneous and musculoskeletal diseases. Alternative applications of FPC banking include biopharmaceutical therapeutic product manufacturing, thereby indirectly and synergistically enhancing the power of modern therapeutic armamentariums. It is hypothesized that a single qualifying fetal organ donation is sufficient to sustain decades of scientific, medical, and industrial developments, as technological optimization and standardization enable high efficiency.
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Affiliation(s)
- Alexis Laurent
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
- Tec-Pharma SA, Bercher, Switzerland
- LAM Biotechnologies SA, Épalinges, Switzerland
| | - Nathalie Hirt-Burri
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
| | - Corinne Scaletta
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
| | - Murielle Michetti
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
| | - Anthony S. de Buys Roessingh
- Children and Adolescent Surgery Service, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Wassim Raffoul
- Plastic, Reconstructive and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Lee Ann Applegate
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
- Oxford Suzhou Center for Advanced Research, Science and Technology Co., Ltd., Oxford University, Suzhou, China
- Competence Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland
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11
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Safarikia S, Carpino G, Overi D, Cardinale V, Venere R, Franchitto A, Onori P, Alvaro D, Gaudio E. Distinct EpCAM-Positive Stem Cell Niches Are Engaged in Chronic and Neoplastic Liver Diseases. Front Med (Lausanne) 2020; 7:479. [PMID: 32984373 PMCID: PMC7492539 DOI: 10.3389/fmed.2020.00479] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 07/15/2020] [Indexed: 12/12/2022] Open
Abstract
In normal human livers, EpCAMpos cells are mostly restricted in two distinct niches, which are (i) the bile ductules and (ii) the mucous glands present inside the wall of large intrahepatic bile ducts (the so-called peribiliary glands). These EpCAMpos cell niches have been proven to harbor stem/progenitor cells with great importance in liver and biliary tree regeneration and in the pathophysiology of human diseases. The EpCAMpos progenitor cells within bile ductules are engaged in driving regenerative processes in chronic diseases affecting hepatocytes or interlobular bile ducts. The EpCAMpos population within peribiliary glands is activated when regenerative needs are finalized to repair large intra- or extra-hepatic bile ducts affected by chronic pathologies, including primary sclerosing cholangitis and ischemia-induced cholangiopathies after orthotopic liver transplantation. Finally, the presence of distinct EpCAMpos cell populations may explain the histological and molecular heterogeneity characterizing cholangiocarcinoma, based on the concept of multiple candidate cells of origin. This review aimed to describe the precise anatomical distribution of EpCAMpos populations within the liver and the biliary tree and to discuss their contribution in the pathophysiology of human liver diseases, as well as their potential role in regenerative medicine of the liver.
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Affiliation(s)
- Samira Safarikia
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico," Rome, Italy
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Rosanna Venere
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
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12
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Lee JY, Hong SH. Hematopoietic Stem Cells and Their Roles in Tissue Regeneration. Int J Stem Cells 2020; 13:1-12. [PMID: 31887851 PMCID: PMC7119209 DOI: 10.15283/ijsc19127] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 11/18/2019] [Accepted: 12/01/2019] [Indexed: 12/22/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are regarded as one of essential cell sources for treating regenerative diseases. Among many stem cells, the feasibility of using adult-derived hematopoietic stem cells in therapeutic approaches is very diverse, and is unarguably regarded as an important cell source in stem cell biology. So far, many investigators are exploring HSCs and modified HSCs for use in clinical and basic science. In the present review, we briefly summarized HSCs and their application in pathophysiologic conditions, including non-hematopoietic tissue regeneration as well as blood disorders. HSCs and HSCs-derived progenitors are promising cell sources in regenerative medicine and their contributions can be properly applied to treat pathophysiologic conditions. Among many adult stem cells, HSCs are a powerful tool to treat patients with diseases such as hematologic malignancies and liver disease. Since HSCs can be differentiated into diverse progenitors including endothelial progenitors, they may be useful for constructing strategies for effective therapy.
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Affiliation(s)
- Ji Yoon Lee
- CHA Advanced Research Institute, CHA University, Seongnam, Korea
| | - Seok-Ho Hong
- Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea
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13
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Functions and the Emerging Role of the Foetal Liver into Regenerative Medicine. Cells 2019; 8:cells8080914. [PMID: 31426422 PMCID: PMC6721721 DOI: 10.3390/cells8080914] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/09/2019] [Accepted: 08/12/2019] [Indexed: 12/13/2022] Open
Abstract
During foetal life, the liver plays the important roles of connection and transient hematopoietic function. Foetal liver cells develop in an environment called a hematopoietic stem cell niche composed of several cell types, where stem cells can proliferate and give rise to mature blood cells. Embryologically, at about the third week of gestation, the liver appears, and it grows rapidly from the fifth to 10th week under WNT/β-Catenin signaling pathway stimulation, which induces hepatic progenitor cells proliferation and differentiation into hepatocytes. Development of new strategies and identification of new cell sources should represent the main aim in liver regenerative medicine and cell therapy. Cells isolated from organs with endodermal origin, like the liver, bile ducts, and pancreas, could be preferable cell sources. Furthermore, stem cells isolated from these organs could be more susceptible to differentiate into mature liver cells after transplantation with respect to stem cells isolated from organs or tissues with a different embryological origin. The foetal liver possesses unique features given the co-existence of cells having endodermal and mesenchymal origin, and it could be highly available source candidate for regenerative medicine in both the liver and pancreas. Taking into account these advantages, the foetal liver can be the highest potential and available cell source for cell therapy regarding liver diseases and diabetes.
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14
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Ye S, Boeter JWB, Penning LC, Spee B, Schneeberger K. Hydrogels for Liver Tissue Engineering. Bioengineering (Basel) 2019; 6:E59. [PMID: 31284412 PMCID: PMC6784004 DOI: 10.3390/bioengineering6030059] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 06/28/2019] [Accepted: 07/03/2019] [Indexed: 12/14/2022] Open
Abstract
Bioengineered livers are promising in vitro models for drug testing, toxicological studies, and as disease models, and might in the future be an alternative for donor organs to treat end-stage liver diseases. Liver tissue engineering (LTE) aims to construct liver models that are physiologically relevant. To make bioengineered livers, the two most important ingredients are hepatic cells and supportive materials such as hydrogels. In the past decades, dozens of hydrogels have been developed to act as supportive materials, and some have been used for in vitro models and formed functional liver constructs. However, currently none of the used hydrogels are suitable for in vivo transplantation. Here, the histology of the human liver and its relationship with LTE is introduced. After that, significant characteristics of hydrogels are described focusing on LTE. Then, both natural and synthetic materials utilized in hydrogels for LTE are reviewed individually. Finally, a conclusion is drawn on a comparison of the different hydrogels and their characteristics and ideal hydrogels are proposed to promote LTE.
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Affiliation(s)
- Shicheng Ye
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Jochem W B Boeter
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Louis C Penning
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Bart Spee
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Kerstin Schneeberger
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands.
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15
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Hyaluronan-Based Grafting Strategies for Liver Stem Cell Therapy and Tracking Methods. Stem Cells Int 2019; 2019:3620546. [PMID: 31354838 PMCID: PMC6636496 DOI: 10.1155/2019/3620546] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 04/29/2019] [Accepted: 05/27/2019] [Indexed: 12/20/2022] Open
Abstract
Cell adhesion is essential for survival, it plays important roles in physiological cell functions, and it is an innovative target in regenerative medicine. Among the molecular interactions and the pathways triggered during cell adhesion, the binding of cluster of differentiation 44 (CD44), a cell-surface glycoprotein involved in cell-cell interactions, to hyaluronic acid (HA), a major component of the extracellular matrix, is a crucial step. Cell therapy has emerged as a promising treatment for advanced liver diseases; however, so far, it has led to low cell engraftment and limited cell repopulation of the target tissue. Currently, different strategies are under investigation to improve cell grafting in the liver, including the use of organic and inorganic biomatrices that mimic the microenvironment of the extracellular matrix. Hyaluronans, major components of stem cell niches, are attractive candidates for coating stem cells since they improve viability, proliferation, and engraftment in damaged livers. In this review, we will discuss the new strategies that have been adopted to improve cell grafting and track cells after transplantation.
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16
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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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17
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Iansante V, Chandrashekran A, Dhawan A. Cell-based liver therapies: past, present and future. Philos Trans R Soc Lond B Biol Sci 2019; 373:rstb.2017.0229. [PMID: 29786563 DOI: 10.1098/rstb.2017.0229] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/23/2017] [Indexed: 12/16/2022] Open
Abstract
Liver transplantation represents the standard treatment for people with an end-stage liver disease and some liver-based metabolic disorders; however, shortage of liver donor tissues limits its availability. Furthermore, whole liver replacement eliminates the possibility of using native liver as a possible target for future gene therapy in case of liver-based metabolic defects. Cell therapy has emerged as a potential alternative, as cells can provide the hepatic functions and engraft in the liver parenchyma. Various options have been proposed, including human or other species hepatocytes, hepatocyte-like cells derived from stem cells or more futuristic alternatives, such as combination therapies with different cell types, organoids and cell-biomaterial combinations. In this review, we aim to give an overview of the cell therapies developed so far, highlighting preclinical and/or clinical achievements as well as the limitations that need to be overcome to make them fully effective and safe for clinical applications.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'.
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Affiliation(s)
- Valeria Iansante
- Dhawan Lab, Paediatric Liver GI and Nutrition Center and MowatLabs, Institute of Liver Studies, King's College London at King's College Hospital, London SE5 9PJ, UK
| | - Anil Chandrashekran
- Dhawan Lab, Paediatric Liver GI and Nutrition Center and MowatLabs, Institute of Liver Studies, King's College London at King's College Hospital, London SE5 9PJ, UK
| | - Anil Dhawan
- Dhawan Lab, Paediatric Liver GI and Nutrition Center and MowatLabs, Institute of Liver Studies, King's College London at King's College Hospital, London SE5 9PJ, UK
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18
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Impact of Percoll purification on isolation of primary human hepatocytes. Sci Rep 2019; 9:6542. [PMID: 31024069 PMCID: PMC6484008 DOI: 10.1038/s41598-019-43042-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 04/12/2019] [Indexed: 01/21/2023] Open
Abstract
Research and therapeutic applications create a high demand for primary human hepatocytes. The limiting factor for their utilization is the availability of metabolically active hepatocytes in large quantities. Centrifugation through Percoll, which is commonly performed during hepatocyte isolation, has so far not been systematically evaluated in the scientific literature. 27 hepatocyte isolations were performed using a two-step perfusion technique on tissue obtained from partial liver resections. Cells were seeded with or without having undergone the centrifugation step through 25% Percoll. Cell yield, function, purity, viability and rate of bacterial contamination were assessed over a period of 6 days. Viable yield without Percoll purification was 42.4 × 106 (SEM ± 4.6 × 106) cells/g tissue. An average of 59% of cells were recovered after Percoll treatment. There were neither significant differences in the functional performance of cells, nor regarding presence of non-parenchymal liver cells. In five cases with initial viability of <80%, viability was significantly increased by Percoll purification (71.6 to 87.7%, p = 0.03). Considering our data and the massive cell loss due to Percoll purification, we suggest that this step can be omitted if the initial viability is high, whereas low viabilities can be improved by Percoll centrifugation.
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19
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Barahman M, Asp P, Roy-Chowdhury N, Kinkhabwala M, Roy-Chowdhury J, Kabarriti R, Guha C. Hepatocyte Transplantation: Quo Vadis? Int J Radiat Oncol Biol Phys 2018; 103:922-934. [PMID: 30503786 DOI: 10.1016/j.ijrobp.2018.11.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 10/10/2018] [Accepted: 11/10/2018] [Indexed: 12/21/2022]
Abstract
Orthotopic liver transplantation (OLT) has been effective in managing end-stage liver disease since the advent of cyclosporine immunosuppression therapy in 1980. The major limitations of OLT are organ supply, monetary cost, and the burden of lifelong immunosuppression. Hepatocyte transplantation, as a substitute for OLT, has been an exciting topic of investigation for several decades. HT is potentially minimally invasive and can serve as a vehicle for delivery of personalized medicine through autologous cell transplant after modification ex vivo. However, 3 major hurdles have prevented large-scale clinical application: (1) availability of transplantable cells; (2) safe and efficient ex vivo gene therapy methods; and (3) engraftment and repopulation efficiency. This review will discuss new sources for transplantable liver cells obtained by lineage reprogramming, clinically acceptable methods of genetic manipulation, and the development of hepatic irradiation-based preparative regimens for enhancing engraftment and repopulation of transplanted hepatocytes. We will also review the results of the first 3 patients with genetic liver disorders who underwent preparative hepatic irradiation before hepatocyte transplantation.
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Affiliation(s)
- Mark Barahman
- Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Patrik Asp
- Department of Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Namita Roy-Chowdhury
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Milan Kinkhabwala
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Jayanta Roy-Chowdhury
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Department of Genetics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Rafi Kabarriti
- Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Chandan Guha
- Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Department of Urology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.
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20
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Zhang Y, Li Y, Li W, Cai J, Yue M, Jiang L, Xu R, Zhang L, Li J, Zhu C. Therapeutic Effect of Human Umbilical Cord Mesenchymal Stem Cells at Various Passages on Acute Liver Failure in Rats. Stem Cells Int 2018; 2018:7159465. [PMID: 30538751 PMCID: PMC6261392 DOI: 10.1155/2018/7159465] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 08/30/2018] [Accepted: 09/10/2018] [Indexed: 12/14/2022] Open
Abstract
Recent studies have described beneficial effects of an infusion of mesenchymal stem cells (MSCs) derived from Wharton's jelly tissue, for the treatment of acute liver failure (ALF). However, data on the therapeutic potential of culture-expanded MSCs are lacking. We examined the therapeutic potential of passage five (P5) and ten (P10) human umbilical cord- (hUC-) MSCs via their transplantation into Sprague-Dawley (SD) rats with D-galactosamine (D-GalN) and LPS-induced acute liver failure (ALF). SD rats were randomly divided into three groups: control group, P5 hUC-MSCs group, and P10 hUC-MSCs group. After transplantation, P5 hUC-MSCs provided a significant survival benefit. The analysis of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) levels showed that transplantation with P5 hUC-MSCs was more effective than treatment with P10 hUC-MSCs. P5 hUC-MSCs also successfully downregulated the hepatic activity index (HAI) scores. Compared to P10 hUC-MSCs in vivo, P5 hUC-MSCs significantly enhanced the regeneration and inhibited the apoptosis of hepatocytes. CM-Dil-labeled hUC-MSCs were found to engraft within the recipient liver, whereas the homing of cells to the recipient liver in the P10 hUC-MSCs group was less effective compared to the P5 hUC-MSCs group. Previous studies have shown that the concentration of hepatocyte growth factor (HGF) in the injured liver was significantly increased. HGF is commonly known as the ligand of c-Met. The level of c-Met in hUC-MSCs as detected by Western blotting indicated that at a higher passage number, there is a decrease in c-Met. These data suggest that direct transplantation of P5 hUC-MSCs can more efficiently home to an injured liver. Subsequently, the P5 hUC-MSCs can rescue ALF and repopulate the livers of rats through the stimulation of endogenous liver regeneration and inhibition of hepatocellular apoptosis for compensated liver function, which is dependent on the higher level of c-Met than P10 hUC-MSCs.
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Affiliation(s)
- Yongting Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Department of Pediatrics, The Affiliated Hospital of Yangzhou University, Yangzhou 225000, China
| | - Yuwen Li
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Wenting Li
- Third Liver Unit, Department of Infectious Disease, The First Affiliated Hospital of Science and Technology of China, Hefei 230001, China
| | - Jie Cai
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ming Yue
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Longfeng Jiang
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ruirui Xu
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Lili Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jun Li
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Chuanlong Zhu
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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21
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Iansante V, Dhawan A, Masmoudi F, Lee CA, Fernandez-Dacosta R, Walker S, Fitzpatrick E, Mitry RR, Filippi C. A New High Throughput Screening Platform for Cell Encapsulation in Alginate Hydrogel Shows Improved Hepatocyte Functions by Mesenchymal Stromal Cells Co-encapsulation. Front Med (Lausanne) 2018; 5:216. [PMID: 30140676 PMCID: PMC6095031 DOI: 10.3389/fmed.2018.00216] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 07/16/2018] [Indexed: 12/31/2022] Open
Abstract
Hepatocyte transplantation has emerged as an alternative to liver transplant for liver disease. Hepatocytes encapsulated in alginate microbeads have been proposed for the treatment of acute liver failure, as they are able to provide hepatic functions while the liver regenerates. Furthermore, they do not require immunosuppression, as the alginate protects the hepatocytes from the recipient's immune cells. Mesenchymal stromal cells are very attractive candidates for regenerative medicine, being able to differentiate into cells of the mesenchymal lineages and having extensive proliferative ability. When co-cultured with hepatocytes in two-dimensional cultures, they exert a trophic role, drastically improving hepatocytes survival and functions. In this study we aimed to (i) devise a high throughput system (HTS) to allow testing of a variety of different parameters for cell encapsulation and (ii) using this HTS, investigate whether mesenchymal stromal cells could have beneficial effects on the hepatocytes when co-encapsulated in alginate microbeads. Using our HTS platform, we observed some improvement of hepatocyte behavior with MSCs, subsequently confirmed in the low throughput analysis of cell function in alginate microbeads. Therefore, our study shows that mesenchymal stromal cells may be a good option to improve the function of hepatocytes microbeads. Furthermore, the platform developed may be used for HTS studies on cell encapsulation, in which several conditions (e.g., number of cells, combinations of cells, alginate modifications) could be easily compared at the same time.
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Affiliation(s)
- Valeria Iansante
- Dhawan Lab at Mowat Labs, Institute of Liver Studies, King's College London, King's College Hospital, London, United Kingdom
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre, King's College London, King's College Hospital, London, United Kingdom
| | - Fatma Masmoudi
- Dhawan Lab at Mowat Labs, Institute of Liver Studies, King's College London, King's College Hospital, London, United Kingdom
| | - Charlotte A Lee
- Dhawan Lab at Mowat Labs, Institute of Liver Studies, King's College London, King's College Hospital, London, United Kingdom
| | - Raquel Fernandez-Dacosta
- Dhawan Lab at Mowat Labs, Institute of Liver Studies, King's College London, King's College Hospital, London, United Kingdom
| | - Simon Walker
- Dhawan Lab at Mowat Labs, Institute of Liver Studies, King's College London, King's College Hospital, London, United Kingdom
| | - Emer Fitzpatrick
- Paediatric Liver, GI and Nutrition Centre, King's College London, King's College Hospital, London, United Kingdom
| | - Ragai R Mitry
- Dhawan Lab at Mowat Labs, Institute of Liver Studies, King's College London, King's College Hospital, London, United Kingdom
| | - Céline Filippi
- Dhawan Lab at Mowat Labs, Institute of Liver Studies, King's College London, King's College Hospital, London, United Kingdom
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22
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Zhang Y, Li Y, Zhang L, Li J, Zhu C. Mesenchymal stem cells: potential application for the treatment of hepatic cirrhosis. Stem Cell Res Ther 2018; 9:59. [PMID: 29523186 PMCID: PMC5845383 DOI: 10.1186/s13287-018-0814-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Nowadays, orthotopic liver transplantation is considered the most efficient approach to the end stage of chronic hepatic cirrhosis. Because of the limitations of orthotopic liver transplantation, stem cells are an attractive therapeutic option. Mesenchymal stem cells (MSCs) especially show promise as an alternative treatment for hepatic cirrhosis in animal models and during clinical trials. Nevertheless, the homing of transplanted MSCs to the liver occurs in limited numbers. Therefore, we review the strategies for enhancing the homing of MSCs, mainly via the delivery routes, optimizing cell culture conditions, stimulating the target sites, and genetic modification.
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Affiliation(s)
- Yongting Zhang
- Department of Infectious Disease, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Yuwen Li
- Department of Pediatrics, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Lili Zhang
- Department of Infectious Disease, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Jun Li
- Department of Infectious Disease, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Chuanlong Zhu
- Department of Infectious Disease, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
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23
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Proceedings of the signature series event of the international society for cellular therapy: "Advancements in cellular therapies and regenerative medicine in digestive diseases," London, United Kingdom, May 3, 2017. Cytotherapy 2018; 20:461-476. [PMID: 29398624 DOI: 10.1016/j.jcyt.2017.12.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 12/01/2017] [Indexed: 12/18/2022]
Abstract
A summary of the First Signature Series Event, "Advancements in Cellular Therapies and Regenerative Medicine for Digestive Diseases," held on May 3, 2017, in London, United Kingdom, is presented. Twelve speakers from three continents covered major topics in the areas of cellular therapy and regenerative medicine applied to liver and gastrointestinal medicine as well as to diabetes mellitus. Highlights from their presentations, together with an overview of the global impact of digestive diseases and a proposal for a shared online collection and data-monitoring platform tool, are included in this proceedings. Although growing evidence demonstrate the feasibility and safety of exploiting cell-based technologies for the treatment of digestive diseases, regulatory and methodological obstacles will need to be overcome before the successful implementation in the clinic of these novel attractive therapeutic strategies.
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24
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Current Perspectives Regarding Stem Cell-Based Therapy for Liver Cirrhosis. Can J Gastroenterol Hepatol 2018; 2018:4197857. [PMID: 29670867 PMCID: PMC5833156 DOI: 10.1155/2018/4197857] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 01/16/2018] [Indexed: 12/12/2022] Open
Abstract
Liver cirrhosis is a major cause of mortality and a common end of various progressive liver diseases. Since the effective treatment is currently limited to liver transplantation, stem cell-based therapy as an alternative has attracted interest due to promising results from preclinical and clinical studies. However, there is still much to be understood regarding the precise mechanisms of action. A number of stem cells from different origins have been employed for hepatic regeneration with different degrees of success. The present review presents a synopsis of stem cell research for the treatment of patients with liver cirrhosis according to the stem cell type. Clinical trials to date are summarized briefly. Finally, issues to be resolved and future perspectives are discussed with regard to clinical applications.
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Vishwakarma SK, Bardia A, Lakkireddy C, Nagarapu R, Habeeb MA, Khan AA. Bioengineered humanized livers as better three-dimensional drug testing model system. World J Hepatol 2018; 10:22-33. [PMID: 29399275 PMCID: PMC5787681 DOI: 10.4254/wjh.v10.i1.22] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 11/28/2017] [Accepted: 12/28/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To develop appropriate humanized three-dimensional ex-vivo model system for drug testing. METHODS Bioengineered humanized livers were developed in this study using human hepatic stem cells repopulation within the acellularized liver scaffolds which mimics with the natural organ anatomy and physiology. Six cytochrome P-450 probes were used to enable efficient identification of drug metabolism in bioengineered humanized livers. The drug metabolism study in bioengineered livers was evaluated to identify the absorption, distribution, metabolism, excretion and toxicity responses. RESULTS The bioengineered humanized livers showed cellular and molecular characteristics of human livers. The bioengineered liver showed three-dimensional natural architecture with intact vasculature and extra-cellular matrix. Human hepatic cells were engrafted similar to the human liver. Drug metabolism studies provided a suitable platform alternative to available ex-vivo and in vivo models for identifying cellular and molecular dynamics of pharmacological drugs. CONCLUSION The present study paves a way towards the development of suitable humanized preclinical model systems for pharmacological testing. This approach may reduce the cost and time duration of preclinical drug testing and further overcomes on the anatomical and physiological variations in xenogeneic systems.
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Affiliation(s)
- Sandeep Kumar Vishwakarma
- Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Avinash Bardia
- Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Chandrakala Lakkireddy
- Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Raju Nagarapu
- Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Md Aejaz Habeeb
- Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Aleem Ahmed Khan
- Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
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Iansante V, Mitry RR, Filippi C, Fitzpatrick E, Dhawan A. Human hepatocyte transplantation for liver disease: current status and future perspectives. Pediatr Res 2018; 83:232-240. [PMID: 29149103 DOI: 10.1038/pr.2017.284] [Citation(s) in RCA: 150] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 10/02/2017] [Indexed: 12/16/2022]
Abstract
Liver transplantation is the accepted treatment for patients with acute liver failure and liver-based metabolic disorders. However, donor organ shortage and lifelong need for immunosuppression are the main limitations to liver transplantation. In addition, loss of the native liver as a target organ for future gene therapy for metabolic disorders limits the futuristic treatment options, resulting in the need for alternative therapeutic strategies. A potential alternative to liver transplantation is allogeneic hepatocyte transplantation. Over the last two decades, hepatocyte transplantation has made the transition from bench to bedside. Standardized techniques have been established for isolation, culture, and cryopreservation of human hepatocytes. Clinical hepatocyte transplantation safety and short-term efficacy have been proven; however, some major hurdles-mainly concerning shortage of donor organs, low cell engraftment, and lack of a long-lasting effect-need to be overcome to widen its clinical applications. Current research is aimed at addressing these problems, with the ultimate goal of increasing hepatocyte transplantation efficacy in clinical applications.
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Affiliation(s)
- V Iansante
- DhawanLab, Paediatric Liver GI and Nutrition Center and MowatLabs, Institute of Liver Studies, King's College London, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, London, UK
| | - R R Mitry
- DhawanLab, Paediatric Liver GI and Nutrition Center and MowatLabs, Institute of Liver Studies, King's College London, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, London, UK
| | - C Filippi
- DhawanLab, Paediatric Liver GI and Nutrition Center and MowatLabs, Institute of Liver Studies, King's College London, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, London, UK
| | - E Fitzpatrick
- DhawanLab, Paediatric Liver GI and Nutrition Center and MowatLabs, Institute of Liver Studies, King's College London, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, London, UK
| | - A Dhawan
- DhawanLab, Paediatric Liver GI and Nutrition Center and MowatLabs, Institute of Liver Studies, King's College London, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, London, UK
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Abstract
PURPOSE OF REVIEW Organ donation in the United States registered 9079 deceased organ donors in 2015. This high percentage of donations allowed organ transplantation in 29 851 recipients. Despite increasing numbers of transplants performed in comparison with previous years, the numbers of patients that are in need for a transplant increase every year at a higher rate. This reveals that the discrepancy between the demand and availability of organs remains fundamental problem in organ transplantation. RECENT FINDINGS Development of bioengineered organs represents a promising approach to increase the pool of organs for transplantation. The technology involves obtaining complex three-dimensional scaffolds that support cellular activity and functional remodeling though tissue recellularization protocols using progenitor cells. This innovative approach integrates cross-thematic approaches from specific areas of transplant immunology, tissue engineering and stem cell biology, to potentially manufacture an unlimited source of donor organs for transplantation. SUMMARY Although bioengineered organs are thought to escape immune recognition, the potential immune reactivity toward each of its components has not been studied in detail. Here, we summarize the host immune response toward different progenitor cells and discuss the potential implications of using nonself biological scaffolds to develop bioengineered organs.
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Ancey PB, Ecsedi S, Lambert MP, Talukdar FR, Cros MP, Glaise D, Narvaez DM, Chauvet V, Herceg Z, Corlu A, Hernandez-Vargas H. TET-Catalyzed 5-Hydroxymethylation Precedes HNF4A Promoter Choice during Differentiation of Bipotent Liver Progenitors. Stem Cell Reports 2017; 9:264-278. [PMID: 28648900 PMCID: PMC5511103 DOI: 10.1016/j.stemcr.2017.05.023] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 05/16/2017] [Accepted: 05/17/2017] [Indexed: 12/17/2022] Open
Abstract
Understanding the processes that govern liver progenitor cell differentiation has important implications for the design of strategies targeting chronic liver diseases, whereby regeneration of liver tissue is critical. Although DNA methylation (5mC) and hydroxymethylation (5hmC) are highly dynamic during early embryonic development, less is known about their roles at later stages of differentiation. Using an in vitro model of hepatocyte differentiation, we show here that 5hmC precedes the expression of promoter 1 (P1)-dependent isoforms of HNF4A, a master transcription factor of hepatocyte identity. 5hmC and HNF4A expression from P1 are dependent on ten-eleven translocation (TET) dioxygenases. In turn, the liver pioneer factor FOXA2 is necessary for TET1 binding to the P1 locus. Both FOXA2 and TETs are required for the 5hmC-related switch in HNF4A expression. The epigenetic event identified here may be a key step for the establishment of the hepatocyte program by HNF4A.
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Affiliation(s)
- Pierre-Benoit Ancey
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France
| | - Szilvia Ecsedi
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France; MTA-DE Public Health Research Group, University of Debrecen, 4028 Debrecen, Hungary
| | - Marie-Pierre Lambert
- Epissage alternatif et progression tumorale, Centre de Recherche en Cancérologie de Lyon (CRCL), 28 rue Laennec, 69008 Lyon, France
| | - Fazlur Rahman Talukdar
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France
| | - Marie-Pierre Cros
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France
| | - Denise Glaise
- Inserm, Inra, UBL, Nutrition Metabolism and Cancer (NuMeCan), 35033 Rennes Cedex 9, France
| | - Diana Maria Narvaez
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France; Human Genetics Laboratory, Department of Biological Sciences, Universidad de Los Andes, Cr. 1 No. 18A-10 Building M1-2 Floor, Bogotá 110321, Colombia
| | - Veronique Chauvet
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France
| | - Zdenko Herceg
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France
| | - Anne Corlu
- Inserm, Inra, UBL, Nutrition Metabolism and Cancer (NuMeCan), 35033 Rennes Cedex 9, France
| | - Hector Hernandez-Vargas
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France.
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Nevi L, Carpino G, Costantini D, Cardinale V, Riccioni O, Di Matteo S, Melandro F, Berloco PB, Reid L, Gaudio E, Alvaro D. Hyaluronan coating improves liver engraftment of transplanted human biliary tree stem/progenitor cells. Stem Cell Res Ther 2017; 8:68. [PMID: 28320463 PMCID: PMC5360089 DOI: 10.1186/s13287-017-0492-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 01/11/2017] [Accepted: 01/28/2017] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Cell therapy of liver diseases with human biliary tree stem cells (hBTSCs) is biased by low engraftment efficiency. Coating the hBTSCs with hyaluronans (HAs), the primary constituents of all stem cell niches, could facilitate cell survival, proliferation, and, specifically, liver engraftment given that HAs are cleared selectively by the liver. METHODS We developed a fast and easy method to coat hBTSCs with HA and assessed the effects of HA-coating on cell properties in vitro and in vivo. RESULTS The HA coating markedly improved the viability, colony formation, and population doubling of hBTSCs in primary cultures, and resulted in a higher expression of integrins that mediate cell attachment to matrix components. When HA-coated hBTSCs were transplanted via the spleen into the liver of immunocompromised mice, the engraftment efficiency increased to 11% with respect to 3% of uncoated cells. Notably, HA-coated hBTSC transplantation in mice resulted in a 10-fold increase of human albumin gene expression in the liver and in a 2-fold increase of human albumin serum levels with respect to uncoated cells. Studies in distant organs showed minimal ectopic cell distribution without differences between HA-coated and uncoated hBTSCs and, specifically, cell seeding in the kidney was excluded. CONCLUSIONS A ready and economical procedure of HA cell coating greatly enhanced the liver engraftment of transplanted hBTSCs and improved their differentiation toward mature hepatocytes. HA coating could improve outcomes of stem cell therapies of liver diseases and could be immediately translated into the clinic given that GMP-grade HAs are already available for clinical use.
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Affiliation(s)
- Lorenzo Nevi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Daniele Costantini
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Olga Riccioni
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Sabina Di Matteo
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Fabio Melandro
- Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy
| | | | - Lola Reid
- Department of Cell Biology and Physiology and Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy. .,Division of Human Anatomy, Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161, Rome, Italy.
| | - Domenico Alvaro
- Department of Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy. .,Division of Gastroenterology, Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University of Rome, Vialedell'Università 37, 00185, Rome, Italy.
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Ma HC, Wang X, Wu MN, Zhao X, Yuan XW, Shi XL. Interleukin-10 Contributes to Therapeutic Effect of Mesenchymal Stem Cells for Acute Liver Failure via Signal Transducer and Activator of Transcription 3 Signaling Pathway. Chin Med J (Engl) 2017; 129:967-75. [PMID: 27064043 PMCID: PMC4831533 DOI: 10.4103/0366-6999.179794] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background: Mesenchymal stem cells (MSCs) transplantation has been proven to have therapeutic potential for acute liver failure (ALF). However, the mechanism remains controversial. Recently, modulation of inflammation by MSCs has been regarded as a crucial mechanism. The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects in ALF. Methods: MSCs isolated from Sprague-Dawley rats were identified by fluorescence-activated cell sorting analysis. Conditioned medium derived from MSCs (MSCs-CM) was collected and analyzed by a cytokine microarray. MSCs and MSCs-CM were transplanted into rats with D-galactosamine-induced ALF. Liver function, survival rate, histology, and inflammatory factors were determined. Exogenous recombinant rat interleukin (IL)-10, anti-rat IL-10 antibody, and AG490 (signal transducer and activator of transcription 3 [STAT3] signaling pathway inhibitor) were administered to explore the therapeutic mechanism of MSCs-CM. Statistical analysis was performed with SPSS version 19.0, and all data were analyzed by the independent-sample t-test. Results: There are statistical differences of the survival curve between ALF+MSCs group and ALF+Dulbecco's modified Eagle's medium (DMEM) group, as well as ALF+MSCs-CM group and ALF+DMEM group (all P < 0.05). Serum alanine aminotransferase (ALT) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (865.53±52.80 vs. 1709.75±372.12 U/L and 964.72±414.59 vs. 1709.75±372.12 U/L, respectively, all P < 0.05); meanwhile, serum aspartate aminotransferase (AST) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (2440.83±511.94 vs. 4234.35±807.30 U/L and 2739.83±587.33 vs. 4234.35±807.30 U/L, respectively, all P < 0.05). Furthermore, MSCs or MSCs-CM treatment significantly reduced serum interferon-γ (IFN-γ), IL-1β, IL-6 levels and increased serum IL-10 level compared with DMEM (all P < 0.05). Proteome profile analysis of MSCs-CM indicated the presence of anti-inflammatory factors and IL-10 was the most distinct. Blocking of IL-10 confirmed the therapeutic significance of this cytokine. Phosphorylated STAT3 was upregulated after IL-10 infusion and inhibition of STAT3 by AG490 reversed the therapeutic effect of IL-10. Conclusions: The factors released by MSCs, especially IL-10, have the potential for therapeutic recovery of ALF, and the STAT3 signaling pathway may mediate the anti-inflammatory effect of IL-10.
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Affiliation(s)
| | | | | | | | | | - Xiao-Lei Shi
- Department of Hepatobiliary Surgery, Affliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China
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31
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Abstract
Orthotopic liver transplantation remains the only proven cure for end-stage liver failure. Despite significant advances in the field, the clinical demand for donor organs far outweighs the supply. Hepatocyte transplantation has been proposed as an alternative approach to whole liver transplant in select diseases. Several international centers have reported experimental trials of human hepatocyte transplantation in acute liver failure and liver-based metabolic disorders. This chapter provides an introduction to hepatocyte transplantation from both a technical and clinical perspective. We will also focus on the special needs of pediatric patients, since historically the majority of clinical hepatocyte transplants have involved infants and children.
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Carpino G, Gaudio E. Cell sources for regenerative medicine of the liver and endoderm organs: strategies and perspectives. Stem Cell Investig 2016; 3:91. [PMID: 28078271 DOI: 10.21037/sci.2016.11.11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 11/08/2016] [Indexed: 12/28/2022]
Affiliation(s)
- Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro De Bosis 6, 00135, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50, 00161, Rome, Italy
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Stem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration. Stem Cells Int 2016; 2016:3658013. [PMID: 26880956 PMCID: PMC4737003 DOI: 10.1155/2016/3658013] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 11/16/2015] [Accepted: 11/23/2015] [Indexed: 12/28/2022] Open
Abstract
Niches containing stem/progenitor cells are present in different anatomical locations along the human biliary tree and within liver acini. The most primitive stem/progenitors, biliary tree stem/progenitor cells (BTSCs), reside within peribiliary glands located throughout large extrahepatic and intrahepatic bile ducts. BTSCs are multipotent and can differentiate towards hepatic and pancreatic cell fates. These niches' matrix chemistry and other characteristics are undefined. Canals of Hering (bile ductules) are found periportally and contain hepatic stem/progenitor cells (HpSCs), participating in the renewal of small intrahepatic bile ducts and being precursors to hepatocytes and cholangiocytes. The niches also contain precursors to hepatic stellate cells and endothelia, macrophages, and have a matrix chemistry rich in hyaluronans, minimally sulfated proteoglycans, fetal collagens, and laminin. The microenvironment furnishes key signals driving HpSC activation and differentiation. Newly discovered third niches are pericentral within hepatic acini, contain Axin2+ unipotent hepatocytic progenitors linked on their lateral borders to endothelia forming the central vein, and contribute to normal turnover of mature hepatocytes. Their relationship to the other stem/progenitors is undefined. Stem/progenitor niches have important implications in regenerative medicine for the liver and biliary tree and in pathogenic processes leading to diseases of these tissues.
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Therapeutic Potential of HGF-Expressing Human Umbilical Cord Mesenchymal Stem Cells in Mice with Acute Liver Failure. Int J Hepatol 2016; 2016:5452487. [PMID: 27057357 PMCID: PMC4789068 DOI: 10.1155/2016/5452487] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 12/31/2015] [Accepted: 02/04/2016] [Indexed: 02/07/2023] Open
Abstract
Human umbilical cord-derived mesenchymal stem cells (UCMSCs) are particularly attractive cells for cellular and gene therapy in acute liver failure (ALF). However, the efficacy of this cell therapy in animal studies needs to be significantly improved before it can be translated into clinics. In this study, we investigated the therapeutic potential of UCMSCs that overexpress hepatocyte growth factor (HGF) in an acetaminophen-induced acute liver failure mouse model. We found that the HGF-UCMSC cell therapy protected animals from acute liver failure by reducing liver damage and prolonging animal survival. The therapeutic effect of HGF-UCMSCs was associated with the increment in serum glutathione (GSH) and hepatic enzymes that maintain redox homeostasis, including γ-glutamylcysteine synthetase (γ-GCS), superoxide dismutase (SOD), and catalase (CAT). Immunohistochemical staining confirmed that HGF-UCMSCs were mobilized to the injured areas of the liver. Additionally, HGF-UCMSCs modulated apoptosis by upregulating the antiapoptotic Bcl2 and downregulating proapoptotic genes, including Bax and TNFα. Taken together, these data suggest that ectopic expression of HGF in UCMSCs protects animals from acetaminophen-induced acute liver failure through antiapoptosis and antioxidation mechanisms.
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Tsolaki E, Yannaki E. Stem cell-based regenerative opportunities for the liver: State of the art and beyond. World J Gastroenterol 2015; 21:12334-12350. [PMID: 26604641 PMCID: PMC4649117 DOI: 10.3748/wjg.v21.i43.12334] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 09/16/2015] [Accepted: 10/20/2015] [Indexed: 02/06/2023] Open
Abstract
The existing mismatch between the great demand for liver transplants and the number of available donor organs highlights the urgent need for alternative therapeutic strategies in patients with acute or chronic liver failure. The rapidly growing knowledge on stem cell biology and the intrinsic repair processes of the liver has opened new avenues for using stem cells as a cell therapy platform in regenerative medicine for hepatic diseases. An impressive number of cell types have been investigated as sources of liver regeneration: adult and fetal liver hepatocytes, intrahepatic stem cell populations, annex stem cells, adult bone marrow-derived hematopoietic stem cells, endothelial progenitor cells, mesenchymal stromal cells, embryonic stem cells, and induced pluripotent stem cells. All these highly different cell types, used either as cell suspensions or, in combination with biomaterials as implantable liver tissue constructs, have generated great promise for liver regeneration. However, fundamental questions still need to be addressed and critical hurdles to be overcome before liver cell therapy emerges. In this review, we summarize the state-of-the-art in the field of stem cell-based therapies for the liver along with existing challenges and future perspectives towards a successful liver cell therapy that will ultimately deliver its demanding goals.
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Gupta AK, Jadhav SH, Tripathy NK, Nityanand S. Fetal Kidney Cells Can Ameliorate Ischemic Acute Renal Failure in Rats through Their Anti-Inflammatory, Anti-Apoptotic and Anti-Oxidative Effects. PLoS One 2015; 10:e0131057. [PMID: 26086475 PMCID: PMC4472721 DOI: 10.1371/journal.pone.0131057] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 05/29/2015] [Indexed: 12/12/2022] Open
Abstract
Fetal kidney cells may contain multiple populations of kidney stem cells and thus appear to be a suitable cellular therapy for the treatment of acute renal failure (ARF) but their biological characteristics and therapeutic potential have not been adequately explored. We have culture expanded fetal kidney cells derived from rat fetal kidneys, characterized them and evaluated their therapeutic effect in an ischemia reperfusion (IR) induced rat model of ARF. The fetal kidney cells grew in culture as adherent spindle shaped/polygonal cells and expressed CD29, CD44, CD73, CD90, CD105, CD24 and CD133 markers. Administration of PKH26 labeled fetal kidney cells in ARF rats resulted in a significant decrease in the levels of blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin and decreased tubular necrosis in the kidney tissues (p<0.05 for all). The injected fetal kidney cells were observed to engraft around injured tubular cells, and there was increased proliferation and decreased apoptosis of tubular cells in the kidneys (p<0.05 for both). In addition, the kidney tissues of ARF rats treated with fetal kidney cells had a higher gene expression of renotropic growth factors (VEGF-A, IGF-1, BMP-7 and bFGF) and anti-inflammatory cytokine (IL10); up regulation of anti-oxidative markers (HO-1 and NQO-1); and a lower Bax/Bcl2 ratio as compared to saline treated rats (p<0.05 for all). Our data shows that culture expanded fetal kidney cells express mesenchymal and renal progenitor markers, and ameliorate ischemic ARF predominantly by their anti-apoptotic, anti-inflammatory and anti-oxidative effects.
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Affiliation(s)
- Ashwani Kumar Gupta
- Stem Cell Research Facility (SCRF), Department of Hematology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, India
| | - Sachin H Jadhav
- Stem Cell Research Facility (SCRF), Department of Hematology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, India
| | - Naresh Kumar Tripathy
- Stem Cell Research Facility (SCRF), Department of Hematology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, India
| | - Soniya Nityanand
- Stem Cell Research Facility (SCRF), Department of Hematology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, India
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Guo X, Wang S, Dou YL, Guo XF, Chen ZL, Wang XW, Shen ZQ, Qiu ZG, Jin M, Li JW. A Convenient and Efficient Method to Enrich and Maintain Highly Proliferative Human Fetal Liver Stem Cells. Rejuvenation Res 2015; 18:211-24. [PMID: 25556695 DOI: 10.1089/rej.2014.1619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Pluripotent human hepatic stem cells have broad research and clinical applications, which are, however, restricted by both limited resources and technical difficulties with respect to isolation of stem cells from the adult or fetal liver. In this study, we developed a convenient and efficient method involving a two-step in situ collagenase perfusion, gravity sedimentation, and Percoll density gradient centrifugation to enrich and maintain highly proliferative human fetal liver stem cells (hFLSCs). Using this method, the isolated hFLSCs entered into the exponential growth phase within 10 days and maintained sufficient proliferative activity to permit subculture for at least 20 passages without differentiation. Immunocytochemistry, immunofluorescence, and flow cytometry results showed that these cells expressed stem cell markers, such as c-kit, CD44, epithelial cell adhesion molecule (EpCAM), oval cell marker-6 (OV-6), epithelial marker cytokeratin 18 (CK18), biliary ductal marker CK19, and alpha-fetoprotein (AFP). Gene expression analysis showed that these cells had stable mRNA expression of c-Kit, EpCAM, neural cell adhesion molecule (NCAM), CK19, CK18, AFP, and claudin 3 (CLDN-3) throughout each passage while maintaining low levels of ALB, but with complete absence of cytochrome P450 3A4 (C3A4), phosphoenolpyruvate carboxykinase (PEPCK), telomeric repeat binding factor (TRF), and connexin 26 (CX26) expression. When grown in appropriate medium, these isolated liver stem cells could differentiate into hepatocytes, cholangiocytes, osteoblasts, adipocytes, or endothelial cells. Thus, we have demonstrated a more economical and efficient method to isolate hFLSCs than magnetic-activated cell sorting (MACS). This novel approach may provide an excellent tool to isolate highly proliferative hFLSCs for tissue engineering and regenerative therapies.
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Affiliation(s)
- Xuan Guo
- 1 Institute of Health and Environmental Medicine , Tianjin, China .,2 Key Laboratory of Risk Assessment and Control for Environment & Food Safety , Tianjin, China
| | - Shu Wang
- 1 Institute of Health and Environmental Medicine , Tianjin, China .,2 Key Laboratory of Risk Assessment and Control for Environment & Food Safety , Tianjin, China
| | - Ya-ling Dou
- 3 Peking Union Medical College Hospital , Chinese Medical Academy, Beijing, China
| | - Xiang-fei Guo
- 1 Institute of Health and Environmental Medicine , Tianjin, China .,2 Key Laboratory of Risk Assessment and Control for Environment & Food Safety , Tianjin, China
| | - Zhao-li Chen
- 1 Institute of Health and Environmental Medicine , Tianjin, China .,2 Key Laboratory of Risk Assessment and Control for Environment & Food Safety , Tianjin, China
| | - Xin-wei Wang
- 1 Institute of Health and Environmental Medicine , Tianjin, China .,2 Key Laboratory of Risk Assessment and Control for Environment & Food Safety , Tianjin, China
| | - Zhi-qiang Shen
- 1 Institute of Health and Environmental Medicine , Tianjin, China .,2 Key Laboratory of Risk Assessment and Control for Environment & Food Safety , Tianjin, China
| | - Zhi-gang Qiu
- 1 Institute of Health and Environmental Medicine , Tianjin, China .,2 Key Laboratory of Risk Assessment and Control for Environment & Food Safety , Tianjin, China
| | - Min Jin
- 1 Institute of Health and Environmental Medicine , Tianjin, China .,2 Key Laboratory of Risk Assessment and Control for Environment & Food Safety , Tianjin, China
| | - Jun-wen Li
- 1 Institute of Health and Environmental Medicine , Tianjin, China .,2 Key Laboratory of Risk Assessment and Control for Environment & Food Safety , Tianjin, China
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Zhou J, Huang W, Chang SKY, Xiong W, Oo T, Chen W. Longitudinal in-vivo volumetry study for porcine liver regeneration from CT data. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2015; 2014:4743-6. [PMID: 25571052 DOI: 10.1109/embc.2014.6944684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The use of hepatic-like cloned cord lining epithelial cells (CLEC) to enhance liver regeneration has been proposed, but has not been properly investigated in a large animal study. The paper presents a system developed for the longitudinal in-vivo volumetry study on porcine liver regeneration from computed tomography (CT) data. In this system, a rough 3D liver volume is firstly automatically segmented by a 3D mesh deformation-based method. Then a refinement step to eliminate the segmentation error is carried out by a 3D post-editing tool, followed by mesh-volume conversion and volume calculation. This system was applied in a pilot study, which was composed of 4/4 pigs in the Experimental/Control Groups, to measure liver volumes over pre- to post-operative time course. Experimental results suggest that (1) the developed system can perform CT-based porcine liver volumetry efficiently, and (2) the infusion of CLEC to liver remnant may potentially enhance the liver regeneration.
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Cardinale V, Carpino G, Gentile R, Napoletano C, Rahimi H, Franchitto A, Semeraro R, Nuti M, Onori P, Berloco PB, Rossi M, Bosco D, Brunelli R, Fraveto A, Napoli C, Torrice A, Gatto M, Venere R, Bastianelli C, Aliberti C, Salvatori FM, Bresadola L, Bezzi M, Attili AF, Reid L, Gaudio E, Alvaro D. Transplantation of human fetal biliary tree stem/progenitor cells into two patients with advanced liver cirrhosis. BMC Gastroenterol 2014; 14:204. [PMID: 25471120 PMCID: PMC4267130 DOI: 10.1186/s12876-014-0204-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Accepted: 11/19/2014] [Indexed: 12/12/2022] Open
Abstract
Background Efforts to identify cell sources and approaches for cell therapy of liver diseases are ongoing, taking into consideration the limits recognized for adult liver tissue and for other forms of stem cells. In the present study, we described the first procedure of via hepatic artery transplantation of human fetal biliary tree stem cells in patients with advanced cirrhosis. Methods The cells were immune-sorted from human fetal biliary tree by protocols in accordance with current good manufacturing practice (cGMP) and extensively characterized. Two patients with advanced liver cirrhosis (Child-Pugh C) have been submitted to the procedure and observed through a 12 months follow-up. Results The resulting procedure was found absolutely safe. Immuno-suppressants were not required, and the patients did not display any adverse effects correlated with cell transplantation or suggestive of immunological complications. From a clinical point of view, both patients showed biochemical and clinical improvement during the 6 month follow-up and the second patient maintained a stable improvement for 12 months. Conclusion This report represents proof of the concept that the human fetal biliary tree stem cells are a suitable and large source for cell therapy of liver cirrhosis. The isolation procedure can be carried out under cGMP conditions and, finally, the infusion procedure is easy and safe for the patients. This represents the basis for forthcoming controlled clinical trials. Electronic supplementary material The online version of this article (doi:10.1186/s12876-014-0204-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, Latina, 04100, Italy.
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, 00151, Italy.
| | - Raffaele Gentile
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, Latina, 04100, Italy.
| | - Chiara Napoletano
- Department of Experimental Medicine, Viale Regina Elena 324, Rome, 00161, Italy.
| | - Hassan Rahimi
- Department of Experimental Medicine, Viale Regina Elena 324, Rome, 00161, Italy.
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Via Alfonso Borelli 50, Rome, 00185, Italy. .,Eleonora Lorillard Spencer-Cenci Foundation, Rome, 00100, Italy.
| | - Rossella Semeraro
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, Latina, 04100, Italy.
| | - Marianna Nuti
- Department of Experimental Medicine, Viale Regina Elena 324, Rome, 00161, Italy.
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Via Alfonso Borelli 50, Rome, 00185, Italy.
| | | | - Massimo Rossi
- Department of General Surgery and Organ Transplantation, Viale del Policlinico 155, Rome, 00161, Italy.
| | - Daniela Bosco
- Department of Experimental Medicine, Viale Regina Elena 324, Rome, 00161, Italy.
| | - Roberto Brunelli
- Department of Gynecologic-Obstetric and Urologic Sciences, Viale Regina Elena 324, Rome, 00161, Italy.
| | - Alice Fraveto
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, Latina, 04100, Italy.
| | - Cristina Napoli
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, Latina, 04100, Italy.
| | - Alessia Torrice
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, Latina, 04100, Italy.
| | - Manuela Gatto
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, Latina, 04100, Italy.
| | - Rosanna Venere
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, Latina, 04100, Italy.
| | - Carlo Bastianelli
- Department of Gynecologic-Obstetric and Urologic Sciences, Viale Regina Elena 324, Rome, 00161, Italy.
| | - Camilla Aliberti
- Department of Gynecologic-Obstetric and Urologic Sciences, Viale Regina Elena 324, Rome, 00161, Italy.
| | | | - Luciano Bresadola
- Department of Radiological Sciences, Viale Regina Elena 324, Rome, 00161, Italy.
| | - Mario Bezzi
- Department of Radiological Sciences, Viale Regina Elena 324, Rome, 00161, Italy.
| | | | - Lola Reid
- Department of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, USA.
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Via Alfonso Borelli 50, Rome, 00185, Italy.
| | - Domenico Alvaro
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, Latina, 04100, Italy. .,Eleonora Lorillard Spencer-Cenci Foundation, Rome, 00100, Italy.
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Joshi M, Oltean M, Patil PB, Hallberg D, Kleman M, Holgersson J, Olausson M, Sumitran-Holgersson S. Chemokine-mediated robust augmentation of liver engraftment: a novel approach. Stem Cells Transl Med 2014; 4:21-30. [PMID: 25473087 DOI: 10.5966/sctm.2014-0053] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Effective repopulation of the liver is essential for successful clinical hepatocyte transplantation. The objective was to improve repopulation of the liver with human hepatocytes using chemokines. We used flow cytometry and immunohistochemistry assays to identify commonly expressed chemokine receptors on human fetal and adult hepatocytes. The migratory capacity of the cells to various chemokines was tested. For in vivo studies, we used a nude mouse model of partial hepatectomy followed by intraparenchymal injections of chemokine ligands at various concentrations. Human fetal liver cells transformed with human telomerase reverse transcriptase were used for intrasplenic cell transplantation. Repopulation and functionality were assessed 4 weeks after transplantation. The receptor CXCR3 was commonly expressed on both fetal and adult hepatocytes. Both cell types migrated efficiently toward corresponding CXC chemokine ligands 9, 10, and 11. In vivo, animals injected with recombinant chemokines showed the highest cell engraftment compared with controls (p<.05). The engrafted cells expressed several human hepatic markers such as cytokeratin 8 and 18 and albumin as well as transferrin, UGT1A1, hepatocyte nuclear factor (1α, 1β, and 4α), cytochrome CYP3A1, CCAAT/enhancer binding protein (α and β), and human albumin compared with controls. No inflammatory cells were detected in the livers at 4 weeks after transplantation. The improved repopulation of transplanted cells is likely a function of the chemokines to mediate cell homing and retention in the injured liver and might be an attractive strategy to augment repopulation of transplanted hepatocytes in vivo.
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Affiliation(s)
- Meghnad Joshi
- Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden
| | - Mihai Oltean
- Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden
| | - Pradeep B Patil
- Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden
| | - David Hallberg
- Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden
| | - Marika Kleman
- Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden
| | - Jan Holgersson
- Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden
| | - Michael Olausson
- Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden
| | - Suchitra Sumitran-Holgersson
- Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden
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Fomin ME, Togarrati PP, Muench MO. Progress and challenges in the development of a cell-based therapy for hemophilia A. J Thromb Haemost 2014; 12:1954-65. [PMID: 25297648 PMCID: PMC4388483 DOI: 10.1111/jth.12750] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Indexed: 12/11/2022]
Abstract
Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review, we discuss the possibilities, progress, and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific induced pluripotent stem cells.
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Affiliation(s)
- Marina E. Fomin
- Cell Therapy Core, Blood Systems Research Institute, San Francisco, CA
- Department of Laboratory Medicine, University of California, San Francisco, CA
| | - Padma Priya Togarrati
- Cell Therapy Core, Blood Systems Research Institute, San Francisco, CA
- Department of Laboratory Medicine, University of California, San Francisco, CA
| | - Marcus O. Muench
- Cell Therapy Core, Blood Systems Research Institute, San Francisco, CA
- Department of Laboratory Medicine, University of California, San Francisco, CA
- Liver Center, University of California, San Francisco, CA
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Semeraro R, Cardinale V, Carpino G, Gentile R, Napoli C, Venere R, Gatto M, Brunelli R, Gaudio E, Alvaro D. The fetal liver as cell source for the regenerative medicine of liver and pancreas. ANNALS OF TRANSLATIONAL MEDICINE 2014; 1:13. [PMID: 25332958 DOI: 10.3978/j.issn.2305-5839.2012.10.02] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 10/15/2012] [Indexed: 12/11/2022]
Abstract
Patients affected by liver diseases and diabetes mellitus are in need for sources of new cells to enable a better transition into clinic programs of cell therapy and regenerative medicine. In this setting, fetal liver is becoming the most promising and available source of cells. Fetal liver displays unique characteristics given the possibility to isolate cell populations with a wide spectrum of endodermal differentiation and, the co-existence of endodermal and mesenchymal-derived cells. Thus, the fetal liver is a unique and highly available cell source contemporarily candidate for the regenerative medicine of both liver and pancreas. The purpose of this review is to revise the recent literature on the different stem cells populations isolable from fetal liver and candidate to cell therapy of liver diseases and diabetes and to discuss advantages and limitation with respect to other cell sources.
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Affiliation(s)
- Rossella Semeraro
- 1 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, 3 Department of Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy ; 4 Department of Health Sciences, University of Rome "Foro Italico", Rome, Italy ; 5 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
| | - Vincenzo Cardinale
- 1 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, 3 Department of Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy ; 4 Department of Health Sciences, University of Rome "Foro Italico", Rome, Italy ; 5 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
| | - Guido Carpino
- 1 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, 3 Department of Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy ; 4 Department of Health Sciences, University of Rome "Foro Italico", Rome, Italy ; 5 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
| | - Raffaele Gentile
- 1 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, 3 Department of Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy ; 4 Department of Health Sciences, University of Rome "Foro Italico", Rome, Italy ; 5 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
| | - Cristina Napoli
- 1 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, 3 Department of Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy ; 4 Department of Health Sciences, University of Rome "Foro Italico", Rome, Italy ; 5 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
| | - Rosanna Venere
- 1 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, 3 Department of Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy ; 4 Department of Health Sciences, University of Rome "Foro Italico", Rome, Italy ; 5 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
| | - Manuela Gatto
- 1 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, 3 Department of Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy ; 4 Department of Health Sciences, University of Rome "Foro Italico", Rome, Italy ; 5 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
| | - Roberto Brunelli
- 1 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, 3 Department of Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy ; 4 Department of Health Sciences, University of Rome "Foro Italico", Rome, Italy ; 5 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
| | - Eugenio Gaudio
- 1 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, 3 Department of Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy ; 4 Department of Health Sciences, University of Rome "Foro Italico", Rome, Italy ; 5 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
| | - Domenico Alvaro
- 1 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, 3 Department of Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy ; 4 Department of Health Sciences, University of Rome "Foro Italico", Rome, Italy ; 5 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
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Boers SJB, Visser G, Smit PGPA, Fuchs SA. Liver transplantation in glycogen storage disease type I. Orphanet J Rare Dis 2014; 9:47. [PMID: 24716823 PMCID: PMC4113191 DOI: 10.1186/1750-1172-9-47] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 04/01/2014] [Indexed: 12/17/2022] Open
Abstract
Glycogen storage disease type I (GSDI), an inborn error of carbohydrate metabolism, is caused by defects in the glucose-6-transporter/glucose-6-phosphatase complex, which is essential in glucose homeostasis. Two types exist, GSDIa and GSDIb, each caused by different defects in the complex. GSDIa is characterized by fasting intolerance and subsequent metabolic derangements. In addition to these clinical manifestations, patients with GSDIb suffer from neutropenia with neutrophil dysfunction and inflammatory bowel disease. With the feasibility of novel cell-based therapies, including hepatocyte transplantations and liver stem cell transplantations, it is essential to consider long term outcomes of liver replacement therapy. We reviewed all GSDI patients with liver transplantation identified in literature and through personal communication with treating physicians. Our review shows that all 80 GSDI patients showed improved metabolic control and normal fasting tolerance after liver transplantation. Although some complications might be caused by disease progression, most complications seemed related to the liver transplantation procedure and subsequent immune suppression. These results highlight the potential of other therapeutic strategies, like cell-based therapies for liver replacement, which are expected to normalize liver function with a lower risk of complications of the procedure and immune suppression.
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Affiliation(s)
| | | | | | - Sabine A Fuchs
- Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
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Fomin ME, Zhou Y, Beyer AI, Publicover J, Baron JL, Muench MO. Production of factor VIII by human liver sinusoidal endothelial cells transplanted in immunodeficient uPA mice. PLoS One 2013; 8:e77255. [PMID: 24167566 PMCID: PMC3805584 DOI: 10.1371/journal.pone.0077255] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Accepted: 09/02/2013] [Indexed: 12/23/2022] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) form a semi-permeable barrier between parenchymal hepatocytes and the blood. LSECs participate in liver metabolism, clearance of pathological agents, immunological responses, architectural maintenance of the liver and synthesis of growth factors and cytokines. LSECs also play an important role in coagulation through the synthesis of Factor VIII (FVIII). Herein, we phenotypically define human LSECs isolated from fetal liver using flow cytometry and immunofluorescence microscopy. Isolated LSECs were cultured and shown to express endothelial markers and markers specific for the LSEC lineage. LSECs were also shown to engraft the liver when human fetal liver cells were transplanted into immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA) transgene (uPA-NOG mice). Engrafted cells expressed human Factor VIII at levels approaching those found in human plasma. We also demonstrate engraftment of adult LSECs, as well as hepatocytes, transplanted into uPA-NOG mice. We propose that overexpression of uPA provides beneficial conditions for LSEC engraftment due to elevated expression of the angiogenic cytokine, vascular endothelial growth factor. This work provides a detailed characterization of human midgestation LSECs, thereby providing the means for their purification and culture based on their expression of CD14 and CD32 as well as a lack of CD45 expression. The uPA-NOG mouse is shown to be a permissive host for human LSECs and adult hepatocytes, but not fetal hepatoblasts. Thus, these mice provide a useful model system to study these cell types in vivo. Demonstration of human FVIII production by transplanted LSECs encourages further pursuit of LSEC transplantation as a cellular therapy for the treatment of hemophilia A.
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Affiliation(s)
- Marina E. Fomin
- Blood Systems Research Institute, San Francisco, California, United States of America
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America
| | - Yanchen Zhou
- Blood Systems Research Institute, San Francisco, California, United States of America
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America
| | - Ashley I. Beyer
- Blood Systems Research Institute, San Francisco, California, United States of America
| | - Jean Publicover
- Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
- Liver Center, University of California San Francisco, San Francisco, California, United States of America
| | - Jody L. Baron
- Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
- Liver Center, University of California San Francisco, San Francisco, California, United States of America
| | - Marcus O. Muench
- Blood Systems Research Institute, San Francisco, California, United States of America
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America
- Liver Center, University of California San Francisco, San Francisco, California, United States of America
- * E-mail:
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Lanzoni G, Oikawa T, Wang Y, Cui CB, Carpino G, Cardinale V, Gerber D, Gabriel M, Dominguez-Bendala J, Furth ME, Gaudio E, Alvaro D, Inverardi L, Reid LM. Concise review: clinical programs of stem cell therapies for liver and pancreas. Stem Cells 2013; 31:2047-60. [PMID: 23873634 PMCID: PMC3812254 DOI: 10.1002/stem.1457] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Revised: 05/02/2013] [Accepted: 05/15/2013] [Indexed: 12/13/2022]
Abstract
Regenerative medicine is transitioning into clinical programs using stem/progenitor cell therapies for repair of damaged organs. We summarize those for liver and pancreas, organs that share endodermal stem cell populations, biliary tree stem cells (hBTSCs), located in peribiliary glands. They are precursors to hepatic stem/progenitors in canals of Hering and to committed progenitors in pancreatic duct glands. They give rise to maturational lineages along a radial axis within bile duct walls and a proximal-to-distal axis starting at the duodenum and ending with mature cells in the liver or pancreas. Clinical trials have been ongoing for years assessing effects of determined stem cells (fetal-liver-derived hepatic stem/progenitors) transplanted into the hepatic artery of patients with various liver diseases. Immunosuppression was not required. Control subjects, those given standard of care for a given condition, all died within a year or deteriorated in their liver functions. Subjects transplanted with 100-150 million hepatic stem/progenitor cells had improved liver functions and survival extending for several years. Full evaluations of safety and efficacy of transplants are still in progress. Determined stem cell therapies for diabetes using hBTSCs remain to be explored but are likely to occur following ongoing preclinical studies. In addition, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are being used for patients with chronic liver conditions or with diabetes. MSCs have demonstrated significant effects through paracrine signaling of trophic and immunomodulatory factors, and there is limited evidence for inefficient lineage restriction into mature parenchymal or islet cells. HSCs' effects are primarily via modulation of immune mechanisms.
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Affiliation(s)
- Giacomo Lanzoni
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL. 33136
- Department of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy
| | - Tsunekazu Oikawa
- Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599
| | - Yunfang Wang
- The Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Beijing, PR China, 100850
| | - Cai-Bin Cui
- Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, NC 27599
| | - Guido Carpino
- Department of Health Sciences, University of Rome “ForoItalico”, Rome, Italy
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University, Rome, Italy
| | - Vincenzo Cardinale
- Department of Scienze e Biotecnologie Medico-Chirurgiche, Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University, Rome, Italy
| | - David Gerber
- Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, NC 27599
| | - Mara Gabriel
- MGabriel Consulting, 3621 Sweeten Creek Road, Chapel Hill, NC 27514
| | - Juan Dominguez-Bendala
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL. 33136
| | - Mark E. Furth
- Wake Forest Innovations, Wake Forest University School of Medicine, Winston-Salem, NC 27157
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University, Rome, Italy
| | - Domenico Alvaro
- Department of Scienze e Biotecnologie Medico-Chirurgiche, Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University, Rome, Italy
| | - Luca Inverardi
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL. 33136
| | - Lola M. Reid
- Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599
- Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC 27599
- Lineberger Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599
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Abstract
Because of their high proliferative capacity, resistance to cryopreservation, and ability to differentiate into hepatocyte-like cells, stem and progenitor cells have recently emerged as attractive cell sources for liver cell therapy, a technique used as an alternative to orthotopic liver transplantation in the treatment of various hepatic ailments ranging from metabolic disorders to end-stage liver disease. Although stem and progenitor cells have been isolated from various tissues, obtaining them from the liver could be an advantage for the treatment of hepatic disorders. However, the techniques available to isolate these stem/progenitor cells are numerous and give rise to cell populations with different morphological and functional characteristics. In addition, there is currently no established consensus on the tests that need to be performed to ensure the quality and safety of these cells when used clinically. The purpose of this review is to describe the different types of liver stem/progenitor cells currently reported in the literature, discuss their suitability and limitations in terms of clinical applications, and examine how the culture and transplantation techniques can potentially be improved to achieve a better clinical outcome.
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Affiliation(s)
- Catherine A. Lombard
- Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, Pediatric Hepatology and Cell Therapy, Brussels, Belgium
| | - Julie Prigent
- Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, Pediatric Hepatology and Cell Therapy, Brussels, Belgium
| | - Etienne M. Sokal
- Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, Pediatric Hepatology and Cell Therapy, Brussels, Belgium
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Rao MS, Sasikala M, Reddy DN. Thinking outside the liver: induced pluripotent stem cells for hepatic applications. World J Gastroenterol 2013; 19:3385-3396. [PMID: 23801830 PMCID: PMC3683676 DOI: 10.3748/wjg.v19.i22.3385] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Revised: 12/06/2011] [Accepted: 12/15/2011] [Indexed: 02/06/2023] Open
Abstract
The discovery of induced pluripotent stem cells (iPSCs) unraveled a mystery in stem cell research, after identification of four re-programming factors for generating pluripotent stem cells without the need of embryos. This breakthrough in generating iPSCs from somatic cells has overcome the ethical issues and immune rejection involved in the use of human embryonic stem cells. Hence, iPSCs form a great potential source for developing disease models, drug toxicity screening and cell-based therapies. These cells have the potential to differentiate into desired cell types, including hepatocytes, under in vitro as well as under in vivo conditions given the proper microenvironment. iPSC-derived hepatocytes could be useful as an unlimited source, which can be utilized in disease modeling, drug toxicity testing and producing autologous cell therapies that would avoid immune rejection and enable correction of gene defects prior to cell transplantation. In this review, we discuss the induction methods, role of reprogramming factors, and characterization of iPSCs, along with hepatocyte differentiation from iPSCs and potential applications. Further, we discuss the location and detection of liver stem cells and their role in liver regeneration. Although tumor formation and genetic mutations are a cause of concern, iPSCs still form a promising source for clinical applications.
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48
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Booth C, Soker T, Baptista P, Ross CL, Soker S, Farooq U, Stratta RJ, Orlando G. Liver bioengineering: Current status and future perspectives. World J Gastroenterol 2012; 18:6926-34. [PMID: 23322990 PMCID: PMC3531676 DOI: 10.3748/wjg.v18.i47.6926] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Revised: 11/16/2012] [Accepted: 11/24/2012] [Indexed: 02/06/2023] Open
Abstract
The present review aims to illustrate the strategies that are being implemented to regenerate or bioengineer livers for clinical purposes. There are two general pathways to liver bioengineering and regeneration. The first consists of creating a supporting scaffold, either synthetically or by decellularization of human or animal organs, and seeding cells on the scaffold, where they will mature either in bioreactors or in vivo. This strategy seems to offer the quickest route to clinical translation, as demonstrated by the development of liver organoids from rodent livers which were repopulated with organ specific cells of animal and/or human origin. Liver bioengineering has potential for transplantation and for toxicity testing during preclinical drug development. The second possibility is to induce liver regeneration of dead or resected tissue by manipulating cell pathways. In fact, it is well known that the liver has peculiar regenerative potential which allows hepatocyte hyperplasia after amputation of liver volume. Infusion of autologous bone marrow cells, which aids in liver regeneration, into patients was shown to be safe and to improve their clinical condition, but the specific cells responsible for liver regeneration have not yet been determined and the underlying mechanisms remain largely unknown. A complete understanding of the cell pathways and dynamics and of the functioning of liver stem cell niche is necessary for the clinical translation of regenerative medicine strategies. As well, it will be crucial to elucidate the mechanisms through which cells interact with the extracellular matrix, and how this latter supports and drives cell fate.
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Liu WH, Liu ZC, You N, Zhang N, Wang T, Gong ZB, Liu HB, Dou KF. Several important in vitro improvements in the amplification, differentiation and tracing of fetal liver stem/progenitor cells. PLoS One 2012; 7:e47346. [PMID: 23056632 PMCID: PMC3467257 DOI: 10.1371/journal.pone.0047346] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Accepted: 09/11/2012] [Indexed: 01/12/2023] Open
Abstract
OBJECTIVE We previously isolated fetal liver stem/progenitor cells (FLSPCs), but there is an urgent need to properly amplify FLSPCs, effectively induce FLSPCs differentiation, and steadily trace FLSPCs for in vivo therapeutic investigation. METHODS FLSPCs were maintained in vitro as adherent culture or soft agar culture for large-scale amplification. To direct the differentiation of FLSPCs into hepatocytes, FLSPCs were randomly divided into four groups: control, 1% DMSO-treated, 20 ng/ml HGF-treated and 1% DMSO+20 ng/ml HGF-treated. To trace FLSPCs, the GFP gene was introduced into FLSPCs by liposome-mediated transfection. RESULTS For amplifying FLSPCs, the soft agar culture were more suitable than the adherent culture, because the soft agar culture obtained more homogeneous cells. These cells were with high nuclear:cytoplasmic ratio, few cell organelles, high expression of CD90.1 and CD49f, and strong alkaline phosphatase staining. For inducing FLSPCs differentiation, treatment with HGF+DMSO was most effective (P<0.05), which was strongly supported by the typical morphological change and the significant decrease of OV-6 positive cells (P<0.01). In addition, the time of indocyanine green elimination, the percentage of glycogen synthetic cells, and the expressions of ALB, G-6-P, CK-8, CK-18 and CYP450-3A1 in HGF+DMSO-treated group were higher than in any other group. For tracing FLSPCs, after the selection of stable FLSPC transfectants, GFP expression continued over successive generations. CONCLUSIONS FLSPCs can properly self-renew in soft agar culture and effectively differentiate into hepatocyte-like cells by HGF+DMSO induction, and they can be reliably traced by GFP expression.
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Affiliation(s)
- Wei-hui Liu
- PLA Center of General Surgery, General Hospital of Chengdu Army Region, Chengdu, Sichuan Province, People's Republic of China
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
| | - Zheng-cai Liu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
| | - Nan You
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
| | - Ning Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
| | - Tao Wang
- PLA Center of General Surgery, General Hospital of Chengdu Army Region, Chengdu, Sichuan Province, People's Republic of China
| | - Zhen-bin Gong
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
| | - Hong-bao Liu
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
| | - Ke-feng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
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50
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Orlando G, Wood KJ, De Coppi P, Baptista PM, Binder KW, Bitar KN, Breuer C, Burnett L, Christ G, Farney A, Figliuzzi M, Holmes JH, Koch K, Macchiarini P, Mirmalek Sani SH, Opara E, Remuzzi A, Rogers J, Saul JM, Seliktar D, Shapira-Schweitzer K, Smith T, Solomon D, Van Dyke M, Yoo JJ, Zhang Y, Atala A, Stratta RJ, Soker S. Regenerative medicine as applied to general surgery. Ann Surg 2012; 255:867-80. [PMID: 22330032 PMCID: PMC3327776 DOI: 10.1097/sla.0b013e318243a4db] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The present review illustrates the state of the art of regenerative medicine (RM) as applied to surgical diseases and demonstrates that this field has the potential to address some of the unmet needs in surgery. RM is a multidisciplinary field whose purpose is to regenerate in vivo or ex vivo human cells, tissues, or organs to restore or establish normal function through exploitation of the potential to regenerate, which is intrinsic to human cells, tissues, and organs. RM uses cells and/or specially designed biomaterials to reach its goals and RM-based therapies are already in use in several clinical trials in most fields of surgery. The main challenges for investigators are threefold: Creation of an appropriate microenvironment ex vivo that is able to sustain cell physiology and function in order to generate the desired cells or body parts; identification and appropriate manipulation of cells that have the potential to generate parenchymal, stromal and vascular components on demand, both in vivo and ex vivo; and production of smart materials that are able to drive cell fate.
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Affiliation(s)
- Giuseppe Orlando
- Wake Forest Institute for Regenerative Medicine, Winston Salem, NC, USA.
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