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Poudineh M, Mohammadyari F, Parsamanesh N, Jamialahmadi T, Kesharwani P, Sahebkar A. Cell and gene therapeutic approaches in non-alcoholic fatty liver disease. Gene 2025; 956:149466. [PMID: 40189164 DOI: 10.1016/j.gene.2025.149466] [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: 01/06/2025] [Revised: 03/14/2025] [Accepted: 03/31/2025] [Indexed: 04/11/2025]
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a range of conditions marked by the buildup of triglycerides in liver cells, accompanied by inflammation, which contributes to liver damage, clinical symptoms, and histopathological alterations. Multiple molecular pathways contribute to NAFLD pathogenesis, including immune dysregulation, endoplasmic reticulum stress, and tissue injury. Both the innate and adaptive immune systems play crucial roles in disease progression, with intricate crosstalk between liver and immune cells driving NAFLD development. Among emerging therapeutic strategies, cell and gene-based therapies have shown promise. This study reviews the pathophysiological mechanisms of NAFLD and explores the therapeutic potential of cell-based interventions, highlighting their immunomodulatory effects, inhibition of hepatic stellate cells, promotion of hepatocyte regeneration, and potential for hepatocyte differentiation. Additionally, we examine gene delivery vectors designed to target NAFLD, focusing on their role in engineering hepatocytes through gene addition or editing to enhance therapeutic efficacy.
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Affiliation(s)
| | | | - Negin Parsamanesh
- Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran; Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Tananz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pradesh 470003, India.
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Centre for Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Yazdian FA, Samak MM, Larijani A, Ashoobi MT, Kharaqani M, Ghezel MA, Barabadi Z, Vojoudi E. From Cells to Exosomes: a Review of Non-Surgical Biotherapeutic-Based Strategies for Liver Regeneration in the Face of End-Stage Diseases. Stem Cell Rev Rep 2025:10.1007/s12015-025-10872-1. [PMID: 40411652 DOI: 10.1007/s12015-025-10872-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2025] [Indexed: 05/26/2025]
Abstract
Liver diseases, such as hepatitis, cirrhosis, and liver cancer, pose significant public health challenges, ranking as the twelfth leading cause of death globally. Given the liver's critical functions in metabolism, detoxification, and biosynthesis, its impairment can lead to severe consequences, often resulting in end-stage liver failure. Although liver transplantation is regarded as the definitive intervention for advanced liver disease, factors such as a shortage of donors and potential surgical complications necessitate the investigation of non-surgical regenerative medicine alternatives. This manuscript provides a comprehensive review of innovative non-surgical therapies aimed at liver regeneration, with an emphasis on both cell-based and cell-free approaches. It examines the contributions of various stem cell populations, including mesenchymal stem cells, hematopoietic stem cells, and induced pluripotent stem cells, in facilitating liver repair through mechanisms of differentiation and paracrine signaling. Furthermore, it explores the therapeutic potential of exosomes and conditioned media derived from stem cells as biotherapeutic agents in the context of regenerative medicine. By elucidating the mechanisms that underpin liver regeneration, this study aspires to inform the development of effective therapeutic strategies to address liver diseases and slow their progression. By elucidating the underlying mechanisms of liver regeneration, this study aims to contribute to the development of effective therapeutic strategies to address liver diseases and slow their progression.
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Affiliation(s)
| | - Matin Mojaveri Samak
- Department of Internal Medicine, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Amirhossein Larijani
- Student Research Committee, School of Medicine, Guilan University of Medical Science, Rasht, Iran
- Regenerative Medicine, Organ Procurement and Transplantation Multi-Disciplinary Centre, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammad Taghi Ashoobi
- Department of General Surgery, School of Medicine Road Trauma Research Centre, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | | | | | - Zahra Barabadi
- Department of Tissue Engineering, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran.
- School of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran.
| | - Elham Vojoudi
- Regenerative Medicine, Organ Procurement and Transplantation Multi-Disciplinary Centre, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran.
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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Liu Z, Ren J, Qiu C, Wang Y, Zhang T. Application of mesenchymal stem cells in liver fibrosis and regeneration. LIVER RESEARCH 2024; 8:246-258. [PMID: 39958916 PMCID: PMC11771278 DOI: 10.1016/j.livres.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 02/18/2025]
Abstract
Liver transplantation remains the most effective treatment for end-stage liver disease (ESLD), but it is fraught with challenges such as immunosuppression, high risk and cost, and donor shortage. In recent years, stem cell transplantation has emerged as a promising new strategy for ESLD treatment, with mesenchymal stem cells (MSCs) gaining significant attention because of their unique properties. MSCs can regulate signaling pathways, including hepatocyte growth factor/c-Met, Wnt/beta (β)-catenin, Notch, transforming growth factor-β1/Smad, interleukin-6/Janus kinase/signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/PDK/Akt, thereby influencing the progression of liver fibrosis and regeneration. As a promising stem cell type, MSCs offer numerous advantages in liver disease treatment, including low immunogenicity; ease of acquisition; unlimited proliferative ability; pluripotent differentiation potential; immunomodulatory function; and anti-inflammatory, antifibrotic, and antiapoptotic biological characteristics. This review outlines the mechanisms by which MSCs reverse liver fibrosis and promote liver regeneration. MSCs are crucial in reversing liver fibrosis and repairing liver damage through the secretion of growth factors, regulation of signaling pathways, and modulation of immune responses. MSCs have shown good therapeutic effects in preclinical and clinical studies, providing new strategies for liver disease treatment. However, challenges still exist in the clinical application of MSCs, including low differentiation efficiency and limited sources. This review provides a reference for MSC application in liver disease treatment. With the continuous progress in MSC research, MSCs are expected to achieve breakthroughs in liver disease treatment, thereby improving patient treatment outcomes.
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Affiliation(s)
- Zhenyu Liu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Junkai Ren
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cheng Qiu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Ying Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Tong Zhang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
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Kim M, Park Y, Kim YS, Ko S. Cellular Plasticity in Gut and Liver Regeneration. Gut Liver 2024; 18:949-960. [PMID: 39081200 PMCID: PMC11565004 DOI: 10.5009/gnl240005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 06/07/2024] [Accepted: 06/21/2024] [Indexed: 11/16/2024] Open
Abstract
The intestine and liver share a unique regenerative property that sets them apart from other mammalian visceral organs. The intestinal epithelium exhibits rapid renewal, making it one of the fastest renewing tissues in humans. Under physiological conditions, intestinal stem cells within each intestinal crypt continuously differentiate into the different types of intestinal epithelial cells to maintain intestinal homeostasis. However, when exposed to tissue damage or stressful conditions such as inflammation, intestinal epithelial cells in the gastrointestinal tract exhibit plasticity, allowing fully differentiated cells to regain their stem cell properties. Likewise, hepatic epithelial cells possess a remarkable regenerative capacity to restore lost liver mass through proliferation-mediated liver regeneration. When the proliferation-mediated regenerative capacity is impaired, hepatocytes and biliary epithelial cells (BECs) can undergo plasticity-mediated regeneration and replenish each other. The transition of mammalian liver progenitor cells to hepatocytes/BECs can be observed under tightly controlled experimental conditions such as severe hepatocyte injury accompanied by the loss of regenerative capacity. In this review, we will discuss the mechanism by which cellular plasticity contributes to the regeneration process and the potential therapeutic implications of understanding and harnessing cellular plasticity in the gut and liver.
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Affiliation(s)
- Minwook Kim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yoojeong Park
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - You Sun Kim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Krystel-Whittemore M, Petrova-Drus K, Ptashkin RN, Ewalt MD, Yao J, Liu Y, Zhu M, Benhamida J, Durham B, Kumar J, Nafa K, Kiecka I, Bowman AS, Gedvilaite E, Casanova J, Lin YT, Mohanty AS, Rana S, Rema AB, Rijo I, Chaves N, Salazar P, Yun A, Lachhander S, Wang W, Haque MS, Xiao W, Roshal M, Giralt S, Salles G, Rampal R, Stein EM, Perales MA, Horwitz S, Jakubowski A, Ponce D, Markova A, Birsoy O, Mandelker D, Mantha S, Dogan A, Benayed R, Ladanyi M, Berger MF, Brannon AR, Zehir A, Vanderbilt C, Arcila ME. Cell-free DNA from nail clippings as source of normal control for genomic studies in hematologic malignancies. Haematologica 2024; 109:3269-3281. [PMID: 38450530 PMCID: PMC11443392 DOI: 10.3324/haematol.2024.285054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 02/29/2024] [Indexed: 03/08/2024] Open
Abstract
Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patients' management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs of samples. In contrast to solid tumors, in hematologic malignancies conventional sources of normal control material (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell-free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control material, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we found that nail cfDNA is a robust germline control for paired genomic studies. In a subset of patients, nail DNA may be contaminated by tumor DNA, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1,482) than among those with lymphoid diseases (5.4%; 61/1,128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. Donor DNA was identified in 22% (11/50) of nails collected after allogeneic stem-cell transplantation. In this cohort, an association with a recent history of graft-versus-host disease was identified. These findings should be considered as a potential limitation to the use of nails as a source of normal control DNA but could also provide important diagnostic information regarding the disease process.
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Affiliation(s)
| | - Kseniya Petrova-Drus
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ryan N Ptashkin
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mark D Ewalt
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - JinJuan Yao
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ying Liu
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Menglei Zhu
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jamal Benhamida
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Benjamin Durham
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jyoti Kumar
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Khedoudja Nafa
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Iwona Kiecka
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Anita S Bowman
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Erika Gedvilaite
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jacklyn Casanova
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Yun-Te Lin
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Abhinita S Mohanty
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Satshil Rana
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Anoop Balakrishnan Rema
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ivelise Rijo
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nelio Chaves
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Paulo Salazar
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Anita Yun
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sean Lachhander
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Wei Wang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mohammad S Haque
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Wenbin Xiao
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mikhail Roshal
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sergio Giralt
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Gilles Salles
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Raajit Rampal
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Eytan M Stein
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Steven Horwitz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ann Jakubowski
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Doris Ponce
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alina Markova
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ozge Birsoy
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Diana Mandelker
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Simon Mantha
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ahmet Dogan
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ryma Benayed
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Marc Ladanyi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael F Berger
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - A Rose Brannon
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ahmet Zehir
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Chad Vanderbilt
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Maria E Arcila
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
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Baj J, Kołodziej M, Kobak J, Januszewski J, Syty K, Portincasa P, Forma A. Significance of Immune and Non-Immune Cell Stroma as a Microenvironment of Hepatocellular Carcinoma-From Inflammation to Hepatocellular Carcinoma Progression. Int J Mol Sci 2024; 25:10233. [PMID: 39408564 PMCID: PMC11475949 DOI: 10.3390/ijms251910233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer as well as the most prevalent cause of death in the adult patient population with cirrhosis. The occurrence of HCC is primarily caused by chronic liver inflammation that might occur because of a viral infection, non-alcoholic fatty liver disease (NAFLD), or various lifestyle-associated factors. The objective of this review was to summarize the current knowledge regarding the microenvironment of HCC, indicating how immune- and non-immune-cell stroma might affect the onset and progression of HCC. Therefore, in the following narrative review, we described the role of tumor-infiltrating neutrophils, bone-marrow-derived cells, tumor-associated mast cells, cancer-associated fibroblasts, tumor-associated macrophages, liver-sinusoidal endothelial cells, lymphocytes, and certain cytokines in liver inflammation and the further progression to HCC. A better understanding of the HCC microenvironment might be crucial to introducing novel treatment strategies or combined therapies that could lead to more effective clinical outcomes.
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Affiliation(s)
- Jacek Baj
- Department of Correct, Clinical and Imaging Anatomy, Chair of Fundamental Sciences, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (J.J.)
| | - Magdalena Kołodziej
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
| | - Joanna Kobak
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
| | - Jacek Januszewski
- Department of Correct, Clinical and Imaging Anatomy, Chair of Fundamental Sciences, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (J.J.)
| | - Kinga Syty
- Institute of Health Sciences, John Paul the II Catholic University of Lublin, Konstantynów 1G, 20-708 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
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Gemery JM, Forauer AR, Hoffer EK. Platelet Count after Transjugular Intrahepatic Portosystemic Shunt: Response to Wong et al, JVIR, August 2023. J Vasc Interv Radiol 2024; 35:469. [PMID: 38043706 DOI: 10.1016/j.jvir.2023.11.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/17/2023] [Accepted: 11/25/2023] [Indexed: 12/05/2023] Open
Affiliation(s)
- John M Gemery
- Department of Radiology, Dartmouth-Hitchcock Medical Center, Lebanon, NH; Giesel School of Medicine, Dartmouth College, Hanover, NH.
| | - Andrew R Forauer
- Department of Radiology, Pennsylvania State University, Hershey, PA; College of Medicine, Pennsylvania State University, Hershey, PA
| | - Eric K Hoffer
- Department of Radiology, Dartmouth-Hitchcock Medical Center, Lebanon, NH; Giesel School of Medicine, Dartmouth College, Hanover, NH
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9
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Hrncir HR, Hantelys F, Gracz AD. Panic at the Bile Duct: How Intrahepatic Cholangiocytes Respond to Stress and Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1440-1454. [PMID: 36870530 PMCID: PMC10548281 DOI: 10.1016/j.ajpath.2023.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/16/2023] [Accepted: 02/15/2023] [Indexed: 03/06/2023]
Abstract
In the liver, biliary epithelial cells (BECs) line intrahepatic bile ducts (IHBDs) and are primarily responsible for modifying and transporting hepatocyte-produced bile to the digestive tract. BECs comprise only 3% to 5% of the liver by cell number but are critical for maintaining choleresis through homeostasis and disease. To this end, BECs drive an extensive morphologic remodeling of the IHBD network termed ductular reaction (DR) in response to direct injury or injury to the hepatic parenchyma. BECs are also the target of a broad and heterogenous class of diseases termed cholangiopathies, which can present with phenotypes ranging from defective IHBD development in pediatric patients to progressive periductal fibrosis and cancer. DR is observed in many cholangiopathies, highlighting overlapping similarities between cell- and tissue-level responses by BECs across a spectrum of injury and disease. The following core set of cell biological BEC responses to stress and injury may moderate, initiate, or exacerbate liver pathophysiology in a context-dependent manner: cell death, proliferation, transdifferentiation, senescence, and acquisition of neuroendocrine phenotype. By reviewing how IHBDs respond to stress, this review seeks to highlight fundamental processes with potentially adaptive or maladaptive consequences. A deeper understanding of how these common responses contribute to DR and cholangiopathies may identify novel therapeutic targets in liver disease.
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Affiliation(s)
- Hannah R Hrncir
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia
| | - Fransky Hantelys
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia
| | - Adam D Gracz
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia.
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Liu BC, Cheng MR, Lang L, Li L, Si YH, Li AJ, Xu Q, Zhang H. Autologous bone marrow infusion via portal vein combined with splenectomy for decompensated liver cirrhosis: A retrospective study. World J Gastrointest Surg 2023; 15:1919-1931. [PMID: 37901728 PMCID: PMC10600764 DOI: 10.4240/wjgs.v15.i9.1919] [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: 04/06/2023] [Revised: 06/08/2023] [Accepted: 07/11/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND In a previous study, autologous bone marrow infusion (ABMI) was performed in patients with decompensated liver cirrhosis (DLC) and acquired immunodeficiency syndrome and achieved good results, but whether splenectomy affected outcome was unclear. AIM To investigate the efficacy of ABMI combined with splenectomy for treatment of DLC. METHODS Eighty-three patients with DLC were divided into an intervention group (43 cases) and control group (40 cases) according to whether splenectomy was performed. The control group was treated with ABMI through the right omental vein, and the intervention group was additionally treated with splenectomy. RESULTS After ABMI, the prothrombin time, serum total bilirubin levels, ascites volume and model for end-stage liver disease score in both groups were significantly lower, while the albumin levels were significantly higher than before ABMI (P < 0.01), but there were no significant differences between the groups (P > 0.05). After ABMI, the white blood cell and platelets counts in both groups were significantly higher than before ABMI (P < 0.01), and the counts in the intervention group were significantly higher than in the control group (P < 0.01). After ABMI the CD4+ and CD8+ T cell counts in both groups were significantly higher than before ABMI (P < 0.01). The CD8+ T cell counts in the intervention group increased continuously and the increase had a shorter duration compared with control group. CONCLUSION ABMI through the portal vein in patients with DLC can significantly improve liver synthetic and secretory functions, and splenectomy promotes improvement of bone marrow hematopoietic and cellular immune functions.
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Affiliation(s)
- Bao-Chi Liu
- Department of Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
- He Nuo Medical Clinic, Shanghai New Hongqiao International Medical Center, Shanghai 201100, China
| | - Ming-Rong Cheng
- Department of Anorectal Surgery, The Third Affiliated Hospital of Guizhou Medical University, Duyun 558000, Guizhou Province, China
| | - Lin Lang
- He Nuo Medical Clinic, Shanghai New Hongqiao International Medical Center, Shanghai 201100, China
| | - Lei Li
- Department of Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Yan-Hui Si
- Department of Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Ai-Jun Li
- Department of Hepatobiliary Surgery, Oriental Hepatobiliary Surgery Hospital, Shanghai 200433, China
| | - Qing Xu
- Department of Hepatobiliary Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Hui Zhang
- Department of Hepatobiliary Surgery, Shanghai Oriental Hospital Affiliated to Tongji University, Shanghai 200120, China
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Colli A, Fraquelli M, Prati D, Casazza G. Granulocyte colony-stimulating factor with or without stem or progenitor cell or growth factors infusion for people with compensated or decompensated advanced chronic liver disease. Cochrane Database Syst Rev 2023; 6:CD013532. [PMID: 37278488 PMCID: PMC10243114 DOI: 10.1002/14651858.cd013532.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
BACKGROUND Advanced chronic liver disease is characterised by a long compensated phase followed by a rapidly progressive 'decompensated' phase, which is marked by the development of complications of portal hypertension and liver dysfunction. Advanced chronic liver disease is considered responsible for more than one million deaths annually worldwide. No treatment is available to specifically target fibrosis and cirrhosis; liver transplantation remains the only curative option. Researchers are investigating strategies to restore liver functionality to avoid or slow progression towards end-stage liver disease. Cytokine mobilisation of stem cells from the bone marrow to the liver could improve liver function. Granulocyte colony-stimulating factor (G-CSF) is a 175-amino-acid protein currently available for mobilisation of haematopoietic stem cells from the bone marrow. Multiple courses of G-CSF, with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, might be associated with accelerated hepatic regeneration, improved liver function, and survival. OBJECTIVES To evaluate the benefits and harms of G-CSF with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, compared with no intervention or placebo in people with compensated or decompensated advanced chronic liver disease. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two trial registers (October 2022) together with reference-checking and web-searching to identify additional studies. We applied no restrictions on language and document type. SELECTION CRITERIA We only included randomised clinical trials comparing G-CSF, independent of the schedule of administration, as a single treatment or combined with stem or progenitor cell infusion, or with other medical co-interventions, with no intervention or placebo, in adults with chronic compensated or decompensated advanced chronic liver disease or acute-on-chronic liver failure. We included trials irrespective of publication type, publication status, outcomes reported, or language. DATA COLLECTION AND ANALYSIS We followed standard Cochrane procedures. All-cause mortality, serious adverse events, and health-related quality of life were our primary outcomes, and liver disease-related morbidity, non-serious adverse events, and no improvement of liver function scores were our secondary outcomes. We undertook meta-analyses, based on intention-to-treat, and presented results using risk ratios (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI) and I2 statistic values as a marker of heterogeneity. We assessed all outcomes at maximum follow-up. We determined the certainty of evidence using GRADE, evaluated the risk of small-study effects in regression analyses, and conducted subgroup and sensitivity analyses. MAIN RESULTS We included 20 trials (1419 participants; sample size ranged from 28 to 259), which lasted between 11 and 57 months. Nineteen trials included only participants with decompensated cirrhosis; in one trial, 30% had compensated cirrhosis. The included trials were conducted in Asia (15), Europe (four), and the USA (one). Not all trials provided data for our outcomes. All trials reported data allowing intention-to-treat analyses. The experimental intervention consisted of G-CSF alone or G-CSF plus any of the following: growth hormone, erythropoietin, N-acetyl cysteine, infusion of CD133-positive haemopoietic stem cells, or infusion of autologous bone marrow mononuclear cells. The control group consisted of no intervention in 15 trials and placebo (normal saline) in five trials. Standard medical therapy (antivirals, alcohol abstinence, nutrition, diuretics, β-blockers, selective intestinal decontamination, pentoxifylline, prednisolone, and other supportive measures depending on the clinical status and requirement) was administered equally to the trial groups. Very low-certainty evidence suggested a decrease in mortality with G-CSF, administered alone or in combination with any of the above, versus placebo (RR 0.53, 95% CI 0.38 to 0.72; I2 = 75%; 1419 participants; 20 trials). Very low-certainty evidence suggested no difference in serious adverse events (G-CSF alone or in combination versus placebo: RR 1.03, 95% CI 0.66 to 1.61; I2 = 66%; 315 participants; three trials). Eight trials, with 518 participants, reported no serious adverse events. Two trials, with 165 participants, used two components of the quality of life score for assessment, with ranges from 0 to 100, where higher scores indicate better quality of life, with a mean increase from baseline of the physical component summary of 20.7 (95% CI 17.4 to 24.0; very low-certainty evidence) and a mean increase from baseline of the mental component summary of 27.8 (95% CI 12.3 to 43.3; very low-certainty evidence). G-CSF, alone or in combination, suggested a beneficial effect on the proportion of participants who developed one or more liver disease-related complications (RR 0.40, 95% CI 0.17 to 0.92; I2 = 62%; 195 participants; four trials; very low-certainty evidence). When we analysed the occurrences of single complications, there was no suggestion of a difference between G-CSF, alone or in combination, versus control, in participants in need of liver transplantation (RR 0.85, 95% CI 0.39 to 1.85; 692 participants; five trials), in the development of hepatorenal syndrome (RR 0.65, 95% CI 0.33 to 1.30; 520 participants; six trials), in the occurrence of variceal bleeding (RR 0.68, 95% CI 0.37 to 1.23; 614 participants; eight trials), and in the development of encephalopathy (RR 0.56, 95% CI 0.31 to 1.01; 605 participants; seven trials) (very low-certainty evidence). The same comparison suggested that G-CSF reduces the development of infections (including sepsis) (RR 0.50, 95% CI 0.29 to 0.84; 583 participants; eight trials) and does not improve liver function scores (RR 0.67, 95% CI 0.53 to 0.86; 319 participants; two trials) (very low-certainty evidence). AUTHORS' CONCLUSIONS G-CSF, alone or in combination, seems to decrease mortality in people with decompensated advanced chronic liver disease of whatever aetiology and with or without acute-on-chronic liver failure, but the certainty of evidence is very low because of high risk of bias, inconsistency, and imprecision. The results of trials conducted in Asia and Europe were discrepant; this could not be explained by differences in participant selection, intervention, and outcome measurement. Data on serious adverse events and health-related quality of life were few and inconsistently reported. The evidence is also very uncertain regarding the occurrence of one or more liver disease-related complications. We lack high-quality, global randomised clinical trials assessing the effect of G-CSF on clinically relevant outcomes.
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Affiliation(s)
- Agostino Colli
- Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Mirella Fraquelli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Daniele Prati
- Department of Transfusion Medicine and Haematology, Ospedale Alessandro Manzoni, Lecco, Italy
| | - Giovanni Casazza
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Rieux M, Alpaugh M, Salem S, Siddu A, Saint-Pierre M, Denis HL, Rohweder H, Herrmann F, Bazenet C, Lacroix S, Cicchetti F. Understanding the role of the hematopoietic niche in Huntington's disease's phenotypic expression: in vivo evidence using a parabiosis model. Neurobiol Dis 2023; 180:106091. [PMID: 36967065 DOI: 10.1016/j.nbd.2023.106091] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/06/2023] [Accepted: 03/16/2023] [Indexed: 03/31/2023] Open
Abstract
In a previous study, we have shown that parabiotic coupling of a knock-in mouse model (zQ175) of Huntington's disease (HD) to wild-type (WT) littermates resulted in a worsening of the normal phenotype as seen by detection of mutant huntingtin protein (mHTT) aggregates within peripheral organs and the cerebral cortex as well as vascular abnormalities in WT mice. In contrast, parabiosis improved disease features in the zQ175 mice such as reduction of mHTT aggregate number in the liver and cortex, decrease in blood-brain barrier (BBB) permeability and attenuation of mitochondrial impairments. While the shared circulation mediated these effects, no specific factor was identified. To better understand which blood elements were involved in the aforementioned changes, WT and zQ175 mice underwent parabiotic surgery prior to exposing one of the paired animals to irradiation. The irradiation procedure successfully eliminated the hematopoietic niche followed by repopulation with cells originating from the non-irradiated parabiont, as measured by the quantification of mHTT levels in peripheral blood mononuclear cells. Although irradiation of the WT parabiont, causing the loss of healthy hematopoietic cells, did lead to a few alterations in mitochondrial function in the muscle (TOM40 levels), and increased neuroinflammation in the striatum (GFAP levels), most of the changes observed were likely attributable to the irradiation procedure itself (e.g. mHTT aggregates in cortex and liver; cellular stress in peripheral organs). However, factors such as mHTT aggregation in the brain and periphery, and BBB leakage, which were improved in zQ175 mice when paired to WT littermates in the previous parabiosis experiment, were unaffected by perturbation of the hematopoietic niche. It would therefore appear that cells of the hematopoietic stem cell niche are largely uninvolved in the beneficial effects of parabiosis.
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Affiliation(s)
- Marie Rieux
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | - Melanie Alpaugh
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | - Shireen Salem
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | - Alberto Siddu
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | - Martine Saint-Pierre
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada
| | - Hélèna L Denis
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | | | | | | | - Steve Lacroix
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | - Francesca Cicchetti
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada.
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Bittmann S, Villalon G, Moschuring-Alieva E, Luchter E, Bittmann L. Current and Novel Therapeutical Approaches of Classical Homocystinuria in Childhood With Special Focus on Enzyme Replacement Therapy, Liver-Directed Therapy and Gene Therapy. J Clin Med Res 2023; 15:76-83. [PMID: 36895619 PMCID: PMC9990725 DOI: 10.14740/jocmr4843] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 01/09/2023] [Indexed: 03/05/2023] Open
Abstract
Classical homocystinuria is a hereditary defect of the enzyme cystathionine beta synthase, which is produced in the liver. If this enzyme fails, the synthesis pathway of cysteine from methionine is interrupted, leading to the accumulation of homocysteine in the blood plasma and homocysteine in the urine. After birth, the children are unremarkable except for the characteristic laboratory findings. Symptoms rarely appear before the second year of life. The most common symptom is a prolapse of the crystalline lens. This finding is seen in 70% of untreated 10-year-old affected individuals. As the earliest symptom, psychomotor retardation occurs in the majority of patients already during the first two years of life. Limiting factors in terms of life expectancy are thromboembolism, peripheral arterial disease, myocardial infarction, and stroke. These symptoms are due to the damage to the vessels caused by the elevated amino acid levels. About 30% suffer a thromboembolic event by the age of 20, about half by the age of 30. This review focus on present and new therapeutical approaches like the role of enzyme replacement with presentation of different novel targets in research like pegtibatinase, pegtarviliase, CDX-6512, erymethionase, chaperones, proteasome inhibitors and probiotic treatment with SYNB 1353. Furthermore, we analyze the role of liver-directed therapy with three dimensional (3D) bioprinting, liver bioengineering of liver organoids in vitro and liver transplantation. The role of different gene therapy options to treat and cure this extremely rare disease in childhood will be discussed.
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Affiliation(s)
- Stefan Bittmann
- Ped Mind Institute, Department of Pediatrics, Medical and Finance Center Epe, D-48599 Gronau, Germany
| | - Gloria Villalon
- Ped Mind Institute, Department of Pediatrics, Medical and Finance Center Epe, D-48599 Gronau, Germany
| | - Elena Moschuring-Alieva
- Ped Mind Institute, Department of Pediatrics, Medical and Finance Center Epe, D-48599 Gronau, Germany
| | - Elisabeth Luchter
- Ped Mind Institute, Department of Pediatrics, Medical and Finance Center Epe, D-48599 Gronau, Germany
| | - Lara Bittmann
- Ped Mind Institute, Department of Pediatrics, Medical and Finance Center Epe, D-48599 Gronau, Germany
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14
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Human stem cells for decompensated cirrhosis in adults. Cochrane Database Syst Rev 2022; 2022:CD015173. [PMCID: PMC9531721 DOI: 10.1002/14651858.cd015173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of stem cell treatment in adults with decompensated cirrhosis, regardless of ethnicity, sex, types of stem cells, route of stem cell injection, and administered dose.
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15
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Solitary extrahepatic hepatocellular carcinoma in vertebrae without a primary lesion in the liver might originate from bone marrow: a case report and new hypothesis based on a review of the literature and the latest findings. Clin J Gastroenterol 2022; 15:1115-1123. [DOI: 10.1007/s12328-022-01701-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 09/06/2022] [Indexed: 02/07/2023]
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Liver Regeneration by Hematopoietic Stem Cells: Have We Reached the End of the Road? Cells 2022; 11:cells11152312. [PMID: 35954155 PMCID: PMC9367594 DOI: 10.3390/cells11152312] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/22/2022] [Accepted: 07/22/2022] [Indexed: 02/01/2023] Open
Abstract
The liver is the organ with the highest regenerative capacity in the human body. However, various insults, including viral infections, alcohol or drug abuse, and metabolic overload, may cause chronic inflammation and fibrosis, leading to irreversible liver dysfunction. Despite advances in surgery and pharmacological treatments, liver diseases remain a leading cause of death worldwide. To address the shortage of donor liver organs for orthotopic liver transplantation, cell therapy in liver disease has emerged as a promising regenerative treatment. Sources include primary hepatocytes or functional hepatocytes generated from the reprogramming of induced pluripotent stem cells (iPSC). Different types of stem cells have also been employed for transplantation to trigger regeneration, including hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs) as well as adult and fetal liver progenitor cells. HSCs, usually defined by the expression of CD34 and CD133, and MSCs, defined by the expression of CD105, CD73, and CD90, are attractive sources due to their autologous nature, ease of isolation and cryopreservation. The present review focuses on the use of bone marrow HSCs for liver regeneration, presenting evidence for an ongoing crosstalk between the hematopoietic and the hepatic system. This relationship commences during embryogenesis when the fetal liver emerges as the crossroads between the two systems converging the presence of different origins of cells (mesoderm and endoderm) in the same organ. Ample evidence indicates that the fetal liver supports the maturation and expansion of HSCs during development but also later on in life. Moreover, the fact that the adult liver remains one of the few sites for extramedullary hematopoiesis—albeit pathological—suggests that this relationship between the two systems is ongoing. Can, however, the hematopoietic system offer similar support to the liver? The majority of clinical studies using hematopoietic cell transplantation in patients with liver disease report favourable observations. The underlying mechanism—whether paracrine, fusion or transdifferentiation or a combination of the three—remains to be confirmed.
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17
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Diversity of the Origin of Cancer Stem Cells in Oral Squamous Cell Carcinoma and Its Clinical Implications. Cancers (Basel) 2022; 14:cancers14153588. [PMID: 35892847 PMCID: PMC9332248 DOI: 10.3390/cancers14153588] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/17/2022] [Accepted: 07/21/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Oral squamous cell carcinoma (OSCC) histopathologically accounts for ≥90% of oral cancer. In this review article, we focus on the diversity of the origin of OSCC and also discuss cancer stem cells (CSCs). CSCs are a subset of cancer cells that occupy a very small portion of the cancer mass and have characteristics of stem cells. When gene abnormalities accumulate in somatic stem cells, those cells transform into CSCs. CSCs as the origin of cancer then autonomously grow and develop into cancer. The histopathological phenotype of cancer cells is determined by the original characteristics of the somatic stem cells and/or surrounding environment. OSCC may be divided into the following three categories with different malignancy based on the origin of CSCs: cancer from oral epithelial stem cell-derived CSCs, cancer from stem cells in salivary gland-derived CSCs, and cancer from bone marrow-derived stem cell-derived CSCs. Abstract Oral squamous cell carcinoma (OSCC) histopathologically accounts for ≥90% of oral cancer. Many clinicopathological risk factors for OSCC have also been proposed, and postoperative therapy is recommended in guidelines based on cancer stage and other risk factors. However, even if the standard treatment is provided according to the guidelines, a few cases rapidly recur or show cervical and distant metastasis. In this review article, we focus on the diversity of the origin of OSCC. We also discuss cancer stem cells (CSCs) as a key player to explain the malignancy of OSCC. CSCs are a subset of cancer cells that occupy a very small portion of the cancer mass and have characteristics of stem cells. When gene abnormalities accumulate in somatic stem cells, those cells transform into CSCs. CSCs as the origin of cancer then autonomously grow and develop into cancer. The histopathological phenotype of cancer cells is determined by the original characteristics of the somatic stem cells and/or surrounding environment. OSCC may be divided into the following three categories with different malignancy based on the origin of CSCs: cancer from oral epithelial stem cell-derived CSCs, cancer from stem cells in salivary gland-derived CSCs, and cancer from bone marrow-derived stem cell-derived CSCs.
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Yao L, Hu X, Dai K, Yuan M, Liu P, Zhang Q, Jiang Y. Mesenchymal stromal cells: promising treatment for liver cirrhosis. Stem Cell Res Ther 2022; 13:308. [PMID: 35841079 PMCID: PMC9284869 DOI: 10.1186/s13287-022-03001-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/13/2022] [Indexed: 11/11/2022] Open
Abstract
Liver fibrosis is a wound-healing process that occurs in response to severe injuries and is hallmarked by the excessive accumulation of extracellular matrix or scar tissues within the liver. Liver fibrosis can be either acute or chronic and is induced by a variety of hepatotoxic causes, including lipid deposition, drugs, viruses, and autoimmune reactions. In advanced fibrosis, liver cirrhosis develops, a condition for which there is no successful therapy other than liver transplantation. Although liver transplantation is still a viable option, numerous limitations limit its application, including a lack of donor organs, immune rejection, and postoperative complications. As a result, there is an immediate need for a different kind of therapeutic approach. Recent research has shown that the administration of mesenchymal stromal cells (MSCs) is an attractive treatment modality for repairing liver injury and enhancing liver regeneration. This is accomplished through the cell migration into liver sites, immunoregulation, hepatogenic differentiation, as well as paracrine mechanisms. MSCs can also release a huge variety of molecules into the extracellular environment. These molecules, which include extracellular vesicles, lipids, free nucleic acids, and soluble proteins, exert crucial roles in repairing damaged tissue. In this review, we summarize the characteristics of MSCs, representative clinical study data, and the potential mechanisms of MSCs-based strategies for attenuating liver cirrhosis. Additionally, we examine the processes that are involved in the MSCs-dependent modulation of the immune milieu in liver cirrhosis. As a result, our findings lend credence to the concept of developing a cell therapy treatment for liver cirrhosis that is premised on MSCs. MSCs can be used as a candidate therapeutic agent to lengthen the survival duration of patients with liver cirrhosis or possibly reverse the condition in the near future.
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Affiliation(s)
- Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Kai Dai
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Pingji Liu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Qiuling Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.
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Generation of Cancer Stem/Initiating Cells by Cell-Cell Fusion. Int J Mol Sci 2022; 23:ijms23094514. [PMID: 35562905 PMCID: PMC9101717 DOI: 10.3390/ijms23094514] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/10/2022] [Accepted: 04/17/2022] [Indexed: 02/04/2023] Open
Abstract
CS/ICs have raised great expectations in cancer research and therapy, as eradication of this key cancer cell type is expected to lead to a complete cure. Unfortunately, the biology of CS/ICs is rather complex, since no common CS/IC marker has yet been identified. Certain surface markers or ALDH1 expression can be used for detection, but some studies indicated that cancer cells exhibit a certain plasticity, so CS/ICs can also arise from non-CS/ICs. Another problem is intratumoral heterogeneity, from which it can be inferred that different CS/IC subclones must be present in the tumor. Cell–cell fusion between cancer cells and normal cells, such as macrophages and stem cells, has been associated with the generation of tumor hybrids that can exhibit novel properties, such as an enhanced metastatic capacity and even CS/IC properties. Moreover, cell–cell fusion is a complex process in which parental chromosomes are mixed and randomly distributed among daughter cells, resulting in multiple, unique tumor hybrids. These, if they have CS/IC properties, may contribute to the heterogeneity of the CS/IC pool. In this review, we will discuss whether cell–cell fusion could also lead to the origin of different CS/ICs that may expand the overall CS/IC pool in a primary tumor.
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Chen L, Yi X, Guo P, Guo H, Chen Z, Hou C, Qi L, Wang Y, Li C, Liu P, Liu Y, Xu Y, Zhang N. The role of bone marrow-derived cells in the origin of liver cancer revealed by single-cell sequencing. Cancer Biol Med 2021; 17:142-153. [PMID: 32296582 PMCID: PMC7142842 DOI: 10.20892/j.issn.2095-3941.2019.0369] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 01/09/2020] [Indexed: 12/21/2022] Open
Abstract
Objective: Epithelial cancers often originate from progenitor cells, while the origin of hepatocellular carcinoma (HCC) is still controversial. HCC, one of the deadliest cancers, is closely linked with liver injuries and chronic inflammation, which trigger massive infiltration of bone marrow-derived cells (BMDCs) during liver repair. Methods: To address the possible roles of BMDCs in HCC origination, we established a diethylnitrosamine (DEN)-induced HCC model in bone marrow transplanted mice. Immunohistochemistry and frozen tissue immunofluorescence were used to verify DEN-induced HCC in the pathology of the disease. The cellular origin of DEN-induced HCC was further studied by single cell sequencing, single-cell nested PCR, and immunofluorescence-fluorescence in situ hybridization. Results: Studies by using single cell sequencing and biochemical analysis revealed that HCC cells in these mice were coming from donor mice BMDCs, and not from recipient mice. Furthermore, the copy numbers of mouse orthologs of several HCC-related genes previously reported in human HCC were also altered in our mouse model. DEN-induced HCCs exhibited a similar histological phenotype and genomic profile as human HCCs. Conclusions: These results suggested that BMDCs are an important origin of HCC, which provide important clues to HCC prevention, detection, and treatments.
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Affiliation(s)
- Lu Chen
- The concrete information of affiliations should be presented, for instance, Department of Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300070, China
| | - Xianfu Yi
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China
| | - Piao Guo
- The concrete information of affiliations should be presented, for instance, Department of Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300070, China
| | - Hua Guo
- The concrete information of affiliations should be presented, for instance, Department of Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300070, China
| | - Ziye Chen
- The concrete information of affiliations should be presented, for instance, Department of Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300070, China
| | - Chunyu Hou
- The Center for Translational Cancer Research, Peking University First Hospital, Beijing 100034, China
| | - Lisha Qi
- The concrete information of affiliations should be presented, for instance, Department of Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300070, China
| | - Yongrong Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.,CAMS Key Laboratory for Prevention and Control of Hematological Disease Treatment Related Infection, Tianjin 300020, China
| | - Chengwen Li
- Cytogenetics Laboratory, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China
| | - Peng Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Yucun Liu
- The Center for Translational Cancer Research, Peking University First Hospital, Beijing 100034, China
| | - Yuanfu Xu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.,CAMS Key Laboratory for Prevention and Control of Hematological Disease Treatment Related Infection, Tianjin 300020, China
| | - Ning Zhang
- The concrete information of affiliations should be presented, for instance, Department of Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300070, China.,The Center for Translational Cancer Research, Peking University First Hospital, Beijing 100034, China
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Bram Y, Nguyen DHT, Gupta V, Park J, Richardson C, Chandar V, Schwartz RE. Cell and Tissue Therapy for the Treatment of Chronic Liver Disease. Annu Rev Biomed Eng 2021; 23:517-546. [PMID: 33974812 PMCID: PMC8864721 DOI: 10.1146/annurev-bioeng-112619-044026] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Liver disease is an important clinical problem, impacting 600 million people worldwide. It is the 11th-leading cause of death in the world. Despite constant improvement in treatment and diagnostics, the aging population and accumulated risk factors led to increased morbidity due to nonalcoholic fatty liver disease and steatohepatitis. Liver transplantation, first established in the 1960s, is the second-most-common solid organ transplantation and is the gold standard for the treatment of liver failure. However, less than 10% of the global need for liver transplantation is met at the current rates of transplantation due to the paucity of available organs. Cell- and tissue-based therapies present an alternative to organ transplantation. This review surveys the approaches and tools that have been developed, discusses the distinctive challenges that exist for cell- and tissue-based therapies, and examines the future directions of regenerative therapies for the treatment of liver disease.
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Affiliation(s)
- Yaron Bram
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
| | - Duc-Huy T Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
| | - Vikas Gupta
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
| | - Jiwoon Park
- Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, NY 10065, USA
| | - Chanel Richardson
- Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA
| | - Vasuretha Chandar
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
| | - Robert E Schwartz
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; .,Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, NY 10065, USA
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22
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Nourbakhsh A, Colbert BM, Nisenbaum E, El-Amraoui A, Dykxhoorn DM, Koehler KR, Chen ZY, Liu XZ. Stem Cells and Gene Therapy in Progressive Hearing Loss: the State of the Art. J Assoc Res Otolaryngol 2021; 22:95-105. [PMID: 33507440 PMCID: PMC7943682 DOI: 10.1007/s10162-020-00781-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022] Open
Abstract
Progressive non-syndromic sensorineural hearing loss (PNSHL) is the most common cause of sensory impairment, affecting more than a third of individuals over the age of 65. PNSHL includes noise-induced hearing loss (NIHL) and inherited forms of deafness, among which is delayed-onset autosomal dominant hearing loss (AD PNSHL). PNSHL is a prime candidate for genetic therapies due to the fact that PNSHL has been studied extensively, and there is a potentially wide window between identification of the disorder and the onset of hearing loss. Several gene therapy strategies exist that show potential for targeting PNSHL, including viral and non-viral approaches, and gene editing versus gene-modulating approaches. To fully explore the potential of these therapy strategies, a faithful in vitro model of the human inner ear is needed. Such models may come from induced pluripotent stem cells (iPSCs). The development of new treatment modalities by combining iPSC modeling with novel and innovative gene therapy approaches will pave the way for future applications leading to improved quality of life for many affected individuals and their families.
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Affiliation(s)
- Aida Nourbakhsh
- Department of Otolaryngology–Head and Neck Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, 5th Floor, Miami, FL 33136 USA
| | - Brett M. Colbert
- Department of Otolaryngology–Head and Neck Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, 5th Floor, Miami, FL 33136 USA
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136 USA
- Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Eric Nisenbaum
- Department of Otolaryngology–Head and Neck Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, 5th Floor, Miami, FL 33136 USA
| | - Aziz El-Amraoui
- Unit Progressive Sensory Disorders, Institut Pasteur, INSERM-UMRS1120, Sorbonne Université, 25 rue du Dr. Roux, 75015 Paris, France
| | - Derek M. Dykxhoorn
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Karl Russell Koehler
- Department of Otolaryngology-Head and Neck Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115 USA
| | - Zheng-yi Chen
- Department of Otology and Laryngology, Harvard Medical School and Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114 USA
| | - Xue Z. Liu
- Department of Otolaryngology–Head and Neck Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, 5th Floor, Miami, FL 33136 USA
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136 USA
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Hasegawa T, Nakashiro KI, Fukumoto C, Hyodo T, Sawatani Y, Shimura M, Kamimura R, Kuribayashi N, Fujita A, Uchida D, Kawamata H. Oral squamous cell carcinoma may originate from bone marrow-derived stem cells. Oncol Lett 2021; 21:170. [PMID: 33552287 PMCID: PMC7798092 DOI: 10.3892/ol.2021.12431] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/21/2020] [Indexed: 01/11/2023] Open
Abstract
Molecules that demonstrate a clear association with the aggressiveness of oral squamous cell carcinoma (OSCC) have not yet been identified. The current study hypothesized that tumor cells in OSCC have three different origins: Epithelial stem cells, oral tissue stem cells from the salivary gland and bone marrow (BM) stem cells. It was also hypothesized that carcinomas derived from less-differentiated stem cells have a greater malignancy. In the present study, sex chromosome analysis by fluorescence in situ hybridization and/or microdissection PCR was performed in patients with OSCC that developed after hematopoietic stem cell transplantation (HSCT) from the opposite sex. OSCC from 3 male patients among the 6 total transplanted patients were considered to originate from donor-derived BM cells. A total of 2/3 patients had distant metastasis, resulting in a poor prognosis. In a female patient with oral potentially malignant disorder who underwent HSCT, there were 10.7% Y-containing cells in epithelial cells, suggesting that some epithelial cells were from the donor. Subsequently, gene expression patterns in patients with possible BM stem cell-derived OSCC were compared with those in patients with normally developed OSCC by microarray analysis. A total of 3 patients with BM stem cell-derived OSCC exhibited a specific pattern of gene expression. Following cluster analysis by the probes identified on BM stem cell-derived OSCC, 2 patients with normally developed OSCC were included in the cluster of BM stem cell-derived OSCC. If the genes that could discriminate the origin of OSCC were identified, OSCCs were classified into the three aforementioned categories. If diagnosis can be performed based on the origin of the cancer cells, a more specific therapeutic strategy may be implemented to improve prognosis. This would be a paradigm shift in diagnostic and therapeutic strategies for OSCC.
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Affiliation(s)
- Tomonori Hasegawa
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Koh-Ichi Nakashiro
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan
| | - Chonji Fukumoto
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Toshiki Hyodo
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Yuta Sawatani
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Michiko Shimura
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Ryouta Kamimura
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Nobuyuki Kuribayashi
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan
| | - Atsushi Fujita
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Daisuke Uchida
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan
| | - Hitoshi Kawamata
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
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Stem Cells an Overview. Stem Cells 2021. [DOI: 10.1007/978-981-16-1638-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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25
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Li F, Chen J, Gong M, Bi Y, Hu C, Zhang Y, Li M. Isolation and Characterization of Human Synovial Fluid-Derived Mesenchymal Stromal Cells from Popliteal Cyst. Stem Cells Int 2020; 2020:7416493. [PMID: 33014069 PMCID: PMC7519976 DOI: 10.1155/2020/7416493] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 08/03/2020] [Accepted: 08/21/2020] [Indexed: 12/02/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent progenitor cells in adult tissues. The aim of this study is to isolate and identify synovial fluid-derived mesenchymal stromal cells (SF-MSCs) from the popliteal cyst fluid of pediatric patients. SF-MSCs were collected from the popliteal cyst fluid of pediatric patients during cystectomy surgery. After cyst fluid extraction and adherent culturing, in vitro morphology, growth curve, and cell cycle were observed. The expression of stem cell surface markers was analyzed by flow cytometry, and expression of cell marker protein was detected by immunofluorescence. SF-MSCs were cultured in osteogenic, adipogenic, and chondrogenic differentiation medium. The differentiation potential of SF-MSCs was analyzed by alkaline phosphatase (Alizarin Red), Oil Red O, and Alcian blue. Antibody detection of human angiogenesis-related proteins was performed compared with bone marrow mesenchymal stem cells (BM-MSCs). The results show that SF-MSCs from the popliteal cyst fluid of pediatric patients showed a shuttle appearance and logarithmic growth. Flow cytometry analysis revealed that SF-MSCs were negative for hematopoietic lineage markers (CD34, CD45) and positive for MSC markers (CD44, CD73, CD90, and CD105). Interstitial cell marker (vimentin) and myofibroblast-like cell marker alpha-smooth muscle actin (α-SMA) were positive. These cells could differentiate into osteogenic, adipogenic, and chondrogenic lineages, respectively. Several types of human angiogenesis-related proteins were detected in the cell secretory fluid. These results show that we successfully obtained SF-MSCs from the popliteal cyst fluid of pediatric patients, which have the potential to be a valuable source of MSCs.
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Affiliation(s)
- Fang Li
- Department of Orthopedics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Department of Pediatric Research Institute, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jianglin Chen
- Department of Orthopedics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Department of Pediatric Research Institute, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Mengjia Gong
- Department of Orthopedics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Department of Pediatric Research Institute, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yang Bi
- Department of Orthopedics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Department of Pediatric Research Institute, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Chengchen Hu
- Department of Pediatric Research Institute, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yuanyuan Zhang
- Department of Pediatric Research Institute, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ming Li
- Department of Orthopedics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Department of Pediatric Research Institute, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
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26
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Advantages of adipose tissue stem cells over CD34 + mobilization to decrease hepatic fibrosis in Wistar rats. Ann Hepatol 2020; 18:620-626. [PMID: 31147180 DOI: 10.1016/j.aohep.2018.12.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 12/04/2018] [Accepted: 11/01/2018] [Indexed: 02/06/2023]
Abstract
INTRODUCTION AND OBJECTIVES Chronic liver inflammation may lead to hepatic cirrhosis, limiting its regenerative capacity. The clinical standard of care is transplantation, although stem cell therapy may be an alternative option. The study aim was to induce endogenous hematopoietic stem cells (HSCs) with granulocyte colony stimulating factor (G-CSF) and/or intravenous administration of adipose tissue-derived mesenchymal stem cells (MSCs) to decrease hepatic fibrosis in an experimental model. MATERIAL AND METHODS A liver fibrosis model was developed with female Wistar rats via multiple intraperitoneal doses of carbon tetrachloride. Three rats were selected to confirm cirrhosis, and the rest were set into experimental groups to evaluate single and combined therapies of G-CSF-stimulated HSC mobilization and intravenous MSC administration. RESULTS Treatment with MSCs and G-CSF significantly improved alanine amino transferase levels, while treatment with G-CSF, MSCs, and G-CSF+MSCs decreased aspartate amino transferase levels. Hepatocyte growth factor (HGF) and interleukin 10 levels increased with MSC treatment. Transforming growth factor β levels were lower with MSC treatment. Interleukin 1β and tumor necrosis factor alpha levels decreased in all treated groups. Histopathology showed that MSCs and G-CSF reduced liver fibrosis from F4 to F2. CONCLUSIONS MSC treatment improves liver function, decreases hepatic fibrosis, and plays an anti-inflammatory role; it promotes HGF levels and increased proliferating cell nuclear antigen when followed by MSC treatment mobilization using G-CSF. When these therapies were combined, however, fibrosis improvement was less evident.
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Wei S, Tang J, Cai X. Founder cells for hepatocytes during liver regeneration: from identification to application. Cell Mol Life Sci 2020; 77:2887-2898. [PMID: 32060582 PMCID: PMC11105049 DOI: 10.1007/s00018-020-03457-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 01/02/2020] [Accepted: 01/10/2020] [Indexed: 12/12/2022]
Abstract
Liver regeneration (LR) capacity in vertebrates developed through natural selection over a hundred million years of evolution. To maintain homeostasis or recover from various injuries, liver cells must regenerate; this process includes the renewal of parenchymal and nonparenchymal cells as well as the formation of liver structures. The cellular origin of newly grown tissue is one of the critical questions in this area and has been a subject of prolonged debate. The regenerative tissue may derive from either hepatocyte self-duplication or liver stem/progenitor cells (LSPCs). Recently, hepatocyte subpopulations and cholangiocytes were also described as important founder cells. The niche that triggers the proliferation of hepatocytes and the differentiation of LSPCs has been extensively studied. Meanwhile, in vitro culture systems for liver founder cells and organoids have been developed rapidly for mechanistic studies and potential therapeutic purposes. This review summarizes the cellular sources and niches that give rise to renewed hepatocytes during LR, and it also describes in vitro culture studies of those founder cells for future applications, as well as current reports for stem cell-based therapies for liver diseases.
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Affiliation(s)
- Saisai Wei
- Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
| | - Jiacheng Tang
- Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
| | - Xiujun Cai
- Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
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Donor-derived DNA variability in fingernails of acute myeloid leukemia patients after allogeneic hematopoietic stem cell transplantation detected by direct PCR. Bone Marrow Transplant 2020; 55:1021-1022. [PMID: 32388533 DOI: 10.1038/s41409-020-0938-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 11/09/2022]
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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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Dörnen J, Sieler M, Weiler J, Keil S, Dittmar T. Cell Fusion-Mediated Tissue Regeneration as an Inducer of Polyploidy and Aneuploidy. Int J Mol Sci 2020; 21:E1811. [PMID: 32155721 PMCID: PMC7084716 DOI: 10.3390/ijms21051811] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/28/2020] [Accepted: 03/04/2020] [Indexed: 12/20/2022] Open
Abstract
The biological phenomenon of cell fusion plays a crucial role in several physiological processes, including wound healing and tissue regeneration. Here, it is assumed that bone marrow-derived stem cells (BMSCs) could adopt the specific properties of a different organ by cell fusion, thereby restoring organ function. Cell fusion first results in the production of bi- or multinucleated hybrid cells, which either remain as heterokaryons or undergo ploidy reduction/heterokaryon-to-synkaryon transition (HST), thereby giving rise to mononucleated daughter cells. This process is characterized by a merging of the chromosomes from the previously discrete nuclei and their subsequent random segregation into daughter cells. Due to extra centrosomes concomitant with multipolar spindles, the ploidy reduction/HST could also be associated with chromosome missegregation and, hence, induction of aneuploidy, genomic instability, and even putative chromothripsis. However, while the majority of such hybrids die or become senescent, aneuploidy and genomic instability appear to be tolerated in hepatocytes, possibly for stress-related adaption processes. Likewise, cell fusion-induced aneuploidy and genomic instability could also lead to a malignant conversion of hybrid cells. This can occur during tissue regeneration mediated by BMSC fusion in chronically inflamed tissue, which is a cell fusion-friendly environment, but is also enriched for mutagenic reactive oxygen and nitrogen species.
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Affiliation(s)
| | | | | | | | - Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany; (J.D.); (M.S.); (J.W.); (S.K.)
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Tricot T, De Boeck J, Verfaillie C. Alternative Cell Sources for Liver Parenchyma Repopulation: Where Do We Stand? Cells 2020; 9:E566. [PMID: 32121068 PMCID: PMC7140465 DOI: 10.3390/cells9030566] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/20/2020] [Accepted: 02/22/2020] [Indexed: 12/28/2022] Open
Abstract
Acute and chronic liver failure is a highly prevalent medical condition with high morbidity and mortality. Currently, the therapy is orthotopic liver transplantation. However, in some instances, chiefly in the setting of metabolic diseases, transplantation of individual cells, specifically functional hepatocytes, can be an acceptable alternative. The gold standard for this therapy is the use of primary human hepatocytes, isolated from livers that are not suitable for whole organ transplantations. Unfortunately, primary human hepatocytes are scarcely available, which has led to the evaluation of alternative sources of functional hepatocytes. In this review, we will compare the ability of most of these candidate alternative cell sources to engraft and repopulate the liver of preclinical animal models with the repopulation ability found with primary human hepatocytes. We will discuss the current shortcomings of the different cell types, and some of the next steps that we believe need to be taken to create alternative hepatocyte progeny capable of regenerating the failing liver.
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32
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Yang B, Duan W, Wei L, Zhao Y, Han Z, Wang J, Wang M, Dai C, Zhang B, Chen D, Chen Z. Bone Marrow Mesenchymal Stem Cell-Derived Hepatocyte-Like Cell Exosomes Reduce Hepatic Ischemia/Reperfusion Injury by Enhancing Autophagy. Stem Cells Dev 2020; 29:372-379. [PMID: 31969065 DOI: 10.1089/scd.2019.0194] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Ischemia/reperfusion (I/R) injury remains a major problem in liver transplantation. I/R causes inflammatory cytokine release, apoptosis, and necrosis. Bone marrow-mesenchymal stem cells (BM-MSCs) can differentiate into hepatocytes in vivo, and differentiation further increases when hepatocytes are damaged. Exosomes are important mediators of cellular connections. Recently, exosomes of hepatocytes have been shown to play a pivotal role in inhibiting hepatocyte apoptosis and promoting hepatocyte regeneration. Therefore, we induced MSCs to differentiate into hepatocyte-like cells and extracted their exosomes; we then injected the exosomes into a mouse hepatic I/R model through the tail vein. Simultaneously, CoCl2 was used to mimic I/R in vitro. Our data indicated that in vivo, mesenchymal stem cell-derived hepatocyte-like cell exosomes (MSC-Heps-Exo) effectively relieve hepatic I/R damage, reduce hepatocyte apoptosis, and decrease liver enzyme levels. Consistent with the in vivo results, the in vitro experiments confirmed that exosomes effectively increased hepatocyte tolerance to ischemia and reduced hepatocyte apoptosis. We thus found that autophagy enhancement may be the mechanism by which exosomes protect the liver from I/R injury. These results indicate that exosomes play a protective role in hepatic I/R, and that the use of BM-MSCs for hepatocyte induction and exosome extraction may provide a new clinical treatment method through bioengineering.
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Affiliation(s)
- Bo Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.,The National Hurricane Center Key Laboratory of Organ Transplantation, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Wu Duan
- Division of Endocrinology, Department of Internal Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Lai Wei
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.,The National Hurricane Center Key Laboratory of Organ Transplantation, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Yuanyuan Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.,The National Hurricane Center Key Laboratory of Organ Transplantation, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhenyi Han
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.,The National Hurricane Center Key Laboratory of Organ Transplantation, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Jin Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.,The National Hurricane Center Key Laboratory of Organ Transplantation, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Meixi Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.,The National Hurricane Center Key Laboratory of Organ Transplantation, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Chen Dai
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.,The National Hurricane Center Key Laboratory of Organ Transplantation, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Bo Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.,The National Hurricane Center Key Laboratory of Organ Transplantation, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Dong Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.,The National Hurricane Center Key Laboratory of Organ Transplantation, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhishui Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.,The National Hurricane Center Key Laboratory of Organ Transplantation, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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33
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Colli A, Prati D, Fraquelli M, Casazza G, Cochrane Hepato‐Biliary Group. Granulocyte colony‐stimulating factor with or without stem or progenitor cell infusion for people with compensated or decompensated advanced chronic liver disease. Cochrane Database Syst Rev 2020; 2020:CD013532. [PMCID: PMC7005932 DOI: 10.1002/14651858.cd013532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of granulocyte colony‐stimulating factor with or without stem or progenitor cell infusion in people with compensated or decompensated advanced chronic liver disease.
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Affiliation(s)
- Agostino Colli
- A Manzoni Hospital ASST LeccoDepartment of Internal MedicineVia dell'Eremo, 9/11LeccoItaly23900
| | - Daniele Prati
- Ospedale Alessandro ManzoniDepartment of Transfusion Medicine and HaematologyLeccoItaly
| | - Mirella Fraquelli
- Fondazione IRCCS Ca´ Granda ‐ Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di MilanoGastroenterology and Endoscopy UnitVia F. Sforza, 35MilanItaly20122
| | - Giovanni Casazza
- Università degli Studi di MilanoDipartimento di Scienze Biomediche e Cliniche "L. Sacco"via GB Grassi 74MilanItaly20157
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34
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He F, Yu C, Liu T, Jia H. Ginsenoside Rg1 as an Effective Regulator of Mesenchymal Stem Cells. Front Pharmacol 2020; 10:1565. [PMID: 32038244 PMCID: PMC6989539 DOI: 10.3389/fphar.2019.01565] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 12/03/2019] [Indexed: 12/16/2022] Open
Abstract
Recently, breakthroughs have been made in the use of mesenchymal stem cells (MSCs) to treat various diseases. Several stem cell types have been authorized as drugs by the European Medicines Agency and the U.S. Food and Drug Administration. The Chinese official document “Notification of the management of stem cell clinical research (trial)” was also published in August 2015. Currently, China has approved 106 official stem cell clinical research filing agencies and 62 clinical research projects, which are mostly focused on MSC therapy. Hence, the optimization and development of stem cell drugs is imperative. During this process, maximizing MSC expansion, minimizing cell loss during MSC transplantation, improving the homing rate, precisely regulating the differentiation of MSCs, and reducing MSC senescence and apoptosis are major issues in MSC preclinical research. Similar to artemisinin extracted from the stems and leaves of Artemisia annua, ginsenoside Rg1 (Rg1) is purified from the root or stem of ginseng. In the human body, Rg1 regulates organ function, which is inseparable from its regulation of adult stem cells. Rg1 treatment may effectively regulate the proliferation, differentiation, senescence, and apoptosis of MSCs in different microenvironments in vitro or in vivo. In this review, we discuss recent advances in understanding the effect of Rg1 on MSCs and describe the issues that must be addressed and prospects regarding Rg1 regulation of MSCs in preclinical or clinical studies.
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Affiliation(s)
- Fang He
- Key Laboratory of Cell Engineering of Guizhou Province, The Affiliated Hospital of Zunyi Medical University, Zunyi, China.,Department of Oral and Maxillofacial Surgery, University Hospital of Tübingen, Tübingen, Germany
| | - Changyin Yu
- Department of Neurology, The Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Tao Liu
- Department of Neurology, The Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Huilin Jia
- School of Stomatology, Xi'an Medical University, Xi'an, China
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35
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Kuse Y, Taniguchi H. Present and Future Perspectives of Using Human-Induced Pluripotent Stem Cells and Organoid Against Liver Failure. Cell Transplant 2019; 28:160S-165S. [PMID: 31838891 PMCID: PMC7016460 DOI: 10.1177/0963689719888459] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Organ failure manifests severe symptoms affecting the whole body that may cause death. However, the number of organ donors is not enough for patients requiring transplantation worldwide. Illegal transplantation is also sometimes conducted. To help address this concern, primary hepatocytes are clinically transplanted in the liver. However, donor shortage and host rejection via instant blood-mediated inflammatory reactions are worrisome. Induced pluripotent stem cell-derived hepatocyte-like cells have been developed as an alternative treatment. Recently, organoid technology has been developed to investigate the pathology and mechanism of organoids in cultures. Organoids can be transplanted with vascularization and connected to host blood vessels, and functionally mature better in vivo than in vitro. Hepatic organoids improve pathology in liver disease models. In this review, we introduce induced pluripotent stem cell- and organoid-based therapies against liver diseases considering present and future perspectives.
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Affiliation(s)
- Yoshiki Kuse
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Japan
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Japan.,Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Japan
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36
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Gemery JM, Forauer AR, Hoffer EK. Activation of stem cell up-regulation/mobilization: a cardiovascular risk in both mice and humans with implications for liver disease, psoriasis and SLE. Vasc Health Risk Manag 2019; 15:309-316. [PMID: 31692533 PMCID: PMC6716581 DOI: 10.2147/vhrm.s207161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 06/11/2019] [Indexed: 12/20/2022] Open
Abstract
Experimentally induced injury triggers up-regulation and mobilization of stem cells in Apoe -/- mice that causes accelerated atherosclerosis. Abca1 -/- Abcg1-/- mice have chronic activation of stem cell up-regulation/mobilization and accelerated atherosclerosis. In addition, the Abca1 -/- Abcg1-/- mice have elevation of serum cytokines G-CSF, IL-17 and IL-23, each necessary for stem cell mobilization. IL-17 and IL-23 are elevated in two human illnesses that have cardiovascular (CV) risk independent of traditional risk factors—SLE and psoriasis. Serum G-CSF, which can be elevated in liver disease, predicts major adverse cardiovascular events in humans. These serum cytokine elevations suggest activation of the stem cell mobilization mechanism in humans that results, as in mice, in accelerated atherosclerosis. Efforts to reduce CV disease in these patient populations should include mitigation of the diseases that trigger stem cell mobilization. Since activation of the stem cell up-regulation/mobilization mechanism appears to accelerate human atherosclerosis, use of stem cells as therapy for arterial occlusive disease should distinguish between direct administration of stem cells and activation of the stem cell up-regulation/mobilization mechanism.
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Affiliation(s)
- John M Gemery
- Geisel School of Medicine, Dartmouth, Hanover, NH 03755, USA.,Dartmouth-Hitchcock Medical Center, Department of Radiology, Division of Interventional Radiology, One Medical Center Drive, Lebanon, NH 03756, USA
| | - Andrew R Forauer
- Geisel School of Medicine, Dartmouth, Hanover, NH 03755, USA.,Dartmouth-Hitchcock Medical Center, Department of Radiology, Division of Interventional Radiology, One Medical Center Drive, Lebanon, NH 03756, USA
| | - Eric K Hoffer
- Geisel School of Medicine, Dartmouth, Hanover, NH 03755, USA.,Dartmouth-Hitchcock Medical Center, Department of Radiology, Division of Interventional Radiology, One Medical Center Drive, Lebanon, NH 03756, USA
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37
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Abstract
Engineering approaches were adopted for liver microsystems to recapitulate cell arrangements and culture microenvironments in vivo for sensitive, high-throughput and biomimetic drug screening. This review introduces liver microsystems in vitro for drug hepatotoxicity, drug-drug interactions, metabolic function and enzyme induction, based on cell micropatterning, hydrogel biofabrication and microfluidic perfusion. The engineered microsystems provide varied microenvironments for cell culture that feature cell coculture with non-parenchymal cells, in a heterogeneous extracellular matrix and under controllable perfusion. The engineering methods described include cell micropatterning with soft lithography and dielectrophoresis, hydrogel biofabrication with photolithography, micromolding and 3D bioprinting, and microfluidic perfusion with endothelial-like structures and gradient generators. We discuss the major challenges and trends of liver microsystems to study drug response in vitro.
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Affiliation(s)
- Jyong-Huei Lee
- Department of Mechanical Engineering, National Taiwan University, Taipei, Taiwan
| | - Kuan-Lun Ho
- Department of Mechanical Engineering, National Taiwan University, Taipei, Taiwan
| | - Shih-Kang Fan
- Department of Mechanical and Nuclear Engineering, Kansas State University, Manhattan, KS, 66506, USA.
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38
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Khalil S, Ariel Gru A, Saavedra AP. Cutaneous extramedullary haematopoiesis: Implications in human disease and treatment. Exp Dermatol 2019; 28:1201-1209. [DOI: 10.1111/exd.14013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 06/26/2019] [Accepted: 07/11/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Shadi Khalil
- Department of Dermatology University of Virginia School of Medicine Charlottesville Virginia
| | - Alejandro Ariel Gru
- Department of Pathology University of Virginia School of Medicine Charlottesville Virginia
| | - Arturo P. Saavedra
- Department of Dermatology University of Virginia School of Medicine Charlottesville Virginia
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39
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Abstract
The ability to generate new microvessels in desired numbers and at desired locations has been a long-sought goal in vascular medicine, engineering, and biology. Historically, the need to revascularize ischemic tissues nonsurgically (so-called therapeutic vascularization) served as the main driving force for the development of new methods of vascular growth. More recently, vascularization of engineered tissues and the generation of vascularized microphysiological systems have provided additional targets for these methods, and have required adaptation of therapeutic vascularization to biomaterial scaffolds and to microscale devices. Three complementary strategies have been investigated to engineer microvasculature: angiogenesis (the sprouting of existing vessels), vasculogenesis (the coalescence of adult or progenitor cells into vessels), and microfluidics (the vascularization of scaffolds that possess the open geometry of microvascular networks). Over the past several decades, vascularization techniques have grown tremendously in sophistication, from the crude implantation of arteries into myocardial tunnels by Vineberg in the 1940s, to the current use of micropatterning techniques to control the exact shape and placement of vessels within a scaffold. This review provides a broad historical view of methods to engineer the microvasculature, and offers a common framework for organizing and analyzing the numerous studies in this area of tissue engineering and regenerative medicine. © 2019 American Physiological Society. Compr Physiol 9:1155-1212, 2019.
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Affiliation(s)
- Joe Tien
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA
- Division of Materials Science and Engineering, Boston University, Brookline, Massachusetts, USA
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40
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Wang J, Sun M, Liu W, Li Y, Li M. Stem Cell-Based Therapies for Liver Diseases: An Overview and Update. Tissue Eng Regen Med 2019; 16:107-118. [PMID: 30989038 DOI: 10.1007/s13770-019-00178-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 01/04/2019] [Accepted: 01/08/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver disease is one of the top causes of death globally. Although liver transplantation is a very effective treatment strategy, the shortage of available donor organs, waiting list mortality, and high costs of surgery remain huge problems. Stem cells are undifferentiated cells that can differentiate into a variety of cell types. Scientists are exploring the possibilities of generating hepatocytes from stem cells as an alternative for the treatment of liver diseases. METHODS In this review, we summarized the updated researches in the field of stem cell-based therapies for liver diseases as well as the current challenges and future expectations for a successful cell-based liver therapy. RESULTS Several cell types have been investigated for liver regeneration, such as embryonic stem cells, induced pluripotent stem cells, liver stem cells, mesenchymal stem cells, and hematopoietic stem cells. In vitro and in vivo studies have demonstrated that stem cells are promising cell sources for the liver regeneration. CONCLUSION Stem cell-based therapy could be a promising therapeutic method for patients with end-stage liver disease, which may alleviate the need for liver transplantation in the future.
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Affiliation(s)
- Jie Wang
- 1Department of Neurology, The China-Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun, 130033 Jilin China
| | - Meiyan Sun
- Medical Examination College, Jilin Medical University, No. 5 Jilin Street, Changchun, Jilin, 132013 China
| | - Wei Liu
- Medical Examination College, Jilin Medical University, No. 5 Jilin Street, Changchun, Jilin, 132013 China
| | - Yan Li
- Medical Examination College, Jilin Medical University, No. 5 Jilin Street, Changchun, Jilin, 132013 China
| | - Miao Li
- 3Department of Neurosurgery, The China-Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun, 130033 China
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41
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Myerson D, Parkin RK. Donor-derived hepatocytes in human hematopoietic cell transplant recipients: evidence of fusion. Virchows Arch 2018; 474:365-374. [PMID: 30539318 DOI: 10.1007/s00428-018-2497-8] [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: 07/23/2018] [Revised: 11/13/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Reconstitution of hepatocytes by hematopoietic stem cells-a phenomenon which occurs in rodents under highly selective conditions-results from infrequent fusion between incoming myelomonocytes and host hepatocytes, with subsequent proliferation. Human hematopoietic stem cell transplant recipients have been little studied, with some support for transdifferentiation (direct differentiation). We studied routinely obtained autopsy liver tissue of four female hematopoietic cell transplant recipients with male donors, using a highly specific conjoint immunohistochemistry in situ hybridization light microscopic technique. Hepatocyte nuclei were identified by cytokeratin (Cam5.2) staining and evaluated for X and Y chromosome content. Over 1.6 million hepatocytes were assessed for rare instances of donor origin, revealing a Y chromosome in 67. Mixed tetraploids (XXXY) and their nuclear truncation products (XXY, XY, Y) were directly demonstrated, with no detection of the male tetraploids (XXYY) that may result from transdifferentiation with subsequent tetraploidization, nor their unique truncation products (XYY, YY), implicating fusion as the mechanism. To determine whether it is the sole mechanism, we modeled the chromosome distribution based on the same probability of detection of each X chromosome, deriving parameters of sensitivity and female tetraploidy by best fit. We then hypothesized that the distribution of Y chromosome-containing cells could be predicted by a similar model. After modification to account for "clumpy" Y chromosomes, the observed results were in accord with the predicted results (p = 0.6). These results suggest that all the Y-containing cells, including apparent XY cells, derive from mixed tetraploids, consistent with fusion as the sole mechanism.
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Affiliation(s)
- David Myerson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA, 98109, USA. .,Department of Pathology, University of Washington, Seattle, WA, 98195, USA.
| | - Rachael K Parkin
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA, 98109, USA
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42
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Lee YJ, Yi KW. Bone marrow-derived stem cells contribute to regeneration of the endometrium. Clin Exp Reprod Med 2018; 45:149-153. [PMID: 30538944 PMCID: PMC6277671 DOI: 10.5653/cerm.2018.45.4.149] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 10/24/2018] [Accepted: 11/07/2018] [Indexed: 12/22/2022] Open
Abstract
Stem cells are undifferentiated cells capable of self-renewal and differentiation into various cell lineages. Stem cells are responsible for the development of organs and regeneration of damaged tissues. The highly regenerative nature of the human endometrium during reproductive age suggests that stem cells play a critical role in endometrial physiology. Bone marrow-derived cells migrate to the uterus and participate in the healing and restoration of functionally or structurally damaged endometrium. This review summarizes recent research into the potential therapeutic effects of bone marrow-derived stem cells in conditions involving endometrial impairment.
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Affiliation(s)
- Youn Jeong Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Korea
| | - Kyong Wook Yi
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Korea
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43
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Rackov G, Garcia-Romero N, Esteban-Rubio S, Carrión-Navarro J, Belda-Iniesta C, Ayuso-Sacido A. Vesicle-Mediated Control of Cell Function: The Role of Extracellular Matrix and Microenvironment. Front Physiol 2018; 9:651. [PMID: 29922170 PMCID: PMC5996101 DOI: 10.3389/fphys.2018.00651] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 05/14/2018] [Indexed: 12/20/2022] Open
Abstract
Extracellular vesicles (EVs) — including exosomes, microvesicles and apoptotic bodies — have received much scientific attention last decade as mediators of a newly discovered cell-to-cell communication system, acting at short and long distances. EVs carry biologically active molecules, thus providing signals that influence a spectrum of functions in recipient cells during various physiological and pathological processes. Recent findings point to EVs as very attractive immunomodulatory therapeutic agents, vehicles for drug delivery and diagnostic and prognostic biomarkers in liquid biopsies. In addition, EVs interact with and regulate the synthesis of extracellular matrix (ECM) components, which is crucial for organ development and wound healing, as well as bone and cardiovascular calcification. EVs carrying matrix metalloproteinases (MMPs) are involved in ECM remodeling, thus modifying tumor microenvironment and contributing to premetastatic niche formation and angiogenesis. Here we review the role of EVs in control of cell function, with emphasis on their interaction with ECM and microenvironment in health and disease.
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Affiliation(s)
| | | | - Susana Esteban-Rubio
- Fundación de Investigación HM Hospitales, Madrid, Spain.,Facultad de Medicina (IMMA), Universidad CEU San Pablo, Madrid, Spain
| | | | | | - Angel Ayuso-Sacido
- IMDEA Nanoscience Institute, Madrid, Spain.,Fundación de Investigación HM Hospitales, Madrid, Spain.,Facultad de Medicina (IMMA), Universidad CEU San Pablo, Madrid, Spain
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44
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Simoni M, Taylor HS. Therapeutic strategies involving uterine stem cells in reproductive medicine. Curr Opin Obstet Gynecol 2018; 30:209-216. [PMID: 29652725 DOI: 10.1097/gco.0000000000000457] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW The current review provides an update on recent advances in stem cell biology relevant to female reproduction. RECENT FINDINGS Stem cells are undifferentiated cells that often serve as a reservoir of cells to regenerate tissue in settings or injury or cell loss. The endometrium has progenitor stem cells that can replace all of the endometrium during each menstrual cycle. In addition, multipotent endometrial cells replace these progenitor cells when depleted. Recruitment of stem cells from outside of the uterus occurs in setting of increased demand such as ischemia or injury. Bone marrow-derived multipotent stem cells are recruited to the uterus by estrogen or injury-induced expression of the chemokine CXCL12. In the setting of overwhelming injury, especially in the setting of low estrogen levels, there may be insufficient stem cell recruitment to adequately repair the uterus resulting in conditions such as Asherman syndrome or other endometrial defects. In contrast, excessive recruitment of stem cells underlies endometriosis. Enhanced understanding of stem-cell mobilization, recruitment, and engraftment has created the possibility of improved therapy for endometrial defects and endometriosis through enhanced manipulation of stem-cell trafficking. Further, the normal endometrium is a rich source of multipotent stem cells that can be used for numerous applications in regenerative medicine beyond reproduction. SUMMARY A better understanding of reproductive stem-cell biology may allow improved treatment of endometrial disease such as Asherman syndrome and other endometrial receptivity defects. Inhibiting stem-cell mobilization may also be helpful in endometriosis therapy. Finally, endometrial derived multipotent stem cells may play a crucial role in cell therapy for regenerative medicine.
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Affiliation(s)
- Michael Simoni
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
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45
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Makar T, Nimmagadda VK, Guda PR, Hampton B, Huang W, Kane MA, Fishman PS, Pessac B, Bever CT, Trisler D. A subset of mobilized human hematopoietic stem cells express germ layer lineage genes which can be modulated by culture conditions. Stem Cell Res Ther 2018; 9:127. [PMID: 29720239 PMCID: PMC5930965 DOI: 10.1186/s13287-018-0858-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/20/2018] [Accepted: 04/02/2018] [Indexed: 12/15/2022] Open
Abstract
Background Adult bone marrow contains stem cells that replenish the myeloid and lymphoid lineages. A subset of human and mouse CD34+ bone marrow stem cells can be propagated in culture to autonomously express embryonic stem cell genes and embryonic germ layer lineage genes. The current study was undertaken to determine whether these CD34+ stem cells could be obtained from human blood, whether gene expression could be modulated by culture conditions and whether the cells produce insulin. Methods Human peripheral blood buffy coat cells and mobilized CD34+ cells from human blood and from blood from C57Bl/6 J mice were cultured in hybridoma medium or neural stem cell induction medium supplemented with interleukin (IL)-3, IL-6, and stem cell factor (SCF). Changes in mRNA and protein expression were assessed by Western blot analysis and by immunohistochemistry. Mass spectrometry was used to assess insulin production. Results We were able to culture CD34+ cells expressing embryonic stem cell and embryonic germ layer lineage genes from adult human peripheral blood after standard mobilization procedures and from mouse peripheral blood. Gene expression could be modulated by culture conditions, and the cells produced insulin in culture. Conclusion These results suggest a practical method for obtaining large numbers of CD34+ cells from humans to allow studies on their potential to differentiate into other cell types. Electronic supplementary material The online version of this article (10.1186/s13287-018-0858-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tapas Makar
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.,Multiple Sclerosis Center of Excellence, East VA Maryland Health Care System, Baltimore, MD, 21201, USA.,VA Maryland Health Care System, Baltimore, 21201, USA
| | - Vamshi K Nimmagadda
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.,VA Maryland Health Care System, Baltimore, 21201, USA
| | - Poornachander R Guda
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.,VA Maryland Health Care System, Baltimore, 21201, USA
| | - Brian Hampton
- Protein Analysis Laboratory, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Weiliang Huang
- University of Maryland School of Pharmacy, Department of Pharmaceutical Sciences, Baltimore, MD, 21201, USA.,Mass Spectrometry Center, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA
| | - Maureen A Kane
- University of Maryland School of Pharmacy, Department of Pharmaceutical Sciences, Baltimore, MD, 21201, USA.,Mass Spectrometry Center, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA
| | - Paul S Fishman
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.,VA Maryland Health Care System, Baltimore, 21201, USA
| | - Bernard Pessac
- CNRS UMR 8118, Université Paris Descartes, 45 rue des Saints-Pères, 75006, Paris, France.,Académie Nationale de Médecine, 16 rue Bonaparte, 75006, Paris, France
| | - Christopher T Bever
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. .,Multiple Sclerosis Center of Excellence, East VA Maryland Health Care System, Baltimore, MD, 21201, USA. .,VA Maryland Health Care System, Baltimore, 21201, USA.
| | - David Trisler
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.,Multiple Sclerosis Center of Excellence, East VA Maryland Health Care System, Baltimore, MD, 21201, USA.,VA Maryland Health Care System, Baltimore, 21201, USA
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46
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Pereyra D, Starlinger P. Shaping the future of liver surgery: Implementation of experimental insights into liver regeneration. Eur Surg 2018; 50:132-136. [PMID: 29875802 PMCID: PMC5968067 DOI: 10.1007/s10353-018-0515-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 02/07/2018] [Indexed: 02/07/2023]
Abstract
Background While liver surgery has become a safe and feasible operation technique, the incidence of postoperative liver dysfunction still remains a central problem. Approximately 10% of patients undergoing liver resection were shown to develop liver dysfunction, which is associated with an increased risk of morbidity and mortality. Yet, to date there is no effective treatment option for postoperative liver dysfunction available. The development of postoperative liver dysfunction was linked to a disruption in the liver's potential to regenerate. Thus, it is importance to elucidate the underlying mechanisms of liver regeneration and to find potential therapeutic targets for the treatment of patients with postoperative liver dysfunction. Methods A review of the literature was carried out. Results We report on potential future interventions for improvement of liver regeneration after surgical resection. Moreover, we evaluate the benefits and drawbacks of hepatic progenitor cell therapy and hematopoietic stem cell therapy. However, the most significant improvement seems to come from molecular targets. Indeed, von Willebrand factor and its pharmacologic manipulation are among the most promising therapeutic targets to date. Furthermore, using the example of platelet-based therapy, we stress the potentially adverse effects of treatments for postoperative liver dysfunction. Conclusion The present review reports on the newest advances in the field of regenerative science, but also underlines the need for more research in the field of postoperative liver regeneration, especially in regard to translational studies.
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Affiliation(s)
- D. Pereyra
- Department of Surgery, General Hospital, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
| | - P. Starlinger
- Department of Surgery, General Hospital, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
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Lizier M, Castelli A, Montagna C, Lucchini F, Vezzoni P, Faggioli F. Cell fusion in the liver, revisited. World J Hepatol 2018; 10:213-221. [PMID: 29527257 PMCID: PMC5838440 DOI: 10.4254/wjh.v10.i2.213] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 12/28/2017] [Accepted: 02/06/2018] [Indexed: 02/06/2023] Open
Abstract
There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, muscle and placenta. In other organs, such as the cerebellum, cell fusion is controversial. The liver contains a considerable number of polyploid cells: They are commonly believed to originate by genome endoreplication, although the contribution of cell fusion to polyploidization has not been excluded. Here, we address the topic of cell fusion in the liver from a historical point of view. We discuss experimental evidence clearly supporting the hypothesis that cell fusion occurs in the liver, specifically when bone marrow cells were injected into mice and shown to rescue genetic hepatic degenerative defects. Those experiments-carried out in the latter half of the last century-were initially interpreted to show “transdifferentiation”, but are now believed to demonstrate fusion between donor macrophages and host hepatocytes, raising the possibility that physiologically polyploid cells, such as hepatocytes, could originate, at least partially, through homotypic cell fusion. In support of the homotypic cell fusion hypothesis, we present new data generated using a chimera-based model, a much simpler model than those previously used. Cell fusion as a road to polyploidization in the liver has not been extensively investigated, and its contribution to a variety of conditions, such as viral infections, carcinogenesis and aging, remains unclear.
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Affiliation(s)
- Michela Lizier
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
| | - Alessandra Castelli
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
| | - Cristina Montagna
- Department of Genetics and Pathology Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, United States
| | - Franco Lucchini
- Centro Ricerche Biotecnologiche, Università Cattolica del Sacro Cuore, Cremona 26100, Italy
| | - Paolo Vezzoni
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
| | - Francesca Faggioli
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
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48
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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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Babaei A, Katoonizadeh A, Ranjbar A, Naderi M, Ahmadbeigi N. Directly injected native bone-marrow stem cells cannot incorporate into acetaminophen-induced liver injury. Biologicals 2018; 52:55-58. [PMID: 29317122 DOI: 10.1016/j.biologicals.2017.12.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Revised: 12/26/2017] [Accepted: 12/29/2017] [Indexed: 01/09/2023] Open
Abstract
The paucity of liver donation highlights the use of cell-based strategies for end-stage liver failure. We recently showed that bone marrow-derived aggregates (BMDAs) can completely restore the hematopoietic system in gamma-irradiated mice. These aggregates are stem and progenitor cells in the bone marrow (BM), composed of both hematopoietic and non-hematopoietic lineages. Furthermore, reports showed that resident BM cells migrate to the liver and integrate themselves into the tissue in small numbers. Hence, we hypothesized that direct delivery of BMDAs to the damaged liver might enhance the integration of BM cells in the liver because of its stemness property, intact BM architecture, the physical proximity of these niche-like structures to the damaged sites and the existence of liver paracrine factors. To this aim, we made an acute liver model by intraperitoneal injection of acetaminophen. Then, GFP-expressing BMDAs were intrahepatically injected. Despite the detection of GFP-expressing cells five days after intrahepatic injection, these cells were not detectable at days 15 and 60, indicating that the puzzle of BM cell integration in the liver still has more missing pieces other than stemness, physical proximity, and paracrine factors. Actually, it seems that even intact BM structures need further signals to be qualified for integration.
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Affiliation(s)
- Azadeh Babaei
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azam Katoonizadeh
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azam Ranjbar
- SABZ Biomedicals Science-based Company, Tehran, Iran
| | - Mahmood Naderi
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Naser Ahmadbeigi
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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50
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Current Cell-Based Therapies in the Chronic Liver Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1103:243-253. [PMID: 30484233 DOI: 10.1007/978-4-431-56847-6_13] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Liver diseases account for one of the leading causes of deaths in global health care. Furthermore, chronic liver failure such as liver cirrhosis is, namely, responsible for these fatal conditions. However, only liver transplantation is an established treatment for this end-stage condition, although the availability of this salvage treatment option is quite limited. Thus, the novel therapy such as artificial liver devices or cellular administration has been regarded as feasible. Especially cellular therapies have been proposed in decades. The technical advancement and progress of understanding of cellular differentiation have contributed to the development of basis of cellular therapy. This attractive therapeutic option has been advanced from original embryonic stem cells to more effective cellular fractions such as Muse cells. Indeed several cellular therapies including bone marrow-derived stem cells or peripheral blood-derived stem cells were initiated; the recent most organized clinical trials could not demonstrate its efficacy. Thus, truly innovative cellular therapy is needed to meet the scientific demands, and Muse cell administration is the remaining approach to this. In this article, we will discuss the current development and status of cellular therapy toward chronic liver failure.
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