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Zhang WH, Xiang WY, Yi L, Fang R. The status and hotspot analysis of research on extracellular vesicles and osteoarthritis: a bibliometric analysis. Front Pharmacol 2025; 16:1484437. [PMID: 40230694 PMCID: PMC11994722 DOI: 10.3389/fphar.2025.1484437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 03/19/2025] [Indexed: 04/16/2025] Open
Abstract
Background Degenerative joint disease, known as osteoarthritis (OA), is characterized by pain, swelling, and decreased mobility. The illness has a major negative influence on patients' quality of life and is common around the world, especially among older people. Nevertheless, there are insufficient possibilities for early diagnosis and therapy. Extracellular vesicles, or EVs, control the immune response, tissue healing, and cellular communication. Methods This work offers a bibliometric representation of the areas of focus and correlations between extracellular vesicles and osteoarthritis. We searched for osteoarthritis and extracellular vesicles in publications in the Web of Science Core Collection (WoSCC) database. Bibliometrics, an R package, CiteSpace 6.1. R2, and VOSviewer 1.6.17 were used to perform bibliometric analyses of concentration fields, trends, and relevant factors. Results 944 papers from 59 nations were published; the countries that contributed the most to the field were China, the USA, and Italy. Professors Laura and Enrico are the top contributors. Sichuan University, Istituto Ortopedico Galeazzi, and Shanghai Jiao Tong University are the top three universities. The International Journal of Molecular Sciences is an excellent publication. Exosome, expression, knee osteoarthritis, extracellular vesicle, mesenchymal stem cell, osteoarthritis, and inflammation are the most often occurring keywords. Conclusion These results suggest areas of interest and focus for future research on EVs and OA. This trend suggests that the volume of literature on OA and EVs will continue to rise, with more research being published in the future. This study helps scholars understand current research hotspots in the field and may inspire future research.
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Affiliation(s)
- Wen Hao Zhang
- The Fourth Clinical College of Xinjiang Medical University, Urumqi, China
| | - Wen Yuan Xiang
- The Fourth Clinical College of Xinjiang Medical University, Urumqi, China
- Department of Orthopaedic, Institute of Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Department of Orthopaedic, Xinjiang Uygur Autonomous Region Institute of Traditional Chinese Medicine, Urumqi, China
- Department of orthopaedic, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Lin Yi
- The Fourth Clinical College of Xinjiang Medical University, Urumqi, China
- Department of Orthopaedic, Institute of Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Department of Orthopaedic, Xinjiang Uygur Autonomous Region Institute of Traditional Chinese Medicine, Urumqi, China
- Department of orthopaedic, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Rui Fang
- The Fourth Clinical College of Xinjiang Medical University, Urumqi, China
- Department of Orthopaedic, Institute of Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Department of Orthopaedic, Xinjiang Uygur Autonomous Region Institute of Traditional Chinese Medicine, Urumqi, China
- Department of orthopaedic, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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Sorrentino FS, Di Terlizzi P, De Rosa F, Salati C, Spadea L, Gagliano C, Musa M, Zeppieri M. New frontiers in retinal transplantation. World J Transplant 2024; 14:97690. [PMID: 39697450 PMCID: PMC11438945 DOI: 10.5500/wjt.v14.i4.97690] [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: 06/05/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 09/20/2024] Open
Abstract
New frontiers about retinal cell transplantation for retinal degenerative diseases start from the idea that acting on stem cells can help regenerate retinal layers and establish new synapses among retinal cells. Deficiency or alterations of synaptic input and neurotrophic factors result in trans-neuronal degeneration of the inner retinal cells. Thus, the disruption of photoreceptors takes place. However, even in advanced forms of retinal degeneration, a good percentage of the ganglion cells and the inner nuclear layer neurons remain intact. This phenomenon provides evidence for obtaining retinal circuitry through the transplantation of photoreceptors into the subretinal region. The eye is regarded as an optimal organ for cell transplantation because of its immunological privilege and the relatively small number of cells collaborating to carry out visual activities. The eyeball's immunological privilege, characterized by the suppression of delayed-type hypersensitivity responses in ocular tissues, is responsible for the low rate of graft rejection in transplant patients. The main discoveries highlight the capacity of embryonic stem cells (ESCs) and induced pluripotent stem cells to regenerate damaged retinal regions. Recent progress has shown significant enhancements in transplant procedures and results. The research also explores the ethical ramifications linked to the utilization of stem cells, emphasizing the ongoing issue surrounding ESCs. The analysis centers on recent breakthroughs, including the fabrication of three-dimensional retinal organoids and the innovation of scaffolding for cell transportation. Moreover, researchers are currently assessing the possibility of CRISPR and other advanced gene editing technologies to enhance the outcomes of retinal transplantation. The widespread use of universally recognized safe surgical and imaging methods enables retinal transplantation and monitoring of transplanted cell growth toward the correct location. Currently, most therapy approaches are in the first phases of development and necessitate further research, including both pre-clinical and clinical trials, to attain favorable visual results for individuals suffering from retinal degenerative illnesses.
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Affiliation(s)
| | - Patrick Di Terlizzi
- Department of Surgical Sciences, Unit of Ophthalmology, Ospedale Maggiore, Bologna 40100, Italy
| | - Francesco De Rosa
- Department of Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”, Meldola 47014, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, "Sapienza" University of Rome, Rome 00142, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna "Kore", Enna 94100, Italy
- Eye Clinic, Catania University San Marco Hospital, Catania 95121, Italy
| | - Mutali Musa
- Department of Optometry, University of Benin, Benin 300283, Nigeria
- Department of Ophthalmology, Centre for Sight Africa, Nkpor, Onitsha 434112, Nigeria
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
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3
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Andrews PW. Germ cell tumors, cell surface markers, and the early search for human pluripotent stem cells. Bioessays 2024; 46:e2400094. [PMID: 39115324 PMCID: PMC11589668 DOI: 10.1002/bies.202400094] [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: 04/17/2024] [Revised: 07/27/2024] [Accepted: 07/31/2024] [Indexed: 11/27/2024]
Abstract
Many strands of research by different groups, starting from teratocarcinomas in the laboratory mouse, later moving the corresponding human tumors, contributed to the isolation and description of human pluripotent stem cells (PSCs). In this review, I highlight the contributions from my own research, particularly at the Wistar Institute during the 1980s, when with my colleagues we characterized one of the first clonal lines of pluripotent human embryonal carcinoma (EC) cells, the stem cells of teratocarcinomas, and identified key features including cell surface antigen markers that have since found a place in the study and exploitation of human PSC. Much of this research depended upon close teamwork with colleagues, many in other laboratories, who contributed different expertise and experience. It was also often driven by circumstance and chance rather than pursuit of a grand design.
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Affiliation(s)
- Peter W. Andrews
- The Centre for Stem Cell BiologyThe School of BiosciencesThe University of SheffieldWestern BankSheffieldUK
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4
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Yasuda S, Bando K, Henry MP, Libertini S, Watanabe T, Bando H, Chen C, Fujimori K, Harada K, Kuroda T, Lemmens M, Marginean D, Moss D, Pereira Mouriès L, Nicholas NS, Smart MJK, Terai O, Sato Y. Detection of residual pluripotent stem cells in cell therapy products utilizing droplet digital PCR: an international multisite evaluation study. Stem Cells Transl Med 2024; 13:1001-1014. [PMID: 39120125 PMCID: PMC11465167 DOI: 10.1093/stcltm/szae058] [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: 02/28/2024] [Accepted: 06/08/2024] [Indexed: 08/10/2024] Open
Abstract
The presence of residual undifferentiated pluripotent stem cells (PSCs) in PSC-derived cell therapy products (CTPs) is a major safety issue for their clinical application, due to the potential risk of PSC-derived tumor formation. An international multidisciplinary multisite study to evaluate a droplet digital PCR (ddPCR) approach to detect residual undifferentiated PSCs in PSC-derived CTPs was conducted as part of the Health and Environmental Sciences Institute Cell Therapy-TRAcking, Circulation & Safety Technical Committee. To evaluate the use of ddPCR in quantifying residual iPSCs in a cell sample, different quantities of induced pluripotent stem cells (iPSCs) were spiked into a background of iPSC-derived cardiomyocytes (CMs) to mimic different concentrations of residual iPSCs. A one step reverse transcription ddPCR (RT-ddPCR) was performed to measure mRNA levels of several iPSC-specific markers and to evaluate the assay performance (precision, sensitivity, and specificity) between and within laboratories. The RT-ddPCR assay variability was initially assessed by measuring the same RNA samples across all participating facilities. Subsequently, each facility independently conducted the entire process, incorporating the spiking step, to discern the parameters influencing potential variability. Our results show that a RT-ddPCR assay targeting ESRG, LINC00678, and LIN28A genes offers a highly sensitive and robust detection of impurities of iPSC-derived CMs and that the main contribution to variability between laboratories is the iPSC-spiking procedure, and not the RT-ddPCR. The RT-ddPCR assay would be generally applicable for tumorigenicity evaluation of PSC-derived CTPs with appropriate marker genes suitable for each CTP.
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Affiliation(s)
- Satoshi Yasuda
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kawasaki, Japan
| | | | | | | | | | | | - Connie Chen
- Health and Environmental Sciences Institute, Washington, DC, United States
| | | | - Kosuke Harada
- Takeda Pharmaceutical Company Limited, Fujisawa, Japan
| | - Takuya Kuroda
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kawasaki, Japan
| | | | | | - David Moss
- Cell and Gene Therapy Catapult, London, United Kingdom
| | | | | | | | | | - Yoji Sato
- Division of Drugs, National Institute of Health Sciences, Kawasaki, Japan
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Hallenberger TJ, von Seth E, Roethlisberger M, Guzman R, Soleman J. Pituitary germinoma after resection of a mature third ventricular teratoma: illustrative case. JOURNAL OF NEUROSURGERY. CASE LESSONS 2024; 8:CASE2443. [PMID: 38976916 DOI: 10.3171/case2443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 03/28/2024] [Indexed: 07/10/2024]
Abstract
BACKGROUND Metachronous intracranial germ cell tumors (iGCTs)-unrelated, histologically different iGCTs occurring at different time points-occurring within the same patient remain a rarity. Herein, the authors report such a case and discuss the literature and potential pathophysiological mechanisms leading to this phenomenon. OBSERVATIONS A 9-year-old boy presented with new-onset impaired balance, headaches, nausea, visual disturbances, and left facial paresis. Magnetic resonance imaging (MRI) scans revealed a suspected pineal region teratoma originating from the pineal gland with consecutive obstructive hydrocephalus. A mature teratoma was diagnosed and resected. Postoperative recovery was good, and the patient could return to his normal daily activities. However, a new, slowly progressive lesion in the sellar region with an enlarged infundibular stalk was detected on follow-up MRI 3.5 years after initial pineal region teratoma resection. Biopsy revealed a newly developed pure germinoma. The patient was treated with radiotherapy plus chemotherapy and remained relapse free at the last follow-up. Sixteen other cases have reported a surgically resected primary mature teratoma, wherein patients developed metachronous germinomas during follow-up. Different theories try to elaborate this phenomenon, yet none can completely account for it. LESSONS Although rare, metachronous iGCT is a phenomenon neurosurgeons should be aware of. In patients treated for iGCT, close long-term clinical, imaging, and laboratory follow-up is recommended. https://thejns.org/doi/10.3171/CASE2443.
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Affiliation(s)
- Tim J Hallenberger
- Department of Neurosurgery, University Hospital Basel, Basel, Switzerland
- Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Emma von Seth
- Division of Pediatric Neurosurgery, Children's University Hospital Basel, Basel, Switzerland
- School of Neuroscience, King's College London, London, United Kingdom
| | - Michel Roethlisberger
- Department of Neurosurgery, University Hospital Basel, Basel, Switzerland
- Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Raphael Guzman
- Department of Neurosurgery, University Hospital Basel, Basel, Switzerland
- Division of Pediatric Neurosurgery, Children's University Hospital Basel, Basel, Switzerland
- Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Jehuda Soleman
- Department of Neurosurgery, University Hospital Basel, Basel, Switzerland
- Division of Pediatric Neurosurgery, Children's University Hospital Basel, Basel, Switzerland
- Faculty of Medicine, University of Basel, Basel, Switzerland
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Andrews PW. The origins of human pluripotent stem cells: the road from a cancer to regenerative medicine. In Vitro Cell Dev Biol Anim 2024; 60:514-520. [PMID: 38396072 PMCID: PMC11126438 DOI: 10.1007/s11626-024-00865-8] [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: 01/15/2024] [Accepted: 01/31/2024] [Indexed: 02/25/2024]
Abstract
The notion of using pluripotent stem cells (PSCs) as a source of differentiated cell types for replacement of disease or damaged tissues in regenerative medicine is now an active area of research, with approaches to treating eye diseases such as age-related macular degeneration or Parkinson's disease now on the horizon. But the foundations for this research lie in a quite different area of science, namely the role of genetics of cancer. In this review, we trace the evolution of ideas starting with the discovery that strain 129 mice are particularly subject to develop germ cell tumors, through the identification of embryonal carcinoma (EC) cells as the stem cells of the teratocarcinoma manifestation of these tumors, to the recognition of their relationship to pluripotent cells of the early embryo, and eventually their role in the derivation of embryonic stem cells, first from mouse embryos and then from primates including humans. This is a story that illustrates how science commonly develops through the interests and insights of individual investigators, often with unexpected and unintended outcomes.
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Affiliation(s)
- Peter W Andrews
- The Centre for Stem Cell Biology, The School of Biosciences, The University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
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7
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Hartley A, Burger L, Wincek CL, Dons L, Li T, Grewenig A, Taşgın T, Urban M, Roig-Merino A, Ghazvini M, Harbottle RP. A Simple Nonviral Method to Generate Human Induced Pluripotent Stem Cells Using SMAR DNA Vectors. Genes (Basel) 2024; 15:575. [PMID: 38790204 PMCID: PMC11121542 DOI: 10.3390/genes15050575] [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: 03/12/2024] [Revised: 04/21/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Induced pluripotent stem cells (iPSCs) are a powerful tool for biomedical research, but their production presents challenges and safety concerns. Yamanaka and Takahashi revolutionised the field by demonstrating that somatic cells could be reprogrammed into pluripotent cells by overexpressing four key factors for a sufficient time. iPSCs are typically generated using viruses or virus-based methods, which have drawbacks such as vector persistence, risk of insertional mutagenesis, and oncogenesis. The application of less harmful nonviral vectors is limited as conventional plasmids cannot deliver the levels or duration of the factors necessary from a single transfection. Hence, plasmids that are most often used for reprogramming employ the potentially oncogenic Epstein-Barr nuclear antigen 1 (EBNA-1) system to ensure adequate levels and persistence of expression. In this study, we explored the use of nonviral SMAR DNA vectors to reprogram human fibroblasts into iPSCs. We show for the first time that iPSCs can be generated using nonviral plasmids without the use of EBNA-1 and that these DNA vectors can provide sufficient expression to induce pluripotency. We describe an optimised reprogramming protocol using these vectors that can produce high-quality iPSCs with comparable pluripotency and cellular function to those generated with viruses or EBNA-1 vectors.
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Affiliation(s)
- Anna Hartley
- DNA Vector Laboratory, German Cancer Research Center, 69120 Heidelberg, Germany; (A.H.); (A.G.); (A.R.-M.)
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Luisa Burger
- DNA Vector Laboratory, German Cancer Research Center, 69120 Heidelberg, Germany; (A.H.); (A.G.); (A.R.-M.)
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Cornelia L. Wincek
- DNA Vector Laboratory, German Cancer Research Center, 69120 Heidelberg, Germany; (A.H.); (A.G.); (A.R.-M.)
| | - Lieke Dons
- Erasmus MC iPS Core Facility, Erasmus Medical Centre, 3015 GD Rotterdam, The Netherlands (M.G.)
| | - Tracy Li
- Erasmus MC iPS Core Facility, Erasmus Medical Centre, 3015 GD Rotterdam, The Netherlands (M.G.)
| | - Annabel Grewenig
- DNA Vector Laboratory, German Cancer Research Center, 69120 Heidelberg, Germany; (A.H.); (A.G.); (A.R.-M.)
| | - Toros Taşgın
- DNA Vector Laboratory, German Cancer Research Center, 69120 Heidelberg, Germany; (A.H.); (A.G.); (A.R.-M.)
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Manuela Urban
- DNA Vector Laboratory, German Cancer Research Center, 69120 Heidelberg, Germany; (A.H.); (A.G.); (A.R.-M.)
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Alicia Roig-Merino
- DNA Vector Laboratory, German Cancer Research Center, 69120 Heidelberg, Germany; (A.H.); (A.G.); (A.R.-M.)
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Mehrnaz Ghazvini
- Erasmus MC iPS Core Facility, Erasmus Medical Centre, 3015 GD Rotterdam, The Netherlands (M.G.)
| | - Richard P. Harbottle
- DNA Vector Laboratory, German Cancer Research Center, 69120 Heidelberg, Germany; (A.H.); (A.G.); (A.R.-M.)
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Kim J, Kim J, Kim D, Bello AB, Kim BJ, Cha B, Lee S. Therapeutic potential of mesenchymal stem cells from human iPSC-derived teratomas for osteochondral defect regeneration. Bioeng Transl Med 2024; 9:e10629. [PMID: 38435815 PMCID: PMC10905541 DOI: 10.1002/btm2.10629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 11/08/2023] [Accepted: 11/14/2023] [Indexed: 03/05/2024] Open
Abstract
Human induced pluripotent stem cells (iPSCs) hold great promise for personalized medicine, as they can be differentiated into specific cell types, especially mesenchymal stem cells (MSCs). Therefore, our study sought to assess the feasibility of deriving MSCs from teratomas generated from human iPSCs. Teratomas serve as a model to mimic multilineage human development, thus enriching specific somatic progenitors and stem cells. Here, we discovered a small, condensed mass of MSCs within iPSC-generated teratomas. Afterward, we successfully isolated MSCs from this condensed mass, which was a byproduct of teratoma development. To evaluate the characteristics and cell behaviors of iPSC-derived MSCs (iPSC-MSCs), we conducted comprehensive assessments using qPCR, immunophenotype analysis, and cell proliferation-related assays. Remarkably, iPSC-MSCs exhibited an immunophenotype resembling that of conventional MSCs, and they displayed robust proliferative capabilities, similar to those of higher pluripotent stem cell-derived MSCs. Furthermore, iPSC-MSCs demonstrated the ability to differentiate into multiple lineages in vitro. Finally, we evaluated the therapeutic potential of iPSC-MSCs using an osteochondral defect model. Our findings demonstrated that teratomas are a promising source for the isolation of condensed MSCs. More importantly, our results suggest that iPSC-MSCs derived from teratomas possess the capacity for tissue regeneration, highlighting their promise for future therapeutic applications.
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Affiliation(s)
- Jiseong Kim
- Department of Biomedical TechnologyDongguk UniversityGoyang‐siRepublic of Korea
| | - Jin‐Su Kim
- Department of Biomedical ScienceCHA UniversitySeongnam‐siRepublic of Korea
- Biomaterials Research CenterCELLINBIO Co., Ltd.Suwon‐siGyeonggi‐doRepublic of Korea
| | - Dohyun Kim
- Department of Biomedical TechnologyDongguk UniversityGoyang‐siRepublic of Korea
| | - Alvin Bacero Bello
- Department of Biomedical TechnologyDongguk UniversityGoyang‐siRepublic of Korea
- Department of Integrative EngineeringChung‐Ang UniversitySeoulRepublic of Korea
| | - Byoung Ju Kim
- Department of Rearch & Development teamATEMsSeoulRepublic of Korea
| | - Byung‐Hyun Cha
- Division of Biomedical ConvergenceCollege of Biomedical Science, Kangwon National UniversityChuncheon‐siRepublic of Korea
| | - Soo‐Hong Lee
- Department of Biomedical TechnologyDongguk UniversityGoyang‐siRepublic of Korea
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Andrews PW, Gokhale PJ. A short history of pluripotent stem cells markers. Stem Cell Reports 2024; 19:1-10. [PMID: 38157849 PMCID: PMC10828816 DOI: 10.1016/j.stemcr.2023.11.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 01/03/2024] Open
Abstract
The expression of one or more of a small number of molecules, typically cell surface-associated antigens, or transcription factors, is widely used for identifying pluripotent stem cells (PSCs) or for monitoring their differentiation. However, none of these marker molecules are uniquely expressed by PSCs and all are expressed by stem cells that have lost the ability to differentiate. Consequently, none are indicators of pluripotency, per se. Here we summarize the nature and characteristics of several markers that are in wide use, including the cell surface antigens, stage-specific embryonic antigen (SSEA)-1, SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, GCTM2, and the transcription factors POUF5/OCT4, NANOG, and SOX2, highlighting issues that must be considered when interpreting data about their expression on putative PSCs.
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Affiliation(s)
- Peter W Andrews
- The School of Biosciences, The University of Sheffield, Western Bank, Sheffield S10 2TN, UK
| | - Paul J Gokhale
- The School of Biosciences, The University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
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10
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Bangari DS, Lanigan LG, Cramer SD, Grieves JL, Meisner R, Rogers AB, Galbreath EJ, Bolon B. Toxicologic Neuropathology of Novel Biotherapeutics. Toxicol Pathol 2023; 51:414-431. [PMID: 38380881 DOI: 10.1177/01926233241230542] [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] [Indexed: 02/22/2024]
Abstract
Biotherapeutic modalities such as cell therapies, gene therapies, nucleic acids, and proteins are increasingly investigated as disease-modifying treatments for severe and life-threatening neurodegenerative disorders. Such diverse bio-derived test articles are fraught with unique and often unpredictable biological consequences, while guidance regarding nonclinical experimental design, neuropathology evaluation, and interpretation is often limited. This paper summarizes key messages offered during a half-day continuing education course on toxicologic neuropathology of neuro-targeted biotherapeutics. Topics included fundamental neurobiology concepts, pharmacology, frequent toxicological findings, and their interpretation including adversity decisions. Covered biotherapeutic classes included cell therapies, gene editing and gene therapy vectors, nucleic acids, and proteins. If agents are administered directly into the central nervous system, initial screening using hematoxylin and eosin (H&E)-stained sections of currently recommended neural organs (brain [7 levels], spinal cord [3 levels], and sciatic nerve) may need to expand to include other components (e.g., more brain levels, ganglia, and/or additional nerves) and/or special neurohistological procedures to characterize possible neural effects (e.g., cell type-specific markers for reactive glial cells). Scientists who evaluate the safety of novel biologics will find this paper to be a practical reference for preclinical safety testing and risk assessment.
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Affiliation(s)
| | | | | | | | - René Meisner
- Denali Therapeutics, South San Francisco, California, USA
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11
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Teratoma Assay for Testing Pluripotency and Malignancy of Stem Cells: Insufficient Reporting and Uptake of Animal-Free Methods-A Systematic Review. Int J Mol Sci 2023; 24:ijms24043879. [PMID: 36835305 PMCID: PMC9967860 DOI: 10.3390/ijms24043879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/28/2023] [Accepted: 02/06/2023] [Indexed: 02/17/2023] Open
Abstract
Pluripotency describes the ability of stem cells to differentiate into derivatives of the three germ layers. In reporting new human pluripotent stem cell lines, their clonal derivatives or the safety of differentiated derivatives for transplantation, assessment of pluripotency is essential. Historically, the ability to form teratomas in vivo containing different somatic cell types following injection into immunodeficient mice has been regarded as functional evidence of pluripotency. In addition, the teratomas formed can be analyzed for the presence of malignant cells. However, use of this assay has been subject to scrutiny for ethical reasons on animal use and due to the lack of standardization in how it is used, therefore questioning its accuracy. In vitro alternatives for assessing pluripotency have been developed such as ScoreCard and PluriTest. However, it is unknown whether this has resulted in reduced use of the teratoma assay. Here, we systematically reviewed how the teratoma assay was reported in publications between 1998 (when the first human embryonic stem cell line was described) and 2021. Our analysis of >400 publications showed that in contrast to expectations, reporting of the teratoma assay has not improved: methods are not yet standardized, and malignancy was examined in only a relatively small percentage of assays. In addition, its use has not decreased since the implementation of the ARRIVE guidelines on reduction of animal use (2010) or the introduction of ScoreCard (2015) and PluriTest (2011). The teratoma assay is still the preferred method to assess the presence of undifferentiated cells in a differentiated cell product for transplantation since the in vitro assays alone are not generally accepted by the regulatory authorities for safety assessment. This highlights the remaining need for an in vitro assay to test malignancy of stem cells.
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12
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Burnham EL, Tomita T. Histogenesis of intracranial germ cell tumors: primordial germ cell vs. embryonic stem cell. Childs Nerv Syst 2023; 39:359-368. [PMID: 36595083 DOI: 10.1007/s00381-022-05808-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2023]
Abstract
INTRODUCTION Intracranial germ cell tumor (iGCT) is a rare disorder and often occurs during childhood and adolescence. iGCTs are frequently localized in pineal region and hypothalamic-neurohypophyseal axis (HNA). In spite of well-established clinical and pathological entity, histogenesis of iGCTs remains unsettled. Current theories of histogenesis of iGCTs include germ cell theory (from primordial germ cells (PGCs) of aberrant migration) and stem cell theory (transformed embryonic stem (ES) cells). In order to comprehend the histogenesis, we revisit the origin, migration, and fate of the human PGCs, and their transformation processes to iGCT. DISCUSSION In "germ cell theory," transformation of ectopic PGCs to iGCT is complex and involves multiple transcription factors. Germinoma is derived from ectopic PGCs and is considered a prototype of all GCTs. Non-germinomatous germ cell tumors (NGGCTs) develop from more differentiated counterparts of embryonic and extra-embryonic tissues. However, there is a distinct genomic/epigenomic landscape between germinoma and NGGCT. ES cells transformed from ectopic PGCs through molecular dysregulation or de-differentiation may become the source of iGCT. "Stem cell theory" is transformation of endogenous ES cells or primitive neural stem cell to iGCTs. It supports histological diversity of NGGCTs because of ES cell's pluripotency. However, neural stem cells are abundantly present along the subependymal zone; therefore, it does not explain why iGCTs almost exclusively occur in pineal and HNA locations. Also, the vast difference of methylation status between germinoma and NGGCT makes it difficult to theorize all iGCTs derive from the common cellular linage. CONCLUSION Transformation of PGCs to ES cells is the most logical mechanism for histogenesis of iGCT. However, its detail remains an enigma and needs further investigations.
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Affiliation(s)
- Emma L Burnham
- Division of Pediatric Neurosurgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Tadanori Tomita
- Division of Pediatric Neurosurgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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13
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Yang B, Li X, Fu C, Cai W, Meng B, Qu Y, Kou X, Zhang Q. Extracellular vesicles in osteoarthritis of peripheral joint and temporomandibular joint. Front Endocrinol (Lausanne) 2023; 14:1158744. [PMID: 36950682 PMCID: PMC10025484 DOI: 10.3389/fendo.2023.1158744] [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] [Received: 02/04/2023] [Accepted: 02/21/2023] [Indexed: 03/08/2023] Open
Abstract
Osteoarthritis (OA) is a disabling disease with significant morbidity worldwide. OA attacks the large synovial joint, including the peripheral joints and temporomandibular joint (TMJ). As a representative of peripheral joint OA, knee OA shares similar symptoms with TMJ OA. However, these two joints also display differences based on their distinct development, anatomy, and physiology. Extracellular vesicles (EVs) are phospholipid bilayer nanoparticles, including exosomes, microvesicles, and apoptotic bodies. EVs contain proteins, lipids, DNA, micro-RNA, and mRNA that regulate tissue homeostasis and cell-to-cell communication, which play an essential role in the progression and treatment of OA. They are likely to partake in mechanical response, extracellular matrix degradation, and inflammatory regulation during OA. More evidence has shown that synovial fluid and synovium-derived EVs may serve as OA biomarkers. More importantly, mesenchymal stem cell-derived EV shows a therapeutic effect on OA. However, the different function of EVs in these two joints is largely unknown based on their distinct biological characteristic. Here, we reviewed the effects of EVs in OA progression and compared the difference between the knee joint and TMJ, and summarized their potential therapeutic role in the treatment of OA.
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Affiliation(s)
- Benyi Yang
- Guangdong Provincial Key Laboratory of Stomatology Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
| | - Xin Li
- Department of Temporomandibular Joint, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou, China
| | - Chaoran Fu
- Guangdong Provincial Key Laboratory of Stomatology Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
| | - Wenyi Cai
- Department of Temporomandibular Joint, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou, China
| | - Bowen Meng
- Guangdong Provincial Key Laboratory of Stomatology Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
| | - Yan Qu
- Guangdong Provincial Key Laboratory of Stomatology Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
| | - Xiaoxing Kou
- Guangdong Provincial Key Laboratory of Stomatology Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
- *Correspondence: Qingbin Zhang, ; Xiaoxing Kou,
| | - Qingbin Zhang
- Department of Temporomandibular Joint, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou, China
- *Correspondence: Qingbin Zhang, ; Xiaoxing Kou,
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14
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Breakthrough of extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis. Bioact Mater 2022; 22:423-452. [PMID: 36311050 PMCID: PMC9588998 DOI: 10.1016/j.bioactmat.2022.10.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/06/2022] [Accepted: 10/10/2022] [Indexed: 11/16/2022] Open
Abstract
Osteoarthritis (OA) is a highly prevalent whole-joint disease that causes disability and pain and affects a patient's quality of life. However, currently, there is a lack of effective early diagnosis and treatment. Although stem cells can promote cartilage repair and treat OA, problems such as immune rejection and tumorigenicity persist. Extracellular vesicles (EVs) can transmit genetic information from donor cells and mediate intercellular communication, which is considered a functional paracrine factor of stem cells. Increasing evidences suggest that EVs may play an essential and complex role in the pathogenesis, diagnosis, and treatment of OA. Here, we introduced the role of EVs in OA progression by influencing inflammation, metabolism, and aging. Next, we discussed EVs from the blood, synovial fluid, and joint-related cells for diagnosis. Moreover, we outlined the potential of modified and unmodified EVs and their combination with biomaterials for OA therapy. Finally, we discuss the deficiencies and put forward the prospects and challenges related to the application of EVs in the field of OA.
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15
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Lezmi E, Benvenisty N. The Tumorigenic Potential of Human Pluripotent Stem Cells. Stem Cells Transl Med 2022; 11:791-796. [PMID: 35679163 PMCID: PMC9397652 DOI: 10.1093/stcltm/szac039] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/24/2022] [Indexed: 11/23/2022] Open
Abstract
Human pluripotent stem cells (hPSCs) are currently evaluated for clinical applications due to their proliferation and differentiation capacities, raising the need to both assess and enhance, the safety of hPSC-based treatments. Distinct molecular features contribute to the tumorigenicity of hPSCs, manifested in the formation of teratoma tumors upon transplantation in vivo. Prolonged in vitro culturing of hPSCs can enhance selection for specific genetic aberrations, either at the chromosome or gene level. Some of these aberrations are tightly linked to human tumor pathology and increase the tumorigenic aggressiveness of the abnormal cells. In this perspective, we describe major tumor-associated risk factors entailed in hPSC-based therapy, and present precautionary and safety measures relevant for the development and application of such therapies.
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Affiliation(s)
- Elyad Lezmi
- The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel
| | - Nissim Benvenisty
- The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel
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16
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Andrews PW. Human pluripotent stem cells: tools for regenerative medicine. BIOMATERIALS TRANSLATIONAL 2021; 2:294-300. [PMID: 35837419 PMCID: PMC9255800 DOI: 10.12336/biomatertransl.2021.04.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/12/2021] [Accepted: 12/20/2021] [Indexed: 01/17/2023]
Abstract
Human embryonic stem cells and induced pluripotent stem cells, together denoted as pluripotent stem cells have opened up unprecedented opportunities for developments in human healthcare over the past 20 years. Although much about the properties and behaviour of these cells required to underpin their applications has been discovered over this time, a number of issues remain. This brief review considers the history of these developments and some of the underlying biology, pointing out some of the problems still to be resolved, particularly in relation to their genetic stability and possible malignancy.
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Affiliation(s)
- Peter W. Andrews
- The Centre for Stem Cell Biology, The School of Bioscience, The University of Sheffield, Sheffield, UK
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17
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Jiang B, Li W, Stewart S, Ou W, Liu B, Comizzoli P, He X. Sand-mediated ice seeding enables serum-free low-cryoprotectant cryopreservation of human induced pluripotent stem cells. Bioact Mater 2021; 6:4377-4388. [PMID: 33997514 PMCID: PMC8111032 DOI: 10.1016/j.bioactmat.2021.04.025] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/14/2021] [Accepted: 04/14/2021] [Indexed: 12/23/2022] Open
Abstract
Human induced pluripotent stem cells (hiPSCs) possess tremendous potential for tissue regeneration and banking hiPSCs by cryopreservation for their ready availability is crucial to their widespread use. However, contemporary methods for hiPSC cryopreservation are associated with both limited cell survival and high concentration of toxic cryoprotectants and/or serum. The latter may cause spontaneous differentiation and/or introduce xenogeneic factors, which may compromise the quality of hiPSCs. Here, sand from nature is discovered to be capable of seeding ice above -10 °C, which enables cryopreservation of hiPSCs with no serum, much-reduced cryoprotectant, and high cell survival. Furthermore, the cryopreserved hiPSCs retain high pluripotency and functions judged by their pluripotency marker expression, cell cycle analysis, and capability of differentiation into the three germ layers. This unique sand-mediated cryopreservation method may greatly facilitate the convenient and ready availability of high-quality hiPSCs and probably many other types of cells/tissues for the emerging cell-based translational medicine.
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Affiliation(s)
- Bin Jiang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
| | - Weijie Li
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
- Institute of Biothermal Technology, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Samantha Stewart
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
| | - Wenquan Ou
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
| | - Baolin Liu
- Institute of Biothermal Technology, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Pierre Comizzoli
- Smithsonian Conservation Biology Institute, National Zoological Park, Washington, DC, 20008, USA
| | - Xiaoming He
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
- Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, MD, 20742, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, 21201, USA
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18
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The Association of Ovarian Teratoma and Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Updated Integrative Review. Int J Mol Sci 2021; 22:ijms222010911. [PMID: 34681570 PMCID: PMC8535897 DOI: 10.3390/ijms222010911] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/26/2021] [Accepted: 10/07/2021] [Indexed: 01/09/2023] Open
Abstract
Ovarian teratomas are by far the most common ovarian germ cell tumor. Most teratomas are benign unless a somatic transformation occurs. The designation of teratoma refers to a neoplasm that differentiates toward somatic-type cell populations. Recent research shows a striking association between ovarian teratomas and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, a rare and understudied paraneoplastic neurological syndrome (PNS). Among teratomas, mature teratomas are thought to have a greater relevance with those neurological impairments. PNS is described as a neurologic deficit triggered by an underlying remote tumor, whereas anti-NMDAR encephalitis is characterized by a complex neuropsychiatric syndrome and the presence of autoantibodies in cerebral spinal fluid against the GluN1 subunit of the NMDAR. This review aims to summarize recent reports on the association between anti-NMDAR encephalitis and ovarian teratoma. In particular, the molecular pathway of pathogenesis and the updated mechanism and disease models would be discussed. We hope to provide an in-depth review of this issue and, therefore, to better understand its epidemiology, diagnostic approach, and treatment strategies.
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19
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Li H, Gao L, Du J, Ma T, Ye Z, Li Z. To Better Generate Organoids, What Can We Learn From Teratomas? Front Cell Dev Biol 2021; 9:700482. [PMID: 34336851 PMCID: PMC8324104 DOI: 10.3389/fcell.2021.700482] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/21/2021] [Indexed: 12/12/2022] Open
Abstract
The genomic profile of animal models is not completely matched with the genomic profile of humans, and 2D cultures do not represent the cellular heterogeneity and tissue architecture found in tissues of their origin. Derived from 3D culture systems, organoids establish a crucial bridge between 2D cell cultures and in vivo animal models. Organoids have wide and promising applications in developmental research, disease modeling, drug screening, precision therapy, and regenerative medicine. However, current organoids represent only single or partial components of a tissue, which lack blood vessels, native microenvironment, communication with near tissues, and a continuous dorsal-ventral axis within 3D culture systems. Although efforts have been made to solve these problems, unfortunately, there is no ideal method. Teratoma, which has been frequently studied in pathological conditions, was recently discovered as a new in vivo model for developmental studies. In contrast to organoids, teratomas have vascularized 3D structures and regions of complex tissue-like organization. Studies have demonstrated that teratomas can be used to mimic multilineage human development, enrich specific somatic progenitor/stem cells, and even generate brain organoids. These results provide unique opportunities to promote our understanding of the vascularization and maturation of organoids. In this review, we first summarize the basic characteristics, applications, and limitations of both organoids and teratomas and further discuss the possibility that in vivo teratoma systems can be used to promote the vascularization and maturation of organoids within an in vitro 3D culture system.
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Affiliation(s)
- Hongyu Li
- Department of Ophthalmology, The Chinese People's Liberation Army General Hospital, Beijing, China
| | - Lixiong Gao
- Department of Ophthalmology, The Chinese People's Liberation Army General Hospital, Beijing, China
| | - Jinlin Du
- Department of Ophthalmology, The Chinese People's Liberation Army General Hospital, Beijing, China
| | - Tianju Ma
- Department of Ophthalmology, The Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zi Ye
- Department of Ophthalmology, The Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zhaohui Li
- Department of Ophthalmology, The Chinese People's Liberation Army General Hospital, Beijing, China
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20
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Pace S, Sacks MA, Goodman LF, Tagge EP, Radulescu A. Antenatal Diagnosis of Retroperitoneal Cystic Mass: Fetiform Teratoma or Fetus in Fetu? A Case Report. AMERICAN JOURNAL OF CASE REPORTS 2021; 22:e929247. [PMID: 33568621 PMCID: PMC7885532 DOI: 10.12659/ajcr.929247] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Teratoma, a tumor containing a variety of tissues, is a broad diagnosis containing mature teratoma, immature teratoma, and teratomas with malignant transformation. The tumor forms during embryological development secondary to unsuccessful migration of primordial germ cells. A specific type of mature teratoma, containing human-like features, is called a fetiform teratoma. The fetiform teratoma is often compared and confused with fetus in fetu, a reabsorbed twin. While these tumors have commonly been described in the gonads, the retroperitoneal location finding on antenatal imaging is rare. The distinction between the aforementioned subtypes is not well established, proving a challenging diagnosis prior to resection. CASE REPORT We present a case of a newborn male with a prenatal diagnosis of retroperitoneal cystic mass. Although prenatal imaging was obtained, the diagnosis remained unclear. After birth, planned surgical excision on day of life 7 showed the suprarenal mass contained contiguous intestinal elements. Histopathology examination revealed a mature cystic teratoma with multiple tissue types, including colonic, brain, respiratory, lymphatics, and nerves, reminiscent of fetiform teratoma. This case report presents an interesting example of differentiating elements straddling the diagnoses mentioned above. CONCLUSIONS This is the first reported case of fetiform teratoma diagnosed in a newborn and is especially unique for having the element of intestinal duplication within the retroperitoneal mass. The differentiating features of fetus in fetu and fetiform teratoma depend on subjective distinctions. The case provides an opportunity to discuss the differentials and management strategies.
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Affiliation(s)
- Spencer Pace
- School of Medicine, Touro University California, Vallejo, CA, USA
| | - Marla A Sacks
- Department of Surgery, Division of Pediatric Surgery, Loma Linda University Children's Hospital, Loma Linda, CA, USA
| | - Laura F Goodman
- Department of Surgery, Division of Pediatric Surgery, Loma Linda University Children's Hospital, Loma Linda, CA, USA
| | - Edward P Tagge
- Department of Surgery, Division of Pediatric Surgery, Loma Linda University Children's Hospital, Loma Linda, CA, USA
| | - Andrei Radulescu
- Department of Surgery, Division of Pediatric Surgery, Loma Linda University Children's Hospital, Loma Linda, CA, USA
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21
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Tezel T, Ruff A. Retinal cell transplantation in retinitis pigmentosa. Taiwan J Ophthalmol 2021; 11:336-347. [PMID: 35070661 PMCID: PMC8757529 DOI: 10.4103/tjo.tjo_48_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 10/10/2021] [Indexed: 11/25/2022] Open
Abstract
Retinitis pigmentosa is the most common hereditary retinal disease. Dietary supplements, neuroprotective agents, cytokines, and lately, prosthetic devices, gene therapy, and optogenetics have been employed to slow down the retinal degeneration or improve light perception. Completing retinal circuitry by transplanting photoreceptors has always been an appealing idea in retinitis pigmentosa. Recent developments in stem cell technology, retinal imaging techniques, tissue engineering, and transplantation techniques have brought us closer to accomplish this goal. The eye is an ideal organ for cell transplantation due to a low number of cells required to restore vision, availability of safe surgical and imaging techniques to transplant and track the cells in vivo, and partial immune privilege provided by the subretinal space. Human embryonic stem cells, induced pluripotential stem cells, and especially retinal organoids provide an adequate number of cells at a desired developmental stage which may maximize integration of the graft to host retina. However, stem cells must be manufactured under strict good manufacturing practice protocols due to known tumorigenicity as well as possible genetic and epigenetic stabilities that may pose a danger to the recipient. Immune compatibility of stem cells still stands as a problem for their widespread use for retinitis pigmentosa. Transplantation of stem cells from different sources revealed that some of the transplanted cells may not integrate the host retina but slow down the retinal degeneration through paracrine mechanisms. Discovery of a similar paracrine mechanism has recently opened a new therapeutic path for reversing the cone dormancy and restoring the sight in retinitis pigmentosa.
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22
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Halliwell J, Barbaric I, Andrews PW. Acquired genetic changes in human pluripotent stem cells: origins and consequences. Nat Rev Mol Cell Biol 2020; 21:715-728. [DOI: 10.1038/s41580-020-00292-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2020] [Indexed: 12/14/2022]
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23
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Magisson J, Sassi A, Xhema D, Kobalyan A, Gianello P, Mourer B, Tran N, Burcez CT, Bou Aoun R, Sigrist S. Safety and function of a new pre-vascularized bioartificial pancreas in an allogeneic rat model. J Tissue Eng 2020; 11:2041731420924818. [PMID: 32523669 PMCID: PMC7257875 DOI: 10.1177/2041731420924818] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/18/2020] [Indexed: 12/17/2022] Open
Abstract
Cell encapsulation could overcome limitations of free islets transplantation but is currently limited by inefficient cells immune protection and hypoxia. As a response to these challenges, we tested in vitro and in vivo the safety and efficacy of a new macroencapsulation device named MailPan®. Membranes of MailPan® device were tested in vitro in static conditions. Its bio-integration and level of oxygenation was assessed after implantation in non-diabetic rats. Immune protection properties were also assessed in rat with injection in the device of allogeneic islets with incompatible Major Histocompatibility Complex. Finally, function was assessed in diabetic rats with a Beta cell line injected in MailPan®. In vitro, membranes of the device showed high permeability to glucose, insulin, and rejected IgG. In rat, the device displayed good bio-integration, efficient vascularization, and satisfactory oxygenation (>5%), while positron emission tomography (PET)-scan and angiography also highlighted rapid exchanges between blood circulation and the MailPan®. The device showed its immune protection properties by preventing formation, by the rat recipient, of antibodies against encapsulated allogenic islets. Injection of a rat beta cell line into the device normalized fasting glycemia of diabetic rat with retrieval of viable cell clusters after 2 months. These data suggest that MailPan® constitutes a promising encapsulation device for widespread use of cell therapy for type 1 diabetes.
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Affiliation(s)
| | | | - Daela Xhema
- Laboratory of Experimental Surgery, Université Catholique de Louvain, Brussels, Belgium
| | | | - Pierre Gianello
- Laboratory of Experimental Surgery, Université Catholique de Louvain, Brussels, Belgium
| | - Brice Mourer
- Ecole de Chirurgie de Nancy-Lorraine, Vandoeuvre-lès-Nancy, France
| | - Nguyen Tran
- Ecole de Chirurgie de Nancy-Lorraine, Vandoeuvre-lès-Nancy, France
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Haraguchi S, Dang-Nguyen TQ, Wells D, Fuchimoto D, Fukuda T, Tokunaga T. Establishment of porcine nuclear transfer-derived embryonic stem cells using induced pluripotent stem cells as donor nuclei. J Reprod Dev 2020; 66:163-174. [PMID: 31983707 PMCID: PMC7175389 DOI: 10.1262/jrd.2019-137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We investigated whether sequential reprogramming via porcine induced pluripotent stem cells (piPSCs) or exposure to oocyte cytoplasm following nuclear transfer could generate nuclear transfer-derived ESCs (piPSCs-ntESCs). Nuclear transfer embryos were reconstructed with piPSCs possessing a ZsGreen fluorescent marker for expression of exogenous Nanog and Lin28. Reconstructed oocytes developed to morphologically normal 8-cell/morulae (35/93, 37.6%) and blastocysts (12/93, 12.9%). Although most green fluorescent protein-positive blastocysts showed efficient outgrowth (8/10, 80%), none formed primary colonies and all cultures degenerated. Conversely, 15% of fluorescent positive 8-cell/morula stage embryos showed outgrowth (6/40), with three forming primary colonies (7.5%). All three were expanded and maintained as piPSC-ntESC lines. These cell lines expressed stem cell marker genes and proteins. Despite inactivation of one X chromosome, all piPSC-ntESC lines formed teratomas comprising derivatives from all three embryonic germ layers. Strong SSEA1, 3, and 4 expression was detected at the 8-cell/morula stage in embryos reconstructed from both piPSCs and porcine embryonic fibroblasts (PEFs). SSEA3 was notably absent from IVF controls at pre-implantation embryo stages. Finally, we attempted to establish ntESCs from 8-cell/morulae reconstructed with PEFs using the same culture conditions as those for piPSC-ntESC derivation. Although eight primary colonies arose from 107 embryos (7.5%), they all degenerated after the first passage culture. Early and sustained expression of key reprogramming regulatory factors may be critical for pluripotent stem cell derivation to derive piPSC-ntESCs from 8-cell/morula stages, while the expression of SSEAs may be involved in the initial stem cell colony formation phases.
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Affiliation(s)
- Seiki Haraguchi
- Animal Biotechnology Unit, Institute of Agrobiological Sciences, NARO, Ibaraki 305-0901, Japan
| | - Thanh Quang Dang-Nguyen
- Reproductive Biology Unit, Institute of Agrobiological Sciences, NARO, Ibaraki 305-0901, Japan
| | - David Wells
- AgResearch, Ruakura Research Centre, Hamilton, New Zealand
| | - Daiichiro Fuchimoto
- Animal Biotechnology Unit, Institute of Agrobiological Sciences, NARO, Ibaraki 305-0901, Japan
| | - Tomokazu Fukuda
- Laboratory of Cell Engineering and Molecular Genetics, Iwate University, Iwate 020-8550, Japan
| | - Tomoyuki Tokunaga
- Animal Biotechnology Unit, Institute of Agrobiological Sciences, NARO, Ibaraki 305-0901, Japan
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25
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The dual character of exosomes in osteoarthritis: Antagonists and therapeutic agents. Acta Biomater 2020; 105:15-25. [PMID: 32006653 DOI: 10.1016/j.actbio.2020.01.040] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 01/19/2020] [Accepted: 01/23/2020] [Indexed: 02/06/2023]
Abstract
Exosomes have gained increasing attention as they participate in cell cross-talk in pathological environments and are functional paracrine factors of therapeutic stem cells. Osteoarthritis (OA) is a common age-related degenerative joint disease, leading to a debilitating lifestyle for sufferers. However, currently no drugs on the market promote cartilage repair, and the patients usually have to undergo arthroplasty in the late stage of OA. Although significant progress has been made in the development of stem cells for the treatment of OA and cartilage injury, problems like immune rejection remain. Recently, increasing evidence has demonstrated that exosomes from the joint microenvironment ("negative" exosomes) could play vital and complicated roles in the progression of OA. Moreover, exosomes from therapeutic cells ("therapeutic" exosomes) have also shown enormous potential for OA therapy/cartilage repair. Here, we first discuss the definition and biological background of exosomes. Then, we critically examine the roles of the "negative" exosomes in OA-affected joint. Then, we will cover the potential of the "therapeutic" exosomes for OA therapy/cartilage repair. Next, the recent progress of tissue engineering with exosomes, especially for OA therapy/cartilage repair, will also be discussed. Finally, the limitations and opportunities of exosome-based OA therapy will be outlined. STATEMENT OF SIGNIFICANCE: As natural extracellular vesicles, exosomes participate in the intercellular communication. On the basis of biological characteristics of exosomes, exosomes have their two sides for osteoarthritis (OA). On the one hand, exosomes in the OA microenvironment are involved in pathology of OA. On the other hand, exosomes from therapeutic cells have the potential as advanced strategies for OA therapy. In addition, the development of tissue engineering technology is beneficial to the exosome-based OA therapy. According to the latest research status, exosomes are of great significance and interest for the personalized and precision treatment of OA in the future, despite the limitations and challenges.
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Dou X, Tong P, Huang H, Zellmer L, He Y, Jia Q, Zhang D, Peng J, Wang C, Xu N, Liao DJ. Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology. J Cancer 2020; 11:2887-2920. [PMID: 32226506 PMCID: PMC7086263 DOI: 10.7150/jca.41324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 02/08/2020] [Indexed: 11/08/2022] Open
Abstract
Modern research into carcinogenesis has undergone three phases. Surgeons and pathologists started the first phase roughly 250 years ago, establishing morphological traits of tumors for pathologic diagnosis, and setting immortality and autonomy as indispensable criteria for neoplasms. A century ago, medical doctors, biologists and chemists started to enhance "experimental cancer research" by establishing many animal models of chemical-induced carcinogenesis for studies of cellular mechanisms. In this second phase, the two-hit theory and stepwise carcinogenesis of "initiation-promotion" or "initiation-promotion-progression" were established, with an illustrious finding that outgrowths induced in animals depend on the inducers, and thus are not authentically neoplastic, until late stages. The last 40 years are the third incarnation, molecular biologists have gradually dominated the carcinogenesis research fraternity and have established numerous genetically-modified animal models of carcinogenesis. However, evidence has not been provided for immortality and autonomy of the lesions from most of these models. Probably, many lesions had already been collected from animals for analyses of molecular mechanisms of "cancer" before the lesions became autonomous. We herein review the monumental work of many predecessors to reinforce that evidence for immortality and autonomy is essential for confirming a neoplastic nature. We extrapolate that immortality and autonomy are established early during sporadic human carcinogenesis, unlike the late establishment in most animal models. It is imperative to resume many forerunners' work by determining the genetic bases for initiation, promotion and progression, the genetic bases for immortality and autonomy, and which animal models are, in fact, good for identifying such genetic bases.
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Affiliation(s)
- Xixi Dou
- Shandong Provincial Key Laboratory of Transmucosal and Transdermal Drug Delivery, Shandong Freda Pharmaceutical Group Co., Ltd., Jinan 250101, Shandong Province, P.R. China
| | - Pingzhen Tong
- Department of Pathology, The Second Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, P.R. China
| | - Hai Huang
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, P.R. China
| | - Lucas Zellmer
- Masonic Cancer Center, University of Minnesota, 435 E. River Road, Minneapolis, MN 55455, USA
| | - Yan He
- Key Lab of Endemic and Ethnic Diseases of The Ministry of Education of China in Guizhou Medical University, Guiyang, Guizhou Province 550004, P. R. China
| | - Qingwen Jia
- Shandong Provincial Key Laboratory of Transmucosal and Transdermal Drug Delivery, Shandong Freda Pharmaceutical Group Co., Ltd., Jinan 250101, Shandong Province, P.R. China
| | - Daizhou Zhang
- Shandong Provincial Key Laboratory of Transmucosal and Transdermal Drug Delivery, Shandong Freda Pharmaceutical Group Co., Ltd., Jinan 250101, Shandong Province, P.R. China
| | - Jiang Peng
- Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, P.R. China
| | - Chenguang Wang
- Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, P.R. China
| | - Ningzhi Xu
- Tianjin LIPOGEN Gene Technology Ltd., #238 Baidi Road, Nankai District, Tianjin 300192, P.R. China
| | - Dezhong Joshua Liao
- Department of Pathology, The Second Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, P.R. China
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Plazibat M, Katušić Bojanac A, Himerleich Perić M, Gamulin O, Rašić M, Radonić V, Škrabić M, Krajačić M, Krasić J, Sinčić N, Jurić-Lekić G, Balarin M, Bulić-Jakuš F. Embryo-derived teratoma in vitro biological system reveals antitumor and embryotoxic activity of valproate. FEBS J 2020; 287:4783-4800. [PMID: 32056377 PMCID: PMC7687280 DOI: 10.1111/febs.15248] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 12/10/2019] [Accepted: 02/12/2020] [Indexed: 12/19/2022]
Abstract
Antiepileptic/teratogen valproate (VPA) is a histone deacetylase inhibitor/epigenetic drug proposed for the antitumor therapy where it is generally crucial to target poorly or undifferentiated cells to prevent a recurrence. Transplanted rodent gastrulating embryos‐proper (primitive streak and three germ layers) are the source of teratoma/teratocarcinoma tumors. Human primitive‐streak remnants develop sacrococcygeal teratomas that may recur even when benign (well differentiated). To screen for unknown VPA impact on teratoma‐type tumors, we used original 2‐week embryo‐derived teratoma in vitro biological system completed by a spent media metabolome analysis. Gastrulating 9.5‐day‐old rat embryos‐proper were cultivated in Eagle's minimal essential medium (MEM) with 50% rat serum (controls) or with the addition of 2 mmVPA. Spent media metabolomes were analyzed by FTIR. Compared to controls, VPA acetylated histones; significantly diminished overall teratoma growth, impaired survival, increased the apoptotic index, and decreased proliferation index and incidence of differentiated tissues (e.g., neural tissue). Control teratomas continued to grow and differentiate for 14 days in isotransplants in vivo, but in vitro VPA‐treated teratomas resorbed. Principal component analysis of FTIR results showed that spent media metabolomes formed well‐separated clusters reflecting the treatment and day of cultivation. In metabolomes of VPA‐treated teratomas, we found elevation of previously described histone acetylation biomarkers [amide I α‐helix and A(CH3)/A(CH2)]) with apoptotic biomarkers within the amide I region for β‐sheets, and unordered and CH2 vibrations of lipids. VPA may be proposed for therapy of the undifferentiated component of teratoma tumors and this biological system completed by metabolome analysis, for a faster dual screening of antitumor/embryotoxic agents.
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Affiliation(s)
- Milvija Plazibat
- Department of Pediatrics, Hospital Zabok, Croatia.,Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, Croatia.,Dental Medicine and Health, School of Medicine, University of Osijek, Croatia
| | - Ana Katušić Bojanac
- Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, Croatia.,Department of Medical Biology, School of Medicine, University of Zagreb, Croatia
| | - Marta Himerleich Perić
- Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, Croatia.,Department of Medical Biology, School of Medicine, University of Zagreb, Croatia
| | - Ozren Gamulin
- Department of Physics, School of Medicine, University of Zagreb, Croatia.,Center of Excellence for Advanced Materials and Sensing Devices, Research Unit New Functional Materials, School of Medicine, University of Zagreb, Croatia
| | - Mario Rašić
- Department of Physics, School of Medicine, University of Zagreb, Croatia.,Department of Head and Neck Surgery, Tumor Clinic,Clinical Hospital Center Sisters of Charity, Zagreb, Croatia
| | - Vedran Radonić
- Department of Physics, School of Medicine, University of Zagreb, Croatia.,Department Of Cardiology, Clinical Hospital Merkur, Zagreb, Croatia
| | - Marko Škrabić
- Department of Physics, School of Medicine, University of Zagreb, Croatia.,Center of Excellence for Advanced Materials and Sensing Devices, Research Unit New Functional Materials, School of Medicine, University of Zagreb, Croatia
| | - Maria Krajačić
- Department of Physics, School of Medicine, University of Zagreb, Croatia
| | - Jure Krasić
- Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, Croatia.,Department of Medical Biology, School of Medicine, University of Zagreb, Croatia
| | - Nino Sinčić
- Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, Croatia.,Department of Medical Biology, School of Medicine, University of Zagreb, Croatia
| | - Gordana Jurić-Lekić
- Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, Croatia.,Department of Histology and Embryology, School of Medicine, University of Zagreb, Croatia
| | - Maja Balarin
- Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, Croatia.,Department of Physics, School of Medicine, University of Zagreb, Croatia
| | - Floriana Bulić-Jakuš
- Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, Croatia.,Department of Medical Biology, School of Medicine, University of Zagreb, Croatia
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28
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Umehara R, Kurata A, Takanashi M, Hashimoto H, Fujita K, Nagao T, Kuroda M. Fascin as a Useful Marker for Identifying Neural Components in Immature Teratomas of Human Ovary and Those Derived From Murine Embryonic Stem Cells. Int J Gynecol Pathol 2019; 38:377-385. [PMID: 29851865 DOI: 10.1097/pgp.0000000000000528] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Immature teratoma of the human ovary is a rare disease, and its diagnosis and grading are currently based on histologic evaluation of the presence and amount of immature neural components in the tumor. Despite the importance of tumor grading, immature neural components especially without rosette formation are difficult to identify, partly because useful biomarkers for them are not yet available. Toward this goal, we investigated 16 immature teratomas from human ovaries as well as 10 of those derived from murine embryonic stem cells transplanted into immunodeficient mice. Immunohistochemistry was performed for cytokeratin, glial fibrillary acidic protein, S100, and fascin. It was demonstrated that glial fibrillary acidic protein and S100 expression was not observed in the immature neural components of immature teratomas derived from both human ovary and embryonic stem cells, although their expression was detected in mature neural tissues. In contrast, fascin immunopositivity was clearly found in both mature and immature neural components regardless of rosette formation in immature teratomas derived from both human ovary and embryonic stem cells. Assessment of immature neural components by fascin immunostaining yielded the same or slightly increased quantity than quantification based on hematoxylin and eosin staining. These results suggest that fascin immunostaining is useful as a biomarker in correctly diagnosing and grading human immature teratomas. Further, fascin immunostaining may contribute to the development of regenerative medicine through accurate assessment of the maturation status of pluripotent stem cell-derived tumors transplanted into immunodeficient mice.
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Affiliation(s)
- Ryunosuke Umehara
- Tokyo Medical University (R.U.) Departments of Molecular Pathology (A.K., M.T., K.F., M.K.) Anatomic Pathology (T.N.), Tokyo Medical University Department of Diagnostic Pathology, NTT Medical Center Tokyo (H.H.), Tokyo, Japan
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29
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Lobo J, Gillis AJM, Jerónimo C, Henrique R, Looijenga LHJ. Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic. Int J Mol Sci 2019; 20:E258. [PMID: 30634670 PMCID: PMC6359418 DOI: 10.3390/ijms20020258] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 12/25/2018] [Accepted: 01/07/2019] [Indexed: 02/03/2023] Open
Abstract
Current (high throughput omics-based) data support the model that human (malignant) germ cell tumors are not initiated by somatic mutations, but, instead through a defined locked epigenetic status, representative of their cell of origin. This elegantly explains the role of both genetic susceptibility as well as environmental factors in the pathogenesis, referred to as 'genvironment'. Moreover, it could also explain various epidemiological findings, including the rising incidence of this type of cancer in Western societies. In addition, it allows for identification of clinically relevant and informative biomarkers both for diagnosis and follow-up of individual patients. The current status of these findings will be discussed, including the use of high throughput DNA methylation profiling for determination of differentially methylated regions (DMRs) as well as chromosomal copy number variation (CNV). Finally, the potential value of methylation-specific tumor DNA fragments (i.e., XIST promotor) as well as embryonic microRNAs as molecular biomarkers for cancer detection in liquid biopsies will be presented.
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Affiliation(s)
- João Lobo
- Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal;.
| | - Ad J M Gillis
- Laboratory of Experimental Patho-Oncology (LEPO), Josephine Nefkens Building, Erasmus MC, Department of Pathology, University Medical Center, Cancer Institute, Be-432A, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal;.
| | - Rui Henrique
- Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal;.
| | - Leendert H J Looijenga
- Laboratory of Experimental Patho-Oncology (LEPO), Josephine Nefkens Building, Erasmus MC, Department of Pathology, University Medical Center, Cancer Institute, Be-432A, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.
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30
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Abstract
Humans develop from a unique group of pluripotent cells in early embryos that can produce all cells of the human body. While pluripotency is only transiently manifest in the embryo, scientists have identified conditions that sustain pluripotency indefinitely in the laboratory. Pluripotency is not a monolithic entity, however, but rather comprises a spectrum of different cellular states. Questions regarding the scientific value of examining the continuum of pluripotent stem (PS) cell states have gained increased significance in light of attempts to generate interspecies chimeras between humans and animals. In this chapter, I review our ever-evolving understanding of the continuum of pluripotency. Historically, the discovery of two different PS cell states in mice fostered a general conception of pluripotency comprised of two distinct attractor states: naïve and primed. Naïve pluripotency has been defined by competence to form germline chimeras and governance by unique KLF-based transcription factor (TF) circuitry, whereas primed state is distinguished by an inability to generate chimeras and alternative TF regulation. However, the discovery of many alternative PS cell states challenges the concept of pluripotency as a binary property. Moreover, it remains unclear whether the current molecular criteria used to classify human naïve-like pluripotency also identify human chimera-competent PS cells. Therefore, I examine the pluripotency continuum more closely in light of recent advances in PS cell research and human interspecies chimera research.
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31
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Salvatori DCF, Dorssers LCJ, Gillis AJM, Perretta G, van Agthoven T, Gomes Fernandes M, Stoop H, Prins JB, Oosterhuis JW, Mummery C, Looijenga LHJ. The MicroRNA-371 Family as Plasma Biomarkers for Monitoring Undifferentiated and Potentially Malignant Human Pluripotent Stem Cells in Teratoma Assays. Stem Cell Reports 2018; 11:1493-1505. [PMID: 30503260 PMCID: PMC6294243 DOI: 10.1016/j.stemcr.2018.11.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 11/01/2018] [Accepted: 11/01/2018] [Indexed: 01/09/2023] Open
Abstract
Predicting developmental potency and risk of posttransplantation tumor formation by human pluripotent stem cells (hPSCs) and their derivatives largely rely on classical histological analysis of teratomas. Here, we investigated whether an assay based on microRNAs (miRNA) in blood plasma is able to detect potentially malignant elements. Several hPSCs and human malignant germ cell tumor (hGCT) lines were investigated in vitro and in vivo after mouse xenografting. The multiple conventional hPSC lines generated mature teratomas, while xenografts from induced hPSCs (hiPSCs) with reactivated reprogramming transgenes and hGCT lines contained undifferentiated and potentially malignant components. The presence of these elements was reflected in the mRNA and miRNA profiles of the xenografts with OCT3/4 mRNA and the miR-371 and miR-302 families readily detectable. miR-371 family members were also identified in mouse plasma faithfully reporting undifferentiated elements in the xenografts. This study demonstrated that undifferentiated and potentially malignant cells could be detected in vivo.
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Affiliation(s)
- Daniela C F Salvatori
- Central Laboratory Animal Facility, Leiden University Medical Center, Einthovenweg 20, Leiden 2333 ZC, the Netherlands.
| | - Lambert C J Dorssers
- Department of Pathology, Laboratory for Experimental Patho-Oncology, Erasmus MC Cancer Institute, Be-432A, PO Box 2040, 3000 CA Rotterdam, the Netherlands
| | - Ad J M Gillis
- Department of Pathology, Laboratory for Experimental Patho-Oncology, Erasmus MC Cancer Institute, Be-432A, PO Box 2040, 3000 CA Rotterdam, the Netherlands
| | - Gemma Perretta
- Fondazione Guido Bernardini, Via Manfredo Camperio, 10, 20123 Milano, Italy
| | - Ton van Agthoven
- Department of Pathology, Laboratory for Experimental Patho-Oncology, Erasmus MC Cancer Institute, Be-432A, PO Box 2040, 3000 CA Rotterdam, the Netherlands
| | - Maria Gomes Fernandes
- Central Laboratory Animal Facility, Leiden University Medical Center, Einthovenweg 20, Leiden 2333 ZC, the Netherlands
| | - Hans Stoop
- Department of Pathology, Laboratory for Experimental Patho-Oncology, Erasmus MC Cancer Institute, Be-432A, PO Box 2040, 3000 CA Rotterdam, the Netherlands
| | - Jan-Bas Prins
- Central Laboratory Animal Facility, Leiden University Medical Center, Einthovenweg 20, Leiden 2333 ZC, the Netherlands
| | - J Wolter Oosterhuis
- Department of Pathology, Laboratory for Experimental Patho-Oncology, Erasmus MC Cancer Institute, Be-432A, PO Box 2040, 3000 CA Rotterdam, the Netherlands
| | - Christine Mummery
- Department of Anatomy & Embryology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands
| | - Leendert H J Looijenga
- Department of Pathology, Laboratory for Experimental Patho-Oncology, Erasmus MC Cancer Institute, Be-432A, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
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Liang Q, Monetti C, Shutova MV, Neely EJ, Hacibekiroglu S, Yang H, Kim C, Zhang P, Li C, Nagy K, Mileikovsky M, Gyongy I, Sung HK, Nagy A. Linking a cell-division gene and a suicide gene to define and improve cell therapy safety. Nature 2018; 563:701-704. [PMID: 30429614 DOI: 10.1038/s41586-018-0733-7] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 09/27/2018] [Indexed: 12/20/2022]
Abstract
Human pluripotent cell lines hold enormous promise for the development of cell-based therapies. Safety, however, is a crucial prerequisite condition for clinical applications. Numerous groups have attempted to eliminate potentially harmful cells through the use of suicide genes1, but none has quantitatively defined the safety level of transplant therapies. Here, using genome-engineering strategies, we demonstrate the protection of a suicide system from inactivation in dividing cells. We created a transcriptional link between the suicide gene herpes simplex virus thymidine kinase (HSV-TK) and a cell-division gene (CDK1); this combination is designated the safe-cell system. Furthermore, we used a mathematical model to quantify the safety level of the cell therapy as a function of the number of cells that is needed for the therapy and the type of genome editing that is performed. Even with the highly conservative estimates described here, we anticipate that our solution will rapidly accelerate the entry of cell-based medicine into the clinic.
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Affiliation(s)
- Qin Liang
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Claudio Monetti
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Maria V Shutova
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Eric J Neely
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Sabiha Hacibekiroglu
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Huijuan Yang
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Christopher Kim
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Puzheng Zhang
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Chengjin Li
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Kristina Nagy
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Maria Mileikovsky
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Istvan Gyongy
- School of Mathematics and Maxwell Institute, The University of Edinburgh, Edinburgh, UK
| | - Hoon-Ki Sung
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Andras Nagy
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. .,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. .,Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia. .,Department of Obstetrics & Gynaecology, University of Toronto, Toronto, Ontario, Canada.
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Human Teratoma-Derived Hematopoiesis Is a Highly Polyclonal Process Supported by Human Umbilical Vein Endothelial Cells. Stem Cell Reports 2018; 11:1051-1060. [PMID: 30344010 PMCID: PMC6234902 DOI: 10.1016/j.stemcr.2018.09.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 09/19/2018] [Accepted: 09/20/2018] [Indexed: 12/29/2022] Open
Abstract
Hematopoietic stem cells (HSCs) ensure a life-long regeneration of the blood system and are therefore an important source for transplantation and gene therapy. The teratoma environment supports the complex development of functional HSCs from human pluripotent stem cells, which is difficult to recapitulate in culture. This model mimics various aspects of early hematopoiesis, but is restricted by the low spontaneous hematopoiesis rate. In this study, a feasible protocol for robust hematopoiesis has been elaborated. We achieved a significant increase of the teratoma-derived hematopoietic population when teratomas were generated in the NSGS mouse, which provides human cytokines, together with co-injection of human umbilical vein endothelial cells. Since little is known about hematopoiesis in teratomas, we addressed localization and clonality of the hematopoietic lineage. Our results indicate that early human hematopoiesis is closely reflected in teratoma formation, and thus highlight the value of this model.
Robust human hematopoiesis in teratomas with co-injected HUVECs in NSGS mice Hematopoietic progenitors localize inside vascular structures in teratomas CD45+ cells are present in mesenchymal tissue in teratomas Teratoma formation and subsequent hematopoiesis are polyclonal events
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Yasuda S, Kusakawa S, Kuroda T, Miura T, Tano K, Takada N, Matsuyama S, Matsuyama A, Nasu M, Umezawa A, Hayakawa T, Tsutsumi H, Sato Y. Tumorigenicity-associated characteristics of human iPS cell lines. PLoS One 2018; 13:e0205022. [PMID: 30286143 PMCID: PMC6171902 DOI: 10.1371/journal.pone.0205022] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 09/18/2018] [Indexed: 01/06/2023] Open
Abstract
Human induced pluripotent stem cells (hiPSCs) represent promising raw materials of human cell-based therapeutic products (hCTPs). As undifferentiated hiPSCs exhibit intrinsic tumorigenicity properties that enable them to form teratomas, hCTPs containing residual undifferentiated hiPSCs may cause tumor formation following transplantation. We first established quantitative and sensitive tumorigenicity testing of hiPSCs dissociated into single cells using NOD/Shi-scid IL2Rγnull (NOG) mice by inhibiting apoptosis of hiPSCs with a Rho kinase inhibitor. To examine different features in tumorigenicity of various hiPSCs, 10 commonly available hiPSC lines were subjected to in vivo tumorigenicity testing. Transplanted hiPSC lines showed remarkable variation in tumor incidence, formation latency, and volumes. Most of the tumors formed were classified as immature teratomas. However, no signs of malignancies, such as carcinoma and sarcoma, were recognized in the tumors. Characteristics associated tumorigenicity of hiPSCs were investigated with microarray analysis, karyotype analysis, and whole exome sequencing. Gene expression profiling and pathway analysis supported different features of hiPSC lines in tumorigenicity. hiPSC lines showed chromosomal abnormalities in some lines and 61-77 variants of cancer-related genes carrying effective nonsynonymous mutations, which were confirmed in the COSMIC databases. In this study, the chromosomal abnormalities and cancer-related gene mutations observed in hiPSC lines did not lead to the malignancy of tumors derived from hiPSCs. Our results suggest that the potential tumorigenicity risk of hCTPs containing residual undifferentiated hiPSCs is dependent on not only amounts of undifferentiated hiPSCs but also features of the cell lines used as raw materials, a finding that should be considered from the perspective of quality of hCTPs used.
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Affiliation(s)
- Satoshi Yasuda
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kawasaki, Japan
| | - Shinji Kusakawa
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kawasaki, Japan
| | - Takuya Kuroda
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kawasaki, Japan
| | - Takumi Miura
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kawasaki, Japan
| | - Keiko Tano
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kawasaki, Japan
| | - Nozomi Takada
- Center for Rare Disease Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Satoko Matsuyama
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kawasaki, Japan
- Center for Rare Disease Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Akifumi Matsuyama
- Center for Rare Disease Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Michiyo Nasu
- Center for Regenerative Medicine, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Takao Hayakawa
- Pharmaceutical Research and Technology Institute, Kindai University, Osaka, Japan
| | | | - Yoji Sato
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kawasaki, Japan
- Department of Quality Assurance Science for Pharmaceuticals, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
- Department of Cellular & Gene Therapy Products, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
- Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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Allison TF, Andrews PW, Avior Y, Barbaric I, Benvenisty N, Bock C, Brehm J, Brüstle O, Damjanov I, Elefanty A, Felkner D, Gokhale PJ, Halbritter F, Healy LE, Hu TX, Knowles BB, Loring JF, Ludwig TE, Mayberry R, Micallef S, Mohamed JS, Müller FJ, Mummery CL, Nakatsuji N, Ng ES, Oh SKW, O’Shea O, Pera MF, Reubinoff B, Robson P, Rossant J, Schuldt BM, Solter D, Sourris K, Stacey G, Stanley EG, Suemori H, Takahashi K, Yamanaka S. Assessment of established techniques to determine developmental and malignant potential of human pluripotent stem cells. Nat Commun 2018; 9:1925. [PMID: 29765017 PMCID: PMC5954055 DOI: 10.1038/s41467-018-04011-3] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 03/26/2018] [Indexed: 12/12/2022] Open
Abstract
The International Stem Cell Initiative compared several commonly used approaches to assess human pluripotent stem cells (PSC). PluriTest predicts pluripotency through bioinformatic analysis of the transcriptomes of undifferentiated cells, whereas, embryoid body (EB) formation in vitro and teratoma formation in vivo provide direct tests of differentiation. Here we report that EB assays, analyzed after differentiation under neutral conditions and under conditions promoting differentiation to ectoderm, mesoderm, or endoderm lineages, are sufficient to assess the differentiation potential of PSCs. However, teratoma analysis by histologic examination and by TeratoScore, which estimates differential gene expression in each tumor, not only measures differentiation but also allows insight into a PSC's malignant potential. Each of the assays can be used to predict pluripotent differentiation potential but, at this stage of assay development, only the teratoma assay provides an assessment of pluripotency and malignant potential, which are both relevant to the pre-clinical safety assessment of PSCs.
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Immunomodulatory Behavior of Mesenchymal Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1119:73-84. [DOI: 10.1007/5584_2018_255] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Blair NF, Frith TJR, Barbaric I. Regenerative Medicine: Advances from Developmental to Degenerative Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1007:225-239. [PMID: 28840560 DOI: 10.1007/978-3-319-60733-7_12] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Chronic tissue and organ failure caused by an injury, disease, ageing or congenital defects represents some of the most complex therapeutic challenges and poses a significant financial healthcare burden. Regenerative medicine strategies aim to fulfil the unmet clinical need by restoring the normal tissue function either through stimulating the endogenous tissue repair or by using transplantation strategies to replace the missing or defective cells. Stem cells represent an essential pillar of regenerative medicine efforts as they provide a source of progenitors or differentiated cells for use in cell replacement therapies. Whilst significant leaps have been made in controlling the stem cell fates and differentiating them to cell types of interest, transitioning bespoke cellular products from an academic environment to off-the-shelf clinical treatments brings about a whole new set of challenges which encompass manufacturing, regulatory and funding issues. Notwithstanding the need to resolve such issues before cell replacement therapies can benefit global healthcare, mounting progress in the field has highlighted regenerative medicine as a realistic prospect for treating some of the previously incurable conditions.
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Affiliation(s)
- Nicholas F Blair
- Wellcome Trust - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Thomas J R Frith
- Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield, UK
| | - Ivana Barbaric
- Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield, UK.
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