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Kurzawa-Akanbi M, Tzoumas N, Corral-Serrano JC, Guarascio R, Steel DH, Cheetham ME, Armstrong L, Lako M. Pluripotent stem cell-derived models of retinal disease: Elucidating pathogenesis, evaluating novel treatments, and estimating toxicity. Prog Retin Eye Res 2024; 100:101248. [PMID: 38369182 DOI: 10.1016/j.preteyeres.2024.101248] [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: 12/07/2023] [Revised: 02/13/2024] [Accepted: 02/14/2024] [Indexed: 02/20/2024]
Abstract
Blindness poses a growing global challenge, with approximately 26% of cases attributed to degenerative retinal diseases. While gene therapy, optogenetic tools, photosensitive switches, and retinal prostheses offer hope for vision restoration, these high-cost therapies will benefit few patients. Understanding retinal diseases is therefore key to advance effective treatments, requiring in vitro models replicating pathology and allowing quantitative assessments for drug discovery. Pluripotent stem cells (PSCs) provide a unique solution given their limitless supply and ability to differentiate into light-responsive retinal tissues encompassing all cell types. This review focuses on the history and current state of photoreceptor and retinal pigment epithelium (RPE) cell generation from PSCs. We explore the applications of this technology in disease modelling, experimental therapy testing, biomarker identification, and toxicity studies. We consider challenges in scalability, standardisation, and reproducibility, and stress the importance of incorporating vasculature and immune cells into retinal organoids. We advocate for high-throughput automation in data acquisition and analyses and underscore the value of advanced micro-physiological systems that fully capture the interactions between the neural retina, RPE, and choriocapillaris.
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2
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Homan K, Onodera T, Matsuoka M, Iwasaki N. Glycosphingolipids in Osteoarthritis and Cartilage-Regeneration Therapy: Mechanisms and Therapeutic Prospects Based on a Narrative Review of the Literature. Int J Mol Sci 2024; 25:4890. [PMID: 38732111 PMCID: PMC11084896 DOI: 10.3390/ijms25094890] [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: 03/02/2024] [Revised: 04/23/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Glycosphingolipids (GSLs), a subtype of glycolipids containing sphingosine, are critical components of vertebrate plasma membranes, playing a pivotal role in cellular signaling and interactions. In human articular cartilage in osteoarthritis (OA), GSL expression is known notably to decrease. This review focuses on the roles of gangliosides, a specific type of GSL, in cartilage degeneration and regeneration, emphasizing their regulatory function in signal transduction. The expression of gangliosides, whether endogenous or augmented exogenously, is regulated at the enzymatic level, targeting specific glycosyltransferases. This regulation has significant implications for the composition of cell-surface gangliosides and their impact on signal transduction in chondrocytes and progenitor cells. Different levels of ganglioside expression can influence signaling pathways in various ways, potentially affecting cell properties, including malignancy. Moreover, gene manipulations against gangliosides have been shown to regulate cartilage metabolisms and chondrocyte differentiation in vivo and in vitro. This review highlights the potential of targeting gangliosides in the development of therapeutic strategies for osteoarthritis and cartilage injury and addresses promising directions for future research and treatment.
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Affiliation(s)
| | - Tomohiro Onodera
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan; (K.H.); (M.M.); (N.I.)
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3
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Frljak S, Gozdowska R, Klimczak-Tomaniak D, Kucia M, Kuch M, Jadczyk T, Vrtovec B, Sanz-Ruiz R. Stem Cells in Heart Failure: Future Perspective. CARDIOVASCULAR APPLICATIONS OF STEM CELLS 2023:491-514. [DOI: 10.1007/978-981-99-0722-9_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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4
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Gullapalli VK, Zarbin MA. New Prospects for Retinal Pigment Epithelium Transplantation. Asia Pac J Ophthalmol (Phila) 2022; 11:302-313. [PMID: 36041145 DOI: 10.1097/apo.0000000000000521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/28/2022] [Indexed: 11/26/2022] Open
Abstract
ABSTRACT Retinal pigment epithelium (RPE) transplants rescue photoreceptors in selected animal models of retinal degenerative disease. Early clinical studies of RPE transplants as treatment for age-related macular degeneration (AMD) included autologous and allogeneic transplants of RPE suspensions and RPE sheets for atrophic and neovascular complications of AMD. Subsequent studies explored autologous RPE-Bruch membrane-choroid transplants in patients with neovascular AMD with occasional marked visual benefit, which establishes a rationale for RPE transplants in late-stage AMD. More recent work has involved transplantation of autologous and allogeneic stem cell-derived RPE for patients with AMD and those with Stargardt disease. These early-stage clinical trials have employed RPE suspensions and RPE monolayers on biocompatible scaffolds. Safety has been well documented, but evidence of efficacy is variable. Current research involves development of better scaffolds, improved modulation of immune surveillance, and modification of the extracellular milieu to improve RPE survival and integration with host retina.
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Affiliation(s)
| | - Marco A Zarbin
- Iinstitute of Ophthalmology and visual Science, Rutgers-New Jersey Medical School, Rutgers University, Newark, NJ, US
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5
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The Induced Pluripotent Stem Cells in Articular Cartilage Regeneration and Disease Modelling: Are We Ready for Their Clinical Use? Cells 2022; 11:cells11030529. [PMID: 35159338 PMCID: PMC8834349 DOI: 10.3390/cells11030529] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/29/2022] [Accepted: 02/01/2022] [Indexed: 02/01/2023] Open
Abstract
The development of induced pluripotent stem cells has brought unlimited possibilities to the field of regenerative medicine. This could be ideal for treating osteoarthritis and other skeletal diseases, because the current procedures tend to be short-term solutions. The usage of induced pluripotent stem cells in the cell-based regeneration of cartilage damages could replace or improve on the current techniques. The patient’s specific non-invasive collection of tissue for reprogramming purposes could also create a platform for drug screening and disease modelling for an overview of distinct skeletal abnormalities. In this review, we seek to summarise the latest achievements in the chondrogenic differentiation of pluripotent stem cells for regenerative purposes and disease modelling.
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Ahmed I, Johnston RJ, Singh MS. Pluripotent stem cell therapy for retinal diseases. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1279. [PMID: 34532416 PMCID: PMC8421932 DOI: 10.21037/atm-20-4747] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 12/04/2020] [Indexed: 12/20/2022]
Abstract
Pluripotent stem cells (PSCs), which include human embryonic stem cells (hESCs) and induced pluripotent stem cell (iPSC), have been used to study development of disease processes, and as potential therapies in multiple organ systems. In recent years, there has been increasing interest in the use of PSC-based transplantation to treat disorders of the retina in which retinal cells have been functionally damaged or lost through degeneration. The retina, which consists of neuronal tissue, provides an excellent system to test the therapeutic utility of PSC-based transplantation due to its accessibility and the availability of high-resolution imaging technology to evaluate effects. Preclinical trials in animal models of retinal diseases have shown improvement in visual outcomes following subretinal transplantation of PSC-derived photoreceptors or retinal pigment epithelium (RPE) cells. This review focuses on preclinical studies and clinical trials exploring the use of PSCs for retinal diseases. To date, several phase I/II clinical trials in patients with age-related macular degeneration (AMD) and Stargardt disease (STGD1) have demonstrated the safety and feasibility of PSC-derived RPE transplantation. Additional phase I/II clinical trials using PSC-derived RPE or photoreceptor cells for the treatment of AMD, STGD1, and also retinitis pigmentosa (RP) are currently in the pipeline. As this field continues to evolve, additional technologies may enhance PSC-derived cell transplantation through gene-editing of autologous cells, transplantation of more complex cellular structures such as organoids, and monitoring of transplanted cells through novel imaging technologies.
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Affiliation(s)
- Ishrat Ahmed
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Mandeep S Singh
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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7
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Yu Y, Wang K, Fahira A, Yang Q, Sun R, Li Z, Wang Z, Shi Y. Systematic comparative study of computational methods for HLA typing from next-generation sequencing. HLA 2021; 97:481-492. [PMID: 33655664 DOI: 10.1111/tan.14244] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/21/2021] [Accepted: 02/25/2021] [Indexed: 12/25/2022]
Abstract
The human leukocyte antigen (HLA) system plays an important role in hematopoietic stem cell transplantation (HSCT) and organ transplantations, immune disorders as well as oncological immunotherapy. However, HLA typing remains a challenging task due to the high level of polymorphism and homology among HLA genes. Based on the high-throughput next-generation sequencing data, new HLA typing algorithms and software tools were developed. But there is still a deficit of systematic comparative studies to assist in the selection of the optimal analytical approaches under different conditions. Here, we present a detailed comparison of eight software tools for HLA typing on different real datasets (whole-genome sequencing, whole-exome sequencing and transcriptomic sequencing data) and in-silico samples with different sequencing lengths, depths, and error rates. We figure out the algorithms with the best efficiency in different scenarios, and demonstrate the effect of different raw reads on analytical performances. Our results provide a comprehensive picture of specifications and performances of the eight existing HLA genotyping algorithms, which could assist researchers in selecting the most appropriate tool for specific raw datasets.
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Affiliation(s)
- Yuechun Yu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Ke Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Aamir Fahira
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Qiangzhen Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Renliang Sun
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Zhiqiang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Zhuo Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Yongyong Shi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
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8
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Nath SC, Harper L, Rancourt DE. Cell-Based Therapy Manufacturing in Stirred Suspension Bioreactor: Thoughts for cGMP Compliance. Front Bioeng Biotechnol 2020; 8:599674. [PMID: 33324625 PMCID: PMC7726241 DOI: 10.3389/fbioe.2020.599674] [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: 08/27/2020] [Accepted: 10/30/2020] [Indexed: 12/23/2022] Open
Abstract
Cell-based therapy (CBT) is attracting much attention to treat incurable diseases. In recent years, several clinical trials have been conducted using human pluripotent stem cells (hPSCs), and other potential therapeutic cells. Various private- and government-funded organizations are investing in finding permanent cures for diseases that are difficult or expensive to treat over a lifespan, such as age-related macular degeneration, Parkinson’s disease, or diabetes, etc. Clinical-grade cell manufacturing requiring current good manufacturing practices (cGMP) has therefore become an important issue to make safe and effective CBT products. Current cell production practices are adopted from conventional antibody or protein production in the pharmaceutical industry, wherein cells are used as a vector to produce the desired products. With CBT, however, the “cells are the final products” and sensitive to physico- chemical parameters and storage conditions anywhere between isolation and patient administration. In addition, the manufacturing of cellular products involves multi-stage processing, including cell isolation, genetic modification, PSC derivation, expansion, differentiation, purification, characterization, cryopreservation, etc. Posing a high risk of product contamination, these can be time- and cost- prohibitive due to maintenance of cGMP. The growing demand of CBT needs integrated manufacturing systems that can provide a more simple and cost-effective platform. Here, we discuss the current methods and limitations of CBT, based upon experience with biologics production. We review current cell manufacturing integration, automation and provide an overview of some important considerations and best cGMP practices. Finally, we propose how multi-stage cell processing can be integrated into a single bioreactor, in order to develop streamlined cGMP-compliant cell processing systems.
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Affiliation(s)
- Suman C Nath
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Lane Harper
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Derrick E Rancourt
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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9
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Sullivan S, Fairchild PJ, Marsh SGE, Müller CR, Turner ML, Song J, Turner D. Haplobanking induced pluripotent stem cells for clinical use. Stem Cell Res 2020; 49:102035. [PMID: 33221677 DOI: 10.1016/j.scr.2020.102035] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 07/20/2020] [Accepted: 10/05/2020] [Indexed: 02/08/2023] Open
Abstract
The development of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka and colleagues in 2006 has led to a potential new paradigm in cellular therapeutics, including the possibility of producing patient-specific, disease-specific and immune matched allogeneic cell therapies. One can envisage two routes to immunologically compatible iPSC therapies: using genetic modification to generate a 'universal donor' with reduced expression of Human Leukocyte Antigens (HLA) and other immunological targets or developing a haplobank containing iPSC lines specifically selected to provide HLA matched products to large portions of the population. HLA matched lines can be stored in a designated physical or virtual global bank termed a 'haplobank'. The process of 'iPSC haplobanking' refers to the banking of iPSC cell lines, selected to be homozygous for different HLA haplotypes, from which therapeutic products can be derived and matched immunologically to patient populations. By matching iPSC and derived products to a patient's HLA class I and II molecules, one would hope to significantly reduce the risk of immune rejection and the use of immunosuppressive medication. Immunosuppressive drugs are used in several conditions (including autoimmune disease and in transplantation procedures) to reduce rejection of infused cells, or transplanted tissue and organs, due to major and minor histocompatibility differences between donor and recipient. Such regimens can lead to immune compromise and pathological consequences such as opportunistic infections or malignancies due to decreased cancer immune surveillance. In this article, we will discuss what is practically involved if one is developing and executing an iPSC haplobanking strategy.
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Affiliation(s)
- Stephen Sullivan
- Global Alliance for iPSC Therapies, Jack Copland Centre, Heriot-Watt Research Park, Edinburgh, UK.
| | - Paul J Fairchild
- University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK
| | - Steven G E Marsh
- HLA Informatics Group, Anthony Nolan Research Institute, Royal Free Campus, London, UK; UCL Cancer Institute, University College London, London, UK
| | - Carlheinz R Müller
- Zentrales Knochenmarkspender-Register Deutschland (ZKRD), Helmholtzstraße, 1089081 Ulm, Germany
| | - Marc L Turner
- Global Alliance for iPSC Therapies, Jack Copland Centre, Heriot-Watt Research Park, Edinburgh, UK; Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh, UK
| | - Jihwan Song
- Global Alliance for iPSC Therapies, Jack Copland Centre, Heriot-Watt Research Park, Edinburgh, UK; Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - David Turner
- Global Alliance for iPSC Therapies, Jack Copland Centre, Heriot-Watt Research Park, Edinburgh, UK; Histocompatibility and Immunogenetics Laboratory, Royal Infirmary of Edinburgh, Edinburgh, UK
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10
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Mehler VJ, Burns CJ, Stauss H, Francis RJ, Moore ML. Human iPSC-Derived Neural Crest Stem Cells Exhibit Low Immunogenicity. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 16:161-171. [PMID: 32055644 PMCID: PMC7005462 DOI: 10.1016/j.omtm.2019.12.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 12/28/2019] [Indexed: 12/14/2022]
Abstract
Recent clinical trials are evaluating induced pluripotent stem cells (iPSCs) as a cellular therapy in the field of regenerative medicine. The widespread clinical utility of iPSCs is expected to be realized using allogeneic cells that have undergone thorough safety evaluations, including assessment of their immunogenicity. IPSC-derived neural crest stem cells (NCSCs) have significant potential in regenerative medicine; however, their application in cellular therapy has not been widely studied to date, and no reports on their potential immunogenicity have been published so far. In this study, we have assessed the expression of immune-related antigens in iPSC-NCSCs, including human leukocyte antigen (HLA) class I and II and co-stimulatory molecules. To investigate functional immunogenicity, we used iPSC-NCSCs as stimulator cells in a one-way mixed lymphocyte reaction. In these experiments, iPSC-NCSCs did not stimulate detectable proliferation of CD3+ and CD3+CD8+ T cells or induce cytokine production. We show that this was not a result of any immunosuppressive features of iPSC-NCSCs, but rather more consistent with their non-immunogenic molecular phenotype. These results are encouraging for the potential future use of iPSC-NCSCs as a cellular therapy.
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Affiliation(s)
- Vera J Mehler
- Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, Potters Bar EN6 3QG, UK.,Division of Infection and Immunity, University College London, Gower Street, London WC1E 6BT, UK
| | - Chris J Burns
- Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, Potters Bar EN6 3QG, UK
| | - Hans Stauss
- Division of Infection and Immunity, University College London, Gower Street, London WC1E 6BT, UK
| | - Robert J Francis
- Biological Imaging Group, Analytical and Biological Sciences, NIBSC, Blanche Lane, Potters Bar EN6 3QG, UK
| | - Melanie L Moore
- Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, Potters Bar EN6 3QG, UK
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11
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Enrich E, Campos E, Martorell L, Herrero MJ, Vidal F, Querol S, Rudilla F. HLA-A, -B, -C, -DRB1, and -DQB1 allele and haplotype frequencies: An analysis of umbilical cord blood units at the Barcelona Cord Blood Bank. HLA 2019; 94:347-359. [PMID: 31353832 DOI: 10.1111/tan.13644] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 07/18/2019] [Accepted: 07/25/2019] [Indexed: 12/16/2022]
Abstract
Allele-level HLA compatibility in cord blood transplantation has been associated with better transplant outcomes and is recommended as a selection criterion. It is also a crucial aspect for other therapeutic applications involving cord blood-derived cells. Determination of high-resolution HLA frequencies is an important step towards improving the quality of cord blood banks. We analyzed HLA-A, -B, -C, -DRB1, and -DQB1 allele frequencies in 5458 high-quality cord blood units from the Barcelona Cord Blood Bank and identified 275 class I and 121 class II HLA alleles. A*02:01, B*44:03, C*07:01, DRB1*07:01 and DQB1*03:01 were the most frequent alleles at each locus. We detected 26 novel alleles and were able to determine the presence or absence of some null alleles, including C*04:09N, in a large number of units. We also analyzed maternal HLA typing information for 1877 units to determine real haplotype frequencies and linkage disequilibrium. A*29:02-B*44:03-C*16:01-DRB1*07:01-DQB1*02:02 was the most frequent HLA haplotype and the DRB1-DQB1 gene pair contained the two-locus haplotypes with the strongest linkage disequilibrium values. Four of the 11 unique haplotypes identified in the HLA-homozygous cord blood units were the top-ranking haplotypes identified and were present in 18% of the cohort. This is the first study to report on HLA allele and haplotype frequencies for umbilical cord blood units from the Barcelona Cord Blood Bank and the largest study to date involving two fields of HLA resolution typing of Spanish registry data.
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Affiliation(s)
- Emma Enrich
- Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits, Barcelona, Spain
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
| | - Eva Campos
- Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits, Barcelona, Spain
| | - Lluís Martorell
- Congenital Coagulopathy Laboratory, Banc de Sang i Teixits, Barcelona, Spain
- Cell Therapy Unit, Banc de Sang i Teixits, Barcelona, Spain
| | - María José Herrero
- Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits, Barcelona, Spain
| | - Francisco Vidal
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
- Congenital Coagulopathy Laboratory, Banc de Sang i Teixits, Barcelona, Spain
- CIBER of Cardiovascular Diseases (CIBERCV), Madrid, Spain
| | - Sergi Querol
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
- Cell Therapy Unit, Banc de Sang i Teixits, Barcelona, Spain
| | - Francesc Rudilla
- Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits, Barcelona, Spain
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
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12
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Abstract
The availability of noninvasive high-resolution imaging technology, the immune-suppressive nature of the subretinal space, and the existence of surgical techniques that permit transplantation surgery to be a safe procedure all render the eye an ideal organ in which to begin cell-based therapy in the central nervous system. A number of early stage clinical trials are underway to assess the safety and feasibility of cell-based therapy for retinal blindness. Cell-based therapy using embryonic stem cell-derived differentiated cells (e.g., retinal pigment epithelium (RPE)), neural progenitor cells, photoreceptor precursors, and bone marrow-derived hematopoietic stem/progenitor cells has demonstrated successful rescue and/or replacement in preclinical models of human retinal degenerative disease. Additional research is needed to identify the mechanisms that control synapse formation/disjunction (to improve photoreceptor transplant efficacy), to identify factors that limit RPE survival in areas of geographic atrophy (to improve RPE transplant efficacy in eyes with age-related macular degeneration), and to identify factors that regulate immune surveillance of the subretinal space (to improve long-term photoreceptor and RPE transplant survival).
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Affiliation(s)
- Marco Zarbin
- Institute of Ophthalmology and Visual Science, Rutgers-New Jersey Medical School, Rutgers University, Newark, NJ, USA.
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13
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Gasparini SJ, Llonch S, Borsch O, Ader M. Transplantation of photoreceptors into the degenerative retina: Current state and future perspectives. Prog Retin Eye Res 2018; 69:1-37. [PMID: 30445193 DOI: 10.1016/j.preteyeres.2018.11.001] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/29/2018] [Accepted: 11/06/2018] [Indexed: 12/12/2022]
Abstract
The mammalian retina displays no intrinsic regenerative capacities, therefore retinal degenerative diseases such as age-related macular degeneration (AMD) or retinitis pigmentosa (RP) result in a permanent loss of the light-sensing photoreceptor cells. The degeneration of photoreceptors leads to vision impairment and, in later stages, complete blindness. Several therapeutic strategies have been developed to slow down or prevent further retinal degeneration, however a definitive cure i.e. replacement of the lost photoreceptors, has not yet been established. Cell-based treatment approaches, by means of photoreceptor transplantation, have been studied in pre-clinical animal models over the last three decades. The introduction of pluripotent stem cell-derived retinal organoids represents, in principle, an unlimited source for the generation of transplantable human photoreceptors. However, safety, immunological and reproducibility-related issues regarding the use of such cells still need to be solved. Moreover, the recent finding of cytoplasmic material transfer between donor and host photoreceptors demands reinterpretation of several former transplantation studies. At the same time, material transfer between healthy donor and dysfunctional patient photoreceptors also offers a potential alternative strategy for therapeutic intervention. In this review we discuss the history and current state of photoreceptor transplantation, the techniques used to assess rescue of visual function, the prerequisites for effective transplantation as well as the main roadblocks, including safety and immune response to the graft, that need to be overcome for successful clinical translation of photoreceptor transplantation approaches.
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Affiliation(s)
- Sylvia J Gasparini
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany
| | - Sílvia Llonch
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany
| | - Oliver Borsch
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany
| | - Marius Ader
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany.
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14
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Banno K, Yoder MC. Tissue regeneration using endothelial colony-forming cells: promising cells for vascular repair. Pediatr Res 2018; 83:283-290. [PMID: 28915234 DOI: 10.1038/pr.2017.231] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 07/07/2017] [Indexed: 12/24/2022]
Abstract
Repairing and rebuilding damaged tissue in diseased human subjects remains a daunting challenge for clinical medicine. Proper vascular formation that serves to deliver blood-borne nutrients and adequate levels of oxygen and to remove wastes is critical for successful tissue regeneration. Endothelial colony-forming cells (ECFC) represent a promising cell source for revascularization of damaged tissue. ECFCs are identified by displaying a hierarchy of clonal proliferative potential and by pronounced postnatal vascularization ability in vivo. In this review, we provide a brief overview of human ECFC isolation and characterization, a survey of a number of animal models of human disease in which ECFCs have been shown to have prominent roles in tissue repair, and a summary of current challenges that must be overcome before moving ECFC into human subjects as a cell therapy.
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Affiliation(s)
- Kimihiko Banno
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Mervin C Yoder
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
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15
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Morishima Y, Azuma F, Kashiwase K, Matsumoto K, Orihara T, Yabe H, Kato S, Kato K, Kai S, Mori T, Nakajima K, Morishima S, Satake M, Takanashi M, Yabe T. Risk of HLA Homozygous Cord Blood Transplantation: Implications for Induced Pluripotent Stem Cell Banking and Transplantation. Stem Cells Transl Med 2017; 7:173-179. [PMID: 29274116 PMCID: PMC5788882 DOI: 10.1002/sctm.17-0169] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 11/13/2017] [Indexed: 01/22/2023] Open
Abstract
Clinical application of induced pluripotent stem cells (iPS) in autologous settings has just begun. To overcome the high time and cost barriers in the individual production of autologous iPS, the use of allogeneic iPS with a homozygous human leukocyte antigen (HLA) haplotype (HLA‐homo HP) has been proposed. Cord blood transplantation (CBT) is a suitable model for evaluating the allogeneic immunogenicity of iPS transplantation from HLA‐homo donors. We analyzed 1,374 Japanese single cord blood transplant pairs who were retrospectively typed as HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, and ‐DPB1. Among these, six pairs with donor HLA homo—patient‐HLA hetero (homo‐hetero) were found, all of which showed favorable neutrophil engraftment. Multivariate analysis revealed a significantly elevated engraftment risk (HR = 1.59) compared with hetero‐hetero pairs with HLA 1‐2 locus mismatch (789 pts) and comparative risk (HR = 1.23) compared with hetero‐hetero pairs with 0 mismatch (104 pts). These results for CBT with HLA‐homo HP cord blood carry an important implication, namely the possibility that HLA‐homo iPS transplantation results in favorable engraftment. Furthermore, we obtained detailed information on HLA alleles and haplotypes of HLA‐homo. All donor HLA‐homo HPs had a common specific ethnicity and high conservation of the HLA region, and one of two patient heterogeneous HPs invariably shared the same HP as donor HLA‐homo HP, and another non‐shared patient HP was mismatched with 1 to 4 HLA alleles of HLA‐A, ‐B, ‐C, and ‐DRB1 loci in the GVH direction. These findings indicate that patients possessing a single common HLA haplotype have a higher chance of yielding HLA‐homo iPS. Stem Cells Translational Medicine2018;7:173–179
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Affiliation(s)
- Yasuo Morishima
- Central Japan Cord Blood Bank, Seto, Japan.,Aichi Cancer Center Research Institute, Nagoya, Japan.,Aichi Medical University School of Medicine, Nagakute, Japan
| | - Fumihiro Azuma
- Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan
| | - Koichi Kashiwase
- Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan
| | | | | | | | | | - Koji Kato
- Central Japan Cord Blood Bank, Seto, Japan
| | - Shunro Kai
- Hyogo Cord Blood Bank, Nishinomiya, Japan
| | - Tetsuo Mori
- Japanese Red Cross Kyushu Cord Blood Bank, Chikushino, Japan
| | - Kazunori Nakajima
- Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan
| | - Satoko Morishima
- Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology. Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
| | | | | | - Toshio Yabe
- Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan
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16
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Low immunogenicity of mouse induced pluripotent stem cell-derived neural stem/progenitor cells. Sci Rep 2017; 7:12996. [PMID: 29021610 PMCID: PMC5636829 DOI: 10.1038/s41598-017-13522-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 09/25/2017] [Indexed: 12/11/2022] Open
Abstract
Resolving the immunogenicity of cells derived from induced pluripotent stem cells (iPSCs) remains an important challenge for cell transplant strategies that use banked allogeneic cells. Thus, we evaluated the immunogenicity of mouse fetal neural stem/progenitor cells (fetus-NSPCs) and iPSC-derived neural stem/progenitor cells (iPSC-NSPCs) both in vitro and in vivo. Flow cytometry revealed the low expression of immunological surface antigens, and these cells survived in all mice when transplanted syngeneically into subcutaneous tissue and the spinal cord. In contrast, an allogeneic transplantation into subcutaneous tissue was rejected in all mice, and allogeneic cells transplanted into intact and injured spinal cords survived for 3 months in approximately 20% of mice. In addition, cell survival was increased after co-treatment with an immunosuppressive agent. Thus, the immunogenicity and post-transplantation immunological dynamics of iPSC-NSPCs resemble those of fetus-NSPCs.
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17
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Abstract
Purpose of review Progress in stem cell research for blinding diseases over the past decade is now being applied to patients with retinal degenerative diseases and soon perhaps, glaucoma. However, the field still has much to learn about the conversion of stem cells into various retinal cell types, and the potential delivery methods that will be required to optimize the clinical efficacy of stem cells delivered into the eye. Recent findings Recent groundbreaking human clinical trials have demonstrated both the opportunities and current limitations of stem cell transplantation for retinal diseases. New progress in developing in vitro retinal organoids, coupled with the maturation of bio-printing technology, and non-invasive high-resolution imaging have created new possibilities for repairing and regenerating the diseased retina and rigorously validating its clinical impact in vivo. Summary While promising progress is being made, meticulous clinical trials with cells derived using good manufacturing practice, novel surgical methods, and improved methods to derive all of the neuronal cell types present in the retina will be indispensable for developing stem cell transplantation as a paradigm shift for the treatment of blinding diseases.
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18
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Miyagawa S, Fukushima S, Imanishi Y, Kawamura T, Mochizuki-Oda N, Masuda S, Sawa Y. Building A New Treatment For Heart Failure-Transplantation of Induced Pluripotent Stem Cell-derived Cells into the Heart. Curr Gene Ther 2016; 16:5-13. [PMID: 26785736 PMCID: PMC4997929 DOI: 10.2174/1566523216666160119094143] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 01/07/2016] [Accepted: 01/08/2016] [Indexed: 02/08/2023]
Abstract
Advanced cardiac failure is a progressive intractable disease and is the main cause of mortality and morbidity worldwide. Since this pathology is represented by a definite decrease in cardiomyocyte number, supplementation of functional cardiomyocytes into the heart would hypothetically be an ideal therapeutic option. Recently, unlimited in vitro production of human functional cardiomyocytes was established by using induced pluripotent stem cell (iPSC) technology, which avoids the use of human embryos. A number of basic studies including ours have shown that transplantation of iPSC-derived cardiomyocytes (iPSC-CMs) into the damaged heart leads to recovery of cardiac function, thereby establishing “proof-of-concept” of this iPSC-transplantation therapy. However, considering clinical application of this therapy, its feasibility, safety, and therapeutic efficacy need to be further investigated in the pre-clinical stage. This review summarizes up-to-date important topics related to safety and efficacy of iPSC-CMs transplantation therapy for cardiac disease and discusses the prospects for this treatment in clinical studies.
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Affiliation(s)
| | | | | | | | | | | | - Yoshiki Sawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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19
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Zhu L, Gomez-Duran A, Saretzki G, Jin S, Tilgner K, Melguizo-Sanchis D, Anyfantis G, Al-Aama J, Vallier L, Chinnery P, Lako M, Armstrong L. The mitochondrial protein CHCHD2 primes the differentiation potential of human induced pluripotent stem cells to neuroectodermal lineages. J Cell Biol 2016; 215:187-202. [PMID: 27810911 PMCID: PMC5084643 DOI: 10.1083/jcb.201601061] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 09/19/2016] [Indexed: 01/09/2023] Open
Abstract
Human induced pluripotent stem cell (hiPSC) utility is limited by variations in the ability of these cells to undergo lineage-specific differentiation. We have undertaken a transcriptional comparison of human embryonic stem cell (hESC) lines and hiPSC lines and have shown that hiPSCs are inferior in their ability to undergo neuroectodermal differentiation. Among the differentially expressed candidates between hESCs and hiPSCs, we identified a mitochondrial protein, CHCHD2, whose expression seems to correlate with neuroectodermal differentiation potential of pluripotent stem cells. We provide evidence that hiPSC variability with respect to CHCHD2 expression and differentiation potential is caused by clonal variation during the reprogramming process and that CHCHD2 primes neuroectodermal differentiation of hESCs and hiPSCs by binding and sequestering SMAD4 to the mitochondria, resulting in suppression of the activity of the TGFβ signaling pathway. Using CHCHD2 as a marker for assessing and comparing the hiPSC clonal and/or line differentiation potential provides a tool for large scale differentiation and hiPSC banking studies.
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Affiliation(s)
- Lili Zhu
- Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK
| | - Aurora Gomez-Duran
- Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK.,Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK
| | - Gabriele Saretzki
- Institute for Ageing and Health, Newcastle University, Newcastle NE1 3BZ, England, UK
| | - Shibo Jin
- Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK
| | - Katarzyna Tilgner
- Wellcome Trust-Medical Research Council Stem Cell Institute, Hinxton, Cambridge CB10 1SA, England, UK.,Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, England, UK
| | | | - Georgios Anyfantis
- Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK
| | - Jumana Al-Aama
- Princess Al Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ludovic Vallier
- Wellcome Trust-Medical Research Council Stem Cell Institute, Hinxton, Cambridge CB10 1SA, England, UK
| | - Patrick Chinnery
- Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK
| | - Majlinda Lako
- Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK
| | - Lyle Armstrong
- Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK
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20
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Andreasson KI, Bachstetter AD, Colonna M, Ginhoux F, Holmes C, Lamb B, Landreth G, Lee DC, Low D, Lynch MA, Monsonego A, O’Banion MK, Pekny M, Puschmann T, Russek-Blum N, Sandusky LA, Selenica MLB, Takata K, Teeling J, Town T, Van Eldik LJ, Russek-Blum N, Monsonego A, Low D, Takata K, Ginhoux F, Town T, O’Banion MK, Lamb B, Colonna M, Landreth G, Andreasson KI, Sandusky LA, Selenica MLB, Lee DC, Holmes C, Teeling J, Lynch MA, Van Eldik LJ, Bachstetter AD, Pekny M, Puschmann T. Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem 2016; 138:653-93. [PMID: 27248001 PMCID: PMC5433264 DOI: 10.1111/jnc.13667] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 04/01/2016] [Accepted: 04/30/2016] [Indexed: 12/21/2022]
Abstract
Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer's disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Niva Russek-Blum
- The Dead Sea and Arava Science Center, Central Arava Branch, Yair Station, Hazeva, Israel
| | - Alon Monsonego
- The Shraga Segal Dept. of Microbiology, Immunology and Genetics, The Faculty of Health Sciences: The National Institute of Biotechnology in the Negev, and Zlotowski Center for Neuroscience, Ben-Gurion University, Beer-Sheva 84105, Israel
| | - Donovan Low
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
| | - Kazuyuki Takata
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
| | - Terrence Town
- Departments of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089,
| | - M. Kerry O’Banion
- Departments of Neuroscience and Neurology, Del Monte Neuromedicine Institute, University of Rochester School of Medicine & Dentistry, Rochester, NY 14642,
| | - Bruce Lamb
- Department of Neurosciences, Cleveland Clinic, Cleveland, OH 44106
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Gary Landreth
- Department of Neurosciences, Case Western Reserve University 44106
| | - Katrin I. Andreasson
- Department of Neurology and Neurological Sciences, Stanford Neuroscience Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Leslie A. Sandusky
- USF Health Byrd Alzheimer’s Institute, Tampa, FL 33613
- College of Pharmacy & Pharmaceutical Sciences, Tampa, FL 33613
| | - Maj-Linda B. Selenica
- USF Health Byrd Alzheimer’s Institute, Tampa, FL 33613
- College of Pharmacy & Pharmaceutical Sciences, Tampa, FL 33613
| | - Daniel C. Lee
- USF Health Byrd Alzheimer’s Institute, Tampa, FL 33613
- College of Pharmacy & Pharmaceutical Sciences, Tampa, FL 33613
| | - Clive Holmes
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 7YD, United Kingdom
| | - Jessica Teeling
- Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 7YD, United Kingdom
| | | | | | | | - Milos Pekny
- Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, SE-405 30 Gothenburg, Sweden
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
- Hunter Medical Research Institute, University of Newcastle, New South Wales, Australia
| | - Till Puschmann
- Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, SE-405 30 Gothenburg, Sweden
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21
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Thiruvalluvan A, Czepiel M, Kap YA, Mantingh-Otter I, Vainchtein I, Kuipers J, Bijlard M, Baron W, Giepmans B, Brück W, 't Hart BA, Boddeke E, Copray S. Survival and Functionality of Human Induced Pluripotent Stem Cell-Derived Oligodendrocytes in a Nonhuman Primate Model for Multiple Sclerosis. Stem Cells Transl Med 2016; 5:1550-1561. [PMID: 27400790 DOI: 10.5966/sctm.2016-0024] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 04/07/2016] [Indexed: 12/21/2022] Open
Abstract
: Fast remyelination by endogenous oligodendrocyte precursor cells (OPCs) is essential to prevent axonal and subsequent retrograde neuronal degeneration in demyelinating lesions in multiple sclerosis (MS). In chronic lesions, however, the remyelination capacity of OPCs becomes insufficient. Cell therapy with exogenous remyelinating cells may be a strategy to replace the failing endogenous OPCs. Here, we differentiated human induced pluripotent stem cells (hiPSCs) into OPCs and validated their proper functionality in vitro as well as in vivo in mouse models for MS. Next, we intracerebrally injected hiPSC-derived OPCs in a nonhuman primate (marmoset) model for progressive MS; the grafted OPCs specifically migrated toward the MS-like lesions in the corpus callosum where they myelinated denuded axons. hiPSC-derived OPCs may become the first therapeutic tool to address demyelination and neurodegeneration in the progressive forms of MS. SIGNIFICANCE This study demonstrates for the first time that human induced pluripotent stem cell (iPSC)-derived oligodendrocyte precursor cells (OPCs), after intracortical implantation in a nonhuman primate model for progressive multiple sclerosis (MS), migrate to the lesions and remyelinate denuded axons. These findings imply that human iPSC-OPCs can be a therapeutic tool for MS. The results of this feasibility study on the potential use of hiPSC-derived OPCs are of great importance for all MS researchers focusing on the stimulation of remyelination in MS patients. Further optimization and research on practical issues related to the safe production and administration of iPSC-derived cell grafts will likely lead to a first clinical trial in a small group of secondary progressive MS patients. This would be the first specific therapeutic approach aimed at restoring myelination and rescuing axons in MS patients, since there is no treatment available for this most debilitating aspect of MS.
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Affiliation(s)
- Arun Thiruvalluvan
- Department of Neuroscience, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Marcin Czepiel
- Department of Neuroscience, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Yolanda A Kap
- Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Ietje Mantingh-Otter
- Department of Neuroscience, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Ilia Vainchtein
- Department of Neuroscience, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Jeroen Kuipers
- Department of Cell Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Marjolein Bijlard
- Department of Cell Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Wia Baron
- Department of Cell Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Ben Giepmans
- Department of Cell Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Wolfgang Brück
- Department of Neuropathology, University Medical Centre Göttingen, Göttingen, Germany
| | - Bert A 't Hart
- Department of Neuroscience, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
- Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Erik Boddeke
- Department of Neuroscience, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Sjef Copray
- Department of Neuroscience, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
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22
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Song MJ, Bharti K. Looking into the future: Using induced pluripotent stem cells to build two and three dimensional ocular tissue for cell therapy and disease modeling. Brain Res 2016; 1638:2-14. [PMID: 26706569 PMCID: PMC4837038 DOI: 10.1016/j.brainres.2015.12.011] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 11/24/2015] [Accepted: 12/08/2015] [Indexed: 01/02/2023]
Abstract
Retinal degenerative diseases are the leading cause of irreversible vision loss in developed countries. In many cases the diseases originate in the homeostatic unit in the back of the eye that contains the retina, retinal pigment epithelium (RPE) and the choriocapillaris. RPE is a central and a critical component of this homeostatic unit, maintaining photoreceptor function and survival on the apical side and choriocapillaris health on the basal side. In diseases like age-related macular degeneration (AMD), it is thought that RPE dysfunctions cause disease-initiating events and as the RPE degenerates photoreceptors begin to die and patients start loosing vision. Patient-specific induced pluripotent stem (iPS) cell-derived RPE provides direct access to a patient's genetics and allow the possibility of identifying the initiating events of RPE-associated degenerative diseases. Furthermore, iPS cell-derived RPE cells are being tested as a potential cell replacement in disease stages with RPE atrophy. In this article we summarize the recent progress in the field of iPS cell-derived RPE "disease modeling" and cell therapies and also discuss the possibilities of developing a model of the entire homeostatic unit to aid in studying disease processes in the future. This article is part of a Special Issue entitled SI: PSC and the brain.
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Affiliation(s)
- Min Jae Song
- Unit on Ocular and Stem Cell Translational Research National Eye Institute, 10 Center Drive, Room 10B10, Bethesda, MD 20892, United States
| | - Kapil Bharti
- Unit on Ocular and Stem Cell Translational Research National Eye Institute, 10 Center Drive, Room 10B10, Bethesda, MD 20892, United States.
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23
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Sackett SD, Brown ME, Tremmel DM, Ellis T, Burlingham WJ, Odorico JS. Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation. Transplant Rev (Orlando) 2016; 30:61-70. [PMID: 26970668 DOI: 10.1016/j.trre.2016.02.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 02/05/2016] [Indexed: 01/20/2023]
Abstract
Tissues derived from induced pluripotent stem cells (iPSCs) are a promising source of cells for building various regenerative medicine therapies; from simply transplanting cells to reseeding decellularized organs to reconstructing multicellular tissues. Although reprogramming strategies for producing iPSCs have improved, the clinical use of iPSCs is limited by the presence of unique human leukocyte antigen (HLA) genes, the main immunologic barrier to transplantation. In order to overcome the immunological hurdles associated with allogeneic tissues and organs, the generation of patient-histocompatible iPSCs (autologous or HLA-matched cells) provides an attractive platform for personalized medicine. However, concerns have been raised as to the fitness, safety and immunogenicity of iPSC derivatives because of variable differentiation potential of different lines and the identification of genetic and epigenetic aberrations that can occur during the reprogramming process. In addition, significant cost and regulatory barriers may deter commercialization of patient specific therapies in the short-term. Nonetheless, recent studies provide some evidence of immunological benefit for using autologous iPSCs. Yet, more studies are needed to evaluate the immunogenicity of various autologous and allogeneic human iPSC-derived cell types as well as test various methods to abrogate rejection. Here, we present perspectives of using allogeneic vs. autologous iPSCs for transplantation therapies and the advantages and disadvantages of each related to differentiation potential, immunogenicity, genetic stability and tumorigenicity. We also review the current literature on the immunogenicity of syngeneic iPSCs and discuss evidence that questions the feasibility of HLA-matched iPSC banks. Finally, we will discuss emerging methods of abrogating or reducing host immune responses to PSC derivatives.
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Affiliation(s)
- S D Sackett
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - M E Brown
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - D M Tremmel
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - T Ellis
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - W J Burlingham
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - J S Odorico
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
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24
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Kempf H, Andree B, Zweigerdt R. Large-scale production of human pluripotent stem cell derived cardiomyocytes. Adv Drug Deliv Rev 2016; 96:18-30. [PMID: 26658242 DOI: 10.1016/j.addr.2015.11.016] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Revised: 11/19/2015] [Accepted: 11/25/2015] [Indexed: 12/20/2022]
Abstract
Regenerative medicine, including preclinical studies in large animal models and tissue engineering approaches as well as innovative assays for drug discovery, will require the constant supply of hPSC-derived cardiomyocytes and other functional progenies. Respective cell production processes must be robust, economically viable and ultimately GMP-compliant. Recent research has enabled transition of lab scale protocols for hPSC expansion and cardiomyogenic differentiation towards more controlled processing in industry-compatible culture platforms. Here, advanced strategies for the cultivation and differentiation of hPSCs will be reviewed by focusing on stirred bioreactor-based techniques for process upscaling. We will discuss how cardiomyocyte mass production might benefit from recent findings such as cell expansion at the cardiovascular progenitor state. Finally, remaining challenges will be highlighted, specifically regarding three dimensional (3D) hPSC suspension culture and critical safety issues ahead of clinical translation.
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Affiliation(s)
- Henning Kempf
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiac, Thoracic-, Transplantation and Vascular Surgery, Hannover Medical School, Germany; REBIRTH-Cluster of Excellence, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
| | - Birgit Andree
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiac, Thoracic-, Transplantation and Vascular Surgery, Hannover Medical School, Germany; REBIRTH-Cluster of Excellence, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
| | - Robert Zweigerdt
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiac, Thoracic-, Transplantation and Vascular Surgery, Hannover Medical School, Germany; REBIRTH-Cluster of Excellence, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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25
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Zarbin M. Cell-Based Therapy for Degenerative Retinal Disease. Trends Mol Med 2016; 22:115-134. [PMID: 26791247 DOI: 10.1016/j.molmed.2015.12.007] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Revised: 12/16/2015] [Accepted: 12/17/2015] [Indexed: 12/21/2022]
Abstract
Stem cell-derived retinal pigment epithelium (RPE) and photoreceptors (PRs) have restored vision in preclinical models of human retinal degenerative disease. This review discusses characteristics of stem cell therapy in the eye and the challenges to clinical implementation that are being confronted today. Based on encouraging results from Phase I/II trials, the first Phase II clinical trials of stem cell-derived RPE transplantation are underway. PR transplant experiments have demonstrated restoration of visual function in preclinical models of retinitis pigmentosa and macular degeneration, but also indicate that no single approach is likely to succeed in overcoming PR loss in all cases. A greater understanding of the mechanisms controlling synapse formation as well as the immunoreactivity of transplanted retinal cells is urgently needed.
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Affiliation(s)
- Marco Zarbin
- Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
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26
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Asprer JST, Lakshmipathy U. Current methods and challenges in the comprehensive characterization of human pluripotent stem cells. Stem Cell Rev Rep 2016; 11:357-72. [PMID: 25504379 DOI: 10.1007/s12015-014-9580-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Pluripotent stem cells (PSCs) are powerful tools for basic scientific research and promising agents for drug discovery and regenerative medicine. Technological advances have made it increasingly easy to generate PSCs but the various lines generated may differ in their characteristics based on their origin, derivation, number of passages, and culture conditions. In order to confirm the pluripotency, quality, identity, and safety of pluripotent cell lines as they are derived and maintained, it is critical to perform a panel of characterization assays. Functional pluripotency is determined using tests that rely on the expression of specific markers in the undifferentiated and differentiated states; tests for quality, identity and safety are less specialized. This article provides a comprehensive review of current practices in PSC characterization and explores challenges in the field, from the selection of markers to the development of simple and scalable methods. It also delves into emerging trends like the adoption of alternative assays that could be used to supplement or replace traditional methods, specifically the use of in silico assays for determining pluripotency.
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Affiliation(s)
- Joanna S T Asprer
- Cell Biology, Life Sciences Solutions, Thermo Fisher Scientific, 5781 Van Allen Way, Carlsbad, CA, 92008, USA
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27
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Abstract
The discovery of induced pluripotent stem cells (iPSCs) and concurrent development of protocols for their cell-type specific differentiation have revolutionized studies of diseases and raised the possibility that personalized medicine may be achievable. Realizing the full potential of iPSC will require addressing the challenges inherent in obtaining appropriate cells for millions of individuals while meeting the regulatory requirements of delivering therapy and keeping costs affordable. Critical to making PSC based cell therapy widely accessible is determining which mode of cell collection, storage and distribution, will work. In this manuscript we suggest that moderate sized bank where a diverse set of lines carrying different combinations of commonly present HLA alleles are banked and differentiated cells are made available to matched recipients as need dictates may be a solution. We discuss the issues related to developing such a bank and how it could be constructed and propose a bank of selected HLA phenotypes from carefully screened healthy individuals as a solution to delivering personalized medicine.
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Affiliation(s)
- Susan Solomon
- New York Stem Cell Foundation, 1995 S. Broadway, New York, NY, 10023, USA
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28
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Gamm DM, Wong R. Report on the National Eye Institute Audacious Goals Initiative: Photoreceptor Regeneration and Integration Workshop. Transl Vis Sci Technol 2015; 4:2. [PMID: 26629398 DOI: 10.1167/tvst.4.6.2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 10/15/2015] [Indexed: 01/16/2023] Open
Abstract
The National Eye Institute (NEI) hosted a workshop on May 2, 2015, as part of the Audacious Goals Initiative (AGI) to foster a concerted effort to develop novel therapies for outer retinal diseases. The central goal of this initiative is to "demonstrate by 2025 the restoration of usable vision in humans through the regeneration of neurons and neural connections in the eye and visual system." More specifically, the AGI identified two neural retinal cell classes-ganglion cells and photoreceptors-as challenging, high impact targets for these efforts. A prior workshop and subsequent white paper provided a foundation to begin addressing issues regarding optic nerve regeneration, whereas the major objective of the May 2015 workshop was to review progress toward photoreceptor replacement and identify research gaps and barriers that are limiting advancement of the field. The present report summarizes that discussion and input, which was gathered from a panel of distinguished basic science and clinical investigators with diverse technical expertise and experience with different model systems. Four broad discussion categories were put forth during the workshop, each addressing a critical area of need in the pursuit of functional photoreceptor regeneration: (1) cell sources for photoreceptor regeneration, (2) cell delivery and/or integration, (3) outcome assessment, and (4) preclinical models and target patient populations. For each category, multiple challenges and opportunities for research discovery and tool production were identified and vetted. The present report summarizes the dialogue that took place and seeks to encourage continued interactions within the vision science community on this topic. It also serves as a guide for funding to support the pursuit of cell and circuit repair in diseases leading to photoreceptor degeneration.
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Affiliation(s)
- David M Gamm
- Department of Ophthalmology and Visual Sciences and McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI, USA
| | - Rachel Wong
- Department of Biological Structure, University of Washington, Seattle, WA, USA
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Epsztejn-Litman S, Cohen-Hadad Y, Aharoni S, Altarescu G, Renbaum P, Levy-Lahad E, Schonberger O, Eldar-Geva T, Zeligson S, Eiges R. Establishment of Homozygote Mutant Human Embryonic Stem Cells by Parthenogenesis. PLoS One 2015; 10:e0138893. [PMID: 26473610 PMCID: PMC4608834 DOI: 10.1371/journal.pone.0138893] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 09/04/2015] [Indexed: 01/07/2023] Open
Abstract
We report on the derivation of a diploid 46(XX) human embryonic stem cell (HESC) line that is homozygous for the common deletion associated with Spinal muscular atrophy type 1 (SMA) from a pathenogenetic embryo. By characterizing the methylation status of three different imprinted loci (MEST, SNRPN and H19), monitoring the expression of two parentally imprinted genes (SNRPN and H19) and carrying out genome-wide SNP analysis, we provide evidence that this cell line was established from the activation of a mutant oocyte by diploidization of the entire genome. Therefore, our SMA parthenogenetic HESC (pHESC) line provides a proof-of-principle for the establishment of diseased HESC lines without the need for gene manipulation. As mutant oocytes are easily obtained and readily available during preimplantation genetic diagnosis (PGD) cycles, this approach should provide a powerful tool for disease modelling and is especially advantageous since it can be used to induce large or complex mutations in HESCs, including gross DNA alterations and chromosomal rearrangements, which are otherwise hard to achieve.
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Affiliation(s)
- Silvina Epsztejn-Litman
- Stem Cell Research Laboratory, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Yaara Cohen-Hadad
- Stem Cell Research Laboratory, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Shira Aharoni
- Stem Cell Research Laboratory, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Gheona Altarescu
- Zohar PGD Lab, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Paul Renbaum
- Zohar PGD Lab, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Ephrat Levy-Lahad
- Zohar PGD Lab, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Oshrat Schonberger
- IVF Unit, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Talia Eldar-Geva
- IVF Unit, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Sharon Zeligson
- Zohar PGD Lab, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Rachel Eiges
- Stem Cell Research Laboratory, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
- * E-mail:
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Vanhee S, Vandekerckhove B. Pluripotent stem cell based gene therapy for hematological diseases. Crit Rev Oncol Hematol 2015; 97:238-46. [PMID: 26381313 DOI: 10.1016/j.critrevonc.2015.08.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 07/04/2015] [Accepted: 08/26/2015] [Indexed: 01/26/2023] Open
Abstract
Standard treatment for severe inherited hematopoietic diseases consists of allogeneic stem cell transplantation. Alternatively, patients can be treated with gene therapy: gene-corrected autologous hematopoietic stem and progenitor cells (HSPC) are transplanted. By using retro- or lentiviral vectors, a copy of the functional gene is randomly inserted in the DNA of the HSPC and becomes constitutively expressed. Gene therapy is currently limited to monogenic diseases for which clinical trials are being actively conducted in highly specialized centers around the world. This approach, although successful, carries with it inherent safety and efficacy issues. Recently, two technologies became available that, when combined, may enable treatment of genetic defects by HSPC that have the non-functional allele replaced by a functional copy. One technology consists of the generation of induced pluripotent stem cells (iPSC) from patient blood samples or skin biopsies, the other concerns nuclease-mediated gene editing. Both technologies have been successfully combined in basic research and appear applicable in the clinic. This paper reviews recent literature, discusses what can be achieved in the clinic using present knowledge and points out further research directions.
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Affiliation(s)
- Stijn Vanhee
- Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Belgium
| | - Bart Vandekerckhove
- Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Belgium.
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31
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Collart-Dutilleul PY, Chaubron F, Vos JD, Cuisinier FJ. Allogenic banking of dental pulp stem cells for innovative therapeutics. World J Stem Cells 2015; 7:1010-1021. [PMID: 26328017 PMCID: PMC4550625 DOI: 10.4252/wjsc.v7.i7.1010] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 04/10/2015] [Accepted: 06/19/2015] [Indexed: 02/06/2023] Open
Abstract
Medical research in regenerative medicine and cell-based therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells (DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products (ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen (HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues (dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice (GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat.
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Li K, Javed E, Scura D, Hala TJ, Seetharam S, Falnikar A, Richard JP, Chorath A, Maragakis NJ, Wright MC, Lepore AC. Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury. Exp Neurol 2015. [PMID: 26216662 DOI: 10.1016/j.expneurol.2015.07.020] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Transplantation-based replacement of lost and/or dysfunctional astrocytes is a promising therapy for spinal cord injury (SCI) that has not been extensively explored, despite the integral roles played by astrocytes in the central nervous system (CNS). Induced pluripotent stem (iPS) cells are a clinically-relevant source of pluripotent cells that both avoid ethical issues of embryonic stem cells and allow for homogeneous derivation of mature cell types in large quantities, potentially in an autologous fashion. Despite their promise, the iPS cell field is in its infancy with respect to evaluating in vivo graft integration and therapeutic efficacy in SCI models. Astrocytes express the major glutamate transporter, GLT1, which is responsible for the vast majority of glutamate uptake in spinal cord. Following SCI, compromised GLT1 expression/function can increase susceptibility to excitotoxicity. We therefore evaluated intraspinal transplantation of human iPS cell-derived astrocytes (hIPSAs) following cervical contusion SCI as a novel strategy for reconstituting GLT1 expression and for protecting diaphragmatic respiratory neural circuitry. Transplant-derived cells showed robust long-term survival post-injection and efficiently differentiated into astrocytes in injured spinal cord of both immunesuppressed mice and rats. However, the majority of transplant-derived astrocytes did not express high levels of GLT1, particularly at early times post-injection. To enhance their ability to modulate extracellular glutamate levels, we engineered hIPSAs with lentivirus to constitutively express GLT1. Overexpression significantly increased GLT1 protein and functional GLT1-mediated glutamate uptake levels in hIPSAs both in vitro and in vivo post-transplantation. Compared to human fibroblast control and unmodified hIPSA transplantation, GLT1-overexpressing hIPSAs reduced (1) lesion size within the injured cervical spinal cord, (2) morphological denervation by respiratory phrenic motor neurons at the diaphragm neuromuscular junction, and (3) functional diaphragm denervation as measured by recording of spontaneous EMGs and evoked compound muscle action potentials. Our findings demonstrate that hiPSA transplantation is a therapeutically-powerful approach for SCI.
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Affiliation(s)
- Ke Li
- Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, PA 19107, United States.
| | - Elham Javed
- Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, PA 19107, United States.
| | - Daniel Scura
- Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, PA 19107, United States.
| | - Tamara J Hala
- Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, PA 19107, United States.
| | - Suneil Seetharam
- Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, PA 19107, United States.
| | - Aditi Falnikar
- Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, PA 19107, United States.
| | - Jean-Philippe Richard
- Department of Neurology, Johns Hopkins University School of Medicine, 855N. Wolfe St., Rangos 250, Baltimore, MD 21205, United States.
| | - Ashley Chorath
- Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, PA 19107, United States.
| | - Nicholas J Maragakis
- Department of Neurology, Johns Hopkins University School of Medicine, 855N. Wolfe St., Rangos 250, Baltimore, MD 21205, United States.
| | - Megan C Wright
- Department of Biology, Arcadia University, 450S. Easton Rd., 220 Boyer Hall, Glenside, PA 19038, United States.
| | - Angelo C Lepore
- Department of Neuroscience, Farber Institute for Neurosciences, Sidney Kimmel Medical College at Thomas Jefferson University, 900 Walnut Street, JHN 469, Philadelphia, PA 19107, United States.
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33
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Bolton EM, Bradley JA. Avoiding immunological rejection in regenerative medicine. Regen Med 2015; 10:287-304. [DOI: 10.2217/rme.15.11] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
One of the major goals of regenerative medicine is repair or replacement of diseased and damaged tissues by transfer of differentiated stem cells or stem cell-derived tissues. The possibility that these tissues will be destroyed by immunological rejection remains a challenge that can only be overcome through a better understanding of the nature and expression of potentially immunogenic molecules associated with cell replacement therapy and the mechanisms and pathways resulting in their immunologic rejection. This review draws on clinical experience of organ and tissue transplantation, and on transplantation immunology research to consider practical approaches for avoiding and overcoming the possibility of rejection of stem cell-derived tissues.
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Affiliation(s)
- Eleanor M Bolton
- Department of Surgery, University of Cambridge, Box 202, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - John Andrew Bradley
- Department of Surgery, University of Cambridge, Box 202, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
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34
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Carpenter MK, Rao MS. Concise review: making and using clinically compliant pluripotent stem cell lines. Stem Cells Transl Med 2015; 4:381-8. [PMID: 25722426 DOI: 10.5966/sctm.2014-0202] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
The field of pluripotent stem cells (PSCs) is in a state of dynamic flux driven by significant advances in the derivation of specific phenotypes from embryonic stem cells, breakthroughs in somatic cell nuclear transfer, and dramatic improvements in generating induced PSCs using zero footprint methods. Spurred by these technological advances, companies have begun to plan clinical studies using human PSC derivatives manufactured in current Good Manufacturing Practice-compliant conditions. In the present review, we discuss the challenges in making these biological products, starting from tissue sourcing to the processes involved in manufacture, storage, and distribution. Additional challenges exist to meeting the regulatory requirements and keeping costs affordable. A model is described that has been proposed by the U.S. National Institutes of Health for reducing the costs and permitting flexibility and innovation by individual investigators. This model, combined with small adjustments in the regulatory processes tailored to address the unique properties of PSCs, has the potential of significantly accelerating the implementation of PSC-based cell therapy.
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Affiliation(s)
- Melissa K Carpenter
- Carpenter Group Consulting Inc., Black Diamond, Washington, USA; NxCell Inc., Novato, California, USA; Q Therapeutics Inc., Salt Lake City, Utah, USA
| | - Mahendra S Rao
- Carpenter Group Consulting Inc., Black Diamond, Washington, USA; NxCell Inc., Novato, California, USA; Q Therapeutics Inc., Salt Lake City, Utah, USA
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35
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Schlinker AC, Radwanski K, Wegener C, Min K, Miller WM. Separation of in-vitro-derived megakaryocytes and platelets using spinning-membrane filtration. Biotechnol Bioeng 2014; 112:788-800. [PMID: 25312394 DOI: 10.1002/bit.25477] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 09/22/2014] [Accepted: 09/30/2014] [Indexed: 02/06/2023]
Abstract
In-vitro-derived platelets (PLTs) could potentially overcome problems associated with donated PLTs, including contamination and alloimmunization. Although several groups have produced functional PLTs from stem cells in vitro, the challenge of developing this technology to yield transfusable PLT units has yet to be addressed. The asynchronous nature of in vitro PLT generation makes a single harvest point infeasible for collecting PLTs as soon as they are formed. The current standard of performing manual centrifugations to separate PLTs from nucleated cells at multiple points during culture is labor-intensive, imprecise, and difficult to standardize in accordance with current Good Manufacturing Practices (cGMP). In an effort to develop a more effective method, we adapted a commercially-available, spinning-membrane filtration device to separate in-vitro-derived PLTs from nucleated cells and recover immature megakaryocytes (MKs), the precursor cells to PLTs, for continued culture. Processing a mixture of in-vitro-derived MKs and PLTs on the adapted device yielded a pure PLT population and did not induce PLT pre-activation. MKs recovered from the separation process were unaffected with respect to viability and ploidy, and were able to generate PLTs after reseeding in culture. Being able to efficiently harvest in-vitro-derived PLTs brings this technology one step closer to clinical relevance.
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Affiliation(s)
- Alaina C Schlinker
- Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Rd., Tech E136, Evanston, Illinois, 60208-3120
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36
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Diecke S, Jung SM, Lee J, Ju JH. Recent technological updates and clinical applications of induced pluripotent stem cells. Korean J Intern Med 2014; 29:547-57. [PMID: 25228828 PMCID: PMC4164716 DOI: 10.3904/kjim.2014.29.5.547] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Accepted: 07/22/2014] [Indexed: 12/23/2022] Open
Abstract
Induced pluripotent stem cells (iPSCs) were first described in 2006 and have since emerged as a promising cell source for clinical applications. The rapid progression in iPSC technology is still ongoing and directed toward increasing the efficacy of iPSC production and reducing the immunogenic and tumorigenic potential of these cells. Enormous efforts have been made to apply iPSC-based technology in the clinic, for drug screening approaches and cell replacement therapy. Moreover, disease modeling using patient-specific iPSCs continues to expand our knowledge regarding the pathophysiology and prospective treatment of rare disorders. Furthermore, autologous stem cell therapy with patient-specific iPSCs shows great propensity for the minimization of immune reactions and the provision of a limitless supply of cells for transplantation. In this review, we discuss the recent updates in iPSC technology and the use of iPSCs in disease modeling and regenerative medicine.
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Affiliation(s)
- Sebastian Diecke
- Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Seung Min Jung
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jaecheol Lee
- Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Ji Hyeon Ju
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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37
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Potential and limitation of HLA-based banking of human pluripotent stem cells for cell therapy. J Immunol Res 2014; 2014:518135. [PMID: 25126584 PMCID: PMC4121106 DOI: 10.1155/2014/518135] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 06/06/2014] [Accepted: 06/18/2014] [Indexed: 12/13/2022] Open
Abstract
Great hopes have been placed on human pluripotent stem (hPS) cells for therapy. Tissues or organs derived from hPS cells could be the best solution to cure many different human diseases, especially those who do not respond to standard medication or drugs, such as neurodegenerative diseases, heart failure, or diabetes. The origin of hPS is critical and the idea of creating a bank of well-characterized hPS cells has emerged, like the one that already exists for cord blood. However, the main obstacle in transplantation is the rejection of tissues or organ by the receiver, due to the three main immunological barriers: the human leukocyte antigen (HLA), the ABO blood group, and minor antigens. The problem could be circumvented by using autologous stem cells, like induced pluripotent stem (iPS) cells, derived directly from the patient. But iPS cells have limitations, especially regarding the disease of the recipient and possible difficulties to handle or prepare autologous iPS cells. Finally, reaching standards of good clinical or manufacturing practices could be challenging. That is why well-characterized and universal hPS cells could be a better solution. In this review, we will discuss the interest and the feasibility to establish hPS cells bank, as well as some economics and ethical issues.
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MHC-matched induced pluripotent stem cells can attenuate cellular and humoral immune responses but are still susceptible to innate immunity in pigs. PLoS One 2014; 9:e98319. [PMID: 24927426 PMCID: PMC4057111 DOI: 10.1371/journal.pone.0098319] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Accepted: 04/30/2014] [Indexed: 12/16/2022] Open
Abstract
Recent studies have revealed negligible immunogenicity of induced pluripotent stem (iPS) cells in syngeneic mice and in autologous monkeys. Therefore, human iPS cells would not elicit immune responses in the autologous setting. However, given that human leukocyte antigen (HLA)-matched allogeneic iPS cells would likely be used for medical applications, a more faithful model system is needed to reflect HLA-matched allogeneic settings. Here we examined whether iPS cells induce immune responses in the swine leukocyte antigen (SLA)-matched setting. iPS cells were generated from the SLA-defined C1 strain of Clawn miniature swine, which were confirmed to develop teratomas in mice, and transplanted into the testes (n = 4) and ovary (n = 1) of C1 pigs. No teratomas were found in pigs on 47 to 125 days after transplantation. A Mixed lymphocyte reaction revealed that T-cell responses to the transplanted MHC-matched (C1) iPS cells were significantly lower compared to allogeneic cells. The humoral immune responses were also attenuated in the C1-to-C1 setting. More importantly, even MHC-matched iPS cells were susceptible to innate immunity, NK cells and serum complement. iPS cells lacked the expression of SLA class I and sialic acids. The in vitro cytotoxic assay showed that C1 iPS cells were targeted by NK cells and serum complement of C1. In vivo, the C1 iPS cells developed larger teratomas in NK-deficient NOG (T-B-NK-) mice (n = 10) than in NK-competent NOD/SCID (T-B-NK+) mice (n = 8) (p<0.01). In addition, C1 iPS cell failed to form teratomas after incubation with the porcine complement-active serum. Taken together, MHC-matched iPS cells can attenuate cellular and humoral immune responses, but still susceptible to innate immunity in pigs.
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39
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Induced pluripotent stem cells in hematology: current and future applications. Blood Cancer J 2014; 4:e211. [PMID: 24813079 PMCID: PMC4042300 DOI: 10.1038/bcj.2014.30] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 03/26/2014] [Accepted: 04/02/2014] [Indexed: 12/18/2022] Open
Abstract
Reprogramming somatic cells into induced pluripotent stem (iPS) cells is nowadays approaching effectiveness and clinical grade. Potential uses of this technology include predictive toxicology, drug screening, pathogenetic studies and transplantation. Here, we review the basis of current iPS cell technology and potential applications in hematology, ranging from disease modeling of congenital and acquired hemopathies to hematopoietic stem and other blood cell transplantation.
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40
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Liu H, Zhu S, Zhang C, Lu P, Hu J, Yin Z, Ma Y, Chen X, OuYang H. Crucial transcription factors in tendon development and differentiation: their potential for tendon regeneration. Cell Tissue Res 2014; 356:287-98. [PMID: 24705622 DOI: 10.1007/s00441-014-1834-8] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 01/30/2014] [Indexed: 12/22/2022]
Abstract
Tendons that connect muscles to bone are often the targets of sports injuries. The currently unsatisfactory state of tendon repair is largely attributable to the limited understanding of basic tendon biology. A number of tendon lineage-related transcription factors have recently been uncovered and provide clues for the better understanding of tendon development. Scleraxis and Mohawk have been identified as critical transcription factors in tendon development and differentiation. Other transcription factors, such as Sox9 and Egr1/2, have also been recently reported to be involved in tendon development. However, the molecular mechanisms and application of these transcription factors remain largely unclear and this prohibits their use in tendon therapy. Here, we systematically review and analyze recent findings and our own data concerning tendon transcription factors and tendon regeneration. Based on these findings, we provide interaction and temporal programming maps of transcription factors, as a basis for future tendon therapy. Finally, we discuss future directions for tendon regeneration with differentiation and trans-differentiation approaches based on transcription factors.
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Affiliation(s)
- Huanhuan Liu
- Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, 310058, China
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41
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Ebrahimkhani S, Farjadian S, Ebrahimi M. The Royan Public Umbilical Cord Blood Bank: Does It Cover All Ethnic Groups in Iran Based on HLA Diversity? ACTA ACUST UNITED AC 2014; 41:134-8. [PMID: 24847189 DOI: 10.1159/000357997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 09/03/2013] [Indexed: 11/19/2022]
Abstract
BACKGROUND Umbilical cord blood (UCB) stem cells allow the transplantation of partially human leukocyte antigen (HLA)-matched grafts and are a valuable resource for the treatment of hematologic malignancies and heritable hematologic, immunologic and metabolic diseases, especially when a compatible bone marrow donor is unavailable. The aim of this study was to determine how many ethnic groups in Iran are covered by the available UCB units based on HLA diversity. METHODS From 2009 until mid-2013, 4,981 (30.3%) of the 16,437 UCB samples collected met the storage criteria and were cryopreserved at a public cord blood bank (CBB) in Tehran, Iran. HLA-A, -B and -DRB1 were typed in 1,793 samples. RESULTS The mean volume of the cryopreserved samples was 81.25 ± 20.3 ml. The range of total nucleated cells per unit was 51 × 10(7)-107 × 10(7). The most common HLA alleles were HLA-A*2 (17%) and HLA-A*24 (15.6%), HLA-B*35 (16.8%) and HLA-B*51 (13.9%), and HLA-DRB1*11 (20%) and HLA-DRB1*15 (14%). The predominant haplotypes were HLA-A*24-B*35-DRB1*11 (2%), HLA-A*02-B*50-DR*07 (1.8%), and HLA-A*02-B*51-DRB1*11 (1.5%). CONCLUSIONS Based on the HLA-DRB1 profiles, the UCB units available at the Royan public UCB bank are a potentially adequate resource for hematopoietic stem cell transplantation for Iranian recipients belonging to particular ethnic groups. Regular educational programs to improve the public knowledge of UCB for transplantation can enhance the public CBB stocks for all Iranian ethnic groups in the future.
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Affiliation(s)
- Saeideh Ebrahimkhani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Shirin Farjadian
- Department of Immunology, Shiraz University of Medical Sciences, Tehran, Iran
| | - Marzieh Ebrahimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran ; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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Lee J, Kim Y, Yi H, Diecke S, Kim J, Jung H, Rim YA, Jung SM, Kim M, Kim YG, Park SH, Kim HY, Ju JH. Generation of disease-specific induced pluripotent stem cells from patients with rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 2014; 16:R41. [PMID: 24490617 PMCID: PMC3978583 DOI: 10.1186/ar4470] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 01/15/2014] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Since the concept of reprogramming mature somatic cells to generate induced pluripotent stem cells (iPSCs) was demonstrated in 2006, iPSCs have become a potential substitute for embryonic stem cells (ESCs) given their pluripotency and "stemness" characteristics, which resemble those of ESCs. We investigated to reprogram fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) to generate iPSCs using a 4-in-1 lentiviral vector system. METHODS A 4-in-1 lentiviral vector containing Oct4, Sox2, Klf4, and c-Myc was transduced into RA and OA FLSs isolated from the synovia of two RA patients and two OA patients. Immunohistochemical staining and real-time PCR studies were performed to demonstrate the pluripotency of iPSCs. Chromosomal abnormalities were determined based on the karyotype. SCID-beige mice were injected with iPSCs and sacrificed to test for teratoma formation. RESULTS After 14 days of transduction using the 4-in-1 lentiviral vector, RA FLSs and OA FLSs were transformed into spherical shapes that resembled embryonic stem cell colonies. Colonies were picked and cultivated on matrigel plates to produce iPSC lines. Real-time PCR of RA and OA iPSCs detected positive markers of pluripotency. Immunohistochemical staining tests with Nanog, Oct4, Sox2, Tra-1-80, Tra-1-60, and SSEA-4 were also positive. Teratomas that comprised three compartments of ectoderm, mesoderm, and endoderm were formed at the injection sites of iPSCs. Established iPSCs were shown to be compatible by karyotyping. Finally, we confirmed that the patient-derived iPSCs were able to differentiate into osteoblast, which was shown by an osteoimage mineralization assay. CONCLUSION FLSs derived from RA and OA could be cell resources for iPSC reprogramming. Disease- and patient-specific iPSCs have the potential to be applied in clinical settings as source materials for molecular diagnosis and regenerative therapy.
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Considerations for pre-clinical models and clinical trials of pluripotent stem cell-derived cardiomyocytes. Stem Cell Res Ther 2014; 5:1. [PMID: 24405778 PMCID: PMC4055070 DOI: 10.1186/scrt390] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Pluripotent stem cells (PSCs) represent an appealing source from which to develop cell replacement therapies. Different initiatives have been launched to promote their development toward clinical applications. This article will review the main questions that should be considered before translating PSC-derived cardiomyocytes into clinical investigations, including the development of good manufacturing practice-level PSC lines, the development of efficient protocols to generate pure populations of cardiac myocytes, and the development of techniques to improve the retention and survival rate of transplanted cells.
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Ramsden CM, Powner MB, Carr AJF, Smart MJK, da Cruz L, Coffey PJ. Stem cells in retinal regeneration: past, present and future. Development 2013; 140:2576-85. [PMID: 23715550 DOI: 10.1242/dev.092270] [Citation(s) in RCA: 176] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Stem cell therapy for retinal disease is under way, and several clinical trials are currently recruiting. These trials use human embryonic, foetal and umbilical cord tissue-derived stem cells and bone marrow-derived stem cells to treat visual disorders such as age-related macular degeneration, Stargardt's disease and retinitis pigmentosa. Over a decade of analysing the developmental cues involved in retinal generation and stem cell biology, coupled with extensive surgical research, have yielded differing cellular approaches to tackle these retinopathies. Here, we review these various stem cell-based approaches for treating retinal diseases and discuss future directions and challenges for the field.
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Affiliation(s)
- Conor M Ramsden
- The London Project to Cure Blindness, Division of ORBIT, Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK
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du Pré BC, Doevendans PA, van Laake LW. Stem cells for cardiac repair: an introduction. JOURNAL OF GERIATRIC CARDIOLOGY : JGC 2013; 10:186-97. [PMID: 23888179 PMCID: PMC3708059 DOI: 10.3969/j.issn.1671-5411.2013.02.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 02/16/2013] [Accepted: 04/22/2013] [Indexed: 12/11/2022]
Abstract
Cardiovascular disease is a major cause of morbidity and mortality throughout the world. Most cardiovascular diseases, such as ischemic heart disease and cardiomyopathy, are associated with loss of functional cardiomyocytes. Unfortunately, the heart has a limited regenerative capacity and is not able to replace these cardiomyocytes once lost. In recent years, stem cells have been put forward as a potential source for cardiac regeneration. Pre-clinical studies that use stem cell-derived cardiac cells show promising results. The mechanisms, though, are not well understood, results have been variable, sometimes transient in the long term, and often without a mechanistic explanation. There are still several major hurdles to be taken. Stem cell-derived cardiac cells should resemble original cardiac cell types and be able to integrate in the damaged heart. Integration requires administration of stem cell-derived cardiac cells at the right time using the right mode of delivery. Once delivered, transplanted cells need vascularization, electrophysiological coupling with the injured heart, and prevention of immunological rejection. Finally, stem cell therapy needs to be safe, reproducible, and affordable. In this review, we will give an introduction to the principles of stem cell based cardiac repair.
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Affiliation(s)
- Bastiaan C du Pré
- Departments of Cardiology and Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, P.O. box 85500, 3508 GA Utrecht, the Netherlands
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