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Zou YX, Kantapan J, Wang HL, Li JC, Su HW, Dai J, Dechsupa N, Wang L. Iron-Quercetin complex enhances mesenchymal stem cell-mediated HGF secretion and c-Met activation to ameliorate acute kidney injury through the prevention of tubular cell apoptosis. Regen Ther 2025; 28:169-182. [PMID: 39802634 PMCID: PMC11720445 DOI: 10.1016/j.reth.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/20/2024] [Accepted: 12/04/2024] [Indexed: 01/16/2025] Open
Abstract
Background Acute kidney injury (AKI) is a life-threatening clinical syndrome with no effective treatment currently available. This study aims to investigate whether Iron-Quercetin complex (IronQ) pretreatment can enhance the therapeutic efficacy of Mesenchymal stem cells (MSCs) in AKI and explore the underlying mechanisms. Methods A cisplatin-induced AKI model was established in male C57BL/6 mice, followed by the intravenous administration of 1x10ˆ6 MSCs or IronQ-pretreated MSCs (MSCIronQ). Renal function, histology, and tubular cell apoptosis were analyzed three days post-treatment. In vitro, apoptosis was induced in mouse tubular epithelial cells (mTECs) using cisplatin, followed by treatment with MSCs or MSCIronQ conditioned medium (CM). Apoptosis was evaluated using TUNEL assay, RT-PCR, and western blotting. Furthermore, RNA sequencing (RNA-seq) was performed on MSCIronQ to explore the underlying mechanisms. Results Compared to MSC-treated AKI mice, those treated with MSCIronQ showed significantly improved renal function and histological outcomes, with reduced tubular cell apoptosis. A similar effect was observed in cisplatin-treated mTECs exposed to MSCIronQ-CM. Mechanistically, RNA-seq and subsequent validation revealed that IronQ treatment markedly upregulated the expression and secretion of hepatocyte growth factor (HGF) in MSCs. Furthermore, RNA interference or antibody-mediated neutralization of HGF effectively abolished the anti-apoptotic effects of MSCIronQ on mTECs. This mechanistic insight was reinforced by pharmacological inhibition of c-Met, the specific receptor of HGF, in both in vitro and in vivo models. Conclusions IronQ pretreatment enhances MSCs efficacy in AKI by promoting HGF expression and secretion, activating the HGF/c-Met pathway to suppress tubular cell apoptosis. These findings indicate that IronQ improves MSC-based therapies and offers insights into molecular mechanisms, supporting the development of better AKI treatments.
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Affiliation(s)
- Yuan-Xia Zou
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
- Research Center for Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Children's Diagnosis and Treatment Center, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Jiraporn Kantapan
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Hong-Lian Wang
- Research Center for Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Jian-Chun Li
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
- Research Center for Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Hong-Wei Su
- Department of Urology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Jian Dai
- Research Center for Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Neurology, The Third People's Hospital, Luzhou, 646000, China
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Li Wang
- Research Center for Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China
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Riedel A, Faul C, Reuss K, Schröder JC, Lang PJ, Lengerke C, Weissert N, Hengel H, Gröschel S, Schoels L, Bethge WA. Allogeneic hematopoietic cell transplantation for adult metachromatic leukodystrophy: a case series. Blood Adv 2024; 8:1504-1508. [PMID: 38330194 PMCID: PMC10966161 DOI: 10.1182/bloodadvances.2023011836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 01/19/2024] [Accepted: 01/29/2024] [Indexed: 02/10/2024] Open
Abstract
ABSTRACT Metachromatic leukodystrophy (MLD) is a rare genetic disorder caused by pathogenic variants of the ARSA gene, leading to a deficiency of the arylsulfatase A enzyme (ARSA) and consecutive accumulation of galactosylceramide-3-0-sulfate in the nervous system. The condition leads to severe neurological deficits and subsequently results in profound intellectual and motoric disability. Especially, the adult form of MLD, which occurs in individuals aged >16 years, poses significant challenges for treating physicians because of the rarity of cases, limited therapeutic options, and different allogeneic hematopoietic cell transplantation (allo-HCT) protocols worldwide. Here, we report the results of allo-HCT treatment in 4 patients with a confirmed adult MLD diagnosis. Bone marrow or mobilized peripheral progenitor cells were infused after a reduced intensity conditioning regime consisting of fludarabine and treosulfan. In 3 patients, allo-HCT was followed by an infusion of mesenchymal cells to further consolidate ARSA production. We observed a good tolerability and an increase in ARSA levels up to normal range values in all patients. A full donor chimerism was detected in 3 patients within the first 12 months. In a 1-year follow-up, patients with complete donor chimerism showed a neurological stable condition. Only 1 patient with an increasing autologous chimerism showed neurological deterioration and a decline in ARSA levels in the first year. In summary, allo-HCT offers a therapeutic option for reconstituting ARSA enzyme levels in adult patients with MLD, with tolerable side effects.
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Affiliation(s)
- Andreas Riedel
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Christoph Faul
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Kristina Reuss
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Jan C. Schröder
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Peter J. Lang
- Department I, General Pediatrics, Hematology and Oncology, University Children's Hospital Tuebingen, Tuebingen, Germany
| | - Claudia Lengerke
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Nadine Weissert
- Deutsches Zentrum für Neurodegenerative Erkrankungen, Tuebingen, Germany
- Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
| | - Holger Hengel
- Deutsches Zentrum für Neurodegenerative Erkrankungen, Tuebingen, Germany
- Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
| | - Samuel Gröschel
- Department III, Neuropediatrics, University Children's Hospital Tuebingen, Tuebingen, Germany
| | - Ludger Schoels
- Deutsches Zentrum für Neurodegenerative Erkrankungen, Tuebingen, Germany
- Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
| | - Wolfgang A. Bethge
- Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
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Laugwitz L, Schoenmakers DH, Adang LA, Beck-Woedl S, Bergner C, Bernard G, Bley A, Boyer A, Calbi V, Dekker H, Eichler F, Eklund E, Fumagalli F, Gavazzi F, Grønborg SW, van Hasselt P, Langeveld M, Lindemans C, Mochel F, Oberg A, Ram D, Saunier-Vivar E, Schöls L, Scholz M, Sevin C, Zerem A, Wolf NI, Groeschel S. Newborn screening in metachromatic leukodystrophy - European consensus-based recommendations on clinical management. Eur J Paediatr Neurol 2024; 49:141-154. [PMID: 38554683 DOI: 10.1016/j.ejpn.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 02/29/2024] [Accepted: 03/04/2024] [Indexed: 04/02/2024]
Abstract
INTRODUCTION Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder resulting from arylsulfatase A enzyme deficiency, leading to toxic sulfatide accumulation. As a result affected individuals exhibit progressive neurodegeneration. Treatments such as hematopoietic stem cell transplantation (HSCT) and gene therapy are effective when administered pre-symptomatically. Newborn screening (NBS) for MLD has recently been shown to be technically feasible and is indicated because of available treatment options. However, there is a lack of guidance on how to monitor and manage identified cases. This study aims to establish consensus among international experts in MLD and patient advocates on clinical management for NBS-identified MLD cases. METHODS A real-time Delphi procedure using eDELPHI software with 22 experts in MLD was performed. Questions, based on a literature review and workshops, were answered during a seven-week period. Three levels of consensus were defined: A) 100%, B) 75-99%, and C) 50-74% or >75% but >25% neutral votes. Recommendations were categorized by agreement level, from strongly recommended to suggested. Patient advocates participated in discussions and were involved in the final consensus. RESULTS The study presents 57 statements guiding clinical management of NBS-identified MLD patients. Key recommendations include timely communication by MLD experts with identified families, treating early-onset MLD with gene therapy and late-onset MLD with HSCT, as well as pre-treatment monitoring schemes. Specific knowledge gaps were identified, urging prioritized research for future evidence-based guidelines. DISCUSSION Consensus-based recommendations for NBS in MLD will enhance harmonized management and facilitate integration in national screening programs. Structured data collection and monitoring of screening programs are crucial for evidence generation and future guideline development. Involving patient representatives in the development of recommendations seems essential for NBS programs.
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Affiliation(s)
- Lucia Laugwitz
- Neuropediatrics, General Pediatrics, Diabetology, Endocrinology and Social Pediatrics, University of Tuebingen, University Hospital Tübingen, 72016, Tübingen, Germany; Institute for Medical Genetics and Applied Genomics, University of Tübingen, 72070, Tübingen, Germany.
| | - Daphne H Schoenmakers
- Department of Child Neurology, Emma's Children's Hospital, Amsterdam UMC Location Vrije Universiteit, Amsterdam, the Netherlands; Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Amsterdam, the Netherlands; Medicine for Society, Platform at Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands
| | - Laura A Adang
- Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Stefanie Beck-Woedl
- Institute for Medical Genetics and Applied Genomics, University of Tübingen, 72070, Tübingen, Germany
| | - Caroline Bergner
- Leukodystrophy Center, Departement of Neurology, University Hospital Leipzig, Germany
| | - Geneviève Bernard
- Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, Canada; Department Specialized Medicine, Division of Medical Genetics, McGill University Health Center, Montreal, Canada; Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, Canada
| | | | | | - Valeria Calbi
- Pediatric Immuno-Hematology Unit, Ospedale San Raffaele Milan, Italy; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Milan, Italy
| | - Hanka Dekker
- Dutch Association for Inherited Metabolic Diseases (VKS), the Netherlands
| | | | - Erik Eklund
- Pediatrics, Clinical Sciences, Lund University, Sweden
| | - Francesca Fumagalli
- Pediatric Immuno-Hematology Unit, Ospedale San Raffaele Milan, Italy; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Milan, Italy; Unit of Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Gavazzi
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Sabine W Grønborg
- Center for Inherited Metabolic Diseases, Department of Pediatrics and Adolescent Medicine and Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Peter van Hasselt
- Department of Metabolic Diseases, University Medical Center Utrecht, the Netherlands
| | - Mirjam Langeveld
- Department of Endocrinology and Metabolism, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, University of Amsterdam, Amsterdam, the Netherlands
| | - Caroline Lindemans
- Department of Pediatric Hematopoietic Stem Cell Transplantation, UMC Utrecht and Princess Maxima Center, the Netherlands
| | - Fanny Mochel
- Reference Center for Adult Leukodystrophy, Department of Medical Genetics, Sorbonne University, Paris Brain Institute, La Pitié-Salpêtrière University Hospital, Paris, France
| | - Andreas Oberg
- Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Norway
| | - Dipak Ram
- Department of Paediatric Neurology, Royal Manchester Children's Hospital, Manchester, UK
| | | | - Ludger Schöls
- Department of Neurology and Hertie-Institute for Clinical Brain Research, German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany
| | | | | | - Ayelet Zerem
- Pediatric Neurology Institute, Leukodystrophy Center, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nicole I Wolf
- Department of Child Neurology, Emma's Children's Hospital, Amsterdam UMC Location Vrije Universiteit, Amsterdam, the Netherlands; Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Amsterdam, the Netherlands
| | - Samuel Groeschel
- Neuropediatrics, General Pediatrics, Diabetology, Endocrinology and Social Pediatrics, University of Tuebingen, University Hospital Tübingen, 72016, Tübingen, Germany
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Franklin RJM, Bodini B, Goldman SA. Remyelination in the Central Nervous System. Cold Spring Harb Perspect Biol 2024; 16:a041371. [PMID: 38316552 PMCID: PMC10910446 DOI: 10.1101/cshperspect.a041371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
The inability of the mammalian central nervous system (CNS) to undergo spontaneous regeneration has long been regarded as a central tenet of neurobiology. However, while this is largely true of the neuronal elements of the adult mammalian CNS, save for discrete populations of granule neurons, the same is not true of its glial elements. In particular, the loss of oligodendrocytes, which results in demyelination, triggers a spontaneous and often highly efficient regenerative response, remyelination, in which new oligodendrocytes are generated and myelin sheaths are restored to denuded axons. Yet remyelination in humans is not without limitation, and a variety of demyelinating conditions are associated with sustained and disabling myelin loss. In this work, we will (1) review the biology of remyelination, including the cells and signals involved; (2) describe when remyelination occurs and when and why it fails, including the consequences of its failure; and (3) discuss approaches for therapeutically enhancing remyelination in demyelinating diseases of both children and adults, both by stimulating endogenous oligodendrocyte progenitor cells and by transplanting these cells into demyelinated brain.
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Affiliation(s)
- Robin J M Franklin
- Altos Labs Cambridge Institute of Science, Cambridge CB21 6GH, United Kingdom
| | - Benedetta Bodini
- Sorbonne Université, Paris Brain Institute, CNRS, INSERM, Paris 75013, France
- Saint-Antoine Hospital, APHP, Paris 75012, France
| | - Steven A Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA
- University of Copenhagen Faculty of Medicine, Copenhagen 2200, Denmark
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Kozisek T, Samuelson L, Hamann A, Pannier AK. Systematic comparison of nonviral gene delivery strategies for efficient co-expression of two transgenes in human mesenchymal stem cells. J Biol Eng 2023; 17:76. [PMID: 38062439 PMCID: PMC10704746 DOI: 10.1186/s13036-023-00394-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 11/20/2023] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND Human mesenchymal stem cells (hMSCs) are being researched for cell-based therapies due to a host of unique properties, however, genetic modification of hMSCs, accomplished through nonviral gene delivery, could greatly advance their therapeutic potential. Furthermore, expression of multiple transgenes in hMSCs could greatly advance their clinical significance for treatment of multifaceted diseases, as individual transgenes could be expressed that target separate pathogenic drivers of complex diseases. Expressing multiple transgenes can be accomplished by delivering multiple DNA vectors encoding for each transgene, or by delivering a single poly-cistronic vector that encodes for each transgene and accomplishes expression through either use of multiple promoters, an internal ribosome entry site (IRES), or a 2A peptide sequence. These different transgene expression strategies have been used to express multiple transgenes in various mammalian cells, however, they have not been fully evaluated in difficult-to-transfect primary cells, like hMSCs. This study systematically compared four transgene expression and delivery strategies for expression of two reporter transgenes in four donors of hMSCs from two tissue sources using lipid- and polymer-mediate transfection, as follows: (i) delivery of separate DNA vectors in separate nanoparticles; (ii) delivery of separate DNA vectors combined in the same nanoparticle; (iii) delivery of a bi-cistronic DNA vector with an IRES sequence via nanoparticles; and (iv) delivery of a bi-cistronic DNA vector with a dual 2A peptide sequence via nanoparticles. RESULTS Our results indicate that expression of two transgenes in hMSCs, independent of expression or delivery strategy, is inefficient compared to expressing a single transgene. However, delivery of separate DNA vectors complexed in the same nanoparticle, or delivery of a bi-cistronic DNA vector with a dual 2A peptide sequence, significantly increased the number of hMSCs expressing both transgenes compared to other conditions tested. CONCLUSION Separate DNA vectors delivered in the same nanoparticle and bi-cistronic DNA vectors with dual 2A peptide sequences are highly efficient at simultaneously expressing two transgenes in multiple donors of hMSCs from different tissue sources. The data presented in this work can guide the development of hMSC transfection systems for delivery of multiple transgenes, with the goal of producing clinically relevant, genetically modified hMSCs.
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Affiliation(s)
- Tyler Kozisek
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE, 68583-0900, USA
| | - Luke Samuelson
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE, 68583-0900, USA
| | - Andrew Hamann
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE, 68583-0900, USA
| | - Angela K Pannier
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE, 68583-0900, USA.
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Zhang Y, Gu J, Wang X, Li L, Fu L, Wang D, Wang X, Han X. Opportunities and challenges: mesenchymal stem cells in the treatment of multiple sclerosis. Int J Neurosci 2023; 133:1031-1044. [PMID: 35579409 DOI: 10.1080/00207454.2022.2042690] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 01/08/2022] [Accepted: 02/09/2022] [Indexed: 10/18/2022]
Abstract
Multiple sclerosis (MS) was once considered an untreatable disease. Through years of research, many drugs have been discovered and are widely used for the treatment of MS. However, the current treatment can only alleviate the clinical symptoms of MS and has serious side effects. Mesenchymal stem cells (MSCs) provide neuroprotection by migrating to injured tissues, suppressing inflammation, and fostering neuronal repair. Therefore, MSCs therapy holds great promise for MS treatment. This review aimed to assess the feasibility and safety of use of MSCs in MS treatment as well as its development prospect in clinical treatment by analysing the existing clinical studies.
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Affiliation(s)
- Yingyu Zhang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Jiebing Gu
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Xiaoshuang Wang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Linfang Li
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Lingling Fu
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Di Wang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Xiuting Wang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Xuemei Han
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
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Asserson DB. Allogeneic Mesenchymal Stem Cells After In Vivo Transplantation: A Review. Cell Reprogram 2023; 25:264-276. [PMID: 37971885 DOI: 10.1089/cell.2023.0084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023] Open
Abstract
Autologous mesenchymal stem cells (MSCs) are ideal for tissue regeneration because of their ability to circumvent host rejection, but their procurement and processing present logistical and time-sensitive challenges. Allogeneic MSCs provide an alternative cell-based therapy capable of positively affecting all human organ systems, and can be readily available. Extensive research has been conducted in the treatment of autoimmune, degenerative, and inflammatory diseases with such stem cells, and has demonstrated predominantly safe outcomes with minimal complications. Nevertheless, continued clinical trials are necessary to ascertain optimal harvest and transplant techniques.
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Affiliation(s)
- Derek B Asserson
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
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da Rocha LR, Dias RB, Fernandes MBC, Prinz R, Eirado TP, Costa IDS, Monteiro MJ, da Silva CER, Dos Santos CT, Fogagnolo F. A new option for bone regeneration: a rapid methodology for cellularization of allograft with human bone marrow stromal cells with in vivo bone-forming potential. Injury 2023; 54 Suppl 6:110777. [PMID: 38143129 DOI: 10.1016/j.injury.2023.05.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/26/2023] [Accepted: 05/01/2023] [Indexed: 12/26/2023]
Abstract
The treatment of severe musculoskeletal injuries, such as loss of bone tissue and consolidation disorders, requires bone transplantation, and the success of this bone reconstruction depends on the grafts transplant's osteogenic, osteoconductive, and osteoinductive properties. Although the gold standard is autograft, it is limited by availability, morbidity, and infection risk. Despite their low capacity for osteoinduction and osteogenesis, decellularized bone allografts have been used in the search for alternative therapeutic strategies to improve bone regeneration. Considering that bone marrow stromal cells (BMSCs) are responsible for the maintenance of bone turnover throughout life, we believe that associating BMSCs with allograft could produce a material that is biologically similar to autologous bone graft. For this reason, this study evaluated the osteogenic potential of bone allograft cellularized with BMSCs. First, BMSC was characterized and allograft decellularization was confirmed by histology, scanning electron microscopy, and DNA quantification. Subsequently, the BMSCs and allografts were associated and evaluated for adhesion, proliferation, and in vitro and in vivo osteogenic potential. We demonstrated that, after 2 hours, BMSCs had already adhered to the surface of allografts and remained viable for 14 days. In vitro osteogenic assays indicated increased osteogenic potential of allografts compared with beta-tricalcium phosphate (β-TCP). In vivo transplantation assays in immunodeficient mice confirmed the allograft's potential to induce bone formation, with significantly better results than β-TCP. Finally, our results indicate that allograft can provide structural support for BMSC adhesion, offering a favorable microenvironment for cell survival and differentiation and inducing new bone formation. Taken together, our data indicate that this rapid methodology for cellularization of allograft with BMSCs might be a new therapeutic alternative in regenerative medicine and bone bioengineering.
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Affiliation(s)
- Leonardo Rosa da Rocha
- Teaching and Research Division, Instituto Nacional de Traumatologia e Ortopedia Jamil Haddad (INTO), Av. Brasil, 500, Rio de Janeiro, RJ 20940-070, Brazil.
| | - Rhayra Braga Dias
- Teaching and Research Division, INTO, Av. Brasil, 500, Rio de Janeiro, RJ 20940-070, Brazil
| | | | - Rafael Prinz
- Teaching and Research Division, INTO, Av. Brasil, 500, Rio de Janeiro, RJ 20940-070, Brazil
| | - Thiago Penna Eirado
- Teaching and Research Division, INTO, Av. Brasil, 500, Rio de Janeiro, RJ 20940-070, Brazil
| | - Isabela de Souza Costa
- Teaching and Research Division, INTO, Av. Brasil, 500, Rio de Janeiro, RJ 20940-070, Brazil
| | - Mauricio J Monteiro
- Materials Division, Instituto Nacional de Tecnologia (INT), Av. Venezuela 82, Rio de Janeiro, RJ 20081-312, Brazil.
| | | | | | - Fabricio Fogagnolo
- Department of Orthopaedics and Anaesthesiology, Ribeirão Preto Medical School, Universidade de São Paulo (USP), Av. Bandeirantes, 3900, São Paulo, SP 14049900, Brazil
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Aerts-Kaya F, van Til NP. Gene and Cellular Therapies for Leukodystrophies. Pharmaceutics 2023; 15:2522. [PMID: 38004502 PMCID: PMC10675548 DOI: 10.3390/pharmaceutics15112522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 10/13/2023] [Accepted: 10/20/2023] [Indexed: 11/26/2023] Open
Abstract
Leukodystrophies are a heterogenous group of inherited, degenerative encephalopathies, that if left untreated, are often lethal at an early age. Although some of the leukodystrophies can be treated with allogeneic hematopoietic stem cell transplantation, not all patients have suitable donors, and new treatment strategies, such as gene therapy, are rapidly being developed. Recent developments in the field of gene therapy for severe combined immune deficiencies, Leber's amaurosis, epidermolysis bullosa, Duchenne's muscular dystrophy and spinal muscular atrophy, have paved the way for the treatment of leukodystrophies, revealing some of the pitfalls, but overall showing promising results. Gene therapy offers the possibility for overexpression of secretable enzymes that can be released and through uptake, allow cross-correction of affected cells. Here, we discuss some of the leukodystrophies that have demonstrated strong potential for gene therapy interventions, such as X-linked adrenoleukodystrophy (X-ALD), and metachromatic leukodystrophy (MLD), which have reached clinical application. We further discuss the advantages and disadvantages of ex vivo lentiviral hematopoietic stem cell gene therapy, an approach for targeting microglia-like cells or rendering cross-correction. In addition, we summarize ongoing developments in the field of in vivo administration of recombinant adeno-associated viral (rAAV) vectors, which can be used for direct targeting of affected cells, and other recently developed molecular technologies that may be applicable to treating leukodystrophies in the future.
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Affiliation(s)
- Fatima Aerts-Kaya
- Department of Stem Cell Sciences, Graduate School of Health Sciences, Center for Stem Cell Research and Development, Hacettepe University, 06100 Ankara, Turkey;
- Advanced Technologies Application and Research Center, Hacettepe University, 06800 Ankara, Turkey
| | - Niek P. van Til
- Amsterdam Leukodystrophy Center, Emma Children’s Hospital, Amsterdam University Medical Centers, Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands
- Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
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Mohammadi TC, Jazi K, Bolouriyan A, Soleymanitabar A. Stem cells in treatment of crohn's disease: Recent advances and future directions. Transpl Immunol 2023; 80:101903. [PMID: 37541629 DOI: 10.1016/j.trim.2023.101903] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/11/2023] [Accepted: 07/22/2023] [Indexed: 08/06/2023]
Abstract
BACKGROUND AND AIM Crohn's disease (CD) is an inflammatory bowel disease that can affect any part of the intestine. There is currently no recognized cure for CD because its cause is unknown. One of the modern approaches that have been suggested for the treatment of CD and other inflammatory-based disorders is cell therapy. METHODS Search terms were stem cell therapy, CD, adipose-derived stem cells, mesenchymal stem cells, and fistula. Of 302 related studies, we removed duplicate and irrelevant papers and identified the ones with proper information related to our scope of the research by reviewing all the abstracts and categorizing each study into the proper section. RESULTS AND CONCLUSION Nowadays, stem cell therapy is widely implied in treating CD. Although mesenchymal and adipose-derived tissue stem cells proved to be safe in treating Crohn's-associated fistula, there are still debates on an optimal protocol to use. Additionally, there is still a lack of evidence on the efficacy of stem cell therapy for intestinal involvement of CD. Future investigations should focus on preparing a standard protocol as well as luminal stem cell therapy in patients.
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Affiliation(s)
| | - Kimia Jazi
- Student Research Committee, Faculty of Medicine, Medical University of Qom, Qom, Iran
| | - Alireza Bolouriyan
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
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11
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Gholami Farashah MS, Mohammadi A, Javadi M, Soleimani Rad J, Shakouri SK, Meshgi S, Roshangar L. Bone marrow mesenchymal stem cells' osteogenic potential: superiority or non-superiority to other sources of mesenchymal stem cells? Cell Tissue Bank 2023; 24:663-681. [PMID: 36622494 DOI: 10.1007/s10561-022-10066-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 12/14/2022] [Indexed: 01/10/2023]
Abstract
Skeletal problems are an increasing issue due to the increase in the global aging population. Different statistics reports show that today, the global population is aging that results in skeletal problems, increased health system costs, and even higher mortality associated with skeletal problems. Common treatments such as surgery and bone grafts are not always effective and in some cases, they can even cause secondary problems such as infections or improper repair. Cell therapy is a method that can be utilized along with common treatments independently. Mesenchymal stem cells (MSCs) are a very important and efficient source in terms of different diseases, especially bone problems. These cells are present in different tissues such as bone marrow, adipose tissue, umbilical cord, placenta, dental pulp, peripheral blood, amniotic fluid and others. Among the types of MSCs, bone marrow mesenchymal stem cells (BMMSCs) are the most widely used source of these cells, which have appeared to be very effective and promising in terms of skeletal diseases, especially compared to the other sources of MSCs. This study focuses on the specific potential and content of BMMSCs from which the specific capacity of these cells originates, and compares their osteogenic potential with other types of MSCs, and also the future directions in the application of BMMSCs as a source for cell therapy.
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Affiliation(s)
- Mohammad Sadegh Gholami Farashah
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirhossein Mohammadi
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Javadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Soleimani Rad
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Kazem Shakouri
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahla Meshgi
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Roshangar
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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12
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Parihar A, Kumar A, Panda U, Khan R, Parihar DS, Khan R. Cryopreservation: A Comprehensive Overview, Challenges, and Future Perspectives. Adv Biol (Weinh) 2023; 7:e2200285. [PMID: 36755194 DOI: 10.1002/adbi.202200285] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/05/2023] [Indexed: 02/10/2023]
Abstract
Cryopreservation is the most prevalent method of long-term cell preservation. Effective cell cryopreservation depends on freezing, adequate storage, and correct thawing techniques. Recent advances in cryopreservation techniques minimize the cellular damage which occurs while processing samples. This article focuses on the fundamentals of cryopreservation techniques and how they can be implemented in a variety of clinical settings. The article presents a brief description of each of the standard cryopreservation procedures, such as slow freezing and vitrification. Alongside that, the membrane permeating and nonpermeating cryoprotectants are briefly discussed, along with current advancements in the field of cryopreservation and variables influencing the cryopreservation process. The diminution of cryoinjury incurred by the cell via the resuscitation process will also be highlighted. In the end application of cryopreservation techniques in many fields, with a special emphasis on stem cell preservation techniques and current advancements presented. Furthermore, the challenges while implementing cryopreservation and the futuristic scope of the fields are illustrated herein. The content of this review sheds light on various ways to enhance the output of the cell preservation process and minimize cryoinjury while improving cell revival.
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Affiliation(s)
- Arpana Parihar
- Industrial Waste Utilization, Nano and Biomaterials, CSIR-Advanced Materials and Processes Research Institute (AMPRI), Hoshangabad Road, Bhopal, Madhya Pradesh, 462026, India
| | - Avinash Kumar
- Department of Mechanical Engineering, Indian Institute of Information Technology, Design & Manufacturing (IIITD&M), Kancheepuram, 600127, India
| | - Udwesh Panda
- Department of Mechanical Engineering, Indian Institute of Information Technology, Design & Manufacturing (IIITD&M), Kancheepuram, 600127, India
| | - Rukhsar Khan
- Department of Biosciences, Barkatullah University, Bhopal, Madhya Pradesh, 462026, India
| | | | - Raju Khan
- Industrial Waste Utilization, Nano and Biomaterials, CSIR-Advanced Materials and Processes Research Institute (AMPRI), Hoshangabad Road, Bhopal, Madhya Pradesh, 462026, India
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13
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Mullagulova A, Shaimardanova A, Solovyeva V, Mukhamedshina Y, Chulpanova D, Kostennikov A, Issa S, Rizvanov A. Safety and Efficacy of Intravenous and Intrathecal Delivery of AAV9-Mediated ARSA in Minipigs. Int J Mol Sci 2023; 24:ijms24119204. [PMID: 37298156 DOI: 10.3390/ijms24119204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/17/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Metachromatic leukodystrophy (MLD) is a hereditary neurodegenerative disease characterized by demyelination and motor and cognitive impairments due to deficiencies of the lysosomal enzyme arylsulfatase A (ARSA) or the saposin B activator protein (SapB). Current treatments are limited; however, gene therapy using adeno-associated virus (AAV) vectors for ARSA delivery has shown promising results. The main challenges for MLD gene therapy include optimizing the AAV dosage, selecting the most effective serotype, and determining the best route of administration for ARSA delivery into the central nervous system. This study aims to evaluate the safety and efficacy of AAV serotype 9 encoding ARSA (AAV9-ARSA) gene therapy when administered intravenously or intrathecally in minipigs, a large animal model with anatomical and physiological similarities to humans. By comparing these two administration methods, this study contributes to the understanding of how to improve the effectiveness of MLD gene therapy and offers valuable insights for future clinical applications.
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Affiliation(s)
- Aysilu Mullagulova
- Institute for Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Alisa Shaimardanova
- Institute for Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Valeriya Solovyeva
- Institute for Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Yana Mukhamedshina
- Institute for Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- Department of Histology, Cytology, and Embryology, Kazan State Medical University, 420012 Kazan, Russia
| | - Daria Chulpanova
- Institute for Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Alexander Kostennikov
- Institute for Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Shaza Issa
- Institute for Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- Department of Genetics and Biotechnology, St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Albert Rizvanov
- Institute for Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
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14
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Wong PF, Dharmani M, Ramasamy TS. Senotherapeutics for mesenchymal stem cell senescence and rejuvenation. Drug Discov Today 2023; 28:103424. [PMID: 36332835 DOI: 10.1016/j.drudis.2022.103424] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 10/04/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
Mesenchymal stem cells (MSCs) are susceptible to replicative senescence and senescence-associated functional decline, which hampers their use in regenerative medicine. Senotherapeutics are drugs that target cellular senescence through senolytic and senomorphic functions to induce apoptosis and suppress chronic inflammation caused by the senescence-associated secreted phenotype (SASP), respectively. Therefore, senotherapeutics could delay aging-associated degeneration. They could also be used to eliminate senescent MSCs during in vitro expansion or bioprocessing for transplantation. In this review, we discuss the role of senotherapeutics in MSC senescence, rejuvenation, and transplantation, with examples of some tested compounds in vitro. The prospects, challenges, and the way forward in clinical applications of senotherapeutics in cell-based therapeutics are also discussed.
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Affiliation(s)
- Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Murugan Dharmani
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia.
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15
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MPSI Manifestations and Treatment Outcome: Skeletal Focus. Int J Mol Sci 2022; 23:ijms231911168. [PMID: 36232472 PMCID: PMC9569890 DOI: 10.3390/ijms231911168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/16/2022] [Accepted: 09/17/2022] [Indexed: 11/23/2022] Open
Abstract
Mucopolysaccharidosis type I (MPSI) (OMIM #252800) is an autosomal recessive disorder caused by pathogenic variants in the IDUA gene encoding for the lysosomal alpha-L-iduronidase enzyme. The deficiency of this enzyme causes systemic accumulation of glycosaminoglycans (GAGs). Although disease manifestations are typically not apparent at birth, they can present early in life, are progressive, and include a wide spectrum of phenotypic findings. Among these, the storage of GAGs within the lysosomes disrupts cell function and metabolism in the cartilage, thus impairing normal bone development and ossification. Skeletal manifestations of MPSI are often refractory to treatment and severely affect patients’ quality of life. This review discusses the pathological and molecular processes leading to impaired endochondral ossification in MPSI patients and the limitations of current therapeutic approaches. Understanding the underlying mechanisms responsible for the skeletal phenotype in MPSI patients is crucial, as it could lead to the development of new therapeutic strategies targeting the skeletal abnormalities of MPSI in the early stages of the disease.
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16
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Schepici G, Gugliandolo A, Mazzon E. Serum-Free Cultures: Could They Be a Future Direction to Improve Neuronal Differentiation of Mesenchymal Stromal Cells? Int J Mol Sci 2022; 23:ijms23126391. [PMID: 35742836 PMCID: PMC9223839 DOI: 10.3390/ijms23126391] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/02/2022] [Accepted: 06/06/2022] [Indexed: 02/04/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are undifferentiated cells with multilinear potential, known for their immunomodulatory and regenerative properties. Although the scientific community is working to improve their application, concerns limit their use to repair tissues following neurological damage. One of these obstacles is represented by the use of culture media supplemented with fetal bovine serum (FBS), which, due to its xenogenic nature and the risk of contamination, has increased scientific, ethical and safety problems. Therefore, the use of serum-free media could improve MSC culture methods, avoiding infectious and immunogenic transmission problems as well as MSC bioprocesses, without the use of animal components. The purpose of our review is to provide an overview of experimental studies that demonstrate that serum-free cultures, along with the supplementation of growth factors or chemicals, can lead to a more defined and controlled environment, enhancing the proliferation and neuronal differentiation of MSCs.
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17
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Oliveira Miranda C. Mesenchymal stem cells for lysosomal storage and polyglutamine disorders: Possible shared mechanisms. Eur J Clin Invest 2022; 52:e13707. [PMID: 34751953 DOI: 10.1111/eci.13707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 09/28/2021] [Accepted: 11/07/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Mesenchymal stem cells' (MSC) therapeutic potential has been investigated for the treatment of several neurodegenerative diseases. The fact these cells can mediate a beneficial effect in different neurodegenerative contexts strengthens their competence to target diverse mechanisms. On the other hand, distinct disorders may share similar mechanisms despite having singular neuropathological characteristics. METHODS We have previously shown that MSC can be beneficial for two disorders, one belonging to the groups of Lysosomal Storage Disorders (LSDs) - the Krabbe Disease or Globoid Cell Leukodystrophy, and the other to the family of Polyglutamine diseases (PolyQs) - the Machado-Joseph Disease or Spinocerebellar ataxia type 3. We gave also input into disease characterization since neuropathology and MSC's effects are intrinsically associated. This review aims at describing MSC's multimode of action in these disorders while emphasizing to possible mechanistic alterations they must share due to the accumulation of cellular toxic products. RESULTS Lysosomal storage disorders and PolyQs have different aetiology and associated symptoms, but both result from the accumulation of undegradable products inside neuronal cells due to inefficient clearance by the endosomal/lysosomal pathway. Moreover, numerous cellular mechanisms that become compromised latter are also shared by these two disease groups. CONCLUSIONS Here, we emphasize MSC's effect in improving proteostasis and autophagy cycling turnover, neuronal survival, synaptic activity and axonal transport. LSDs and PolyQs, though rare in their predominance, collectively affect many people and require our utmost dedication and efforts to get successful therapies due to their tremendous impact on patient s' lives and society.
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Affiliation(s)
- Catarina Oliveira Miranda
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
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18
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Cabanillas Stanchi KM, Böhringer J, Strölin M, Groeschel S, Lenglinger K, Treuner C, Kehrer C, Laugwitz L, Bevot A, Kaiser N, Schumm M, Lang P, Handgretinger R, Krägeloh-Mann I, Müller I, Döring M. Hematopoietic stem cell transplantation with mesenchymal stromal cells in children with metachromatic leukodystrophy. Stem Cells Dev 2022; 31:163-175. [PMID: 35323019 DOI: 10.1089/scd.2021.0352] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder primarily affecting the white matter of the nervous system that results from a deficiency of the arylsulfatase A (ARSA). Mesenchymal stem cells (MSCs) are able to secrete ARSA and have shown beneficial effects in MLD patients. In this retrospective analysis, 10 pediatric MLD patients (MSCG) underwent allogeneic hematopoietic stem cell transplantation (HSCT) and received two applications of 2 x 106 MSCs/kg bodyweight at day +30 and +60 after HSCT between 2007 and 2018. MSC safety, occurrence of graft-versus-host disease (GvHD), blood ARSA levels, chimerism, cell regeneration and engraftment, MRI changes, and the gross motor function were assessed within the first year of HSCT. The long-term data included clinical outcomes and safety aspects of MSCs. Data were compared to a control cohort of seven pediatric MLD patients (CG) who underwent HSCT only. The application of MSC in pediatric MLD patients after allogeneic HSCT was safe and well tolerated and long-term potentially MSC-related adverse effects up to 13.5 years after HSCT were not observed. Patients achieved significantly higher ARSA levels (CG: median 1.03 nmol∙10-6, range 0.41-1.73 | MSCG: median 1.58 nmol∙10-6, range 0.44-2.6; p<0.05), as well as significantly higher leukocyte (p<0.05) and thrombocyte (p<0.001) levels within 365 days of MSC application compared to CG patients. Statistically significant effects on acute GvHD, regeneration of immune cells, engraftment, MRI changes, gross motor function, and clinical outcomes were not detected. In conclusion, the application of MSCs in pediatric MLD patients after allogeneic HSCT was safe and well tolerated. The two applications of 2 x 106/kg allogeneic MSCs were followed by improved engraftment and hematopoiesis within the first year after HSCT. Larger, prospective trials are necessary to evaluate the impact of MSC application on engraftment and hematopoietic recovery.
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Affiliation(s)
| | - Judith Böhringer
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Manuel Strölin
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Samuel Groeschel
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Katrin Lenglinger
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
| | - Claudia Treuner
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
| | - Christiane Kehrer
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
| | - Lucia Laugwitz
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Andrea Bevot
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Nadja Kaiser
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Michael Schumm
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
| | - Peter Lang
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
| | - Rupert Handgretinger
- Children's University Hospital, Hematology/Oncology, Hoppe-Seyler-Str. 1, Tuebingen, Germany, 72076;
| | | | - Ingo Müller
- University Medical Center Hamburg-Eppendorf, 37734, Department of Pediatric Hematology and Oncology, Hamburg, Hamburg, Germany;
| | - Michaela Döring
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
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19
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Issa SS, Shaimardanova AA, Valiullin VV, Rizvanov AA, Solovyeva VV. Mesenchymal Stem Cell-Based Therapy for Lysosomal Storage Diseases and Other Neurodegenerative Disorders. Front Pharmacol 2022; 13:859516. [PMID: 35308211 PMCID: PMC8924473 DOI: 10.3389/fphar.2022.859516] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 02/17/2022] [Indexed: 12/11/2022] Open
Abstract
Lysosomal storage diseases (LSDs) are a group of approximately 50 genetic disorders caused by mutations in genes coding enzymes that are involved in cell degradation and transferring lipids and other macromolecules. Accumulation of lipids and other macromolecules in lysosomes leads to the destruction of affected cells. Although the clinical manifestations of different LSDs vary greatly, more than half of LSDs have symptoms of central nervous system neurodegeneration, and within each disorder there is a considerable variation, ranging from severe, infantile-onset forms to attenuated adult-onset disease, sometimes with distinct clinical features. To date, treatment options for this group of diseases remain limited, which highlights the need for further development of innovative therapeutic approaches, that can not only improve the patients' quality of life, but also provide full recovery for them. In many LSDs stem cell-based therapy showed promising results in preclinical researches. This review discusses using mesenchymal stem cells for different LSDs therapy and other neurodegenerative diseases and their possible limitations.
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Affiliation(s)
- Shaza S Issa
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,Faculty of Biology, Saint Petersburg State University, Saint Petersburg, Russia
| | - Alisa A Shaimardanova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Victor V Valiullin
- Department of Histology, Cytology and Embryology, Kazan State Medical University, Kazan, Russia
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Valeriya V Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
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20
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Ringdén O, Moll G, Gustafsson B, Sadeghi B. Mesenchymal Stromal Cells for Enhancing Hematopoietic Engraftment and Treatment of Graft-Versus-Host Disease, Hemorrhages and Acute Respiratory Distress Syndrome. Front Immunol 2022; 13:839844. [PMID: 35371003 PMCID: PMC8973075 DOI: 10.3389/fimmu.2022.839844] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/17/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) possess profound immunomodulatory and regenerative properties that are of clinical use in numerous clinical indications with unmet medical need. Common sources of MSCs include among others, bone marrow (BM), fat, umbilical cord, and placenta-derived decidua stromal cells (DSCs). We here summarize our more than 20-years of scientific experience in the clinical use of MSCs and DSCs in different clinical settings. BM-MSCs were first explored to enhance the engraftment of autografts in hematopoietic cell transplantation (HCT) and osteogenesis imperfecta around 30 years ago. In 2004, our group reported the first anti-inflammatory use of BM-MSCs in a child with grade IV acute graft-versus-host disease (GvHD). Subsequent studies have shown that MSCs appear to be more effective in acute than chronic GvHD. Today BM-MSC-therapy is registered for acute GvHD in Japan and for GvHD in children in Canada and New Zeeland. MSCs first home to the lung following intravenous injection and exert strong local and systemic immunomodulatory effects on the host immune system. Thus, they were studied for ameliorating the cytokine storm in acute respiratory distress syndrome (ARDS). Both, MSCs and DSCs were used to treat SARS-CoV-2 coronavirus-induced disease 2019 (COVID-19)-induced ARDS. In addition, they were also used for other novel indications, such as pneumomediastinum, colon perforation, and radiculomyelopathy. MSC and DSCs trigger coagulation and were thus explored to stop hemorrhages. DSCs appear to be more effective for acute GvHD, ARDS, and hemorrhages, but randomized studies are needed to prove superiority. Stromal cell infusion is safe, well tolerated, and only gives rise to a slight fever in a limited number of patients, but no major side effects have been reported in multiple safety studies and metaanalysis. In this review we summarize current evidence from in vitro studies, animal models, and importantly our clinical experience, to support stromal cell therapy in multiple clinical indications. This encloses MSC's effects on the immune system, coagulation, and their safety and efficacy, which are discussed in relation to prominent clinical trials within the field.
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Affiliation(s)
- Olle Ringdén
- Translational Cell Therapy Research Group, Department of Clinical Sciences, Intervention and Technology (CLNTEC), Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
| | - Guido Moll
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT) and Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, All Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Britt Gustafsson
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Behnam Sadeghi
- Translational Cell Therapy Research Group, Department of Clinical Sciences, Intervention and Technology (CLNTEC), Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
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21
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Mareschi K, Marini E, Niclot AGSB, Barone M, Pinnetta G, Adamini A, Spadea M, Labanca L, Lucania G, Ferrero I, Fagioli F. A New Human Platelet Lysate for Mesenchymal Stem Cell Production Compliant with Good Manufacturing Practice Conditions. Int J Mol Sci 2022; 23:3234. [PMID: 35328655 PMCID: PMC8953582 DOI: 10.3390/ijms23063234] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/08/2022] [Accepted: 03/14/2022] [Indexed: 02/01/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are classified as advanced therapy medicinal products, a new category of GMP (good manufacturing practice)-compliant medicines for clinical use. We isolated MSCs from 5 bone marrow (BM) samples using human platelet lysate (HPL) instead of foetal bovine serum (FBS). We used a new method of HPL production consisting of treating platelet (PLTs) pools with Ca-Gluconate to form a gel clot, then mechanically squeezing to release growth factors. We compared the new HPL (HPL-S) with the standard (HPL-E) obtained by freezing/thawing cycles and by adding heparin. HPL-S had not PLTs and fibrinogen but the quantity of proteins and growth factors was comparable to HPL-E. Therefore, HPL-S needed fewer production steps to be in compliance with GMP conditions. The number of colonies forming unit-fibroblasts (CFU-F) and the maintenance of stem markers showed no significant differences between MSCs with HPL-E and HPL-S. The cumulative population doubling was higher in MSCs with HPL-E in the earlier passages, but we observed an inverted trend of cell growth at the fourth passage. Immunophenotypic analysis showed a significant lower expression of HLA-DR in the MSCs with HPL-S (1.30%) than HPL-E (14.10%). In conclusion, we demonstrated that HPL-S is an effective alternative for MSC production under GMP conditions.
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Affiliation(s)
- Katia Mareschi
- Department of Public Health and Paediatrics, The University of Turin, Piazza Polonia 94, 10126 Torino, Italy; (E.M.); (A.G.S.B.N.); (M.B.); (M.S.); (F.F.)
- Stem Cell Transplantation and Cellular Therapy Laboratory, Paediatric Onco-Haematology Division, Regina Margherita Children’s Hospital, City of Health and Science of Turin, 10126 Torino, Italy; (G.P.); (A.A.); (I.F.)
| | - Elena Marini
- Department of Public Health and Paediatrics, The University of Turin, Piazza Polonia 94, 10126 Torino, Italy; (E.M.); (A.G.S.B.N.); (M.B.); (M.S.); (F.F.)
| | - Alessia Giovanna Santa Banche Niclot
- Department of Public Health and Paediatrics, The University of Turin, Piazza Polonia 94, 10126 Torino, Italy; (E.M.); (A.G.S.B.N.); (M.B.); (M.S.); (F.F.)
| | - Marta Barone
- Department of Public Health and Paediatrics, The University of Turin, Piazza Polonia 94, 10126 Torino, Italy; (E.M.); (A.G.S.B.N.); (M.B.); (M.S.); (F.F.)
| | - Giuseppe Pinnetta
- Stem Cell Transplantation and Cellular Therapy Laboratory, Paediatric Onco-Haematology Division, Regina Margherita Children’s Hospital, City of Health and Science of Turin, 10126 Torino, Italy; (G.P.); (A.A.); (I.F.)
| | - Aloe Adamini
- Stem Cell Transplantation and Cellular Therapy Laboratory, Paediatric Onco-Haematology Division, Regina Margherita Children’s Hospital, City of Health and Science of Turin, 10126 Torino, Italy; (G.P.); (A.A.); (I.F.)
| | - Manuela Spadea
- Department of Public Health and Paediatrics, The University of Turin, Piazza Polonia 94, 10126 Torino, Italy; (E.M.); (A.G.S.B.N.); (M.B.); (M.S.); (F.F.)
| | - Luciana Labanca
- Blood Component Production and Validation Center, City of Health and Science of Turin, S. Anna Hospital, 10126 Turin, Italy; (L.L.); (G.L.)
| | - Graziella Lucania
- Blood Component Production and Validation Center, City of Health and Science of Turin, S. Anna Hospital, 10126 Turin, Italy; (L.L.); (G.L.)
| | - Ivana Ferrero
- Stem Cell Transplantation and Cellular Therapy Laboratory, Paediatric Onco-Haematology Division, Regina Margherita Children’s Hospital, City of Health and Science of Turin, 10126 Torino, Italy; (G.P.); (A.A.); (I.F.)
| | - Franca Fagioli
- Department of Public Health and Paediatrics, The University of Turin, Piazza Polonia 94, 10126 Torino, Italy; (E.M.); (A.G.S.B.N.); (M.B.); (M.S.); (F.F.)
- Stem Cell Transplantation and Cellular Therapy Laboratory, Paediatric Onco-Haematology Division, Regina Margherita Children’s Hospital, City of Health and Science of Turin, 10126 Torino, Italy; (G.P.); (A.A.); (I.F.)
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22
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Modulation of Mesenchymal Stem Cells for Enhanced Therapeutic Utility in Ischemic Vascular Diseases. Int J Mol Sci 2021; 23:ijms23010249. [PMID: 35008675 PMCID: PMC8745455 DOI: 10.3390/ijms23010249] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells are multipotent stem cells isolated from various tissue sources, including but not limited to bone marrow, adipose, umbilical cord, and Wharton Jelly. Although cell-mediated mechanisms have been reported, the therapeutic effect of MSCs is now recognized to be primarily mediated via paracrine effects through the secretion of bioactive molecules, known as the “secretome”. The regenerative benefit of the secretome has been attributed to trophic factors and cytokines that play neuroprotective, anti-angiogenic/pro-angiogenic, anti-inflammatory, and immune-modulatory roles. The advancement of autologous MSCs therapy can be hindered when introduced back into a hostile/disease environment. Barriers include impaired endogenous MSCs function, limited post-transplantation cell viability, and altered immune-modulatory efficiency. Although secretome-based therapeutics have gained popularity, many translational hurdles, including the heterogeneity of MSCs, limited proliferation potential, and the complex nature of the secretome, have impeded the progress. This review will discuss the experimental and clinical impact of restoring the functional capabilities of MSCs prior to transplantation and the progress in secretome therapies involving extracellular vesicles. Modulation and utilization of MSCs–secretome are most likely to serve as an effective strategy for promoting their ultimate success as therapeutic modulators.
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Abstract
Leukodystrophies are a group of genetically determined disorders that affect development or maintenance of central nervous system myelin. Leukodystrophies have an incidence of at least 1 in 4700 live births and significant morbidity and elevated risk of early death. This report includes a discussion of the types of leukodystrophies; their prevalence, clinical presentation, symptoms, and diagnosis; and current and future treatments. Leukodystrophies can present at any age from infancy to adulthood, with variability in disease progression and clinical presentation, ranging from developmental delay to seizures to spasticity. Diagnosis is based on a combination of history, examination, and radiologic and laboratory findings, including genetic testing. Although there are few cures, there are significant opportunities for care and improvements in patient well-being. Rapid advances in imaging and diagnosis, the emergence of and requirement for timely treatments, and the addition of leukodystrophy screening to newborn screening, make an understanding of the leukodystrophies necessary for pediatricians and other care providers for children.
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Affiliation(s)
- Joshua L Bonkowsky
- Division of Pediatric Neurology, Department of Pediatrics, School of Medicine, University of Utah and Brain and Spine Center, Primary Children's Hospital, Salt Lake City, Utah
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24
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Wang X, Li Z, Wang C, Bai H, Wang Z, Liu Y, Bao Y, Ren M, Liu H, Wang J. Enlightenment of Growth Plate Regeneration Based on Cartilage Repair Theory: A Review. Front Bioeng Biotechnol 2021; 9:654087. [PMID: 34150725 PMCID: PMC8209549 DOI: 10.3389/fbioe.2021.654087] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 05/10/2021] [Indexed: 01/21/2023] Open
Abstract
The growth plate (GP) is a cartilaginous region situated between the epiphysis and metaphysis at the end of the immature long bone, which is susceptible to mechanical damage because of its vulnerable structure. Due to the limited regeneration ability of the GP, current clinical treatment strategies (e.g., bone bridge resection and fat engraftment) always result in bone bridge formation, which will cause length discrepancy and angular deformity, thus making satisfactory outcomes difficult to achieve. The introduction of cartilage repair theory and cartilage tissue engineering technology may encourage novel therapeutic approaches for GP repair using tissue engineered GPs, including biocompatible scaffolds incorporated with appropriate seed cells and growth factors. In this review, we summarize the physiological structure of GPs, the pathological process, and repair phases of GP injuries, placing greater emphasis on advanced tissue engineering strategies for GP repair. Furthermore, we also propose that three-dimensional printing technology will play a significant role in this field in the future given its advantage of bionic replication of complex structures. We predict that tissue engineering strategies will offer a significant alternative to the management of GP injuries.
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Affiliation(s)
- Xianggang Wang
- Orthopaedic Medical Center, The Second Hospital of Jilin University, Changchun, China.,Orthopaedic Research Institute of Jilin Province, Changchun, China
| | - Zuhao Li
- Orthopaedic Medical Center, The Second Hospital of Jilin University, Changchun, China.,Orthopaedic Research Institute of Jilin Province, Changchun, China
| | - Chenyu Wang
- Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University, Changchun, China
| | - Haotian Bai
- Orthopaedic Medical Center, The Second Hospital of Jilin University, Changchun, China.,Orthopaedic Research Institute of Jilin Province, Changchun, China
| | - Zhonghan Wang
- Orthopaedic Medical Center, The Second Hospital of Jilin University, Changchun, China.,Orthopaedic Research Institute of Jilin Province, Changchun, China
| | - Yuzhe Liu
- Orthopaedic Medical Center, The Second Hospital of Jilin University, Changchun, China.,Orthopaedic Research Institute of Jilin Province, Changchun, China
| | - Yirui Bao
- Department of Orthopedics, Chinese PLA 965 Hospital, Jilin, China
| | - Ming Ren
- Orthopaedic Medical Center, The Second Hospital of Jilin University, Changchun, China.,Orthopaedic Research Institute of Jilin Province, Changchun, China
| | - He Liu
- Orthopaedic Medical Center, The Second Hospital of Jilin University, Changchun, China.,Orthopaedic Research Institute of Jilin Province, Changchun, China
| | - Jincheng Wang
- Orthopaedic Medical Center, The Second Hospital of Jilin University, Changchun, China.,Orthopaedic Research Institute of Jilin Province, Changchun, China
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25
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Aithal AP, Bairy LK, Seetharam RN. Safety and therapeutic potential of human bone marrow-derived mesenchymal stromal cells in regenerative medicine. Stem Cell Investig 2021; 8:10. [PMID: 34124233 DOI: 10.21037/sci-2020-036] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 03/24/2021] [Indexed: 12/20/2022]
Abstract
Regenerative medicine is considered as an alternative approach to healthcare. Owing to their pluripotent abilities and their relative lack of ethical and legal issues, adult stem cells are considered as optimal candidates for use in the treatment of various diseases. Bone marrow-derived mesenchymal stem cells are among the most promising candidates for clinical applications as they have expressed a higher degree of plasticity in vitro. Many investigators have begun to examine how bone marrow stem cells might be used to rebuild damaged tissues. The systemic administration of cells for therapeutic applications requires efficient migration and homing of cells to the target site. Cell adhesion molecules and their ligands, chemokines, extracellular matrix components and specialized bone marrow niches all participate in the proper regulation of this process. MSCs suppress the pathophysiological process that is mediated by chronic inflammation and contributes to a modification of the microenvironment and tissue regeneration. Due to the intricacy of the mesenchymal stem cell, there is ever-increasing amount of data emerging about their migration and regenerative mechanisms. Many factors influence MSC mobilization and their homing to injured tissues. This review summarizes the current clinical and pre-clinical data available in literature regarding the use of MSC in tissue repair and their prospective therapeutic role in various diseases and the underlying repair mechanisms will be discussed.
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Affiliation(s)
- Ashwini P Aithal
- Department of Anatomy, Melaka Manipal Medical College (Manipal Campus), Manipal Academy of Higher Education, Manipal, India
| | - Laxminarayana K Bairy
- Department of Pharmacology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
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26
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Hwang JJ, Rim YA, Nam Y, Ju JH. Recent Developments in Clinical Applications of Mesenchymal Stem Cells in the Treatment of Rheumatoid Arthritis and Osteoarthritis. Front Immunol 2021; 12:631291. [PMID: 33763076 PMCID: PMC7982594 DOI: 10.3389/fimmu.2021.631291] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 02/04/2021] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cell (MSC) therapies have been used as cell-based treatments for decades, owing to their anti-inflammatory, immunomodulatory, and regenerative properties. With high expectations, many ongoing clinical trials are investigating the safety and efficacy of MSC therapies to treat arthritic diseases. Studies on osteoarthritis (OA) have shown positive clinical outcomes, with improved joint function, pain level, and quality of life. In addition, few clinical MSC trials conducted on rheumatoid arthritis (RA) patients have also displayed some optimistic outlook. The largely positive outcomes in clinical trials without severe side effects establish MSCs as promising tools for arthritis treatment. However, further research is required to investigate its applicability in clinical settings. This review discusses the most recent advances in clinical studies on MSC therapies for OA and RA.
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Affiliation(s)
- Joel Jihwan Hwang
- College of Public Health and Social Justice, Saint Louis University, St. Louis, MO, United States
| | - Yeri Alice Rim
- Catholic Induced Pluripotent Stem Cell Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Yoojun Nam
- Catholic Induced Pluripotent Stem Cell Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Ji Hyeon Ju
- Catholic Induced Pluripotent Stem Cell Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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27
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Kouroupis D, Correa D. Increased Mesenchymal Stem Cell Functionalization in Three-Dimensional Manufacturing Settings for Enhanced Therapeutic Applications. Front Bioeng Biotechnol 2021; 9:621748. [PMID: 33644016 PMCID: PMC7907607 DOI: 10.3389/fbioe.2021.621748] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 01/07/2021] [Indexed: 12/23/2022] Open
Abstract
Mesenchymal stem/stromal cell (MSC) exist within their in vivo niches as part of heterogeneous cell populations, exhibiting variable stemness potential and supportive functionalities. Conventional extensive 2D in vitro MSC expansion, aimed at obtaining clinically relevant therapeutic cell numbers, results in detrimental effects on both cellular characteristics (e.g., phenotypic changes and senescence) and functions (e.g., differentiation capacity and immunomodulatory effects). These deleterious effects, added to the inherent inter-donor variability, negatively affect the standardization and reproducibility of MSC therapeutic potential. The resulting manufacturing challenges that drive the qualitative variability of MSC-based products is evident in various clinical trials where MSC therapeutic efficacy is moderate or, in some cases, totally insufficient. To circumvent these limitations, various in vitro/ex vivo techniques have been applied to manufacturing protocols to induce specific features, attributes, and functions in expanding cells. Exposure to inflammatory cues (cell priming) is one of them, however, with untoward effects such as transient expression of HLA-DR preventing allogeneic therapeutic schemes. MSC functionalization can be also achieved by in vitro 3D culturing techniques, in an effort to more closely recapitulate the in vivo MSC niche. The resulting spheroid structures provide spatial cell organization with increased cell–cell interactions, stable, or even enhanced phenotypic profiles, and increased trophic and immunomodulatory functionalities. In that context, MSC 3D spheroids have shown enhanced “medicinal signaling” activities and increased homing and survival capacities upon transplantation in vivo. Importantly, MSC spheroids have been applied in various preclinical animal models including wound healing, bone and osteochondral defects, and cardiovascular diseases showing safety and efficacy in vivo. Therefore, the incorporation of 3D MSC culturing approach into cell-based therapy would significantly impact the field, as more reproducible clinical outcomes may be achieved without requiring ex vivo stimulatory regimes. In the present review, we discuss the MSC functionalization in 3D settings and how this strategy can contribute to an improved MSC-based product for safer and more effective therapeutic applications.
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Affiliation(s)
- Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami, Miller School of Medicine, Miami, FL, United States.,Diabetes Research Institute & Cell Transplantation Center, University of Miami, Miller School of Medicine, Miami, FL, United States
| | - Diego Correa
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami, Miller School of Medicine, Miami, FL, United States.,Diabetes Research Institute & Cell Transplantation Center, University of Miami, Miller School of Medicine, Miami, FL, United States
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28
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Dabrowska S, Andrzejewska A, Janowski M, Lukomska B. Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cells and Extracellular Vesicles: Therapeutic Outlook for Inflammatory and Degenerative Diseases. Front Immunol 2021; 11:591065. [PMID: 33613514 PMCID: PMC7893976 DOI: 10.3389/fimmu.2020.591065] [Citation(s) in RCA: 130] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/21/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent stem cells derived from mesoderm, which can be easily isolated from many sources such as bone marrow, umbilical cord or adipose tissue. MSCs provide support for hematopoietic stem cells and have an ability to differentiate into multiple cell lines. Moreover, they have proangiogenic, protective and immunomodulatory properties. MSCs have the capacity to modulate both innate and adaptive immune responses, which accompany many diseases, by inhibiting pro-inflammatory reactions and stimulating anti-inflammatory activity. Recent findings revealed that the positive effect of MSCs is at least partly associated with the production of extracellular vesicles (EVs). EVs are small membrane structures, containing proteins, lipids and nuclei acids, which take part in intra-cellular communication. Many studies indicate that EVs contain protective and pro-regenerative properties and can modulate an immune response that is activated in various diseases such as CNS diseases, myocardial infarction, liver injury, lung diseases, ulcerative colitis or kidney injury. Thus, EVs have similar functions as their cells of origin and since they do not carry the risk of cell transplantation, such as tumor formation or small vessel blockage, they can be considered a potential therapeutic tool for cell-free therapy.
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Affiliation(s)
- Sylwia Dabrowska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
| | - Anna Andrzejewska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
| | - Miroslaw Janowski
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.,University of Maryland School of Medicine, Baltimore, MD, United States.,Center for Advanced Imaging Research, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Barbara Lukomska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
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29
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Immunophenotypic characterization and therapeutics effects of human bone marrow- and umbilical cord-derived mesenchymal stromal cells in an experimental model of sepsis. Exp Cell Res 2021; 399:112473. [PMID: 33428902 DOI: 10.1016/j.yexcr.2021.112473] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/11/2020] [Accepted: 12/30/2020] [Indexed: 12/27/2022]
Abstract
Sepsis is a complicated multi-system disorder characterized by a dysregulated host response to infection. Despite substantial progress in the understanding of mechanisms of sepsis, translation of these advances into clinically effective therapies remains challenging. Mesenchymal Stromal Cells (MSCs) possess immunomodulatory properties that have shown therapeutic promise in preclinical models of sepsis. The therapeutic effects of MSCs may vary depending on the source and type of these cells. In this comparative study, the gene expression pattern and surface markers of bone marrow-derived MSCs (BM-MSCs) and umbilical cord-derived MSCs (UC-MSCs) as well as their therapeutic effects in a clinically relevant mouse model of polymicrobial sepsis, cecal ligation and puncture (CLP), were investigated. The results showed remarkable differences in gene expression profile, surface markers and therapeutic potency in terms of enhancing survival and pro/anti-inflammatory responses between the two MSC types. BM-MSCs improved survival concomitant with an enhanced systemic bacterial clearance and improved inflammatory profile post CLP surgery. Despite some improvement in the inflammatory profile of the septic animals, treatment with UC-MSCs did not enhance survival or bacterial clearance. Overall, the beneficial therapeutic effects of BM-MSCs over UC-MSCs may likely be attributed to their pro-inflammatory function, and to some extent anti-inflammatory features, reflected in their gene expression pattern enhancing macrophage polarization to M1/M2 phenotypes resulting in a balanced pro- and anti-inflammatory response against polymicrobial sepsis.
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30
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Chen Q, You Y, Zhang Y, Zhang H, Bai L. Hepatocyte growth factor mediates a novel form of hepatic stem/progenitor cell-induced tolerance in a rat xenogeneic liver rejection model. Int Immunopharmacol 2021; 90:107180. [PMID: 33221167 DOI: 10.1016/j.intimp.2020.107180] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/02/2020] [Accepted: 11/02/2020] [Indexed: 12/17/2022]
Abstract
We have previously identified novel neural/glial antigen 2-expressing hepatic stem/progenitor cells (NG2+ HSPs) that are beneficial for tissue repair by inhibiting the immune cell response. In this in vivo study, we investigated the use of hepatocyte growth factor (HGF)-secreting NG2+ HSPs as a tolerogen in the well-established Syrian golden hamster (SGH) to Lewis (LEW) xenogeneic rat acute liver rejection (ARJ) model. Liver and blood cells were collected for histology and functional analyses using immunofluorescence staining, western blot, ELISA, and TUNEL assays. All recipient rats were randomly divided into 5 groups (n = 14 rats/group) and treated with: (1) ARJ + PBS: (2) ARJ + NG2: tail vein injection of NG2+ HSPs; (3) ARJ + tacrolimus (FK506, oral administration); (4) ARJ + an anti-cMet functional blocking antibody (a-cMet-Ab, I.V) 24 h before the injection of NG2+ HSPs; (5) ARJ + cHGF (clinically used HGF). LEW to LEW syngeneic rats were considered "normal" (n = 14, namely Syn). Significantly prolonged mean survival times (MSTs) and improved graft functions were observed after NG2+ HSP transplantation. An anti-cMet Ab significantly blocked the effect of NG2+ HSPs, suggesting that the effects were likely associated with HGF secreted from NG2+ HSPs. Notably, when intravenously injected into the xenogeneic rat model, the injected cHGF not only prolonged the MST of recipient rats but also increased the number of TUNEL-expressing xenoreactive cytotoxic T lymphocytes (CD8+ T cells). Based on these results, HGF-secreting NG2+ HSPs may specifically target recipient CD8+ T cells by inducing their apoptosis.
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Affiliation(s)
- Quanyu Chen
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, 400715 Chongqing, China; Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Yu You
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Yujun Zhang
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Hongyu Zhang
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China.
| | - Lianhua Bai
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, 400715 Chongqing, China; Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China.
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31
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Jiang Z, Byers S, Casal ML, Smith LJ. Failures of Endochondral Ossification in the Mucopolysaccharidoses. Curr Osteoporos Rep 2020; 18:759-773. [PMID: 33064251 PMCID: PMC7736118 DOI: 10.1007/s11914-020-00626-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/29/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders characterized by abnormal accumulation of glycosaminoglycans (GAGs) in cells and tissues. MPS patients frequently exhibit failures of endochondral ossification during postnatal growth leading to skeletal deformity and short stature. In this review, we outline the current understanding of the cellular and molecular mechanisms underlying failures of endochondral ossification in MPS and discuss associated treatment challenges and opportunities. RECENT FINDINGS Studies in MPS patients and animal models have demonstrated that skeletal cells and tissues exhibit significantly elevated GAG storage from early in postnatal life and that this is associated with impaired cartilage-to-bone conversion in primary and secondary ossification centers, and growth plate dysfunction. Recent studies have begun to elucidate the underlying cellular and molecular mechanisms, including impaired chondrocyte proliferation and hypertrophy, diminished growth factor signaling, disrupted cell cycle progression, impaired autophagy, and increased cell stress and apoptosis. Current treatments such as hematopoietic stem cell transplantation and enzyme replacement therapy fail to normalize endochondral ossification in MPS. Emerging treatments including gene therapy and small molecule-based approaches hold significant promise in this regard. Failures of endochondral ossification contribute to skeletal deformity and short stature in MPS patients, increasing mortality and reducing quality of life. Early intervention is crucial for effective treatment, and there is a critical need for new approaches that normalize endochondral ossification by directly targeting affected cells and signaling pathways.
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Affiliation(s)
- Zhirui Jiang
- Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, 371 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA, 19104, USA
| | - Sharon Byers
- Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia
- Paediatrics, The University of Adelaide, Adelaide, SA, Australia
- Genetics and Evolution, The University of Adelaide, Adelaide, SA, Australia
| | - Margret L Casal
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Lachlan J Smith
- Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, 371 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA, 19104, USA.
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32
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Shaimardanova AA, Chulpanova DS, Solovyeva VV, Mullagulova AI, Kitaeva KV, Allegrucci C, Rizvanov AA. Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches. Front Med (Lausanne) 2020; 7:576221. [PMID: 33195324 PMCID: PMC7606900 DOI: 10.3389/fmed.2020.576221] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/18/2020] [Indexed: 12/31/2022] Open
Abstract
Metachromatic leukodystrophy is a lysosomal storage disease, which is characterized by damage of the myelin sheath that covers most of nerve fibers of the central and peripheral nervous systems. The disease occurs due to a deficiency of the lysosomal enzyme arylsulfatase A (ARSA) or its sphingolipid activator protein B (SapB) and it clinically manifests as progressive motor and cognitive deficiency. ARSA and SapB protein deficiency are caused by mutations in the ARSA and PSAP genes, respectively. The severity of clinical course in metachromatic leukodystrophy is determined by the residual ARSA activity, depending on the type of mutation. Currently, there is no effective treatment for this disease. Clinical cases of bone marrow or cord blood transplantation have been reported, however the therapeutic effectiveness of these methods remains insufficient to prevent aggravation of neurological disorders. Encouraging results have been obtained using gene therapy for delivering the wild-type ARSA gene using vectors based on various serotypes of adeno-associated viruses, as well as using mesenchymal stem cells and combined gene-cell therapy. This review discusses therapeutic strategies for the treatment of metachromatic leukodystrophy, as well as diagnostic methods and modeling of this pathology in animals to evaluate the effectiveness of new therapies.
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Affiliation(s)
- Alisa A Shaimardanova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Daria S Chulpanova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, The Russian Academy of Sciences, Moscow, Russia
| | - Valeriya V Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, The Russian Academy of Sciences, Moscow, Russia
| | - Aysilu I Mullagulova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Kristina V Kitaeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Cinzia Allegrucci
- School of Veterinary Medicine and Science (SVMS) and Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
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33
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Çetin İ, Topçul M. Can mesenchymal stem cells be used to treat COVID-19-induced pneumonia? (Review). Biomed Rep 2020; 13:62. [PMID: 33194191 DOI: 10.3892/br.2020.1369] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 09/08/2020] [Indexed: 12/13/2022] Open
Abstract
The novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which has resulted in the COVID-19 pandemic, infection by which is commonly characterized by a sore throat, fever and cough, was first reported in Wuhan, China on 31st December 2019. This novel disease is mild in certain individuals, usually younger healthy individuals, whereas the elder and those with underlying health conditions develop severe symptoms and may die as a result of the disease or associated complications. Along with pneumonia, hypercytokinemia, also termed a cytokine storm, is one of the most common pathologies observed in patients with COVID-19. As patients react to the infection with the virus differently; in certain individuals, a cytokine storm may result in death. At present, there is no cure or widely available vaccine for the novel coronavirus. However, it has been hypothesized that mesenchymal stem cells may assist in the treatment/management of the cytokine storm due to their immunomodulating properties.
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Affiliation(s)
- İdil Çetin
- Department of Biology, Faculty of Science, Istanbul University, Istanbul 34459, Turkey
| | - Mehmet Topçul
- Department of Biology, Faculty of Science, Istanbul University, Istanbul 34459, Turkey
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Forsberg MH, Kink JA, Hematti P, Capitini CM. Mesenchymal Stromal Cells and Exosomes: Progress and Challenges. Front Cell Dev Biol 2020; 8:665. [PMID: 32766255 PMCID: PMC7379234 DOI: 10.3389/fcell.2020.00665] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 07/01/2020] [Indexed: 12/13/2022] Open
Abstract
Due to their robust immunomodulatory capabilities, mesenchymal stem/stromal cells (MSCs) have been used as a cellular therapy for a number of human diseases. Part of the mechanism of action of MSCs is the production of extracellular vesicles (EVs) that contain proteins, nucleic acids, and lipids that transmit signals to recipient cells that change their biologic behavior. This review briefly summarizes the development of MSCs as a treatment for human diseases as well as describes our present understanding of exosomes; how they exert their effects on target cells, and how they are differentiated from other EVs. The current treatment paradigm for acute radiation syndrome (ARS) is discussed, and how MSCs and MSC derived exosomes are emerging as treatment options for treating patients after radiation exposure. Other conditions such as graft-versus-host disease and cardiovascular disease/stroke are discussed as examples to highlight the immunomodulatory and regenerative capacity of MSC-exosomes. Finally, a consideration is given to how these cell-based therapies could possibly be deployed in the event of a catastrophic radiation exposure event.
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Affiliation(s)
- Matthew H Forsberg
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - John A Kink
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.,Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
| | - Peiman Hematti
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.,Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
| | - Christian M Capitini
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.,Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
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The role of hepatocyte growth factor in mesenchymal stem cell-induced recovery in spinal cord injured rats. Stem Cell Res Ther 2020; 11:178. [PMID: 32410702 PMCID: PMC7227078 DOI: 10.1186/s13287-020-01691-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 04/20/2020] [Accepted: 04/23/2020] [Indexed: 12/21/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have become a promising treatment for spinal cord injury (SCI) due to the fact that they provide a favorable environment. Treatment using MSCs results in a better neurological functional improvement through the promotion of nerve cell regeneration and the modulation of inflammation. Many studies have highlighted that the beneficial effects of MSCs are more likely associated with their secreted factors. However, the identity of the factor that plays a key role in the MSC-induced neurological functional recovery following SCI as well as its molecular mechanism still remains unclear. Methods A conditioned medium (collected from the MSCs) and hepatocyte growth factor (HGF) were used to test the effects on the differentiation of neural stem cells (NSCS) in the presence of BMP4 with or without a c-Met antibody. In SCI rats, Western blot, ELISA, immunohistochemistry, and hematoxylin-eosin staining were used to investigate the biological effects of MSC-conditioned medium and HGF on nerve cell regeneration and inflammation with or without the pre-treatment using a c-Met antibody. In addition, the possible molecular mechanism (cross-talk between HGF/c-Met and the BMP/Smad 1/5/8 signaling pathway) was also detected by Western blot both in vivo and in vitro. Results The conditioned medium from bone marrow-derived MSCs (BMSCs) was able to promote the NSC differentiation into neurons in vitro and the neurite outgrowth in the scar boundary of SCI rats by inhibiting the BMP/Smad signaling pathway as well as reduces the secondary damage through the modulation of the inflammatory process. The supplementation of HGF showed similar biological effects to those of BMSC-CM, whereas a functional blocking of the c-Met antibody or HGF knockdown in BMSCs significantly reversed the functional improvement mediated by the BMSC-CM. Conclusions The MSC-associated biological effects on the recovery of SCI rats mainly depend on the secretion of HGF.
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Beerepoot S, Nierkens S, Boelens JJ, Lindemans C, Bugiani M, Wolf NI. Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective. Orphanet J Rare Dis 2019; 14:240. [PMID: 31684987 PMCID: PMC6829806 DOI: 10.1186/s13023-019-1220-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 10/09/2019] [Indexed: 11/23/2022] Open
Abstract
Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited metabolic disease characterized by deficient activity of the lysosomal enzyme arylsulfatase A. Its deficiency results in accumulation of sulfatides in neural and visceral tissues, and causes demyelination of the central and peripheral nervous system. This leads to a broad range of neurological symptoms and eventually premature death. In asymptomatic patients with juvenile and adult MLD, treatment with allogeneic hematopoietic stem cell transplantation (HCT) provides a symptomatic and survival benefit. However, this treatment mainly impacts brain white matter, whereas the peripheral neuropathy shows no or only limited response. Data about the impact of peripheral neuropathy in MLD patients are currently lacking, although in our experience peripheral neuropathy causes significant morbidity due to neuropathic pain, foot deformities and neurogenic bladder disturbances. Besides, the reasons for residual and often progressive peripheral neuropathy after HCT are not fully understood. Preliminary studies suggest that peripheral neuropathy might respond better to gene therapy due to higher enzyme levels achieved than with HCT. However, histopathological and clinical findings also suggest a role of neuroinflammation in the pathology of peripheral neuropathy in MLD. In this literature review, we discuss clinical aspects, pathological findings, distribution of mutations, and treatment approaches in MLD with particular emphasis on peripheral neuropathy. We believe that future therapies need more emphasis on the management of peripheral neuropathy, and additional research is needed to optimize care strategies.
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Affiliation(s)
- Shanice Beerepoot
- Department of Child Neurology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, and Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, the Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Stefan Nierkens
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.,Pediatric Blood and Marrow Transplantation Program, Princess Máxima Center and University Medical Center Utrecht, Utrecht, the Netherlands
| | - Jaap Jan Boelens
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.,Department of Pediatrics, Stem Cell Transplant and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Caroline Lindemans
- Pediatric Blood and Marrow Transplantation Program, Princess Máxima Center and University Medical Center Utrecht, Utrecht, the Netherlands.,Regenerative medicine institute, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Marianna Bugiani
- Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, the Netherlands
| | - Nicole I Wolf
- Department of Child Neurology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, and Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, the Netherlands.
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Mechanism of Action of Icariin in Bone Marrow Mesenchymal Stem Cells. Stem Cells Int 2019; 2019:5747298. [PMID: 31089330 PMCID: PMC6476003 DOI: 10.1155/2019/5747298] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 02/28/2019] [Accepted: 03/12/2019] [Indexed: 12/19/2022] Open
Abstract
Osteoporosis, femoral head necrosis, and congenital bone defects are orthopedic disorders characterized by reduced bone generation and insufficient bone mass. Bone regenerative therapy primarily relies on the bone marrow mesenchymal stem cells (BMSCs) and their ability to differentiate osteogenically. Icariin (ICA) is the active ingredient of Herba epimedii, a common herb used in traditional Chinese medicine (TCM) formulations, and can effectively enhance BMSC proliferation and osteogenesis. However, the underlying mechanism of ICA action in BMSCs is not completely clear. In this review, we provide an overview of the studies on the role and mechanism of action of ICA in BMSCs, to provide greater insights into its potential clinical use in bone regeneration.
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Sharma A, Mawrie D, Magdalene D, Jaganathan BG. Isolation of Multipotent Mesenchymal Stem Cells from Human Extraocular Muscle Tissue. Bio Protoc 2019; 9:e3167. [PMID: 33654973 DOI: 10.21769/bioprotoc.3167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/20/2019] [Accepted: 01/22/2019] [Indexed: 11/02/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have attracted significant attention as potential therapeutic cells to treat various diseases ranging from tissue injuries, graft versus host disease, degenerative diseases and cancer. Since the initial discovery of MSCs in the bone marrow cells, MSCs have been successfully isolated from various adult and neo-natal tissues, albeit the procedures are often coupled with difficulties in harvesting tissue and produce low yield of cells, requiring extensive expansion in vitro. Here, we explored extra-ocular muscle tissues obtained from patients as a novel source of MSCs which express characteristic cell surface markers of MSCs and show multilineage differentiation potential with high proliferation capacity.
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Affiliation(s)
- Amit Sharma
- Stem Cells and Cancer Biology Group, Department of Biosciences and Bioengineering, Guwahati, India
| | - Darilang Mawrie
- Stem Cells and Cancer Biology Group, Department of Biosciences and Bioengineering, Guwahati, India
| | - Damaris Magdalene
- Department of Pediatric Ophthalmology, Sri Sankaradeva Nethralaya, Guwahati, India
| | - Bithiah Grace Jaganathan
- Stem Cells and Cancer Biology Group, Department of Biosciences and Bioengineering, Guwahati, India
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Kumar SA, Delgado M, Mendez VE, Joddar B. Applications of stem cells and bioprinting for potential treatment of diabetes. World J Stem Cells 2019; 11:13-32. [PMID: 30705712 PMCID: PMC6354103 DOI: 10.4252/wjsc.v11.i1.13] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/26/2018] [Accepted: 01/05/2019] [Indexed: 02/06/2023] Open
Abstract
Currently, there does not exist a strategy that can reduce diabetes and scientists are working towards a cure and innovative approaches by employing stem cell-based therapies. On the other hand, bioprinting technology is a novel therapeutic approach that aims to replace the diseased or lost β-cells, insulin-secreting cells in the pancreas, which can potentially regenerate damaged organs such as the pancreas. Stem cells have the ability to differentiate into various cell lines including insulin-producing cells. However, there are still barriers that hamper the successful differentiation of stem cells into β-cells. In this review, we focus on the potential applications of stem cell research and bioprinting that may be targeted towards replacing the β-cells in the pancreas and may offer approaches towards treatment of diabetes. This review emphasizes on the applicability of employing both stem cells and other cells in 3D bioprinting to generate substitutes for diseased β-cells and recover lost pancreatic functions. The article then proceeds to discuss the overall research done in the field of stem cell-based bioprinting and provides future directions for improving the same for potential applications in diabetic research.
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Affiliation(s)
- Shweta Anil Kumar
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Monica Delgado
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Victor E Mendez
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Binata Joddar
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
- Border Biomedical Research Center, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States.
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Orchard PJ. Cellular Therapy in Rare Childhood Neurologic Disease: Lessons, Outcomes, and Access. J Child Neurol 2018; 33:877-881. [PMID: 30203711 DOI: 10.1177/0883073818797875] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Paul J Orchard
- 1 Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
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Danjuma L, Mok PL, Higuchi A, Hamat RA, Teh SW, Koh AEH, Munusamy MA, Arulselvan P, Rajan M, Nambi A, Swamy K, Vijayaraman K, Murugan K, Natarajaseenivasan K, Subbiah SK. Modulatory and regenerative potential of transplanted bone marrow-derived mesenchymal stem cells on rifampicin-induced kidney toxicity. Regen Ther 2018; 9:100-110. [PMID: 30525080 PMCID: PMC6223029 DOI: 10.1016/j.reth.2018.09.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 09/03/2018] [Indexed: 12/26/2022] Open
Abstract
INTRODUCTION Anti-tuberculosis agent rifampicin is extensively used for its effectiveness. Possible complications of tuberculosis and prolonged rifampicin treatment include kidney damage; these conditions can lead to reduced efficiency of the affected kidney and consequently to other diseases. Bone marrow-derived mesenchymal stem cells (BMMSCs) can be used in conjunction with rifampicin to avert kidney damage; because of its regenerative and differentiating potentials into kidney cells. This research was designed to assess the modulatory and regenerative potentials of MSCs in averting kidney damage due to rifampicin-induced kidney toxicity in Wistar rats and their progenies. BMMSCs used in this research were characterized according to the guidelines of International Society for Cellular Therapy. METHODS The rats (male and female) were divided into three experimental groups, as follows: Group 1: control rats (4 males & 4 females); Group 2: rats treated with rifampicin only (4 males & 4 females); and Group 3: rats treated with rifampicin plus MSCs (4 males & 4 females). Therapeutic doses of rifampicin (9 mg/kg/day for 3-months) and MSCs infusions (twice/month for 3-months) were administered orally and intravenously respectively. At the end of the three months, the animals were bred together to determine if the effects would carry over to the next generation. Following breeding, the rats were sacrificed to harvest serum for biochemical analysis and the kidneys were also harvested for histological analysis and quantification of the glomeruli size, for the adult rats and their progenies. RESULTS The results showed some level of alterations in the biochemical indicators and histopathological damage in the rats that received rifampicin treatment alone, while the control and stem cells treated group showed apparently normal to nearly normal levels of both bio-indicators and normal histological architecture. CONCLUSIONS Intravenous administration of MSCs yielded sensible development, as seen from biochemical indicators, histology and the quantitative cell analysis, hence implying the modulatory and regenerative properties of MSCs.
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Affiliation(s)
- Lawal Danjuma
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Department of Microbiology and Biotechnology, Faculty of Science, Federal University Duste, P.M.B 7156, Duste, Jigawa, Nigeria
| | - Pooi Ling Mok
- Department of Biomedical Science, Faculty of Medicine and Health Science Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Genetics and Regenerative Medicine Research Centre, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, P.O. Box 2014, Sakaka, Aljouf Province, Saudi Arabia
| | - Akon Higuchi
- Department of Chemical and Materials Engineering, National Central University, Jhong-li, Taoyuan, 32001, Taiwan
- Department of Reproduction, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
- Department of Botany and Microbiology, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Rukman Awang Hamat
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Seoh Wei Teh
- Department of Biomedical Science, Faculty of Medicine and Health Science Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Avin Ee-Hwan Koh
- Department of Biomedical Science, Faculty of Medicine and Health Science Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Murugan A. Munusamy
- Department of Botany and Microbiology, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Palanisamy Arulselvan
- Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia
| | - Mariappan Rajan
- Biomaterials in Medicinal Chemistry Laboratory, Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, 625 021, Tamil Nadu, India
| | - Arivudai Nambi
- Faculty of Medicine, Lincoln University College, Malaysia
| | - K.B. Swamy
- Faculty of Medicine, Lincoln University College, Malaysia
| | - Kiruthiga Vijayaraman
- Department of Medical Biotechnology, Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Malaysia
| | - Kadarkarai Murugan
- Division of Entomology, Department of Zoology, School of Life Sciences, Bharathiar University, Coimbatore, Tamil Nadu, 641 046, India
| | - Kalimuthusamy Natarajaseenivasan
- Medical Microbiology Laboratory, Department of Microbiology, Centre of Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli, India
| | - Suresh Kumar Subbiah
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Genetics and Regenerative Medicine Research Centre, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Muthayammal Centre for Advanced Research, Muthayammal College of Arts and Science, Rasipuram, Namakkal, Tamil Nadu, 637408, India
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López-Lucas MD, Pachón-Peña G, García-Hernández AM, Parrado A, Sánchez-Salinas D, García-Bernal D, Algueró MDC, Martinez FI, Blanquer M, Cabañas-Perianes V, Molina-Molina M, Asín-Aguilar C, Moraleda JM, Sackstein R. Production via good manufacturing practice of exofucosylated human mesenchymal stromal cells for clinical applications. Cytotherapy 2018; 20:1110-1123. [PMID: 30170815 DOI: 10.1016/j.jcyt.2018.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 05/25/2018] [Accepted: 07/03/2018] [Indexed: 01/02/2023]
Abstract
BACKGROUND The regenerative and immunomodulatory properties of human mesenchymal stromal cells (hMSCs) have raised great hope for their use in cell therapy. However, when intravenously infused, hMSCs fail to reach sites of tissue injury. Fucose addition in α(1,3)-linkage to terminal sialyllactosamines on CD44 creates the molecule known as hematopoietic cell E-/L-selectin ligand (HCELL), programming hMSC binding to E-selectin that is expressed on microvascular endothelial cells of bone marrow (BM), skin and at all sites of inflammation. Here we describe how this modification on BM-derived hMSCs (BM-hMSCs) can be adapted to good manufacturing practice (GMP) standards. METHODS BM-hMSCs were expanded using xenogenic-free media and exofucosylated using α(1,3)-fucosyltransferases VI (FTVI) or VII (FTVII). Enforced fucosylation converted CD44 into HCELL, and HCELL formation was assessed using Western blot, flow cytometry and cell-binding assays. Untreated (unfucosylated), buffer-treated and exofucosylated BM-hMSCs were each analyzed for cell viability, immunophenotype and differentiation potential, and E-selectin binding stability was assessed at room temperature, at 4°C, and after cryopreservation. Cell product safety was evaluated using microbiological testing, karyotype analysis, and c-Myc messenger RNA (mRNA) expression, and potential effects on genetic reprogramming and in cell signaling were analyzed using gene expression microarrays and receptor tyrosine kinase (RTK) phosphorylation arrays. RESULTS Our protocol efficiently generates HCELL on clinical-scale batches of BM-hMSCs. Exofucosylation yields stable HCELL expression for 48 h at 4°C, with retained expression after cell cryopreservation. Cell viability and identity are unaffected by exofucosylation, without changes in gene expression or RTK phosphorylation. DISCUSSION The described exofucosylation protocol using xenogenic-free reagents enforces HCELL expression on hMSCs endowing potent E-selectin binding without affecting cell viability or native phenotype. This described protocol is readily scalable for GMP-compliant clinical production.
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Affiliation(s)
- María Dolores López-Lucas
- Red de Terapia Celular (TerCel), Instituto de Salud Carlos III. University of Murcia; Stem Cell Transplant and Cell Therapy Unit, Virgen de la Arrixaca Clinic University Hospital and Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain
| | - Gisela Pachón-Peña
- The Program of Excellence in Glycosciences, Harvard Medical School, Boston, Massachusetts, and the Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ana María García-Hernández
- Red de Terapia Celular (TerCel), Instituto de Salud Carlos III. University of Murcia; Stem Cell Transplant and Cell Therapy Unit, Virgen de la Arrixaca Clinic University Hospital and Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain
| | - Antonio Parrado
- Immunology Service, Virgen de la Arrixaca Clinic University Hospital, Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain
| | - Darío Sánchez-Salinas
- Red de Terapia Celular (TerCel), Instituto de Salud Carlos III. University of Murcia; Stem Cell Transplant and Cell Therapy Unit, Virgen de la Arrixaca Clinic University Hospital and Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain
| | - David García-Bernal
- Red de Terapia Celular (TerCel), Instituto de Salud Carlos III. University of Murcia; Stem Cell Transplant and Cell Therapy Unit, Virgen de la Arrixaca Clinic University Hospital and Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain
| | - Maria Del Carmen Algueró
- Red de Terapia Celular (TerCel), Instituto de Salud Carlos III. University of Murcia; Stem Cell Transplant and Cell Therapy Unit, Virgen de la Arrixaca Clinic University Hospital and Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain
| | - Francisca Iniesta Martinez
- Red de Terapia Celular (TerCel), Instituto de Salud Carlos III. University of Murcia; Stem Cell Transplant and Cell Therapy Unit, Virgen de la Arrixaca Clinic University Hospital and Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain
| | - Miguel Blanquer
- Red de Terapia Celular (TerCel), Instituto de Salud Carlos III. University of Murcia; Stem Cell Transplant and Cell Therapy Unit, Virgen de la Arrixaca Clinic University Hospital and Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain
| | - Valentín Cabañas-Perianes
- Red de Terapia Celular (TerCel), Instituto de Salud Carlos III. University of Murcia; Stem Cell Transplant and Cell Therapy Unit, Virgen de la Arrixaca Clinic University Hospital and Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain
| | - Mar Molina-Molina
- Red de Terapia Celular (TerCel), Instituto de Salud Carlos III. University of Murcia; Stem Cell Transplant and Cell Therapy Unit, Virgen de la Arrixaca Clinic University Hospital and Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain
| | - Cira Asín-Aguilar
- Red de Terapia Celular (TerCel), Instituto de Salud Carlos III. University of Murcia; Stem Cell Transplant and Cell Therapy Unit, Virgen de la Arrixaca Clinic University Hospital and Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain
| | - José M Moraleda
- Red de Terapia Celular (TerCel), Instituto de Salud Carlos III. University of Murcia; Stem Cell Transplant and Cell Therapy Unit, Virgen de la Arrixaca Clinic University Hospital and Institute for Biohealth Research (IMIB-Arrixaca), Ctra. Madrid-Cartagena s/n, El Palmar, Murcia, Spain.
| | - Robert Sackstein
- The Program of Excellence in Glycosciences, Harvard Medical School, Boston, Massachusetts, and the Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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Serrano-Mollar A. Cell Therapy in Idiopathic Pulmonary Fibrosis †. Med Sci (Basel) 2018; 6:medsci6030064. [PMID: 30104544 PMCID: PMC6164035 DOI: 10.3390/medsci6030064] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 08/02/2018] [Accepted: 08/08/2018] [Indexed: 12/12/2022] Open
Abstract
Idiopathic pulmonary fibrosis is a fatal disease with no effective or curative treatment options. In recent decades, cell-based therapies using stem cells or lung progenitor cells to regenerate lung tissue have experienced rapid growth in both preclinical animal models and translational clinical studies. In this review, the current knowledge of these cell therapies is summarized. Although further investigations are required, these studies indicate that cell therapies are a promising therapeutic approach for the treatment of idiopathic pulmonary fibrosis.
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Affiliation(s)
- Anna Serrano-Mollar
- Departamento de Patología Experimental, Instituto de Investigaciones Biomédicas de Barcelona IIBB-CSIC-IDIBAPS, Rosselló, 161, 08036 Barcelona, Spain.
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
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Ichim TE, O'Heeron P, Kesari S. Fibroblasts as a practical alternative to mesenchymal stem cells. J Transl Med 2018; 16:212. [PMID: 30053821 PMCID: PMC6064181 DOI: 10.1186/s12967-018-1536-1] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 06/01/2018] [Indexed: 02/08/2023] Open
Abstract
Mesenchymal stem cell (MSC) therapy offers great potential for treatment of disease through the multifunctional and responsive ability of these cells. In numerous contexts, MSC have been shown to reduce inflammation, modulate immune responses, and provide trophic factor support for regeneration. While the most commonly used MSC source, the bone marrow provides relatively little starting material for cellular expansion, and requires invasive extraction means, fibroblasts are easily harvested in large numbers from various biological wastes. Additionally, in vitro expansion of fibroblasts is significantly easier given the robustness of these cells in tissue culture and shorter doubling time compared to typical MSC. In this paper we put forward the concept that in some cases, fibroblasts may be utilized as a more practical, and potentially more effective cell therapy than mesenchymal stem cells. Anti-inflammatory, immune modulatory, and regenerative properties of fibroblasts will be discussed in the context of regenerative medicine.
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Affiliation(s)
| | | | - Santosh Kesari
- Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute and Pacific Neuroscience Institute, Santa Monica, CA, USA
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Tian T, Yu Z, Zhang N, Chang Y, Zhang Y, Zhang L, Zhou S, Zhang C, Feng G, Huang F. Modified acellular nerve-delivering PMSCs improve functional recovery in rats after complete spinal cord transection. Biomater Sci 2018; 5:2480-2492. [PMID: 29106428 DOI: 10.1039/c7bm00485k] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Due to the poor regeneration capacity of neurons and the inhibitory microenvironment, spontaneous regeneration in spinal cord injury (SCI) remains challenging. Tissue engineering is considered a promising approach for enhancing the regeneration of SCI by reconstructing the inherent structure and improving the microenvironment. In this study, the possibility of engineering a nerve complex, which is constructed by acellular nerve delivering placenta mesenchymal stem cells (PMSCs), was assessed for the recovery of a transected spinal cord. Modified acellular nerve grafts were developed, and PMSCs labeled with green fluorescent protein (GFP) were seeded on the graft to construct the engineered nerve complex. Then, the engineered nerve complex was implanted into a 2 mm-length transected gap of the spinal cord. Four weeks after the transplantation, numerous surviving PMSCs were observed in the lesion cavity by immunofluorescence staining. Moreover, co-localization between GFP and neurofilament-200 (NF200) and Neuronal Class III β-Tubulin (Tuj1) was observed at the bridge interface. The PMSCs-graft group exhibited significant function improvement as evaluated by the Basso, Beattie and Bresnahan (BBB) locomotion score and footprint analysis. Eight weeks after surgery, the evoked response was restored in the PMSCs-graft group and numerous thick myelin sheathes were observed compared to that in the control groups. Collectively, our findings suggest that the nerve complex prepared by acellular nerve delivering PMSCs enhanced the structure and function regeneration of the spinal cord after SCI.
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Affiliation(s)
- Ting Tian
- Institute of Human Anatomy and Histology and Embryology, Otology & Neuroscience Center, Binzhou Medical University, 346 Guanhai Road, Laishan District, Shandong Province 264003, China.
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Miller BLK, Garg P, Bronstein B, LaPointe E, Lin H, Charytan DM, Tilles AW, Parekkadan B. Extracorporeal Stromal Cell Therapy for Subjects With Dialysis-Dependent Acute Kidney Injury. Kidney Int Rep 2018; 3:1119-1127. [PMID: 30197978 PMCID: PMC6127415 DOI: 10.1016/j.ekir.2018.05.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 05/14/2018] [Accepted: 05/21/2018] [Indexed: 12/29/2022] Open
Abstract
Introduction The pathophysiology of acute kidney injury (AKI) involves damage to renal epithelial cells, podocytes, and vascular beds that manifests into a deranged, self-perpetuating immune response and peripheral organ dysfunction. Such an injury pattern requires a multifaceted therapeutic to alter the wound healing response systemically. Mesenchymal stromal cells (MSCs) are a unique source of secreted factors that can modulate an inflammatory response to acute organ injury and enhance the repair of injured tissue at the parenchymal and endothelial levels. This phase Ib/IIa clinical trial evaluates SBI-101, a combination product that administers MSCs extracorporeally to overcome pharmacokinetic barriers of MSC transplantation. SBI-101 contains allogeneic human MSCs inoculated into a hollow-fiber hemofilter for the treatment of patients with severe AKI who are receiving continuous renal replacement therapy (CRRT). SBI-101 therapy is designed to reprogram the molecular and cellular components of blood in patients with severe organ injury. Methods This study is a prospective, multicenter, randomized, double-blind, sham-controlled, study of subjects with a clinical diagnosis of AKI who are receiving CRRT. Up to 32 subjects may be enrolled to provide 24 evaluable subjects (as a per protocol population). Subjects will receive CRRT in tandem with a sham control (0 MSCs), or the low- (250 × 106 MSCs) or high-dose (750 × 106 MSCs) SBI-101 therapeutic. Results The study will measure dose-dependent safety, renal efficacy, and exploratory biomarkers to characterize the pharmacokinetics and pharmacodynamics of SBI-101 in treated subjects. Conclusion This first-in-human clinical trial will evaluate the safety and tolerability of SBI-101 in patients with AKI who require CRRT.
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Affiliation(s)
| | - Payal Garg
- Sentien Biotechnologies, Inc., Lexington, Massachusetts, USA
| | - Ben Bronstein
- Cold Spring Venture Advisors, LLC, Watertown, Massachusetts, USA
| | | | - Herb Lin
- Department of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - David M Charytan
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Arno W Tilles
- Sentien Biotechnologies, Inc., Lexington, Massachusetts, USA
| | - Biju Parekkadan
- Sentien Biotechnologies, Inc., Lexington, Massachusetts, USA.,Department of Surgery, Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.,Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, USA
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Park J, Jeong S, Park K, Yang K, Shin S. Expression profile of microRNAs following bone marrow-derived mesenchymal stem cell treatment in lipopolysaccharide-induced acute lung injury. Exp Ther Med 2018; 15:5495-5502. [PMID: 29904430 DOI: 10.3892/etm.2018.6118] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 03/23/2018] [Indexed: 12/11/2022] Open
Abstract
Immunomodulatory or immunosuppressive properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) facilitate the treatment of acute respiratory distress syndrome and acute lung injury (ALI). Dysregulated miRNA (miRNA or miR) expression associated with the effects of BM-MSCs was assessed in a rat model of lipopolysaccharide (LPS)-induced ALI. The present study performed biochemical tests to assess five analytes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate, blood urea nitrogen (BUN), and creatinine (CREA). Total cell count was assessed and the percentage of bronchoalveolar lavage neutrophil content was also examined. The results Histopathological examination of rat upper lobe lung tissue was then used to estimate lung injury score (LIS). The levels of AST, lactate, BUN and creatinine (excluding ALT), released into the circulation upon injury, were significantly lower in ALI rats treated with BM-MSCs than in ALI rats alone (P<0.05). BM-MSC rats exhibited a significantly decreased bronchoalveolar lavage neutrophil percentage and LIS compared with that of LPS treated rats alone (P<0.05). In addition, the miRNA expression profile was determined following treatment with BM-MSCs via microarray analysis. A total of 95/690 miRNAs were differentially expressed following the treatment of BM-MSCs in rats with ALI. Among the 95 miRNAs, 66 were upregulated and 29 were downregulated; 9 miRNAs were significantly upregulated (miR-1843-3p, miR-323-3p, miR-183-5p, miR-182 and miR-196b-3p) or downregulated (miR-547-3p, miR-301b-5p, miR-503-3p and miR-142-3p). A total of 3 miRNAs were inversely expressed in ALI treated with BM-MSCs compared with untreated ALI. Of these 3 miRNAs, the expression of miR-142-3p and miR-503-3p was upregulated in the LPS groups and downregulated in the BM-MSC groups. miR-196b-3p was downregulated in the LPS group and upregulated in the BM-MSC groups. miRNAs have a role in cell proliferation, immune response, inflammation and apoptosis, which may be associated with the therapeutic effects of BM-MSCs in ALI. In summary, BM-MSCs improved multi-organ damage and attenuated lung injury. Different miRNA profiles were expressed following BM-MSC treatment of ALI. These dysregulated miRNAs participated in BM-MSC-mediated immunomodulation of ALI.
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Affiliation(s)
- Joonhong Park
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Sikyoung Jeong
- Department of Emergency Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Kicheol Park
- Clinical Research Institute, Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon 34943, Republic of Korea
| | - Keumjin Yang
- Clinical Research Institute, Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon 34943, Republic of Korea
| | - Soyoung Shin
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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Mirzaei H, Salehi H, Oskuee RK, Mohammadpour A, Mirzaei HR, Sharifi MR, Salarinia R, Darani HY, Mokhtari M, Masoudifar A, Sahebkar A, Salehi R, Jaafari MR. The therapeutic potential of human adipose-derived mesenchymal stem cells producing CXCL10 in a mouse melanoma lung metastasis model. Cancer Lett 2018; 419:30-39. [PMID: 29331419 DOI: 10.1016/j.canlet.2018.01.029] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 01/03/2018] [Accepted: 01/08/2018] [Indexed: 02/07/2023]
Abstract
Interferon γ-induced protein 10 kDa (IP-10) is a potent chemoattractant and has been suggested to enhance antitumor activity and mediate tumor regression through multiple mechanisms of action. Multiple lines of evidence have indicated that genetically-modified adult stem cells represent a potential source for cell-based cancer therapy. In the current study, we assessed therapeutic potential of human adipose derived mesenchymal stem cells (hADSC) genetically-modified to express IP-10 for the treatment of lung metastasis in an immunocompetent mouse model of metastatic melanoma. A Piggybac vector encoding IP-10 was employed to transfect hADSC ex vivo. Expression and bioactivity of the transgenic protein from hADSCs expressing IP-10 were confirmed prior to in vivo studies. Our results indicated that hADSCs expressing IP-10 could inhibit the growth of B16F10 melanoma cells and significantly prolonged survival. Immunohistochemistry analysis, TUNEL assay and western blot analysis indicated that hADSCs expressing IP-10 inhibited tumor cell growth, hindered tumor infiltration of Tregs, restricted angiogenesis and significantly prolonged survival. In conclusion, our results demonstrated that targeting metastatic tumor sites by hADSC expressing IP-10 could reduce melanoma tumor growth and lung metastasis.
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Affiliation(s)
- Hamed Mirzaei
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Salehi
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Reza Kazemi Oskuee
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Mohammadpour
- Faculty of Nursing and Midwifery, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Hamid Reza Mirzaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Clinical Laboratory Sciences, School of Allied Medical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Reza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Reza Salarinia
- Department of Medical Biotechnology, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Hossein Yousofi Darani
- Department of Medical Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mojgan Mokhtari
- Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Aria Masoudifar
- Department of Molecular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran.
| | - Mahmoud Reza Jaafari
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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50
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Cohen JA, Imrey PB, Planchon SM, Bermel RA, Fisher E, Fox RJ, Bar-Or A, Sharp SL, Skaramagas TT, Jagodnik P, Karafa M, Morrison S, Reese Koc J, Gerson SL, Lazarus HM. Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Mult Scler 2018; 24:501-511. [PMID: 28381130 PMCID: PMC5623598 DOI: 10.1177/1352458517703802] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) exhibit immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animals. Clinical trials in several human conditions support the safety and efficacy of MSC transplantation. Published experience in multiple sclerosis (MS) is modest. OBJECTIVE To assess feasibility, safety, and tolerability and explore efficacy of autologous MSC transplantation in MS. METHODS Participants with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS), Expanded Disability Status Scale score 3.0-6.5, disease activity or progression in the prior 2 years, and optic nerve involvement were enrolled. Bone-marrow-derived MSCs were culture-expanded and then cryopreserved. After confirming fulfillment of release criteria, 1-2 × 106 MSCs/kg were thawed and administered IV. RESULTS In all, 24 of 26 screened patients were infused: 16 women and 8 men, 10 RRMS and 14 SPMS, mean age 46.5, mean Expanded Disability Status Scale score 5.2, 25% with gadolinium-enhancing magnetic resonance imaging (MRI) lesions. Mean cell dosage (requiring 1-3 passages) was 1.9 × 106 MSCs/kg (range, 1.5-2.0) with post-thaw viability uniformly ⩾95%. Cell infusion was tolerated well without treatment-related severe or serious adverse events, or evidence of disease activation. CONCLUSION Autologous MSC transplantation in MS appears feasible, safe, and well tolerated. Future trials to assess efficacy more definitively are warranted.
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Affiliation(s)
- Jeffrey A Cohen
- Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Peter B Imrey
- Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA/Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Sarah M Planchon
- Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Robert A Bermel
- Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Elizabeth Fisher
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA/Biogen, Cambridge, MA, USA
| | - Robert J Fox
- Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Amit Bar-Or
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada/Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
| | - Susan L Sharp
- Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Thomai T Skaramagas
- Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Patricia Jagodnik
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Matt Karafa
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Shannon Morrison
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jane Reese Koc
- Case Comprehensive Cancer Center and National Center for Regenerative Medicine, Case Western Reserve University and Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Stanton L Gerson
- Case Comprehensive Cancer Center and National Center for Regenerative Medicine, Case Western Reserve University and Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Hillard M Lazarus
- Case Comprehensive Cancer Center and National Center for Regenerative Medicine, Case Western Reserve University and Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
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