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Santa Cruz-Pavlovich FJ, Bolaños-Chang AJ, Del Rio-Murillo XI, Aranda-Preciado GA, Razura-Ruiz EM, Santos A, Navarro-Partida J. Beyond Vision: An Overview of Regenerative Medicine and Its Current Applications in Ophthalmological Care. Cells 2024; 13:179. [PMID: 38247870 PMCID: PMC10814238 DOI: 10.3390/cells13020179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 12/23/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
Regenerative medicine (RM) has emerged as a promising and revolutionary solution to address a range of unmet needs in healthcare, including ophthalmology. Moreover, RM takes advantage of the body's innate ability to repair and replace pathologically affected tissues. On the other hand, despite its immense promise, RM faces challenges such as ethical concerns, host-related immune responses, and the need for additional scientific validation, among others. The primary aim of this review is to present a high-level overview of current strategies in the domain of RM (cell therapy, exosomes, scaffolds, in vivo reprogramming, organoids, and interspecies chimerism), centering around the field of ophthalmology. A search conducted on clinicaltrials.gov unveiled a total of at least 209 interventional trials related to RM within the ophthalmological field. Among these trials, there were numerous early-phase studies, including phase I, I/II, II, II/III, and III trials. Many of these studies demonstrate potential in addressing previously challenging and degenerative eye conditions, spanning from posterior segment pathologies like Age-related Macular Degeneration and Retinitis Pigmentosa to anterior structure diseases such as Dry Eye Disease and Limbal Stem Cell Deficiency. Notably, these therapeutic approaches offer tailored solutions specific to the underlying causes of each pathology, thus allowing for the hopeful possibility of bringing forth a treatment for ocular diseases that previously seemed incurable and significantly enhancing patients' quality of life. As advancements in research and technology continue to unfold, future objectives should focus on ensuring the safety and prolonged viability of transplanted cells, devising efficient delivery techniques, etc.
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Affiliation(s)
- Francisco J. Santa Cruz-Pavlovich
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64849, Mexico; (F.J.S.C.-P.); (A.J.B.-C.); (X.I.D.R.-M.); (E.M.R.-R.); (A.S.)
| | - Andres J. Bolaños-Chang
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64849, Mexico; (F.J.S.C.-P.); (A.J.B.-C.); (X.I.D.R.-M.); (E.M.R.-R.); (A.S.)
| | - Ximena I. Del Rio-Murillo
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64849, Mexico; (F.J.S.C.-P.); (A.J.B.-C.); (X.I.D.R.-M.); (E.M.R.-R.); (A.S.)
| | | | - Esmeralda M. Razura-Ruiz
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64849, Mexico; (F.J.S.C.-P.); (A.J.B.-C.); (X.I.D.R.-M.); (E.M.R.-R.); (A.S.)
| | - Arturo Santos
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64849, Mexico; (F.J.S.C.-P.); (A.J.B.-C.); (X.I.D.R.-M.); (E.M.R.-R.); (A.S.)
| | - Jose Navarro-Partida
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64849, Mexico; (F.J.S.C.-P.); (A.J.B.-C.); (X.I.D.R.-M.); (E.M.R.-R.); (A.S.)
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Jones OY, McCurdy D. Cell Based Treatment of Autoimmune Diseases in Children. Front Pediatr 2022; 10:855260. [PMID: 35615628 PMCID: PMC9124972 DOI: 10.3389/fped.2022.855260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 03/14/2022] [Indexed: 11/28/2022] Open
Abstract
Mesenchymal stem cells have recently been recoined as medicinal signaling cells (MSC) for their ability to promote tissue homeostasis through immune modulation, angiogenesis and tropism. During the last 20 years, there has been a plethora of publications using MSC in adults and to lesser extent neonates on a variety of illnesses. In parts of the world, autologous and allogeneic MSCs have been purified and used to treat a range of autoimmune conditions, including graft versus host disease, Crohn's disease, multiple sclerosis, refractory systemic lupus erythematosus and systemic sclerosis. Generally, these reports are not part of stringent clinical trials but are of note for good outcomes with minimal side effects. This review is to summarize the current state of the art in MSC therapy, with a brief discussion of cell preparation and safety, insights into mechanisms of action, and a review of published reports of MSC treatment of autoimmune diseases, toward the potential application of MSC in treatment of children with severe autoimmune diseases using multicenter clinical trials and treatment algorithms.
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Affiliation(s)
- Olcay Y. Jones
- Division of Pediatric Rheumatology, Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD, United States
| | - Deborah McCurdy
- Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States
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Xavier M, Kyriazi ME, Lanham S, Alexaki K, Matthews E, El-Sagheer AH, Brown T, Kanaras AG, Oreffo ROC. Enrichment of Skeletal Stem Cells from Human Bone Marrow Using Spherical Nucleic Acids. ACS NANO 2021; 15:6909-6916. [PMID: 33751885 DOI: 10.1021/acsnano.0c10683] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Human bone marrow (BM)-derived stromal cells contain a population of skeletal stem cells (SSCs), with the capacity to differentiate along the osteogenic, adipogenic, and chondrogenic lineages, enabling their application to clinical therapies. However, current methods to isolate and enrich SSCs from human tissues remain, at best, challenging in the absence of a specific SSC marker. Unfortunately, none of the current proposed markers alone can isolate a homogeneous cell population with the ability to form bone, cartilage, and adipose tissue in humans. Here, we have designed DNA-gold nanoparticles able to identify and sort SSCs displaying specific mRNA signatures. The current approach demonstrates the significant enrichment attained in the isolation of SSCs, with potential therein to enhance our understanding of bone cell biology and translational applications.
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Affiliation(s)
- Miguel Xavier
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Human Development and Health, Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
| | - Maria-Eleni Kyriazi
- School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom
| | - Stuart Lanham
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Human Development and Health, Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
| | - Konstantina Alexaki
- School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom
| | - Elloise Matthews
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Human Development and Health, Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
| | - Afaf H El-Sagheer
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom
- Chemistry Branch, Department of Science and Mathematics, Faculty of Petroleum and Mining Engineering, Suez University, Suez 43721, Egypt
| | - Tom Brown
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom
| | - Antonios G Kanaras
- School of Physics and Astronomy, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom
| | - Richard O C Oreffo
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Human Development and Health, Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom
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Fornari C, O'Connor LO, Yates JWT, Cheung SYA, Jodrell DI, Mettetal JT, Collins TA. Understanding Hematological Toxicities Using Mathematical Modeling. Clin Pharmacol Ther 2018; 104:644-654. [PMID: 29604045 DOI: 10.1002/cpt.1080] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 03/09/2018] [Accepted: 03/27/2018] [Indexed: 12/16/2022]
Abstract
Balancing antitumor efficacy with toxicity is a significant challenge, and drug-induced myelosuppression is a common dose-limiting toxicity of cancer treatments. Mathematical modeling has proven to be a powerful ally in this field, scaling results from animal models to humans, and designing optimized treatment regimens. Here we outline existing mathematical approaches for studying bone marrow toxicity, identify gaps in current understanding, and make future recommendations to advance this vital field of safety research further.
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Affiliation(s)
- Chiara Fornari
- Safety and ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK
| | | | - James W T Yates
- DMPK, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK
| | - S Y Amy Cheung
- Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, Cambridge, UK
| | - Duncan I Jodrell
- CRUK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK
| | - Jerome T Mettetal
- Safety and ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Boston, Massachusetts, USA
| | - Teresa A Collins
- Safety and ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK
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Mohammadian M, Sadeghipour HR, Jahromi GP, Jafari M, Nejad AK, Khamse S, Boskabady MH. Simvastatin and bone marrow-derived mesenchymal stem cells (BMSCs) affects serum IgE and lung cytokines levels in sensitized mice. Cytokine 2018; 113:83-88. [PMID: 29914792 DOI: 10.1016/j.cyto.2018.06.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/31/2018] [Accepted: 06/11/2018] [Indexed: 01/31/2023]
Abstract
INTRODUCTION The effects of bone marrow-derived mesenchymal stem cells (BMSCs) and simvastatin combination therapy on serum total and specific IgE levels and lung IL-13 and TGF-β levels in sensitized mouse were examined. MATERIAL AND METHODS Control (n = 5), Sensitized (S), (n = 5), S + BMSC (n = 6), S + simvastatin (n = 6) and S + BMSC + simvastatin (n = 4) groups of BALB/c mice were studied. Mice were sensitized by ovalbumin. Sensitized mice were treated with a single intravenous injection of BMSCs (1 × 106) or daily intraperitoneal injection of simvastatin (40 mg/kg) or both BMSCs and simvastatin on the last week of challenge. Serum total and ovalbumin specific IgE levels as well as IL-13 and TGF-β levels in broncho-alveolar lavage (BAL) fluid were evaluated. RESULTS Serum total and specific IgE levels as well as lung IL-13 and TGF-β levels were significantly increased in S group compared to control group (P < 0.001 for all cases). Treatment with BMSCs, simvastatin and their combination significantly decreased serum total and specific IgE levels (P < 0.05 to P < 0.01). However, IL-13 and TGF-β levels were significantly decreased by BMSCs and BMSC + simvastatin combination therapy (P < 0.05 for all cases). The effect of simvastatin and BMSCs combination therapy on serum specific IgE levels as well as lung IL-13 and TGF-β levels were significantly higher than the effect of BMSCs and simvastatin alone (P < 0.001 for IL-13 and P < 0.01 for other cases). CONCLUSIONS Simvastatin and BMSCs combination therapy affects serum IgE as well as lung IL-13 and TGFβ levels more than BMSC therapy and simvastatin therapy alone which may be due to increased BMSCs migration into the lung tissue.
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Affiliation(s)
- Maryam Mohammadian
- Department of Physiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hamid Reza Sadeghipour
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Gila Pirzad Jahromi
- Neuroscience Research Centre, Baqiyatallah University of Medical Sciences, Tehran
| | - Mahvash Jafari
- Department of Biochemistry, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Kavian Nejad
- Department of Emergency Medical Services, Faculty of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Safoura Khamse
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Boskabady
- Neurogenic Inflammation Research Center and Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Zhang Y, Pan X, Shi Z, Cai H, Gao Y, Zhang W. Sustained release of stem cell factor in a double network hydrogel for ex vivo culture of cord blood-derived CD34 + cells. Cell Prolif 2018; 51:e12407. [PMID: 29143396 PMCID: PMC6528907 DOI: 10.1111/cpr.12407] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Accepted: 10/13/2017] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES Stem cell factor (SCF) is considered as a commonly indispensable cytokine for proliferation of haematopoietic stem cells (HSCs), which is used in large dosages during ex vivo culture. The work presented here aimed to reduce the consumption of SCF by sustained release but still support cells proliferation and maintain the multipotency of HSCs. MATERIALS AND METHODS Stem cell factor was physically encapsulated within a hyaluronic acid/gelatin double network (HGDN) hydrogel to achieve a slow release rate. CD34+ cells were cultured within the SCF-loaded HGDN hydrogel for 14 days. The cell number, phenotype and functional capacity were investigated after culture. RESULTS The HGDN hydrogels had desirable properties and encapsulated SCF kept being released for more than 6 days. SCF remained the native bioactivity, and the proliferation of HSCs within the SCF-loaded HGDN hydrogel was not affected, although the consumption of SCF was only a quarter in comparison with the conventional culture. Moreover, CD34+ cells harvested from the SCF-loaded HGDN hydrogels generated more multipotent colony-forming units (CFU-GEMM). CONCLUSION The data suggested that the SCF-loaded HGDN hydrogel could support ex vivo culture of HSCs, thus providing a cost-effective culture protocol for HSCs.
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Affiliation(s)
- Yuanhao Zhang
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
| | - Xiuwei Pan
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
| | - Zhen Shi
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
| | - Haibo Cai
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
| | - Yun Gao
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
| | - Weian Zhang
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
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Becker C, Laeufer T, Arikkat J, Jakse G. TGFβ-1 and epithelial-mesenchymal interactions promote smooth muscle gene expression in bone marrow stromal cells: Possible application in therapies for urological defects. Int J Artif Organs 2018; 31:951-9. [DOI: 10.1177/039139880803101105] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Purpose For regenerative and cellular therapies of the urinary tract system, autologous bladder smooth muscle cells (SMCs) have several limitations, including constricted in vitro proliferation capacity and, more importantly, inability to be used in malignant conditions. The use of in vitro (pre-)differentiated multipotential adult progenitor cells may help to overcome the shortcomings associated with primary cells. Methods By mimicking environmental conditions of the bladder wall, we investigated in vitro effects of growth factor applications and epithelial-mesenchymal interactions on smooth muscle gene expression and on the morphological appearance of adherent bone marrow stromal cells (BMSCs). Results Transcription growth factor beta-1 (TGFβ-1) upregulated the transcription of myogenic gene desmin and smooth muscle actin-γ2 in cultured BMSCs. Stimulatory effects were significantly increased by coculture with urothelial cells. Prolonged stimulation times and epigenetic modifications further enhanced transcription levels, indicating a dose-response relationship. Immunocytochemical staining of in vitro-differentiated BMSCs revealed expression of myogenic protein α-smooth muscle actin and desmin, and changes in morphological appearance from a fusiform convex shape to a laminar flattened shape with filamentous inclusions similar to the appearance of bladder SMCs. In contrast to the TGFβ-1 action, application of vascular endothelial growth factor (VEGF) did not affect the cells. Conclusions The combined application of TGFβ-1 and epithelial-mesenchymal interactions promoted in vitro outgrowth of cells with a smooth muscle-like phenotype from a selected adherent murine bone marrow-derived cell population.
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Affiliation(s)
- C. Becker
- Department of Urology, University Hospital and Medical Faculty, RWTH Aachen University, Aachen - Germany
| | - T. Laeufer
- Department of Urology, University Hospital and Medical Faculty, RWTH Aachen University, Aachen - Germany
| | - J. Arikkat
- Department of Urology, University Hospital and Medical Faculty, RWTH Aachen University, Aachen - Germany
| | - G. Jakse
- Department of Urology, University Hospital and Medical Faculty, RWTH Aachen University, Aachen - Germany
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8
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Affiliation(s)
- H T Hassan
- Institute of Medical Sciences, University of Lincoln, UK.
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9
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Tura-Ceide O, Lobo B, Paul T, Puig-Pey R, Coll-Bonfill N, García-Lucio J, Smolders V, Blanco I, Barberà JA, Peinado VI. Cigarette smoke challenges bone marrow mesenchymal stem cell capacities in guinea pig. Respir Res 2017; 18:50. [PMID: 28330488 PMCID: PMC5363047 DOI: 10.1186/s12931-017-0530-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 03/03/2017] [Indexed: 01/03/2023] Open
Abstract
Background Cigarette smoke (CS) is associated with lower numbers of circulating stem cells and might severely affect their mobilization, trafficking and homing. Our study was designed to demonstrate in an animal model of CS exposure whether CS affects the homing and functional capabilities of bone marrow-derived mesenchymal stem cells (BM-MSCs). Methods Guinea pigs (GP), exposed or sham-exposed to CS, were administered via tracheal instillation or by vascular administration with 2.5 × 106 BM-MSCs obtained from CS-exposed or sham-exposed animal donors. Twenty-four hours after cell administration, animals were sacrificed and cells were visualised into lung structures by optical microscopy. BM-MSCs from 8 healthy GP and from 8 GP exposed to CS for 1 month were isolated from the femur, cultured in vitro and assessed for their proliferation, migration, senescence, differentiation potential and chemokine gene expression profile. Results CS-exposed animals showed greater BM-MSCs lung infiltration than sham-exposed animals regardless of route of administration. The majority of BM-MSCs localized in the alveolar septa. BM-MSCs obtained from CS-exposed animals showed lower ability to engraft and lower proliferation and migration. In vitro, BM-MSCs exposed to CS extract showed a significant reduction of proliferative, cellular differentiation and migratory potential and an increase in cellular senescence in a dose dependent manner. Conclusion Short-term CS exposure induces BM-MSCs dysfunction. Such dysfunction was observed in vivo, affecting the cell homing and proliferation capabilities of BM-MSCs in lungs exposed to CS and in vitro altering the rate of proliferation, senescence, differentiation and migration capacity. Additionally, CS induced a reduction in CXCL9 gene expression in the BM from CS-exposed animals underpinning a potential mechanistic action of bone marrow dysfunction. Electronic supplementary material The online version of this article (doi:10.1186/s12931-017-0530-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Olga Tura-Ceide
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain.,Biomedical Research Networking Center in Respiratory Diseases (CIBERES), Madrid, Spain
| | - Borja Lobo
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Tanja Paul
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Raquel Puig-Pey
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Núria Coll-Bonfill
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Jéssica García-Lucio
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Valérie Smolders
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Isabel Blanco
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain.,Biomedical Research Networking Center in Respiratory Diseases (CIBERES), Madrid, Spain
| | - Joan A Barberà
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain.,Biomedical Research Networking Center in Respiratory Diseases (CIBERES), Madrid, Spain
| | - Víctor I Peinado
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain. .,Biomedical Research Networking Center in Respiratory Diseases (CIBERES), Madrid, Spain.
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Herzig MC, Cap AP. Challenges in translating mesenchymal stem cell therapies for trauma and critical care. Transfusion 2016; 56:20S-5S. [PMID: 27079318 DOI: 10.1111/trf.13566] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Maryanne C Herzig
- Coagulation and Blood Research Program, US Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas
| | - Andrew P Cap
- Coagulation and Blood Research Program, US Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas
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Mohammadian M, Sadeghipour HR, Kashani IR, Jahromi GP, Omidi A, Nejad AK, Golchoobian R, Boskabady MH. Evaluation of Simvastatin and Bone Marrow-Derived Mesenchymal Stem Cell Combination Therapy on Airway Remodeling in a Mouse Asthma Model. Lung 2016; 194:777-85. [PMID: 27161569 DOI: 10.1007/s00408-016-9884-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 04/22/2016] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The effect of bone marrow-derived mesenchymal stem cells (BMSCs) on asthma treatment was shown in our previous study. Several studies have shown the effect of statins on BMSC preservation and migration to sites of inflammation. In this study, the effects of simvastatin and BMSC combination therapy in an ovalbumin-induced asthma model in mouse were examined. METHODS Four groups of BALB/c mice were studied including control group (animals were not sensitized), asthma group (animals were sensitized by ovalbumin), asthma + simvastatin group (asthmatic animals were treated with simvastatin), and asthma + BMSC + simvastatin group (asthmatic animals were treated with simvastatin and BMSCs). BMSCs were isolated, characterized, labeled with BrdU, and transferred into asthmatic mice. BMSC migration, airways histopathology, and total and differential white blood cell (WBC) count in bronchoalveolar lavage (BAL) fluid were evaluated. RESULTS A significant increase in the number of BrdU-BMSCs was found in the lungs of mice treated with simvastatin + BMSCs compared to mice treated with BMSCs. The histopathological changes, BAL total WBC counts, and the percentage of neutrophils and eosinophils were increased in asthma group compared to the control group. Treatment with simvastatin significantly decreased airway inflammation and inflammatory cell infiltration. Combination therapy improved all measured parameters higher than simvastatin. Goblet cell hyperplasia and subepithelial fibrosis were also decreased in combination therapy group. CONCLUSION These results indicated that simvastatin and BMSC combination therapy was superior to simvastatin therapy and BMSC therapy alone in reduction of airway remodeling and lung inflammation in the ovalbumin-induced asthma model in mouse.
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Affiliation(s)
- Maryam Mohammadian
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Reza Sadeghipour
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Iraj Ragerdi Kashani
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gila Pirzad Jahromi
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amene Omidi
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Kavian Nejad
- Department of Emergency Medical Services, Faculty of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ravie Golchoobian
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Boskabady
- Neurogenic Inflammation Research Center and Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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12
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Xu LB, Liu C. Role of liver stem cells in hepatocarcinogenesis. World J Stem Cells 2014; 6:579-590. [PMID: 25426254 PMCID: PMC4178257 DOI: 10.4252/wjsc.v6.i5.579] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 08/24/2014] [Accepted: 09/01/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the cancer is already advanced, missing the opportunity for surgical resection. Thus, an improved understanding of the mechanisms responsible for liver cancer initiation and progression will facilitate the detection of more reliable tumor markers and the development of new small molecules for targeted therapy of liver cancer. Recently, there is increasing evidence for the “cancer stem cell hypothesis”, which postulates that liver cancer originates from the malignant transformation of liver stem/progenitor cells (liver cancer stem cells). This cancer stem cell model has important significance for understanding the basic biology of liver cancer and has profound importance for the development of new strategies for cancer prevention and treatment. In this review, we highlight recent advances in the role of liver stem cells in hepatocarcinogenesis. Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in liver cancer with pivotal implications in therapeutic perspectives. Although the dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of liver cancer stem cells in liver cancer could result in the degeneration of downstream cells, which makes them potential targets for liver cancer therapies. Therefore, liver stem cells could represent a new target for therapeutic approaches to liver cancer in the near future.
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Genomic landscape of CD34+ hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers. Proc Natl Acad Sci U S A 2014; 111:8589-94. [PMID: 24850867 DOI: 10.1073/pnas.1407688111] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Myelodysplastic syndrome (MDS) includes a group of diseases characterized by dysplasia of bone marrow myeloid lineages with ineffective hematopoiesis and frequent evolution to acute myeloid leukemia (AML). Whole-genome sequencing was performed in CD34(+) hematopoietic stem/progenitor cells (HSPCs) from eight cases of refractory anemia with excess blasts (RAEB), the high-risk subtype of MDS. The nucleotide substitution patterns were found similar to those reported in AML, and mutations of 96 protein-coding genes were identified. Clonal architecture analysis revealed the presence of subclones in six of eight cases, whereas mutation detection of CD34(+) versus CD34(-) cells revealed heterogeneity of HSPC expansion status. With 39 marker genes belonging to eight functional categories, mutations were analyzed in 196 MDS cases including mostly RAEB (n = 89) and refractory cytopenia with multilineage dysplasia (RCMD) (n = 95). At least one gene mutation was detected in 91.0% of RAEB, contrary to that in RCMD (55.8%), suggesting a higher mutational burden in the former group. Gene abnormality patterns differed between MDS and AML, with mutations of activated signaling molecules and NPM1 being rare, whereas those of spliceosome more common, in MDS. Finally, gene mutation profiles also bore prognostic value in terms of overall survival and progression free survival.
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Huang MT, Cao YL, Feng ZM, Ji DJ, Zhang WH, Shi XY, Wang P, Tang M, Tan H, Xie YX, Zhao RT. TIPS combined with autologous bone marrow stem cell transplantation for treatment of decompensated liver cirrhosis. Shijie Huaren Xiaohua Zazhi 2013; 21:3275-3280. [DOI: 10.11569/wcjd.v21.i30.3275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) combined with autologous bone marrow stem cell transplantation in the treatment of decompensated liver cirrhosis.
METHODS: Five patients with decompensated liver cirrhosis caused by hepatitis B, of whom two had Child-Pugh class B and three had Child-Pugh class C disease, underwent simultaneous combination therapy with TIPS and autologous bone marrow stem cell transplantation. All patients were followed for one year. Clinical symptoms, physical signs, biochemical indices, and endoscopic findings were compared between before and after the combination therapy.
RESULTS: Ascites was alleviated in all patients after treatment. Each patient was followed at 1, 4, 12, 25, and 52 wk after treatment. All patients achieved substantial improvement in clinical symptoms and biochemical indices. The varices in the esophagus and gastric fundus were alleviated as shown by endoscopic observation, and no upper gastrointestinal bleeding occurred. During the 52-wk follow-up period, no patients experienced refractory ascites, and the patients showed only small amounts of ascites. Liver function was remarkably improved; albumin (ALB) increased significantly (from 27.3 g/L to 31.5 g/L, P = 0.014), total bilirubin (TB) decreased significantly (from 49.5 μmol/L to 41.8 μmol/L, P = 0.045), and all patients showed decreased alanine aminotransferase (ALT) (from 54.3 IU/L to 45.7 IU/L, P = 0.063) and prothrombin time (PT) (from 18.7 s to 16.5 s, P = 0.063). Liver cirrhosis was classified as Child-Pugh class B in all patients.
CONCLUSION: TIPS in combination with bone marrow stem cell transplantation is associated with remarkable therapeutic effects and minimal adverse reactions in the treatment of decompensated liver cirrhosis.
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Abstract
Despite recent advances in treatment, lung cancer accounts for one third of all cancer-related deaths, underlining the need of development of new therapies. Mesenchymal stem cells (MSCs) possess the ability to specifically home into tumours and their metastases. This property of MSCs could be exploited for the delivery of various anti-tumour agents directly into tumours. However, MSCs are not simple delivery vehicles but cells with active physiological process. This review outlines various agents which can be delivered by MSCs with substantial emphasis on TRAIL (tumour necrosis factor-related apoptosis-inducing ligand).
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Affiliation(s)
- Krishna K Kolluri
- Lungs for Living Research Centre, University College London, London, UK
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Generation and analysis of expressed sequence tags from the bone marrow of Chinese Sika deer. Mol Biol Rep 2011; 39:2981-90. [PMID: 21681423 DOI: 10.1007/s11033-011-1060-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Accepted: 06/08/2011] [Indexed: 10/18/2022]
Abstract
Sika deer is one of the best-known and highly valued animals of China. Despite its economic, cultural, and biological importance, there has not been a large-scale sequencing project for Sika deer to date. With the ultimate goal of sequencing the complete genome of this organism, we first established a bone marrow cDNA library for Sika deer and generated a total of 2,025 reads. After processing the sequences, 2,017 high-quality expressed sequence tags (ESTs) were obtained. These ESTs were assembled into 1,157 unigenes, including 238 contigs and 919 singletons. Comparative analyses indicated that 888 (76.75%) of the unigenes had significant matches to sequences in the non-redundant protein database, In addition to highly expressed genes, such as stearoyl-CoA desaturase, cytochrome c oxidase, adipocyte-type fatty acid-binding protein, adiponectin and thymosin beta-4, we also obtained vascular endothelial growth factor-A and heparin-binding growth-associated molecule, both of which are of great importance for angiogenesis research. There were 244 (21.09%) unigenes with no significant match to any sequence in current protein or nucleotide databases, and these sequences may represent genes with unknown function in Sika deer. Open reading frame analysis of the sequences was performed using the getorf program. In addition, the sequences were functionally classified using the gene ontology hierarchy, clusters of orthologous groups of proteins and Kyoto encyclopedia of genes and genomes databases. Analysis of ESTs described in this paper provides an important resource for the transcriptome exploration of Sika deer, and will also facilitate further studies on functional genomics, gene discovery and genome annotation of Sika deer.
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D'Agostino B, Sullo N, Siniscalco D, De Angelis A, Rossi F. Mesenchymal stem cell therapy for the treatment of chronic obstructive pulmonary disease. Expert Opin Biol Ther 2010; 10:681-7. [PMID: 20384521 DOI: 10.1517/14712591003610614] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Recent studies have revealed that adult stem cells such as bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells may be a potent next-generation therapy for COPD. Pathogenesis of COPD is characterized by an upregulation of inflammatory processes leading to irreversible events such as apoptosis of epithelial cells, proteolysis of the terminal air-space and lung extracellular matrix components. The available pharmacological treatments are essentially symptomatic, therefore, there is a need to develop more effective therapeutic strategies. It has been previously demonstrated that transplanted MSC home to the lung in response to lung injury and adopt phenotypes of alveolar epithelial cells, endothelial cells, fibroblasts and bronchial epithelial cells. However, engraftment and differentiation are now felt to be rare occurrences and other mechanisms might be involved and play a more important role. Importantly, MSCs protect lung tissue through suppression of proinflammatory cytokines, and through triggering production of reparative growth factors. Accordingly, it is not clear if and how these cells will be able to repair, to slow or to prevent the disease. This article reviews recent advances in regenerative medicine in COPD and highlights that their potential application although promising and very attractive, are still a far away opinion.
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Affiliation(s)
- Bruno D'Agostino
- Department of Experimental Medicine, Second University of Naples, Section of Pharmacology L Donatelli, via S Maria di Costantinopoli, 16-80138 Napoli, Italy.
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Abstract
Recent research suggests that mesenchymal stem cells (MSCs) are able to migrate specifically to tumours and their metastases throughout the body. This has led to considerable excitement about the possibility of modifying these cells to express anticancer molecules and using them as specific targeted anticancer agents. However, there are concerns that systemically delivered MSCs may have non-desirable effects, and there are also many unanswered questions including the mechanism of tumour homing. This review investigates the different MSC-delivered anticancer agents, addresses the questions and concerns, and tries to place this potential therapy in future cancer management.
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Affiliation(s)
- Michael R Loebinger
- Centre For Respiratory Research, Rayne Institute, University College London, 5 University Street, London WC1E 6JJ, UK
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Estrov Z. Stem Cells and Somatic Cells: Reprogramming and Plasticity. CLINICAL LYMPHOMA AND MYELOMA 2009; 9:S319-S328. [DOI: 10.3816/clm.2009.s.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Higuchi A, Yang ST, Li PT, Chang Y, Tsai EM, Chen YH, Chen YJ, Wang HC, Hsu ST. Polymeric Materials for Ex vivo Expansion of Hematopoietic Progenitor and Stem Cells. POLYM REV 2009. [DOI: 10.1080/15583720903048185] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Wei A, Tao H, Chung SA, Brisby H, Ma DD, Diwan AD. The fate of transplanted xenogeneic bone marrow-derived stem cells in rat intervertebral discs. J Orthop Res 2009; 27:374-9. [PMID: 18853431 DOI: 10.1002/jor.20567] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Intervertebral disc degeneration is a major cause and a risk factor for chronic low back pain. The potential of using stem cells to treat disc degeneration has been raised. The aims of our study were to assess whether xenogeneic bone-marrow derived stem cells could survive in a rat disc degeneration model and to determine which cell types, if any, survived and differentiated into disc-like cells. Human bone-marrow derived CD34(+) (hematopoietic progenitor cells) and CD34(-) (nonhematopoietic progenitor cells, including mesenchymal stem cells) cells were isolated, fluorescent-labeled, and injected into rat coccygeal discs. The rats were sacrificed at day 1, 10, 21, and 42. Treated discs were examined by histological and immunostaining techniques and compared to control discs. The survival of transplanted cells was further confirmed with a human nuclear specific marker. Fluorescent labeled CD34(-) cells were detected until day 42 in the nucleus pulposus of the injected discs. After 3 weeks these cells had differentiated into cells expressing chondrocytic phenotype (Collagen II and Sox-9). In contrast, the fluorescent labeled CD34(+) cells could not be detected after day 21. No fluorescence-positive cells were detected in the noninjected control discs. Further, no inflammatory cells infiltrated the nucleus pulposus, even though these animals had not received immunosuppressive treatment. Our data provide evidence that transplanted human BM CD34(-) cells survived and differentiated within the relative immune privileged nucleus pulposus of intervertebral disc degeneration.
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Affiliation(s)
- Aiqun Wei
- Department of Orthopaedic Surgery, University of New South Wales, St. George Hospital Campus, Level 2, 4-10 South Street, Kogarah, NSW 2177, Australia
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Abstract
Stem cells divide asymmetrically, leading to self-renewal and the production of a daughter cell committed to differentiation. This property has engendered excitement as to the use of these cells for treatments. The majority of the work with stem cells has used the relatively accessible and well-characterized adult bone marrow stem cell compartment. Initially the focus of this research was on the potential for these stem cells to repair damaged organs by differentiating into epithelial cells to replace the injured areas. More recently it has become clear that engraftment of these stem cells as epithelial tissue is a rare event with perhaps limited clinical significance. Despite this, stem cells appear to have the ability to home to and be specifically recruited to areas of inflammation and injured tissues often characterized by excessive extracellular matrix deposition. As a consequence they are intimately involved in regions of physiological and pathological repair. Coupled with this, autologous hematopoietic stem cells, or the relatively immunoprivileged mesenchymal stem cells, can be expanded and engineered ex vivo and reintroduced without immunomodulation. The prospect of using such cells clinically as a cellular therapy holds much promise for many conditions and organ pathologies. Here we address the evidence for the incorporation of bone marrow stem cells into areas of stroma formation as a prelude to possible future treatment options for common lung diseases.
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Abstract
Human embryonic stem cells are pluripotent cells derived from the inner cell mass of preimplantation stage embryos. Their unique potential to give rise to all differentiated cell types has generated great interest in stem cell research and the potential that it may have in developmental biology, medicine and pharmacology. The main focus of stem cell research has been on cell therapy for pathological conditions with no current methods of treatment, such as neurodegenerative diseases, cardiac pathology, retinal dysfunction and lung and liver disease. The overall aim is to develop methods of application either of pure cell populations or of whole tissue parts to the diseased organ under investigation. In the field of pulmonary research, studies using human embryonic stem cells have succeeded in generating enriched cultures of type II pneumocytes in vitro. On account of their potential of indefinite proliferation in vitro, embryonic stem cells could be a source of an unlimited supply of cells available for transplantation and for use in gene therapy. Uncovering the ability to generate such cell types will expand our understanding of biological processes to such a degree that disease understanding and management could change dramatically.
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Abstract
There has been increasing excitement over the last few years with the suggestion that exogenous stem cells may offer new treatment options for a wide range of diseases. Within respiratory medicine, these cells have been shown to have the ability to differentiate and function as both airway and lung parenchyma epithelial cells in both in vitro and increasingly in vivo experiments. The hypothesis is that these cells may actively seek out damaged tissue to assist in the local repair, and the hope is that their use will open up new cellular and genetic treatment modalities. Such is the promise of these cells that they are being rushed from the benchside to the bedside with the commencement of early clinical trials. However, important questions over their use remain and the field is presently littered with controversy and uncertainty. This review evaluates the progress made and the pitfalls encountered to date, and critically assesses the evidence for the use of stem cells in lung disease.
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Hoogduijn MJ, Crop MJ, Peeters AMA, Van Osch GJVM, Balk AHMM, Ijzermans JNM, Weimar W, Baan CC. Human heart, spleen, and perirenal fat-derived mesenchymal stem cells have immunomodulatory capacities. Stem Cells Dev 2007; 16:597-604. [PMID: 17784833 DOI: 10.1089/scd.2006.0110] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have important tissue repair functions and show potent immunosuppressive capacities in vitro. Although usually isolated from the bone marrow, MSCs have been identified in other tissues, including the skin and liver. In the present study, we isolated and characterized MSCs from human heart, spleen, and perirenal adipose tissue. MSCs from these different tissue sites were similar to those derived from bone marrow in that they expressed comparable levels of the cell-surface markers CD90, CD105, CD166, and HLA class I, were negative for CD34, CD45, HLA class II, CD80, and CD86 expression, and were capable of osteogenic and adipogenic differentiation. Like bone marrow-derived MSCs, MSCs from these different tissue sources inhibited the proliferation of alloactivated peripheral blood mononuclear cells (PBMCs), giving 85%, 79%, 79%, and 81% inhibition, respectively. Also in line with bone marrow-derived MSCs they inhibited proliferative responses of PBMCs to phytohemagglutinin, a nonspecific stimulator of lymphocyte proliferation, and reduced-memory T lymphocyte responses to tetanus toxoid. The results of this study demonstrate that MSCs from various tissues have similar immunophenotypes, in vitro immunosuppressive properties, and differentiation potential.
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Affiliation(s)
- M J Hoogduijn
- Department of Internal Medicine, Transplantation Laboratory, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.
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Chua KN, Chai C, Lee PC, Ramakrishna S, Leong KW, Mao HQ. Functional nanofiber scaffolds with different spacers modulate adhesion and expansion of cryopreserved umbilical cord blood hematopoietic stem/progenitor cells. Exp Hematol 2007; 35:771-81. [PMID: 17577926 PMCID: PMC2376815 DOI: 10.1016/j.exphem.2007.02.002] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVE Nanofiber scaffolds with amino groups conjugated to fiber surface through different spacers (ethylene, butylenes, and hexylene groups, respectively) were prepared and the effect of spacer length on adhesion and expansion of umbilical cord blood hematopoietic stem/ progenitor cells (HSPCs) was investigated. MATERIALS AND METHODS Electrospun polymer nanofiber scaffolds were functionalized with poly(acrylic acid) grafting, followed by conjugation of amino groups with different spacers. HSPCs were expanded on aminated scaffolds for 10 days. Cell proliferation, surface marker expression, clonogenic potential, and nonobese diabetic (NOD)/severe combined immunodeficient (SCID) repopulation potential of the expanded cells were evaluated following expansion culture. RESULTS Aminated nanofiber scaffolds with ethylene and butylene spacers showed high-expansion efficiencies (773- and 805-fold expansion of total cells, 200- and 235-fold expansion of CD34+CD45' cells, respectively). HSPC proliferation on aminated scaffold with hexylene spacer was significantly lower (210-fold expansion of total cells and 86-fold expansion of CD34+CD45+ cells), but maintained the highest CD34+CD45+ cell fraction (41.1%). Colony-forming unit granulocyte-erythrocyte-monocyte-megakaryocyte and long-term culture-initiating cell maintenance was similar for HSPCs expanded on all three aminated nanofiber scaffolds; nevertheless, the NOD/SCID mice engraftment potential of HSPCs expanded on aminoethyl and aminobutyl conjugated nanofibers was significantly higher than that on aminohexyl conjugated nanofibers. CONCLUSION This study demonstrated that aminated nanofibers are superior substrates for ex vivo HSPC expansion, which was correlated with the enhanced HSPC adhesion to these aminated nanofibers. The spacer, through which amino groups were conjugated to nanofiber surface, affected the expansion outcome. Our results highlighted the importance of scaffold topography and cell-substrate interaction to regulating HSPC proliferation and self-renewal in cytokine-supplemented expansion.
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Affiliation(s)
- Kian-Ngiap Chua
- Division of Bioengineering and National University of Singapore Nanoscience and Nanotechnology Initiative, National University of Singapore, Singapore
| | - Chou Chai
- Duke-National University of Singapore Graduate Medical School, Singapore
| | - Peng-Chou Lee
- Duke-National University of Singapore Graduate Medical School, Singapore
| | - Seeram Ramakrishna
- Division of Bioengineering and National University of Singapore Nanoscience and Nanotechnology Initiative, National University of Singapore, Singapore
| | - Kam W. Leong
- Duke-National University of Singapore Graduate Medical School, Singapore
- Department of Biomedical Engineering, Duke University, Durham, NC., USA
| | - Hai-Quan Mao
- Department of Materials Science and Engineering and Whitaker Biomedical Engineering Institute, Johns Hopkins University, Baltimore, Md., USA
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Abstract
Respiratory diseases remain one of the main causes of morbidity and mortality in the world. Interest has increased as to the possibility of optimizing the repair of the lung with the manipulation of stem cells. Embryonic and adult stem cells have been suggested as possibilities. Adult stem cells have traditionally been thought of as having limited differentiation ability and to be organ specific. However, a series of exciting reports over the last 5 to 10 years have suggested that adult bone marrow-derived stem cells may have more plasticity and are able to differentiate into bronchial and alveolar epithelium, vascular endothelium, and interstitial cell types, making them prime candidates for repair. This article critically reviews the evidence for this plasticity and the use of predominantly adult stem cells to help with lung regeneration and repair and assesses how this technology may be utilized in clinical medicine.
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Affiliation(s)
- Michael R Loebinger
- Centre of Respiratory Research, Rayne Building, University College London, 5 University St, London, WC1E 6JJ, UK
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29
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Abstract
As a novel neurotherapeutic strategy, stem cell transplantation has received considerable attention, yet little of this attention has been devoted to the probabilities of success of stem cell therapies for specific neurological disorders. Given the complexities of the cellular organization of the nervous system and the manner in which it is assembled during development, it is unlikely that a cellular replacement strategy will succeed for any but the simplest of neurological disorders in the near future. A general strategy for stem cell transplantation to prevent or minimize neurological disorders is much more likely to succeed. Two broad categories of neurological disease, inherited metabolic disorders and invasive brain tumors, are among the most likely candidates.
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Affiliation(s)
- Philip H Schwartz
- Children's Hospital of Orange County Research Institute, National Human Neural Stem Cell Resource PI, Human Embryonic Stem Cell Culture Training Course, Orange, CA 92868-3874, USA.
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Karussis D, Grigoriadis S, Polyzoidou E, Grigoriadis N, Slavin S, Abramsky O. Neuroprotection in multiple sclerosis. Clin Neurol Neurosurg 2006; 108:250-4. [PMID: 16413962 DOI: 10.1016/j.clineuro.2005.11.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
In chronic inflammatory diseases like multiple sclerosis (MS), neuroprotection refers to strategies aimed at prevention of the irreversible damage of various neuronal and glial cell populations, and promoting regeneration. It is increasingly recognized that MS progression, in addition to demyelination, leads to substantial irreversible damage to, and loss of neurons, resulting in brain atrophy and cumulative disability. One of the most promising neuroprotective strategies involves the use of bone marrow derived stem cells. Both hematopoietic and non-hematopoietic (stromal) cells can, under certain circumstances, differentiate into cells of various neuronal and glial lineages. Neuronal stem cells have also been reported to suppress EAE by exerting direct in situ immunomodulating effects, in addition to their ability to provide a potential source for remyelination and neuroregeneration. Preliminary results from our laboratory indicate that intravenous or intracerebral/intraventricular injection of bone marrow derived stromal cells could differentiate in neuronal/glial cells and suppress the clinical signs of chronic EAE. Both bone marrow and neuronal stem cells may therefore have a therapeutic potential in MS. It seems that future treatment strategies for MS should combine immunomodulation with neuroprotective modalities to achieve maximal clinical benefit.
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Affiliation(s)
- Dimitrios Karussis
- Department of Neurology and the Agnes Ginges Center for Neurogenetics, Laboratory of Neuroimmunology, Hadassah University Hospital, Jerusalem, Ein-Karem IL-91120, Israel.
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Wang Y, Nan X, Li Y, Zhang R, Yue W, Yan F, Pei X. Induction of umbilical cord blood-derived beta2m-c-Met+ cells into hepatocyte-like cells by coculture with CFSC/HGF cells. Liver Transpl 2005; 11:635-43. [PMID: 15915498 DOI: 10.1002/lt.20419] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Several studies have indicated that adult stem cells derived from bone marrow (BM) and cord blood (CB) can differentiate into hepatocyte-like cells. This ability is important for the treatment of hepatic diseases with BM or CB as a potential approach. However, methods are still being developed for the efficient induction of stem cell differentiation and expansion to get enough cells to be useful. In the present study, we enriched a subset of umbilical cord blood beta(2)m(-)c-Met(+) cells (UCBCCs) and investigated the combination effect of liver nonparenchymal cells (cirrhotic fat-storing cells [CFSCs]) and hepatocyte growth factor (HGF) on the induction of UCBCCs into hepatocyte-like cells. UCBCCs were cocultured with CFSC/HGF feeder layers either directly or separately using insert wells. Flow cytometric analysis showed that most UCBCCs were CD34(+/-)CD90(+/-)CD49f(+)CD29(+)Alb(+)AFP(+). After cocultured with transgenic feeder layers for 7 days, UCBCCs displayed some morphologic characteristics of hepatocytes. Reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence cell staining proved that the induced UCBCCs expressed several hepatocyte specific genes including AFP, Alb, CYP1B1 and cytokeratins CK18 and CK19. Furthermore, the induced cells displayed liver specific functions of indocyanine green (ICG) uptake, ammonium metabolism and albumin secretion. Hence, our data have demonstrated that UCBCCs might represent a novel subpopulation of CB-derived stem/progenitor cells capable of successful differentiation into hepatocyte-like cells when incubated with CFSC/HGF cells. In conclusion, not only HGF but also CFSCs and/or the secreted extracellular matrix (ECM) have been shown to be able to serve as essential microenvironment for hepatocyte differentiation.
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Affiliation(s)
- Yunfang Wang
- Department of Stem Cell Biology, Beijing Institute of Transfusion Medicine, Beijing, China
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Egusa H, Schweizer FE, Wang CC, Matsuka Y, Nishimura I. Neuronal differentiation of bone marrow-derived stromal stem cells involves suppression of discordant phenotypes through gene silencing. J Biol Chem 2005; 280:23691-7. [PMID: 15855172 DOI: 10.1074/jbc.m413796200] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Tissue engineering involves the construction of transplantable tissues in which bone marrow aspirates may serve as an accessible source of autogenous multipotential mesenchymal stem cells. Increasing reports indicate that the lineage restriction of adult mesenchymal stem cells may be less established than previously believed, and stem cell-based therapeutics await the establishment of an efficient protocol capable of achieving a prescribed phenotype differentiation. We have investigated how adult mouse bone marrow-derived stromal cells (BMSCs) are guided to neurogenic and osteogenic phenotypes. Naïve BMSCs were found surprisingly active in expression of a wide range of mRNAs and proteins, including those normally reported in terminally differentiated neuronal cells and osteoblasts. The naïve BMSCs were found to exhibit voltage-dependent membrane currents similar to the neuronally guided BMSCs, although with smaller amplitudes. Once BMSCs were exposed to the osteogenic culture condition, the neuronal characteristics quickly disappeared. Our data suggest that the loss of discordant phenotypes during BMSC differentiation cannot be explained by the selection and elimination of unfit cells from the whole BMSC population. The percent ratio of live to dead BMSCs examined did not change during the first 8-10 days in either neurogenic or osteogenic differentiation media, and cell detachment was estimated at <1%. However, during this period, bone-associated extracellular matrix genes were selectively down-regulated in neuronally guided BMSCs. These data indicate that the suppression of discordant phenotypes of differentiating adult stem cells is achieved, at least in part, by silencing of superfluous gene clusters.
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Affiliation(s)
- Hiroshi Egusa
- Division of Advanced Prosthodontics, Biomaterials, and Hospital Dentistry, Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, California 90095, USA
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Affiliation(s)
- H T Hassan
- Institute of Medical Sciences, University of Lincoln, UK.
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34
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Otto WR, Rao J. Tomorrow's skeleton staff: mesenchymal stem cells and the repair of bone and cartilage. Cell Prolif 2004; 37:97-110. [PMID: 14871240 PMCID: PMC6496475 DOI: 10.1111/j.1365-2184.2004.00303.x] [Citation(s) in RCA: 101] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2003] [Accepted: 12/19/2003] [Indexed: 12/26/2022] Open
Abstract
Stem cells are regenerating medicine. Advances in stem cell biology, and bone marrow-derived mesenchymal stem cells in particular, are demonstrating that many clinical options once thought to be science fiction may be attainable as fact. The extra- and intra-cellular signalling used by stem cells as they differentiate into lineages appropriate to their destination are becoming understood. Thus, the growth stimuli afforded by LIF, FGF-2 and HGF, as well as the complementary roles of Wnt and Dickkopf-1 in stem cell proliferation are evident. The ability to direct multi-lineage mesenchymal stem sell (MSC) potential towards an osteogenic phenotype by stimulation with Menin and Shh are important, as are the modulatory roles of Notch-1 and PPARgamma. Control of chondrocytic differentiation is effected by interplay of Brachyury, BMP-4 and TGFbeta3. Smads 1, 4 and 5 also play a role in these phenotypic expressions. The ability to culture MSC has led to their use in tissue repair, both as precursor and differentiated cell substitutes, and with successful animal models of bone and cartilage repair using MSC, their clinical use is accelerating. However, MSC also suppress some T-cell functions in transplanted hosts, and could facilitate tumour growth, so a cautious approach is needed.
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Affiliation(s)
- W R Otto
- Histopathology Unit, Cancer Research UK, London Research Institute, London, UK.
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