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Papetti AV, Jin M, Ma Z, Stillitano AC, Jiang P. Chimeric brain models: Unlocking insights into human neural development, aging, diseases, and cell therapies. Neuron 2025:S0896-6273(25)00256-9. [PMID: 40300597 DOI: 10.1016/j.neuron.2025.03.036] [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: 01/26/2025] [Revised: 03/07/2025] [Accepted: 03/31/2025] [Indexed: 05/01/2025]
Abstract
Human-rodent chimeric brain models serve as a unique platform for investigating the pathophysiology of human cells within a living brain environment. These models are established by transplanting human tissue- or human pluripotent stem cell (hPSC)-derived macroglial, microglial, or neuronal lineage cells, as well as cerebral organoids, into the brains of host animals. This approach has opened new avenues for exploring human brain development, disease mechanisms, and regenerative processes. Here, we highlight recent advancements in using chimeric models to study human neural development, aging, and disease. Additionally, we explore the potential applications of these models for studying human glial cell-replacement therapies, studying in vivo human glial-to-neuron reprogramming, and harnessing single-cell omics and advanced functional assays to uncover detailed insights into human neurobiology. Finally, we discuss strategies to enhance the precision and translational relevance of these models, expanding their impact in stem cell and neuroscience research.
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Affiliation(s)
- Ava V Papetti
- Department of Cell Biology and Neuroscience, Rutgers University-New Brunswick, Piscataway, NJ 08854, USA
| | - Mengmeng Jin
- Department of Cell Biology and Neuroscience, Rutgers University-New Brunswick, Piscataway, NJ 08854, USA
| | - Ziyuan Ma
- Department of Cell Biology and Neuroscience, Rutgers University-New Brunswick, Piscataway, NJ 08854, USA
| | - Alessandro C Stillitano
- Department of Cell Biology and Neuroscience, Rutgers University-New Brunswick, Piscataway, NJ 08854, USA
| | - Peng Jiang
- Department of Cell Biology and Neuroscience, Rutgers University-New Brunswick, Piscataway, NJ 08854, USA.
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2
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Jin M, Ma Z, Zhang H, Papetti AV, Dang R, Stillitano AC, Zou L, Goldman SA, Jiang P. Human-Mouse Chimeric Brain Models to Study Human Glial-Neuronal and Macroglial-Microglial Interactions. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.03.601990. [PMID: 39005270 PMCID: PMC11244967 DOI: 10.1101/2024.07.03.601990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Human-mouse chimeric brain models, generated by transplanting human induced pluripotent stem cell (hiPSC)-derived neural cells, are valuable for studying the development and function of human neural cells in vivo. Understanding glial-glial and glial-neuronal interactions is essential for unraveling the complexities of brain function and developing treatments for neurological disorders. To explore these interactions between human neural cells in vivo, we co-engrafted hiPSC-derived neural progenitor cells together with primitive macrophage progenitors into the neonatal mouse brain. This approach creates human-mouse chimeric brains containing human microglia, macroglia (astroglia and oligodendroglia), and neurons. Using super-resolution imaging and 3D reconstruction techniques, we examine the dynamics between human neurons and glia, and observe human microglia pruning synapses of human neurons, and often engulfing neurons themselves. Single-cell RNA sequencing analysis of the chimeric brain uncovers a close recapitulation of the human glial progenitor cell population, along with a dynamic stage in astroglial development that mirrors the processes found in the human brain. Furthermore, cell-cell communication analysis highlights significant neuronal-glial and macroglial-microglial interactions, especially the interaction between adhesion molecules neurexins and neuroligins between neurons and astroglia, emphasizing their key role in synaptogenesis. We also observed interactions between microglia and astroglia mediated by SPP1, crucial for promoting microglia growth and astrogliosis, and the PTN-MK pathways, instrumental in homeostatic maintenance and development in macroglial progenitors. This innovative co-transplantation model opens up new avenues for exploring the complex pathophysiological mechanisms underlying human neurological diseases. It holds particular promise for studying disorders where glial-neuronal interactions and non-cell-autonomous effects play crucial roles.
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Affiliation(s)
- Mengmeng Jin
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
| | - Ziyuan Ma
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
| | - Haiwei Zhang
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
| | - Ava V. Papetti
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
| | - Rui Dang
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
| | | | - Lisa Zou
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Steven A. Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA
- Center for Translational Neuromedicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | - Peng Jiang
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
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3
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Liu S, Liu B, Li Q, Zheng T, Liu B, Li M, Chen Z. Transplantation of fibrin-thrombin encapsulated human induced neural stem cells promotes functional recovery of spinal cord injury rats through modulation of the microenvironment. Neural Regen Res 2024; 19:440-446. [PMID: 37488909 PMCID: PMC10503599 DOI: 10.4103/1673-5374.379049] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 04/02/2023] [Accepted: 05/29/2023] [Indexed: 07/26/2023] Open
Abstract
Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord, with the expectation that differentiated neurons facilitate recovery. Only a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury microenvironment. Here, we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord injury. Induced neural stem cells reprogrammed from human peripheral blood mononuclear cells, and/or thrombin plus fibrinogen, were transplanted into the lesion site of an immunosuppressed rat spinal cord injury model. Basso, Beattie and Bresnahan score, electrophysiological function, and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function, reduces lesion volume, and promotes axonal neurofilament expression at the lesion core. Examination of the graft and niche components revealed that although the graft only survived for a relatively short period (up to 15 days), it still had a crucial impact on the microenvironment. Altogether, induced neural stem cells and human fibrin reduced the number of infiltrated immune cells, biased microglia towards a regenerative M2 phenotype, and changed the cytokine expression profile at the lesion site. Graft-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions, which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.
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Affiliation(s)
- Sumei Liu
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
| | - Baoguo Liu
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
| | - Qian Li
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
| | - Tianqi Zheng
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
| | - Bochao Liu
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
| | - Mo Li
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
| | - Zhiguo Chen
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China
- Center of Parkinson’s Disease, Beijing Institute for Brain Disorders, Beijing, China
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4
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Liu YV, Santiago CP, Sogunro A, Konar GJ, Hu MW, McNally MM, Lu YC, Flores-Bellver M, Aparicio-Domingo S, Li KV, Li ZL, Agakishiev D, Hadyniak SE, Hussey KA, Creamer TJ, Orzolek LD, Teng D, Canto-Soler MV, Qian J, Jiang Z, Johnston RJ, Blackshaw S, Singh MS. Single-cell transcriptome analysis of xenotransplanted human retinal organoids defines two migratory cell populations of nonretinal origin. Stem Cell Reports 2023; 18:1138-1154. [PMID: 37163980 DOI: 10.1016/j.stemcr.2023.04.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 04/06/2023] [Accepted: 04/11/2023] [Indexed: 05/12/2023] Open
Abstract
Human retinal organoid transplantation could potentially be a treatment for degenerative retinal diseases. How the recipient retina regulates the survival, maturation, and proliferation of transplanted organoid cells is unknown. We transplanted human retinal organoid-derived cells into photoreceptor-deficient mice and conducted histology and single-cell RNA sequencing alongside time-matched cultured retinal organoids. Unexpectedly, we observed human cells that migrated into all recipient retinal layers and traveled long distances. Using an unbiased approach, we identified these cells as astrocytes and brain/spinal cord-like neural precursors that were absent or rare in stage-matched cultured organoids. In contrast, retinal progenitor-derived rods and cones remained in the subretinal space, maturing more rapidly than those in the cultured controls. These data suggest that recipient microenvironment promotes the maturation of transplanted photoreceptors while inducing or facilitating the survival of migratory cell populations that are not normally derived from retinal progenitors. These findings have important implications for potential cell-based treatments of retinal diseases.
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Affiliation(s)
- Ying V Liu
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Clayton P Santiago
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Akin Sogunro
- Department of Biology, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA
| | - Gregory J Konar
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ming-Wen Hu
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Minda M McNally
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yu-Chen Lu
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Miguel Flores-Bellver
- CellSight Ocular Stem Cell and Regeneration Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado, School of Medicine, Aurora, CO, USA
| | - Silvia Aparicio-Domingo
- CellSight Ocular Stem Cell and Regeneration Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado, School of Medicine, Aurora, CO, USA
| | - Kang V Li
- CellSight Ocular Stem Cell and Regeneration Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado, School of Medicine, Aurora, CO, USA
| | - Zhuo-Lin Li
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dzhalal Agakishiev
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sarah E Hadyniak
- Department of Biology, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA
| | - Katarzyna A Hussey
- Department of Biology, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA
| | - Tyler J Creamer
- Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Linda D Orzolek
- Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Derek Teng
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - M Valeria Canto-Soler
- CellSight Ocular Stem Cell and Regeneration Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado, School of Medicine, Aurora, CO, USA
| | - Jiang Qian
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zheng Jiang
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - Robert J Johnston
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biology, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA.
| | - Seth Blackshaw
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Mandeep S Singh
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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5
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Davaa G, Hong JY, Lee JH, Kim MS, Buitrago JO, Li YM, Lee HH, Han DW, Leong KW, Hyun JK, Kim HW. Delivery of Induced Neural Stem Cells Through Mechano-Tuned Silk-Collagen Hydrogels for the Recovery of Contused Spinal Cord in Rats. Adv Healthc Mater 2023; 12:e2201720. [PMID: 36447307 DOI: 10.1002/adhm.202201720] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/16/2022] [Indexed: 12/02/2022]
Abstract
Neural stem cells (NSC) have tremendous potential for therapeutic regeneration of diseased or traumatized neural tissues, including injured spinal cord. However, transplanted NSC suffer from low cell survival and uncontrolled differentiation, limiting in vivo efficacy. Here, this issue is tackled by delivery through silk-collagen protein hydrogels that are stiffness-matched, stress-relaxing, and shear-thinning. The mechanically-tuned hydrogels protect NSC reprogrammed from fibroblasts (iNSC) initially from injection shear-stress, and enhance long-term survival over 12 weeks. Hydrogel-iNSC treatment alleviates neural inflammation, with reduced inflammatory cells and lesions than NSC-only. The iNSC migrate from the hydrogel into surrounding tissues, secrete up-regulated neurotrophic factors, and differentiate into neural cell subtypes, forming synapses. More serotonergic axons are observed in the lesion cavity, and locomotor functions are improved in hydrogel-iNSC than in iNSC-only. This study highlights the ability of mechanically-tuned protein hydrogels to protect iNSC from the injection stress and severe inflammatory environment, allowing them to differentiate and function to recover the injured spinal cord.
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Affiliation(s)
- Ganchimeg Davaa
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.,Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
| | - Jin Young Hong
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.,Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
| | - Jung-Hwan Lee
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.,Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea.,Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea.,Cell & Matter Institute, Dankook University, Cheonan, 31116, Republic of Korea.,UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, Republic of Korea.,Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea
| | - Min Soo Kim
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.,Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
| | - Jennifer O Buitrago
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.,Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea.,Basic Sciences Department, International University of Catalonia (UIC), Barcelona, 08017, Spain
| | - Yu-Meng Li
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.,Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
| | - Hae-Hyoung Lee
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.,Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea.,Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea.,Cell & Matter Institute, Dankook University, Cheonan, 31116, Republic of Korea
| | - Dong Wook Han
- Konkuk University Open-Innovation Center, Institute of Biomedical Science & Technology, Konkuk University, Seoul, 143701, Republic of Korea
| | - Kam W Leong
- Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea.,Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA.,Department of Systems Biology, Columbia University Medical Center, New York, NY, 10032, USA
| | - Jung Keun Hyun
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.,Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea.,Department of Rehabilitation Medicine, College of Medicine, Dankook University, Cheonan, 31116, Republic of Korea.,Wiregene Co., Ltd., Cheonan, 31116, Republic of Korea
| | - Hae-Won Kim
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.,Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea.,Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea.,Cell & Matter Institute, Dankook University, Cheonan, 31116, Republic of Korea.,UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, Republic of Korea.,Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea
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6
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Borda M, Aquino JB, Mazzone GL. Cell-based experimental strategies for myelin repair in multiple sclerosis. J Neurosci Res 2023; 101:86-111. [PMID: 36164729 DOI: 10.1002/jnr.25129] [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: 05/15/2022] [Revised: 08/21/2022] [Accepted: 09/09/2022] [Indexed: 11/10/2022]
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS), diagnosed at a mean age of 32 years. CNS glia are crucial players in the onset of MS, primarily involving astrocytes and microglia that can cause/allow massive oligodendroglial cells death, without immune cell infiltration. Current therapeutic approaches are aimed at modulating inflammatory reactions during relapsing episodes, but lack the ability to induce very significant repair mechanisms. In this review article, different experimental approaches based mainly on the application of different cell types as therapeutic strategies applied for the induction of myelin repair and/or the amelioration of the disease are discussed. Regarding this issue, different cell sources were applied in various experimental models of MS, with different results, both in significant improvements in remyelination and the reduction of neuroinflammation and glial activation, or in neuroprotection. All cell types tested have advantages and disadvantages, which makes it difficult to choose a better option for therapeutic application in MS. New strategies combining cell-based treatment with other applications would result in further improvements and would be good candidates for MS cell therapy and myelin repair.
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Affiliation(s)
- Maximiliano Borda
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Derqui, Pilar, Buenos Aires, Argentina
| | - Jorge B Aquino
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Derqui, Pilar, Buenos Aires, Argentina.,CONICET, Comisión Nacional de Investigaciones Científicas y Técnicas
| | - Graciela L Mazzone
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Derqui, Pilar, Buenos Aires, Argentina.,CONICET, Comisión Nacional de Investigaciones Científicas y Técnicas
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7
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Sarda RK, Sinha R, Sherpa M, Gupta A. Crude Extracts of Bacopa Monnieri Induces Dendrite Formation in Rodent Neural Stem Cell Cultures—A Possible Use in Neuronal Injury. J Neurosci Rural Pract 2022; 13:254-260. [PMID: 35694054 PMCID: PMC9187384 DOI: 10.1055/s-0042-1743215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Background
Repair of nervous tissue injury impairs positive functional outcome. Major challenges involved are formation of new neuronal cells at the site of injury, growth and development of existing or stem cell-derived neuronal cells, and proper anatomical alignment of the cells required for the functional organization of the nervous system. Stem cells and various agents have been tried to overcome the above challenges yielding only limited positive results. Bacopa has been in frequent usage for cognitive impairment in Ayurvedic medicine. The assumption that Bacopa monnieri (BM) extracts may lead to certain specific changes at the cellular structural level benefitting the central nervous system repair, prompted us for the present study.
Objective
This is an in vitro study evaluating the effect of BM extracts (bacopasides and analogues) on the neuronal stem cells (NSC) culture in various concentrations. The study investigates the possibility of BM as an agent for the regeneration and differentiation of nervous tissue injury. This may have clinical and therapeutic implications.
Materials and Methods
NSC were harvested from the newborn albino rats, Rattus norvegicus, and the BM extracts were obtained from product “brahmi” manufactured by Himalaya Drug Company. Aqueous suspension of 2 μL of alcoholic extract of BM was locally added to the culture plates of NSC in concentrations of 5, 10, and 20 µg/mL after development of NSC in the media. The control NSC (without BM) and BM-rich NSC were simultaneously observed at regular unit intervals after inoculation. The morphological change in the NSC were observed and recorded.
Result
NSC could be successfully cultured from the newborn rat's brain harvested at 3 and 6 hours of birth. NSCs derived at 3 hours of birth were more primitive (predominantly neurospheres) than derived those at 6 hours of birth. BM had significant positive effect on the neurospheres, that is, dendritic formation was seen in the NSC predominating when 2 μL of suspensions containing 5 and 10 µg/mL concentration of the extracts were used but showed relatively lesser effect at concentration of 20 µg/mL. The positive effect was biologically significant.
Conclusion
NSC can be cultured from brain of the newborn rodent. BM and its extracts act positively on NSC in terms of dendritic formation when used in proper appropriate concentration. The study opens up a new area of research and explores newer avenues in nervous tissue injury repair. It may have future clinical implication in the treatment of injury of central and peripheral nervous tissue. However, the hypothesis needs to be validated by adequate number of experimental runs as well as in vivo studies to know the reproducibility of the findings in other centers.
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Affiliation(s)
- Rohit Kumar Sarda
- Department of Anatomy, Sikkim Manipal Institute of Medical Sciences, Gangtok, Sikkim, India
| | - Rohan Sinha
- Department of Neurosurgery, JP Hospital Noida, Noida, Uttar Pradesh, India
| | - Mingma Sherpa
- Department of Pathology, Sikkim Manipal Institute of Medical Sciences, Gangtok, Sikkim, India
| | - Amlan Gupta
- Department of Pathology, Sikkim Manipal Institute of Medical Sciences, Gangtok, Sikkim, India
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8
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Lopez-Lozano AP, Arevalo-Niño K, Gutierrez-Puente Y, Montiel-Hernandez JL, Urrutia-Baca VH, Del Angel-Mosqueda C, De la Garza-Ramos MA. SSEA-4 positive dental pulp stem cells from deciduous teeth and their induction to neural precursor cells. Head Face Med 2022; 18:9. [PMID: 35236383 PMCID: PMC8889676 DOI: 10.1186/s13005-022-00313-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 02/17/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Stage-specific embryonic antigen-4 (SSEA-4) is a marker for the identification of multipotent embryonic cells. It is also positive in neuroepithelial cells, precursor neural cells (NPC), and human dental pulp cells. The aim of this study was to evaluate the potential morphodifferentiation and histodifferentiation to NPC of SSEA-4 positive stem cells from human exfoliated deciduous teeth (SHED). METHODS A SHED population in culture, positive to SSEA-4, was obtained by magnetic cell separation. The cells were characterized by immunohistochemistry and flow cytometry. Subsequently, a neurosphere assay was performed in a medium supplemented with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF); afterward, cells were neurodifferenciated with a neurobasal medium. Finally, indirect immunohistochemistry was performed to identify neuronal markers. RESULTS The morphological and histological changes in the SSEA-4 positive SHEDs were observed after induction with epidermal and fibroblast growth factors in neurobasal culture medium. At the end of induction, the markers Nestin, TuJ-1, and GFAP were identified. CONCLUSIONS The findings show that SSEA-4 positive SHEDs have a behavior similar to neuronal precursor cells. Our findings indicate that the dental pulp of deciduous teeth is a promising source for regeneration therapies associated with neurodegenerative diseases or peripheral nerve alterations.
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Affiliation(s)
- Ada Pricila Lopez-Lozano
- Facultad de Ciencias Biológicas, Instituto de Biotecnología, Universidad Autónoma de Nuevo León, Nuevo Leon, San Nicolas de los Garza, Mexico.,Unidad de Odontología Integral y Especialidades, Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autonoma de Nuevo Leon, Nuevo Leon, Monterrey, Mexico
| | - Katiushka Arevalo-Niño
- Facultad de Ciencias Biológicas, Instituto de Biotecnología, Universidad Autónoma de Nuevo León, Nuevo Leon, San Nicolas de los Garza, Mexico
| | - Yolanda Gutierrez-Puente
- Facultad de Ciencias Biológicas, Instituto de Biotecnología, Universidad Autónoma de Nuevo León, Nuevo Leon, San Nicolas de los Garza, Mexico
| | - Jose Luis Montiel-Hernandez
- Facultad De Farmacia, Coordinacion De Posgrado, Universidad Autonoma del Estado de Morelos, Morelos, Cuernavaca, Mexico
| | - Victor Hugo Urrutia-Baca
- Unidad de Odontología Integral y Especialidades, Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autonoma de Nuevo Leon, Nuevo Leon, Monterrey, Mexico
| | | | - Myriam Angelica De la Garza-Ramos
- Facultad de Ciencias Biológicas, Instituto de Biotecnología, Universidad Autónoma de Nuevo León, Nuevo Leon, San Nicolas de los Garza, Mexico. .,Unidad de Odontología Integral y Especialidades, Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autonoma de Nuevo Leon, Nuevo Leon, Monterrey, Mexico. .,Facultad de Odontología, Universidad Autonoma de Nuevo Leon, Nuevo Leon, Monterrey, Mexico. .,Facultad de Odontología/CIDICS, Universidad Autonoma de Nuevo Leon Monterrey, San Nicolás de los Garza, Mexico.
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9
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Yuan H, Fang CL, Deng YP, Huang J, Niu RZ, Chen JL, Chen TB, Zhu ZQ, Chen L, Xiong LL, Wang TH. A2B5-positive oligodendrocyte precursor cell transplantation improves neurological deficits in rats following spinal cord contusion associated with changes in expression of factors involved in the Notch signaling pathway. Neurochirurgie 2022; 68:188-195. [PMID: 34543615 DOI: 10.1016/j.neuchi.2021.09.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/21/2021] [Accepted: 09/04/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Oligodendrocyte precursor cells (OPCs) are myelinated glial cells of the central nervous system (CNS), able to regenerate oligodendrocytes and myelin. This study aimed to elucidate the effect of A2B5-positive (A2B5+) OPC transplantation in rats with spinal cord contusion (SCC) and to investigate changes in expression of various factors involved in the Notch signaling pathway after OPC transplantation. METHODS OPCs were obtained from induced pluripotent stem cells (iPSCs) originating from mouse embryo fibroblasts (MEFs). After identification of iPSCs and iPSC-derived OPCs, A2B5+ OPCs were transplanted into the injured site of rats with SCC one week after SCC insult. Behavioral tests evaluated motor and sensory function 7 days after OPC transplantation. Real-time quantitative polymerase chain reaction (RT-qPCR) determined the expression of various cytokines related to the Notch signaling pathway after OPC transplantation. RESULTS IPSC-derived OPCs were successfully generated from MEFs, as indicated by positive immunostaining of A2B5, PDGFα and NG2. Further differentiation of OPCs was identified by immunostaining of Olig2, Sox10, Nkx2.2, O4, MBP and GFAP. Importantly, myelin formation was significantly enhanced in the SCC+ OPC group and SCI-induced motor and sensory dysfunction was largely alleviated by A2B5+ OPC transplantation. Expression of factors involved in the Notch signaling pathway (Notch-1, Numb, SHARP1 and NEDD4) was significantly increased after OPC transplantation. CONCLUSIONS A2B5+ OPC transplantation attenuates motor and sensory dysfunction in SCC rats by promoting myelin formation, which may be associated with change in expression of factors involved in the Notch signaling pathway.
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Affiliation(s)
- H Yuan
- Institute of Neuroscience, Kunming Medical University, Kunming 650031, Yunnan, China; Department of Spine Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou, China
| | - C-L Fang
- Institute of Neurological Disease, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Department of Anesthesiology, National Traditional Chinese Medicine Clinical Research Base and Western Medicine Translational Medicine Research Center, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Y-P Deng
- Department of Anesthesiology, National Traditional Chinese Medicine Clinical Research Base and Western Medicine Translational Medicine Research Center, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - J Huang
- Institute of Neuroscience, Kunming Medical University, Kunming 650031, Yunnan, China
| | - R-Z Niu
- Laboratory Animal Department, Kunming Medical University, Kunming 650031, Yunnan, China
| | - J-L Chen
- Laboratory Animal Department, Kunming Medical University, Kunming 650031, Yunnan, China
| | - T-B Chen
- Laboratory Animal Department, Kunming Medical University, Kunming 650031, Yunnan, China
| | - Z-Q Zhu
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou, China
| | - L Chen
- Institute of Neurological Disease, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - L-L Xiong
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou, China
| | - T-H Wang
- Institute of Neuroscience, Kunming Medical University, Kunming 650031, Yunnan, China; Laboratory Animal Department, Kunming Medical University, Kunming 650031, Yunnan, China; Institute of Neurological Disease, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
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10
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Rahman MM, Islam MR, Islam MT, Harun-Or-Rashid M, Islam M, Abdullah S, Uddin MB, Das S, Rahaman MS, Ahmed M, Alhumaydhi FA, Emran TB, Mohamed AAR, Faruque MRI, Khandaker MU, Mostafa-Hedeab G. Stem Cell Transplantation Therapy and Neurological Disorders: Current Status and Future Perspectives. BIOLOGY 2022; 11:147. [PMID: 35053145 PMCID: PMC8772847 DOI: 10.3390/biology11010147] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/26/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023]
Abstract
Neurodegenerative diseases are a global health issue with inadequate therapeutic options and an inability to restore the damaged nervous system. With advances in technology, health scientists continue to identify new approaches to the treatment of neurodegenerative diseases. Lost or injured neurons and glial cells can lead to the development of several neurological diseases, including Parkinson's disease, stroke, and multiple sclerosis. In recent years, neurons and glial cells have successfully been generated from stem cells in the laboratory utilizing cell culture technologies, fueling efforts to develop stem cell-based transplantation therapies for human patients. When a stem cell divides, each new cell has the potential to either remain a stem cell or differentiate into a germ cell with specialized characteristics, such as muscle cells, red blood cells, or brain cells. Although several obstacles remain before stem cells can be used for clinical applications, including some potential disadvantages that must be overcome, this cellular development represents a potential pathway through which patients may eventually achieve the ability to live more normal lives. In this review, we summarize the stem cell-based therapies that have been explored for various neurological disorders, discuss the potential advantages and drawbacks of these therapies, and examine future directions for this field.
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Affiliation(s)
- Mohammad Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Touhidul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Harun-Or-Rashid
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mahfuzul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Sabirin Abdullah
- Space Science Center, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia;
| | - Mohammad Borhan Uddin
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Sumit Das
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Saidur Rahaman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Muniruddin Ahmed
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Fahad A. Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia;
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | | | | | - Mayeen Uddin Khandaker
- Centre for Applied Physics and Radiation Technologies, School of Engineering and Technology, Sunway University, Bandar Sunway 47500, Selangor, Malaysia;
| | - Gomaa Mostafa-Hedeab
- Pharmacology Department & Health Sciences Research Unit, Medical College, Jouf University, Sakaka 72446, Saudi Arabia;
- Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef 62521, Egypt
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11
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Chand K, Nano R, Wixey J, Patel J. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:372-382. [PMID: 35485440 PMCID: PMC9052430 DOI: 10.1093/stcltm/szac005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 12/12/2021] [Indexed: 11/25/2022] Open
Abstract
Fetal growth restriction (FGR) occurs when a fetus is unable to grow normally due to inadequate nutrient and oxygen supply from the placenta. Children born with FGR are at high risk of lifelong adverse neurodevelopmental outcomes, such as cerebral palsy, behavioral issues, and learning and attention difficulties. Unfortunately, there is no treatment to protect the FGR newborn from these adverse neurological outcomes. Chronic inflammation and vascular disruption are prevalent in the brains of FGR neonates and therefore targeted treatments may be key to neuroprotection. Tissue repair and regeneration via stem cell therapies have emerged as a potential clinical intervention for FGR babies at risk for neurological impairment and long-term disability. This review discusses the advancement of research into stem cell therapy for treating neurological diseases and how this may be extended for use in the FGR newborn. Leading preclinical studies using stem cell therapies in FGR animal models will be highlighted and the near-term steps that need to be taken for the development of future clinical trials.
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Affiliation(s)
- Kirat Chand
- UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia
| | - Rachel Nano
- Cancer and Ageing Research Program, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Julie Wixey
- Julie Wixey, Faculty of Medicine, Royal Brisbane and Women’s Hospital, The University of Queensland Centre for Clinical Research, Herston 4029 QLD, Australia.
| | - Jatin Patel
- Corresponding authors: Jatin Patel, Translational Research Institute, Queensland University of Technology, 37 Kent Street, Woolloongabba 4102 QLD, Australia.
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12
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Neural Stem Cells: Promoting Axonal Regeneration and Spinal Cord Connectivity. Cells 2021; 10:cells10123296. [PMID: 34943804 PMCID: PMC8699545 DOI: 10.3390/cells10123296] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 11/17/2022] Open
Abstract
Spinal cord injury (SCI) leads to irreversible functional impairment caused by neuronal loss and the disruption of neuronal connections across the injury site. While several experimental strategies have been used to minimize tissue damage and to enhance axonal growth and regeneration, the corticospinal projection, which is the most important voluntary motor system in humans, remains largely refractory to regenerative therapeutic interventions. To date, one of the most promising pre-clinical therapeutic strategies has been neural stem cell (NSC) therapy for SCI. Over the last decade we have found that host axons regenerate into spinal NSC grafts placed into sites of SCI. These regenerating axons form synapses with the graft, and the graft in turn extends very large numbers of new axons from the injury site over long distances into the distal spinal cord. Here we discuss the pathophysiology of SCI that makes the spinal cord refractory to spontaneous regeneration, the most recent findings of neural stem cell therapy for SCI, how it has impacted motor systems including the corticospinal tract and the implications for sensory feedback.
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13
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Assunção Silva RC, Pinto L, Salgado AJ. Cell transplantation and secretome based approaches in spinal cord injury regenerative medicine. Med Res Rev 2021; 42:850-896. [PMID: 34783046 DOI: 10.1002/med.21865] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 07/12/2021] [Accepted: 10/07/2021] [Indexed: 01/01/2023]
Abstract
The axonal growth-restrictive character of traumatic spinal cord injury (SCI) makes finding a therapeutic strategy a very demanding task, due to the postinjury events impeditive to spontaneous axonal outgrowth and regeneration. Considering SCI pathophysiology complexity, it has been suggested that an effective therapy should tackle all the SCI-related aspects and provide sensory and motor improvement to SCI patients. Thus, the current aim of any therapeutic approach for SCI relies in providing neuroprotection and support neuroregeneration. Acknowledging the current SCI treatment paradigm, cell transplantation is one of the most explored approaches for SCI with mesenchymal stem cells (MSCs) being in the forefront of many of these. Studies showing the beneficial effects of MSC transplantation after SCI have been proposing a paracrine action of these cells on the injured tissues, through the secretion of protective and trophic factors, rather than attributing it to the action of cells itself. This manuscript provides detailed information on the most recent data regarding the neuroregenerative effect of the secretome of MSCs as a cell-free based therapy for SCI. The main challenge of any strategy proposed for SCI treatment relies in obtaining robust preclinical evidence from in vitro and in vivo models, before moving to the clinics, so we have specifically focused on the available vertebrate and mammal models of SCI currently used in research and how can SCI field benefit from them.
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Affiliation(s)
- Rita C Assunção Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal.,BnML, Behavioral and Molecular Lab, Braga, Portugal
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal.,BnML, Behavioral and Molecular Lab, Braga, Portugal
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal
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14
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Khazaei M, Ahuja CS, Nakashima H, Nagoshi N, Li L, Wang J, Chio J, Badner A, Seligman D, Ichise A, Shibata S, Fehlings MG. GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents. Sci Transl Med 2021; 12:12/525/eaau3538. [PMID: 31915299 DOI: 10.1126/scitranslmed.aau3538] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 04/08/2019] [Accepted: 11/13/2019] [Indexed: 12/13/2022]
Abstract
Neural progenitor cell (NPC) transplantation is a promising strategy for the treatment of spinal cord injury (SCI). In this study, we show that injury-induced Notch activation in the spinal cord microenvironment biases the fate of transplanted NPCs toward astrocytes in rodents. In a screen for potential clinically relevant factors to modulate Notch signaling, we identified glial cell-derived neurotrophic factor (GDNF). GDNF attenuates Notch signaling by mediating delta-like 1 homolog (DLK1) expression, which is independent of GDNF's effect on cell survival. When transplanted into a rodent model of cervical SCI, GDNF-expressing human-induced pluripotent stem cell-derived NPCs (hiPSC-NPCs) demonstrated higher differentiation toward a neuronal fate compared to control cells. In addition, expression of GDNF promoted endogenous tissue sparing and enhanced electrical integration of transplanted cells, which collectively resulted in improved neurobehavioral recovery. CRISPR-induced knockouts of the DLK1 gene in GDNF-expressing hiPSC-NPCs attenuated the effect on functional recovery, demonstrating that this effect is partially mediated through DLK1 expression. These results represent a mechanistically driven optimization of hiPSC-NPC therapy to redirect transplanted cells toward a neuronal fate and enhance their integration.
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Affiliation(s)
- Mohamad Khazaei
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada
| | - Christopher S Ahuja
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada.,Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Hiroaki Nakashima
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada
| | - Narihito Nagoshi
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada
| | - Lijun Li
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada
| | - Jian Wang
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada
| | - Jonathon Chio
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada.,Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Anna Badner
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada.,Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - David Seligman
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada
| | - Ayaka Ichise
- Electron Microscope Laboratory, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Shinsuke Shibata
- Electron Microscope Laboratory, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Michael G Fehlings
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada. .,Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada.,Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada.,Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
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15
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Huntemer-Silveira A, Patil N, Brickner MA, Parr AM. Strategies for Oligodendrocyte and Myelin Repair in Traumatic CNS Injury. Front Cell Neurosci 2021; 14:619707. [PMID: 33505250 PMCID: PMC7829188 DOI: 10.3389/fncel.2020.619707] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/07/2020] [Indexed: 12/18/2022] Open
Abstract
A major consequence of traumatic brain and spinal cord injury is the loss of the myelin sheath, a cholesterol-rich layer of insulation that wraps around axons of the nervous system. In the central nervous system (CNS), myelin is produced and maintained by oligodendrocytes. Damage to the CNS may result in oligodendrocyte cell death and subsequent loss of myelin, which can have serious consequences for functional recovery. Demyelination impairs neuronal function by decelerating signal transmission along the axon and has been implicated in many neurodegenerative diseases. After a traumatic injury, mechanisms of endogenous remyelination in the CNS are limited and often fail, for reasons that remain poorly understood. One area of research focuses on enhancing this endogenous response. Existing techniques include the use of small molecules, RNA interference (RNAi), and monoclonal antibodies that target specific signaling components of myelination for recovery. Cell-based replacement strategies geared towards replenishing oligodendrocytes and their progenitors have been utilized by several groups in the last decade as well. In this review article, we discuss the effects of traumatic injury on oligodendrocytes in the CNS, the lack of endogenous remyelination, translational studies in rodent models promoting remyelination, and finally human clinical studies on remyelination in the CNS after injury.
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Affiliation(s)
| | - Nandadevi Patil
- Department of Neurosurgery, Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
| | - Megan A. Brickner
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States
| | - Ann M. Parr
- Department of Neurosurgery, Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
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16
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Li Y, Shen PP, Wang B. Induced pluripotent stem cell technology for spinal cord injury: a promising alternative therapy. Neural Regen Res 2021; 16:1500-1509. [PMID: 33433463 PMCID: PMC8323703 DOI: 10.4103/1673-5374.303013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Spinal cord injury has long been a prominent challenge in the trauma repair process. Spinal cord injury is a research hotspot by virtue of its difficulty to treat and its escalating morbidity. Furthermore, spinal cord injury has a long period of disease progression and leads to complications that exert a lot of mental and economic pressure on patients. There are currently a large number of therapeutic strategies for treating spinal cord injury, which range from pharmacological and surgical methods to cell therapy and rehabilitation training. All of these strategies have positive effects in the course of spinal cord injury treatment. This review mainly discusses the problems regarding stem cell therapy for spinal cord injury, including the characteristics and action modes of all relevant cell types. Induced pluripotent stem cells, which represent a special kind of stem cell population, have gained impetus in cell therapy development because of a range of advantages. Induced pluripotent stem cells can be developed into the precursor cells of each neural cell type at the site of spinal cord injury, and have great potential for application in spinal cord injury therapy.
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Affiliation(s)
- Yu Li
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, School of Life Science, Nanjing University, Nanjing, Jiangsu Province, China
| | - Ping-Ping Shen
- State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, School of Life Science, Nanjing University, Nanjing, Jiangsu Province, China
| | - Bin Wang
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
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17
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Sadat-Ali M, Al-Dakheel DA, Ahmed A, Al-Turki HA, Al-Omran AS, Acharya S, Al-Bayat MI. Spinal cord injury regeneration using autologous bone marrow-derived neurocytes and rat embryonic stem cells: A comparative study in rats. World J Stem Cells 2020; 12:1591-1602. [PMID: 33505602 PMCID: PMC7789116 DOI: 10.4252/wjsc.v12.i12.1591] [Citation(s) in RCA: 4] [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: 03/21/2020] [Revised: 08/24/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Spinal cord injury (SCI) is an important cause of traumatic paralysis and is mainly due to motor vehicle accidents. However, there is no definite treatment for spinal cord damage. AIM To assess the outcome of rat embryonic stem cells (rESC) and autologous bone marrow-derived neurocytes (ABMDN) treatment in iatrogenic SCI created in rats, and to compare the efficacy of the two different cell types. METHODS The study comprised 45 male Wistar rats weighing between 250 and 300 g, which were divided into three groups, the control, rESC and ABMDN groups. The anesthetized animals underwent exposure of the thoracic 8th to lumbar 1st vertebrae. A T10-thoracic 12th vertebrae laminectomy was performed to expose the spinal cord. A drop-weight injury using a 10 g weight from a height of 25 cm onto the exposed spinal cord was conducted. The wound was closed in layers. The urinary bladder was manually evacuated twice daily and after each evacuation Ringer lactate 5 mL/100 g was administered, twice daily after each bladder evacuation for the first 7 postoperative days. On the 10th day, the rats underwent nerve conduction studies and behavioral assessment [Basso, Beattie, Brenham (BBB)] to confirm paraplegia. Rat embryonic stem cells, ABMDN and saline were injected on the 10th day. The animals were euthanized after 8 wk and the spinal cord was isolated, removed and placed in 2% formalin for histopathological analysis to assess the healing of neural tissues at the axonal level. RESULTS All the animals tolerated the procedure well. The BBB scale scoring showed that at the end of the first week no recovery was observed in the groups. Post-injection, there was a strong and significant improvement in rats receiving rESC and ABMDN as compared to the control group based on the BBB scale, and the Train-of-four-Watch SX acceleromyography device exhibited statistically significant (P < 0.0001) regeneration of neural tissue after SCI. Histological evaluation of the spinal cord showed maximum vacuolization and least gliosis in the control group compared to the rESC and ABMDN treated animals. In the ABMDN group, limited vacuolization and more prominent gliosis were observed in all specimens as compared to the control and rESC groups. CONCLUSION This study provided strong evidence to support that transplantation of rESC and ABMDN can improve functional recovery after iatrogenic SCI. The transplanted cells showed a beneficial therapeutic effect when compared to the control group.
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Affiliation(s)
- Mir Sadat-Ali
- Department of Orthopedic Surgery, Imam Abdulrahman Bin Faisal University and King Fahd Hospital of the University, Dammam 31952, Saudi Arabia.
| | - Dakheel A Al-Dakheel
- Department of Orthopedic Surgery, Imam Abdulrahman Bin Faisal University, AlKhobar 31952, Saudi Arabia
| | - Ayesha Ahmed
- Department of Pathology, Imam Abdulrahman Bin Faisal University, Dammam 31952, Saudi Arabia
| | - Haifa A Al-Turki
- Department of Obstetrics and Gynecology, Imam Abdulrahman Bin Faisal University, Dammam 31142, Saudi Arabia
| | - Abdallah S Al-Omran
- Department of Orthopedic Surgery, Imam Abdulrahman Bin Faisal University and King Fahd Hospital of the University, AlKhobar 31952, Saudi Arabia
| | - Sadananda Acharya
- Department of Public Health, College of Public Health, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Methal I Al-Bayat
- Department of Pathology, Imam Abdulrahman Bin Faisal University, Dammam 31952, Saudi Arabia
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18
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Sharma AK, Sane HM, Kulkarni PP, Gokulchandran N, Biju H, Badhe PB. Autologous bone marrow mononuclear cell transplantation in patients with chronic traumatic brain injury- a clinical study. CELL REGENERATION (LONDON, ENGLAND) 2020; 9:3. [PMID: 32588151 PMCID: PMC7306831 DOI: 10.1186/s13619-020-00043-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 02/21/2020] [Indexed: 12/14/2022]
Abstract
Background Chronic Traumatic Brain Injury (TBI) is one of the common causes of longterm disability worldwide. Cell transplantation has gained attention as a prospective therapeutic option for neurotraumatic disorders like TBI. The postulated mechanism of cell transplantation which includes angiogenesis, axonal regeneration, neurogenesis and synaptic remodeling, may tackle the pathology of chronic TBI and improve overall functioning. Methods To study the effects of cell transplantation, 50 patients with chronic TBI were enrolled in an open label non-randomized study. The intervention included intrathecal transplantation of autologous bone marrow mononuclear cells and neurorehabilitation. Mean follow up duration was 22 months. Fifteen patients underwent second dose of cell transplantation, 6 months after their first intervention. Percentage analysis was performed to analyze the symptomatic improvements in the patients. Functional independence measure (FIM) was used as an outcome measure to evaluate the functional changes in the patients. Statistical tests were applied on the pre-intervention and post-intervention scores for determining the significance. Comparative Positron Emission Tomography- computed tomography (PET CT) scans were performed in 10 patients to monitor the effect of intervention on brain function. Factors such as age, multiple doses, time since injury and severity of injury were also analyzed to determine their effect on the outcome of cell transplantation. Adverse events were monitored throughout the follow up period. Results Overall 92% patients showed improvements in symptoms such as sitting and standing balance, voluntary control, memory, oromotor skills lower limb activities, ambulation, trunk & upper limb activity, speech, posture, communication, psychological status, cognition, attention and concentration, muscle tone, coordination, activities of daily living. A statistically significant (at p ≤ 0.05 with p-value 0) improvement was observed in the scores of FIM after intervention on the Wilcoxon signed rank test. Better outcome of the intervention was found in patients with mild TBI, age less than 18 years and time since injury less than 5 years. Ten patients who underwent a repeat PET CT scan brain showed improved brain metabolism in areas which correlated to the symptomatic changes. Two patients had an episode of seizures which was managed with medication. They both had an abnormal EEG before the intervention and 1 of them had previous history and was on antiepileptics. No other major adverse events were recorded. Conclusion This study demonstrates the safety and efficacy of cell transplantation in chronic TBI on long term follow up. Early intervention in younger age group of patients with mild TBI showed the best outcome in this study. In combination with neurorehabilitation, cell transplantation can enhance functional recovery and improve quality of life of patients with chronic TBI. PET CT scan brain should be explored as a monitoring tool to study the efficacy of intervention.
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Affiliation(s)
- Alok K Sharma
- Department of Medical Services, NeuroGen Brain & Spine Institute, Plot 19, Sector 40, Next to Seawood Grand Central Station (W), Off Palm Beach Road, Nerul, Navi Mumbai, 400706, India
| | - Hemangi M Sane
- Department Of Research & Development, NeuroGen Brain & Spine Institute, Plot 19, Sector 40, Next to Seawood Grand Central Station [W], Off Palm Beach Road, Nerul, Navi Mumbai, 400706, India
| | - Pooja P Kulkarni
- Department Of Research & Development, NeuroGen Brain & Spine Institute, Plot 19, Sector 40, Next to Seawood Grand Central Station [W], Off Palm Beach Road, Nerul, Navi Mumbai, 400706, India.
| | - Nandini Gokulchandran
- Department of Medical Services, NeuroGen Brain & Spine Institute, Plot 19, Sector 40, Next to Seawood Grand Central Station (W), Off Palm Beach Road, Nerul, Navi Mumbai, 400706, India
| | - Hema Biju
- Department of Neurorehabilitation, NeuroGen Brain & Spine Institute, Plot 19, Sector 40, Next to Seawood Grand Central Station [W], Off Palm Beach Road, Nerul, Navi Mumbai, 400706, India
| | - Prerna B Badhe
- Department of Regenerative Laboratory Services, NeuroGen Brain & Spine Institute, Plot 19, Sector 40, Next to Seawood Grand Central Station [W], Off Palm Beach Road, Nerul, Navi Mumbai, 400706, India
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Xu Z, Li Z. Experimental Study on the Role of Apelin-13 in Alleviating Spinal Cord Ischemia Reperfusion Injury Through Suppressing Autophagy. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1571-1581. [PMID: 32368015 PMCID: PMC7183780 DOI: 10.2147/dddt.s241066] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 03/04/2020] [Indexed: 12/16/2022]
Abstract
Background This study aimed to explore the effect of Apelin-13 in protecting rats against spinal cord ischemia reperfusion injury (SCIR), as well as the related molecular mechanisms. Methods One week prior to the experiment, experimental Sprague–Dawley rats were injected with Apelin-13 and the autophagy activator rapamycin through the tail vein once a day for 7 consecutive days. The SCIR rat model was prepared through the abdominal aorta clamping method. At 72 h after injury, the spinal cord tissue water content, infarct volume, and normal neuron count were determined to evaluate the degree of spinal cord tissue injury in the rats. The Basso–Beattie–Bresnahan scoring standard was adopted for functional scoring of the rat hind leg, to reflect the post-injury motor function. At 72 h after injury, changes in mitochondrial membrane potential, reactive oxygen species content, and mitochondrial ATP were detected. ELISA was carried out to detect the malonaldehyde content, as well as catalase, superoxide dismutase, and glutathione catalase activities in spinal cord tissues at 72 h after injury. Quantitative chemistry was conducted to examine the contents of nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) in spinal cord tissues. Finally, the expression of autophagy-related proteins, Beclin1, ATG5, and LC3, in spinal cord tissues was detected through the Western blotting assay. Results Apelin-13 pretreatment alleviated SCIR, promoted motor function recovery, suppressed mitochondrial dysfunction, resisted oxidative stress, and inhibited autophagy in spinal cord tissues following ischemia reperfusion injury. Conclusion Apelin-3 exerts protection against SCIR by suppressing autophagy.
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Affiliation(s)
- Zhewei Xu
- Department of Orthopedics, Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - Zhiyue Li
- Department of Orthopedics, Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
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Griffin JM, Bradke F. Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem. EMBO Mol Med 2020; 12:e11505. [PMID: 32090481 PMCID: PMC7059014 DOI: 10.15252/emmm.201911505] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 01/07/2020] [Accepted: 01/31/2020] [Indexed: 12/21/2022] Open
Abstract
The recent years saw the advent of promising preclinical strategies that combat the devastating effects of a spinal cord injury (SCI) that are progressing towards clinical trials. However, individually, these treatments produce only modest levels of recovery in animal models of SCI that could hamper their implementation into therapeutic strategies in spinal cord injured humans. Combinational strategies have demonstrated greater beneficial outcomes than their individual components alone by addressing multiple aspects of SCI pathology. Clinical trial designs in the future will eventually also need to align with this notion. The scenario will become increasingly complex as this happens and conversations between basic researchers and clinicians are required to ensure accurate study designs and functional readouts.
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Affiliation(s)
- Jarred M Griffin
- Laboratory for Axonal Growth and Regeneration, German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Frank Bradke
- Laboratory for Axonal Growth and Regeneration, German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany
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21
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Abdul Wahid SF, Law ZK, Ismail NA, Lai NM. Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2019; 12:CD011742. [PMID: 31853962 PMCID: PMC6920743 DOI: 10.1002/14651858.cd011742.pub3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND), is a fatal disease associated with rapidly progressive disability, for which no definitive treatment exists. Current treatment approaches largely focus on relieving symptoms to improve the quality of life of those affected. The therapeutic potential of cell-based therapies in ALS/MND has not been fully evaluated, given the paucity of high-quality clinical trials. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND. This review was first published in 2015 when the first clinical trials of cell-based therapies were still in progress. We undertook this update to incorporate evidence now available from randomised controlled trials (RCTs). OBJECTIVES To assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no treatment. SEARCH METHODS On 31 July 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials registries for ongoing or unpublished studies. SELECTION CRITERIA We included RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowed, provided that they were given to each group equally. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. MAIN RESULTS Two RCTs involving 112 participants were eligible for inclusion in this review. One study compared autologous bone marrow-mesenchymal stem cells (BM-MSC) plus riluzole versus control (riluzole only), while the other study compared combined intramuscular and intrathecal administration of autologous mesenchymal stem cells secreting neurotrophic factors (MSC-NTF) to placebo. The latter study was reported as an abstract and provided no numerical data. Both studies were funded by biotechnology companies. The only study that contributed to the outcome data in the review involved 64 participants, comparing BM-MSC plus riluzole versus control (riluzole only). It reported outcomes after four to six months. It had a low risk of selection bias, detection bias and reporting bias, but a high risk of performance bias and attrition bias. The certainty of evidence was low for all major efficacy outcomes, with imprecision as the main downgrading factor, because the range of plausible estimates, as shown by the 95% confidence intervals (CIs), encompassed a range that would likely result in different clinical decisions. Functional impairment, expressed as the mean change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score from baseline to six months after cell injection was slightly reduced (better) in the BM-MSC group compared to the control group (mean difference (MD) 3.38, 95% CI 1.22 to 5.54; 1 RCT, 56 participants; low-certainty evidence). ALSFRS-R has a range from 48 (normal) to 0 (maximally impaired); a change of 4 or more points is considered clinically important. The trial did not report outcomes at 12 months. There was no clear difference between the BM-MSC and the no treatment group in change in respiratory function (per cent predicted forced vital capacity; FVC%; MD -0.53, 95% CI -5.37 to 4.31; 1 RCT, 56 participants; low-certainty evidence); overall survival at six months (risk ratio (RR) 1.07, 95% CI 0.94 to 1.22; 1 RCT, 64 participants; low-certainty evidence); risk of total adverse events (RR 0.86, 95% CI 0.62 to 1.19; 1 RCT, 64 participants; low-certainty evidence) or serious adverse events (RR 0.47, 95% CI 0.13 to 1.72; 1 RCT, 64 participants; low-certainty evidence). The study did not measure muscle strength. AUTHORS' CONCLUSIONS Currently, there is a lack of high-certainty evidence to guide practice on the use of cell-based therapy to treat ALS/MND. Uncertainties remain as to whether this mode of therapy is capable of restoring muscle function, slowing disease progression, and improving survival in people with ALS/MND. Although one RCT provided low-certainty evidence that BM-MSC may slightly reduce functional impairment measured on the ALSFRS-R after four to six months, this was a small phase II trial that cannot be used to establish efficacy. We need large, prospective RCTs with long-term follow-up to establish the efficacy and safety of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research are to determine the appropriate cell source, phenotype, dose and method of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.
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Affiliation(s)
- S Fadilah Abdul Wahid
- Universiti Kebangsaan Malaysia Medical CentreCell Therapy CenterJalan Yaacob LatifKuala LumpurMalaysia56000
| | - Zhe Kang Law
- Universiti Kebangsaan Malaysia Medical CentreDepartment of Medicine, Faculty of MedicineKuala LumpurMalaysia
| | - Nor Azimah Ismail
- Universiti Kebangsaan Malaysia Medical CentreCell Therapy CenterJalan Yaacob LatifKuala LumpurMalaysia56000
| | - Nai Ming Lai
- Taylor's UniversitySchool of MedicineSubang JayaMalaysia
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Unal DB, Caliari SR, Lampe KJ. Engineering biomaterial microenvironments to promote myelination in the central nervous system. Brain Res Bull 2019; 152:159-174. [PMID: 31306690 DOI: 10.1016/j.brainresbull.2019.07.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 06/09/2019] [Accepted: 07/08/2019] [Indexed: 01/01/2023]
Abstract
Promoting remyelination and/or minimizing demyelination are key therapeutic strategies under investigation for diseases and injuries like multiple sclerosis (MS), spinal cord injury, stroke, and virus-induced encephalopathy. Myelination is essential for efficacious neuronal signaling. This myelination process is originated by oligodendrocyte progenitor cells (OPCs) in the central nervous system (CNS). Resident OPCs are capable of both proliferation and differentiation, and also migration to demyelinated injury sites. OPCs can then engage with these unmyelinated or demyelinated axons and differentiate into myelin-forming oligodendrocytes (OLs). However this process is frequently incomplete and often does not occur at all. Biomaterial strategies can now be used to guide OPC and OL development with the goal of regenerating healthy myelin sheaths in formerly damaged CNS tissue. Growth and neurotrophic factors delivered from such materials can promote proliferation of OPCs or differentiation into OLs. While cell transplantation techniques have been used to replace damaged cells in wound sites, they have also resulted in poor transplant cell viability, uncontrollable differentiation, and poor integration into the host. Biomaterial scaffolds made from extracellular matrix (ECM) mimics that are naturally or synthetically derived can improve transplanted cell survival, support both transplanted and endogenous cell populations, and direct their fate. In particular, stiffness and degradability of these scaffolds are two parameters that can influence the fate of OPCs and OLs. The future outlook for biomaterials research includes 3D in vitro models of myelination / remyelination / demyelination to better mimic and study these processes. These models should provide simple relationships of myelination to microenvironmental biophysical and biochemical properties to inform improved therapeutic approaches.
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Affiliation(s)
- Deniz B Unal
- Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22903, United States
| | - Steven R Caliari
- Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22903, United States; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22903, United States
| | - Kyle J Lampe
- Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22903, United States.
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Ceprian M, Fulton D. Glial Cell AMPA Receptors in Nervous System Health, Injury and Disease. Int J Mol Sci 2019; 20:E2450. [PMID: 31108947 PMCID: PMC6566241 DOI: 10.3390/ijms20102450] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/11/2019] [Accepted: 04/22/2019] [Indexed: 12/16/2022] Open
Abstract
Glia form a central component of the nervous system whose varied activities sustain an environment that is optimised for healthy development and neuronal function. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA)-type glutamate receptors (AMPAR) are a central mediator of glutamatergic excitatory synaptic transmission, yet they are also expressed in a wide range of glial cells where they influence a variety of important cellular functions. AMPAR enable glial cells to sense the activity of neighbouring axons and synapses, and as such many aspects of glial cell development and function are influenced by the activity of neural circuits. However, these AMPAR also render glia sensitive to elevations of the extracellular concentration of glutamate, which are associated with a broad range of pathological conditions. Excessive activation of AMPAR under these conditions may induce excitotoxic injury in glial cells, and trigger pathophysiological responses threatening other neural cells and amplifying ongoing disease processes. The aim of this review is to gather information on AMPAR function from across the broad diversity of glial cells, identify their contribution to pathophysiological processes, and highlight new areas of research whose progress may increase our understanding of nervous system dysfunction and disease.
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Affiliation(s)
- Maria Ceprian
- Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain.
- Departamento de Bioquímica y Biología Molecular, CIBERNED, IRICYS. Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - Daniel Fulton
- Neuroscience and Ophthalmology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
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24
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Logan S, Arzua T, Canfield SG, Seminary ER, Sison SL, Ebert AD, Bai X. Studying Human Neurological Disorders Using Induced Pluripotent Stem Cells: From 2D Monolayer to 3D Organoid and Blood Brain Barrier Models. Compr Physiol 2019; 9:565-611. [PMID: 30873582 PMCID: PMC6705133 DOI: 10.1002/cphy.c180025] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Neurological disorders have emerged as a predominant healthcare concern in recent years due to their severe consequences on quality of life and prevalence throughout the world. Understanding the underlying mechanisms of these diseases and the interactions between different brain cell types is essential for the development of new therapeutics. Induced pluripotent stem cells (iPSCs) are invaluable tools for neurological disease modeling, as they have unlimited self-renewal and differentiation capacity. Mounting evidence shows: (i) various brain cells can be generated from iPSCs in two-dimensional (2D) monolayer cultures; and (ii) further advances in 3D culture systems have led to the differentiation of iPSCs into organoids with multiple brain cell types and specific brain regions. These 3D organoids have gained widespread attention as in vitro tools to recapitulate complex features of the brain, and (iii) complex interactions between iPSC-derived brain cell types can recapitulate physiological and pathological conditions of blood-brain barrier (BBB). As iPSCs can be generated from diverse patient populations, researchers have effectively applied 2D, 3D, and BBB models to recapitulate genetically complex neurological disorders and reveal novel insights into molecular and genetic mechanisms of neurological disorders. In this review, we describe recent progress in the generation of 2D, 3D, and BBB models from iPSCs and further discuss their limitations, advantages, and future ventures. This review also covers the current status of applications of 2D, 3D, and BBB models in drug screening, precision medicine, and modeling a wide range of neurological diseases (e.g., neurodegenerative diseases, neurodevelopmental disorders, brain injury, and neuropsychiatric disorders). © 2019 American Physiological Society. Compr Physiol 9:565-611, 2019.
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Affiliation(s)
- Sarah Logan
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Thiago Arzua
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Scott G. Canfield
- Department of Cellular & Integrative Physiology, IU School of Medicine-Terre Haute, Terre Haute, IN, USA
| | - Emily R. Seminary
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Samantha L. Sison
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Allison D. Ebert
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Xiaowen Bai
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
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25
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Abstract
Cellular transplantation for repair of the injured spinal cord has a rich history with strategies focused on neuroprotection, immunomodulation, and neural reconstruction. The goal of the present review is to provide a concise overview and discussion of five key themes that have become important considerations for rebuilding functional neural networks. The questions raised include: (i) who are the donor cells selected for transplantation, (ii) what is the intended target for repair, (iii) when is the optimal time for transplantation, (iv) where should the cells be delivered, and lastly (v) why does cell transplantation remain an attractive candidate for promoting neural repair after injury? Recent developments in neurobiology and engineering now enable us to start addressing these questions with multidisciplinary expertise and methods.
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Affiliation(s)
- Lyandysha V Zholudeva
- 1 Department of Neurobiology and Anatomy, College of Medicine, Drexel University, Philadelphia, PA, USA.,2 The Spinal Cord Research Center, College of Medicine, Drexel University, Philadelphia, PA, USA
| | - Michael A Lane
- 1 Department of Neurobiology and Anatomy, College of Medicine, Drexel University, Philadelphia, PA, USA.,2 The Spinal Cord Research Center, College of Medicine, Drexel University, Philadelphia, PA, USA
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White N, Sakiyama-Elbert SE. Derivation of Specific Neural Populations From Pluripotent Cells for Understanding and Treatment of Spinal Cord Injury. Dev Dyn 2019; 248:78-87. [PMID: 30324766 PMCID: PMC6640631 DOI: 10.1002/dvdy.24680] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 10/07/2018] [Accepted: 10/09/2018] [Indexed: 12/12/2022] Open
Abstract
Due to the nature of the biological response to traumatic spinal cord injury, there are very limited therapeutic options available to patients. Recent advances in cell transplantation have demonstrated the therapeutic potential of transplanting supportive cell types following spinal cord injury. In particular, pluripotent stem cell derived neural cells are of interest for future investigation. Use of pluripotent stem cells as the source allows many cell types to be produced from a population that can be expanded in vitro. In this review, we will discuss the signaling pathways that have been used to differentiate spinal neural phenotypes from pluripotent stem cells. Additionally, we will highlight methods that have been developed to direct the differentiation of pluripotent stem cells to specific neural fates. Further refinement and elaboration of these techniques might aid in elucidating the multitude of neuronal subtypes endogenous to the spinal cord, as well as produce further therapeutic options for spinal cord injury recovery. Developmental Dynamics 248:78-87, 2019. © 2018 Wiley Periodicals, Inc.
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Affiliation(s)
- Nicholas White
- Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas
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Yousefi F, Lavi Arab F, Saeidi K, Amiri H, Mahmoudi M. Various strategies to improve efficacy of stem cell transplantation in multiple sclerosis: Focus on mesenchymal stem cells and neuroprotection. J Neuroimmunol 2018; 328:20-34. [PMID: 30557687 DOI: 10.1016/j.jneuroim.2018.11.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 11/30/2018] [Indexed: 02/09/2023]
Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which predominantly affect young adults and undergo heavy socioeconomic burdens. Conventional therapeutic modalities for MS mostly downregulate aggressive immune responses and are almost insufficient for management of progressive course of the disease. Mesenchymal stem cells (MSCs), due to both immunomodulatory and neuroprotective properties have been known as practical cells for treatment of neurodegenerative diseases like MS. However, clinical translation of MSCs is associated with some limitations such as short-life engraftment duration, little in vivo trans-differentiation and restricted accessibility into damaged sites. Therefore, laboratory manipulation of MSCs can improve efficacy of MSCs transplantation in MS patients. In this review, we discuss several novel approaches, which can potentially enhance MSCs capabilities for treating MS.
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Affiliation(s)
- Forouzan Yousefi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fahimeh Lavi Arab
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kolsoum Saeidi
- Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Houshang Amiri
- Neurology Research Center, Kerman University of Medical Sciences, Kerman, Iran; Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Mahmoud Mahmoudi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Zibara K, Ballout N, Mondello S, Karnib N, Ramadan N, Omais S, Nabbouh A, Caliz D, Clavijo A, Hu Z, Ghanem N, Gajavelli S, Kobeissy F. Combination of drug and stem cells neurotherapy: Potential interventions in neurotrauma and traumatic brain injury. Neuropharmacology 2018; 145:177-198. [PMID: 30267729 DOI: 10.1016/j.neuropharm.2018.09.032] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 09/17/2018] [Accepted: 09/21/2018] [Indexed: 12/12/2022]
Abstract
Traumatic brain injury (TBI) has been recognized as one of the major public health issues that leads to devastating neurological disability. As a consequence of primary and secondary injury phases, neuronal loss following brain trauma leads to pathophysiological alterations on the molecular and cellular levels that severely impact the neuropsycho-behavioral and motor outcomes. Thus, to mitigate the neuropathological sequelae post-TBI such as cerebral edema, inflammation and neural degeneration, several neurotherapeutic options have been investigated including drug intervention, stem cell use and combinational therapies. These treatments aim to ameliorate cellular degeneration, motor decline, cognitive and behavioral deficits. Recently, the use of neural stem cells (NSCs) coupled with selective drug therapy has emerged as an alternative treatment option for neural regeneration and behavioral rehabilitation post-neural injury. Given their neuroprotective abilities, NSC-based neurotherapy has been widely investigated and well-reported in numerous disease models, notably in trauma studies. In this review, we will elaborate on current updates in cell replacement therapy in the area of neurotrauma. In addition, we will discuss novel combination drug therapy treatments that have been investigated in conjunction with stem cells to overcome the limitations associated with stem cell transplantation. Understanding the regenerative capacities of stem cell and drug combination therapy will help improve functional recovery and brain repair post-TBI. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".
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Affiliation(s)
- Kazem Zibara
- ER045, Laboratory of Stem Cells, PRASE, Lebanese University, Beirut, Lebanon; Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Nissrine Ballout
- ER045, Laboratory of Stem Cells, PRASE, Lebanese University, Beirut, Lebanon
| | - Stefania Mondello
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Nabil Karnib
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon
| | - Naify Ramadan
- Department of Women's and Children's Health (KBH), Division of Clinical Pediatrics, Karolinska Institute, Sweden
| | - Saad Omais
- Department of Biology, American University of Beirut, Beirut, Lebanon
| | - Ali Nabbouh
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon
| | - Daniela Caliz
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA
| | - Angelica Clavijo
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA
| | - Zhen Hu
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA
| | - Noël Ghanem
- Department of Biology, American University of Beirut, Beirut, Lebanon
| | - Shyam Gajavelli
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA.
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon; Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Department of Emergency Medicine, University of Florida, Gainesville, FL, 32611, USA.
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Spinal cord organogenesis model reveals role of Flk1 + cells in self-organization of neural progenitor cells into complex spinal cord tissue. Stem Cell Res 2018; 33:156-165. [PMID: 30368192 DOI: 10.1016/j.scr.2018.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 08/02/2018] [Accepted: 09/05/2018] [Indexed: 12/15/2022] Open
Abstract
A platform for studying spinal cord organogenesis in vivo where embryonic stem cell (ESC)-derived neural progenitor cells (NPC) self-organize into spinal cord-like tissue after transplantation in subarachnoid space of the spinal cord has been described. We advance the applicability of this platform by imaging in vivo the formed graft through T2w magnetic resonance imaging (MRI). Furthermore, we used diffusion tensor imaging (DTI) to verify the stereotypical organization of the graft showing that it mimics the host spinal cord. Within the graft white matter (WM) we identified astrocytes that form glial limitans, myelinating oligodendrocytes, and myelinated axons with paranodes. Within the graft grey matter (GM) we identified cholinergic, glutamatergic, serotonergic and dopaminergic neurons. Furthermore, we demonstrate the presence of ESC-derived complex vasculature that includes the presence of blood brain barrier. In addition to the formation of mature spinal cord tissue, we describe factors that drive this process. Specifically, we identify Flk1+ cells as necessary for spinal cord formation, and synaptic connectivity with the host spinal cord and formation of host-graft chimeric vasculature as contributing factors. This model can be used to study spinal cord organogenesis, and as an in vivo drug discovery platform for screening potential therapeutic compounds and their toxicity.
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30
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Aydin T, Gurcan C, Taheri H, Yilmazer A. Graphene Based Materials in Neural Tissue Regeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1107:129-142. [PMID: 29882208 DOI: 10.1007/5584_2018_221] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Due to its extraordinary features such as large surface area, high electrical conductivity, chemical stability and mechanical properties, graphene attracts great interest in various fields of biomedical sciences including biosensors, cancer therapy, diagnosis and regenerative medicine. The use of graphene-based materials has been of great interest for the design of scaffolds that can promote neural tissue regeneration. Recent studies published over the last few years clearly show that graphene and graphene based materials promote adhesion, proliferation and differentiation of various cells including embryonic stem cells (ESC), neural stem cells (NSC), mesenchymal stem cells (MSC) and induced pluripotent stem cells (iPSC). Therefore graphene based materials are one of the promising nanoplatforms in regenerative medicine for neural tissue injury. With its unique topographic and chemical properties, graphene is used as a scaffold that could provide a bridge between regenerating nerves. More importantly, as a conductive substrate, graphene allows the continuation of electrical conduction between damaged nerve ends. The integration of supportive cells such as glial, neural precursor or stem cells in such a scaffold shows higher regeneration when compared to currently used neural autografts and nerve conduits. This review discusses the details of such studies involving graphene based materials with a special interest on neural stem cells, mesenchymal stem cells or pluripotent stem cells.
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Affiliation(s)
- Tugce Aydin
- Biotechnology Institute, Ankara University, Tandogan/Ankara, Turkey.,Engineering Faculty, Biomedical Engineering Department, Ankara University, Tandogan/Ankara, Turkey
| | - Cansu Gurcan
- Biotechnology Institute, Ankara University, Tandogan/Ankara, Turkey.,Engineering Faculty, Biomedical Engineering Department, Ankara University, Tandogan/Ankara, Turkey
| | - Hadiseh Taheri
- Engineering Faculty, Biomedical Engineering Department, Ankara University, Tandogan/Ankara, Turkey
| | - Açelya Yilmazer
- Engineering Faculty, Biomedical Engineering Department, Ankara University, Tandogan/Ankara, Turkey. .,Stem Cell Institute, Ankara University, Balgat/Ankara, Turkey.
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31
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Dolci S, Pino A, Berton V, Gonzalez P, Braga A, Fumagalli M, Bonfanti E, Malpeli G, Pari F, Zorzin S, Amoroso C, Moscon D, Rodriguez FJ, Fumagalli G, Bifari F, Decimo I. High Yield of Adult Oligodendrocyte Lineage Cells Obtained from Meningeal Biopsy. Front Pharmacol 2017; 8:703. [PMID: 29075188 PMCID: PMC5643910 DOI: 10.3389/fphar.2017.00703] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 09/21/2017] [Indexed: 12/25/2022] Open
Abstract
Oligodendrocyte loss can lead to cognitive and motor deficits. Current remyelinating therapeutic strategies imply either modulation of endogenous oligodendrocyte precursors or transplantation of in vitro expanded oligodendrocytes. Cell therapy, however, still lacks identification of an adequate source of oligodendrocyte present in adulthood and able to efficiently produce transplantable cells. Recently, a neural stem cell-like population has been identified in meninges. We developed a protocol to obtain high yield of oligodendrocyte lineage cells from one single biopsy of adult rat meningeal tissue. From 1 cm2 of adult rat spinal cord meninges, we efficiently expanded a homogenous culture of 10 millions of meningeal-derived oligodendrocyte lineage cells in a short period of time (approximately 4 weeks). Meningeal-derived oligodendrocyte lineage cells show typical mature oligodendrocyte morphology and express specific oligodendrocyte markers, such as galactosylceramidase and myelin basic protein. Moreover, when transplanted in a chemically demyelinated spinal cord model, meningeal-derived oligodendrocyte lineage cells display in vivo-remyelinating potential. This oligodendrocyte lineage cell population derives from an accessible and adult source, being therefore a promising candidate for autologous cell therapy of demyelinating diseases. In addition, the described method to differentiate meningeal-derived neural stem cells into oligodendrocyte lineage cells may represent a valid in vitro model to dissect oligodendrocyte differentiation and to screen for drugs capable to promote oligodendrocyte regeneration.
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Affiliation(s)
- Sissi Dolci
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Annachiara Pino
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Valeria Berton
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Pau Gonzalez
- Group of Molecular Neurology, Hospital Nacional de Parapléjicos, Toledo, Spain
| | - Alice Braga
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Marta Fumagalli
- Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Elisabetta Bonfanti
- Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Giorgio Malpeli
- Section of General and Pancreatic Surgery, Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, Verona, Italy
| | - Francesca Pari
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Stefania Zorzin
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Clelia Amoroso
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Denny Moscon
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | | | - Guido Fumagalli
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Ilaria Decimo
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
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32
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Min KJ, Kim TH, Choi JW. Magnetic Force-Driven Graphene Patterns to Direct Synaptogenesis of Human Neuronal Cells. MATERIALS 2017; 10:ma10101151. [PMID: 28974044 PMCID: PMC5666957 DOI: 10.3390/ma10101151] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 09/27/2017] [Accepted: 09/30/2017] [Indexed: 11/30/2022]
Abstract
Precise control of axonal growth and synaptic junction formation are incredibly important to repair and/or to mimic human neuronal network. Here, we report a graphene oxide (GO)-based hybrid patterns that were proven to be excellent for guiding axonal growth and its consequent synapse formation of human neural cells. Unlike the previous method that utilized micro-contacting printing technique to generate GO patterns, here, GO-encapsulated magnetic nanoparticles were first synthesized and utilized as core materials wherein the external magnetic force facilitated the transfer of GO film to the desired substrate. Owing to the intrinsic property of GO that provides stable cell attachment and growth for long-term culture, human neuronal cells could be effectively patterned on the biocompatible polymer substrates with different pattern sizes. By using magnetic force-driven GO hybrid patterns, we demonstrated that accumulation and expression level of Synaptophysin of neurons could be effectively controlled with varying sizes of each pattern. The synaptic network between each neuron could be precisely controlled and matched by guiding axonal direction. This work provides treatment and modeling of brain diseases and spinal cord injuries.
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Affiliation(s)
- Kyung-Joon Min
- Department of Biomedical Engineering, Sogang University, 35 Baekbeom-ro (Sinsu-dong), Mapo-gu, Seoul 121-742, Korea.
| | - Tae-Hyung Kim
- School of Integrative Engineering, Chung-Ang University, Heukseok-dong, Dongjak-gu, Seoul 156-756, Korea.
| | - Jeong-Woo Choi
- Department of Biomedical Engineering, Sogang University, 35 Baekbeom-ro (Sinsu-dong), Mapo-gu, Seoul 121-742, Korea.
- Department of Chemical and Biomolecular Engineering, Sogang University, 35 Baekbeom-ro (Sinsu-dong), Mapo-gu, Seoul 121-742, Korea.
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33
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Mullin AP, Cui C, Wang Y, Wang J, Troy E, Caggiano AO, Parry TJ, Colburn RW, Pavlopoulos E. rHIgM22 enhances remyelination in the brain of the cuprizone mouse model of demyelination. Neurobiol Dis 2017; 105:142-155. [DOI: 10.1016/j.nbd.2017.05.015] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Revised: 05/04/2017] [Accepted: 05/29/2017] [Indexed: 02/02/2023] Open
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Systemic Neutrophil Depletion Modulates the Migration and Fate of Transplanted Human Neural Stem Cells to Rescue Functional Repair. J Neurosci 2017; 37:9269-9287. [PMID: 28847814 DOI: 10.1523/jneurosci.2785-16.2017] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 06/15/2017] [Accepted: 07/30/2017] [Indexed: 01/19/2023] Open
Abstract
The interaction of transplanted stem cells with local cellular and molecular cues in the host CNS microenvironment may affect the potential for repair by therapeutic cell populations. In this regard, spinal cord injury (SCI), Alzheimer's disease, and other neurological injuries and diseases all exhibit dramatic and dynamic changes to the host microenvironment over time. Previously, we reported that delayed transplantation of human CNS-derived neural stem cells (hCNS-SCns) at 9 or 30 d post-SCI (dpi) resulted in extensive donor cell migration, predominantly neuronal and oligodendrocytic donor cell differentiation, and functional locomotor improvements. Here, we report that acute transplantation of hCNS-SCns at 0 dpi resulted in localized astroglial differentiation of donor cells near the lesion epicenter and failure to produce functional improvement in an all-female immunodeficient mouse model. Critically, specific immunodepletion of neutrophils (polymorphonuclear leukocytes) blocked hCNS-SCns astroglial differentiation near the lesion epicenter and rescued the capacity of these cells to restore function. These data represent novel evidence that a host immune cell population can block the potential for functional repair derived from a therapeutic donor cell population, and support targeting the inflammatory microenvironment in combination with cell transplantation after SCI.SIGNIFICANCE STATEMENT The interaction of transplanted cells with local cellular and molecular cues in the host microenvironment is a key variable that may shape the translation of neurotransplantation research to the clinical spinal cord injury (SCI) human population, and few studies have investigated these events. We show that the specific immunodepletion of polymorphonuclear leukocyte neutrophils using anti-Ly6G inhibits donor cell astrogliosis and rescues the capacity of a donor cell population to promote locomotor improvement after SCI. Critically, our data demonstrate novel evidence that a specific host immune cell population can block the potential for functional repair derived from a therapeutic donor cell population.
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35
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Deng T, Postnikov Y, Zhang S, Garrett L, Becker L, Rácz I, Hölter SM, Wurst W, Fuchs H, Gailus-Durner V, de Angelis MH, Bustin M. Interplay between H1 and HMGN epigenetically regulates OLIG1&2 expression and oligodendrocyte differentiation. Nucleic Acids Res 2017; 45:3031-3045. [PMID: 27923998 PMCID: PMC5389484 DOI: 10.1093/nar/gkw1222] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 11/22/2016] [Indexed: 01/22/2023] Open
Abstract
An interplay between the nucleosome binding proteins H1 and HMGN is known to affect chromatin dynamics, but the biological significance of this interplay is still not clear. We find that during embryonic stem cell differentiation loss of HMGNs leads to down regulation of genes involved in neural differentiation, and that the transcription factor OLIG2 is a central node in the affected pathway. Loss of HMGNs affects the expression of OLIG2 as well as that of OLIG1, two transcription factors that are crucial for oligodendrocyte lineage specification and nerve myelination. Loss of HMGNs increases the chromatin binding of histone H1, thereby recruiting the histone methyltransferase EZH2 and elevating H3K27me3 levels, thus conferring a repressive epigenetic signature at Olig1&2 sites. Embryonic stem cells lacking HMGNs show reduced ability to differentiate towards the oligodendrocyte lineage, and mice lacking HMGNs show reduced oligodendrocyte count and decreased spinal cord myelination, and display related neurological phenotypes. Thus, the presence of HMGN proteins is required for proper expression of neural differentiation genes during embryonic stem cell differentiation. Specifically, we demonstrate that the dynamic interplay between HMGNs and H1 in chromatin epigenetically regulates the expression of OLIG1&2, thereby affecting oligodendrocyte development and myelination, and mouse behavior.
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Affiliation(s)
- Tao Deng
- Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yuri Postnikov
- Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Shaofei Zhang
- Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lillian Garrett
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.,Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
| | - Lore Becker
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
| | - Ildikó Rácz
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.,Institute of Molecular Psychiatry, University of Bonn, 53125 Bonn, Germany
| | - Sabine M Hölter
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.,Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
| | - Wolfgang Wurst
- Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.,Technische Universität München-Weihenstephan, Chair of Developmental Genetics c/o Helmholtz Zentrum München, 85764 Neuherberg, Germany.,German Center for Neurodegenerative Diseases (DZNE) Site Munich, Munich Germany.,Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, 80336 Munich, Germany
| | - Helmut Fuchs
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
| | - Valerie Gailus-Durner
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
| | - Martin Hrabe de Angelis
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum, München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.,Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, 85354 Freising, Germany.,German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Michael Bustin
- Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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36
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Kim BG, Hwang DH, Lee SI, Kim EJ, Kim SU. Stem Cell-Based Cell Therapy for Spinal Cord Injury. Cell Transplant 2017; 16:355-64. [PMID: 17658126 DOI: 10.3727/000000007783464885] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Traumatic injuries to the spinal cord lead to severe and permanent neurological deficits. Although no effective therapeutic option is currently available, recent animal studies have shown that cellular transplantation strategies hold promise to enhance functional recovery after spinal cord injury (SCI). This review is to analyze the experiments where transplantation of stem/progenitor cells produced successful functional outcome in animal models of SCI. There is no consensus yet on what kind of stem/progenitor cells is an ideal source for cellular grafts. Three kinds of stem/progenitor cells have been utilized in cell therapy in animal models of SCI: embryonic stem cells, bone marrow mesenchymal stem cells, and neural stem cells. Neural stem cells or fate-restricted neuronal or glial progenitor cells were preferably used because they have clear capacity to become neurons or glial cells after transplantation into the injured spinal cord. At least a part of functional deficits after SCI is attributable to chronic progressive demyelination. Therefore, several studies transplanted glial-restricted progenitors or oligodendrocyte precursors to target the demyelination process. Directed differentiation of stem/progenitor cells to oligodendrocyte lineage prior to transplantation or modulation of microenvironment in the injured spinal cord to promote oligodendroglial differentiation seems to be an effective strategy to increase the extent of remyelination. Transplanted stem/progenitor cells can also contribute to promoting axonal regeneration by functioning as cellular scaffolds for growing axons. Combinatorial approaches using polymer scaffolds to fill the lesion cavity or introducing regeneration-promoting genes will greatly increase the efficacy of cellular transplantation strategies for SCI.
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Affiliation(s)
- Byung Gon Kim
- Brain Disease Research Center, Ajou University School of Medicine, Suwon, 443-721, Republic of Korea
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37
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Abstract
Stem cells, especially neural stem cells (NSCs), are a very attractive cell source for potential reconstruction of injured spinal cord though either neuroprotection, neural regeneration, remyelination, replacement of lost neural cells, or reconnection of disrupted axons. The later have great potential since recent studies demonstrate long-distance growth and connectivity of axons derived from transplanted NSCs after spinal cord injury (SCI). In addition, transplanted NSCs constitute a permissive environment for host axonal regeneration and serve as new targets for host axonal connection. This reciprocal connection between grafted neurons and host neurons constitutes a neuronal relay formation that could restore functional connectivity after SCI.
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38
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Yang H, Liu C, Chen B, An J, Zhang R, Zhang Q, Zhao J, He B, Hao DJ. Efficient Generation of Functionally Active Spinal Cord Neurons from Spermatogonial Stem Cells. Mol Neurobiol 2017; 54:788-803. [PMID: 27566610 DOI: 10.1007/s12035-016-0057-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 08/15/2016] [Indexed: 12/21/2022]
Abstract
Neural stem cells (NSCs) are hitherto regarded as perspective candidates for cell transplantation in clinical therapies for multilevel spinal cord injury and function restoration. However, the extreme drawbacks of NSCs available for injury transplantation still represent a significant bottleneck in neural regeneration medicine. Therefore, it is essential to establish a suitable cell reservoir as an issue-free alternative. Here, we demonstrate that spermatogonial stem cells (SSCs) derived from rat testis robustly give rise to terminally differentiated, functionally mature spinal cord neurons by using an optimized differentiation protocol. After performing a 3-week in vitro differentiation procedure, most cells exhibited neural morphological features and were Tuj-1 positive. Of note, approximately 60 % of the obtained cells coexpressed choline acetyltransferase (CHAT), acetylcholinesterase (AchE), and calcitonin gene-related peptide (CGRP). More importantly, apart from acquisition of neural antigenic and biochemical properties, nearly all neurons efficiently exhibited in vitro functionality similar to wild-type neurons, such as synapse formation, increased neuronal calcium influx, and electrophysiology. This is the first report revealing consistent and reproducible generation of large amounts of functional neurons from SSCs. Collectively, this system is suitable for studies of SSC transdifferentiation into neuronal cells and can provide sufficient neurons for the treatment of spinal cord injury as well as for genetic and small molecule screenings.
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Affiliation(s)
- Hao Yang
- Shaanxi Spine Medicine Research Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China.
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China.
| | - Cuicui Liu
- Shaanxi Spine Medicine Research Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
| | - Bo Chen
- Shaanxi Spine Medicine Research Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
| | - Jing An
- Shaanxi Spine Medicine Research Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
| | - Rui Zhang
- Shaanxi Spine Medicine Research Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
| | - Qian Zhang
- Shaanxi Spine Medicine Research Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
| | - Jingjing Zhao
- Shaanxi Spine Medicine Research Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China
| | - Baorong He
- Shaanxi Spine Medicine Research Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China.
- Department of Spine Surgery, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China.
| | - Ding-Jun Hao
- Shaanxi Spine Medicine Research Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China.
- Department of Spine Surgery, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, 710054, China.
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Tedeschi A, Omura T, Costigan M. CNS repair and axon regeneration: Using genetic variation to determine mechanisms. Exp Neurol 2017; 287:409-422. [PMID: 27163547 PMCID: PMC5097896 DOI: 10.1016/j.expneurol.2016.05.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 05/02/2016] [Accepted: 05/05/2016] [Indexed: 10/21/2022]
Abstract
The importance of genetic diversity in biological investigation has been recognized since the pioneering studies of Gregor Johann Mendel and Charles Darwin. Research in this area has been greatly informed recently by the publication of genomes from multiple species. Genes regulate and create every part and process in a living organism, react with the environment to create each living form and morph and mutate to determine the history and future of each species. The regenerative capacity of neurons differs profoundly between animal lineages and within the mammalian central and peripheral nervous systems. Here, we discuss research that suggests that genetic background contributes to the ability of injured axons to regenerate in the mammalian central nervous system (CNS), by controlling the regulation of specific signaling cascades. We detail the methods used to identify these pathways, which include among others Activin signaling and other TGF-β superfamily members. We discuss the potential of altering these pathways in patients with CNS damage and outline strategies to promote regeneration and repair by combinatorial manipulation of neuron-intrinsic and extrinsic determinants.
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Affiliation(s)
- Andrea Tedeschi
- German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany.
| | - Takao Omura
- Department of Orthopaedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
| | - Michael Costigan
- FM Kirby Neurobiology Center and Anesthesia Department, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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40
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Shroff G. Transplantation of Human Embryonic Stem Cells in Patients with Multiple Sclerosis and Lyme Disease. AMERICAN JOURNAL OF CASE REPORTS 2016; 17:944-949. [PMID: 27956736 PMCID: PMC5156555 DOI: 10.12659/ajcr.899745] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Case series Patient: Male, 42 • Female, 30 Final Diagnosis: Human embryonic stem cells showed good therapeutic potential for treatment of multiple sclerosis with lyme disease Symptoms: Fatigue • weakness in limbs Medication: — Clinical Procedure: Human embryonic stem cells transplantation Specialty: Transplantology
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Affiliation(s)
- Geeta Shroff
- Department of Stem Cell Therapy, Nutech Mediworld, New Delhi, India
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41
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Abdul Wahid SF, Law ZK, Ismail NA, Azman Ali R, Lai NM. Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2016; 11:CD011742. [PMID: 27822919 PMCID: PMC6464737 DOI: 10.1002/14651858.cd011742.pub2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND) is a fatal disease associated with rapidly progressive disability, for which no definitive treatment as yet exists. Current treatment regimens largely focus on relieving symptoms to improve the quality of life of those affected. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND. OBJECTIVES To assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no additional treatment. SEARCH METHODS On 21 June 2016, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials' registries for ongoing or unpublished studies. SELECTION CRITERIA We planned to include randomised controlled trials (RCTs), quasi-RCTs and cluster RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowable, provided that they were given to each group equally. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. MAIN RESULTS No studies were eligible for inclusion in the review. We identified four ongoing trials. AUTHORS' CONCLUSIONS Currently, there is a lack of high-quality evidence to guide practice on the use of cell-based therapy to treat ALS/MND.We need large, prospective RCTs to establish the efficacy of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research should be to determine the appropriate cell source, phenotype, dose, and route of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.
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Affiliation(s)
| | - Zhe Kang Law
- Universiti Kebangsaan Malaysia Medical CentreDepartment of MedicineJalan Yaacob LatifBandar Tun RazakKuala LumpurMalaysia56000
| | - Nor Azimah Ismail
- Universiti Kebangsaan Malaysia Medical CentreCell Therapy CenterJalan Yaacob LatifKuala LumpurMalaysia56000
| | - Raymond Azman Ali
- Universiti Kebangsaan Malaysia Medical CentreNeurology Unit, Department of MedicineJalan Yaacob LatifBandar Tun RazakKuala LumpurMalaysia56000
| | - Nai Ming Lai
- Taylor's UniversitySchool of MedicineSubang JayaMalaysia
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Goldman SA. Stem and Progenitor Cell-Based Therapy of the Central Nervous System: Hopes, Hype, and Wishful Thinking. Cell Stem Cell 2016; 18:174-88. [PMID: 26849304 DOI: 10.1016/j.stem.2016.01.012] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
A variety of neurological disorders are attractive targets for stem and progenitor cell-based therapy. Yet many conditions are not, whether by virtue of an inhospitable disease environment, poorly understood pathophysiology, or poor alignment of donor cell capabilities with patient needs. Moreover, some disorders may be medically feasible targets but are not practicable, in light of already available treatments, poor risk-benefit and cost-benefit profiles, or resource limitations. This Perspective seeks to define those neurological conditions most appropriate for cell replacement therapy by considering its potential efficacy and clinical feasibility in those disorders, as well as potential impediments to its application.
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Affiliation(s)
- Steven A Goldman
- Center for Translational Neuromedicine and the Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Basic and Translational Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen 2200, Denmark.
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Gervois P, Wolfs E, Ratajczak J, Dillen Y, Vangansewinkel T, Hilkens P, Bronckaers A, Lambrichts I, Struys T. Stem Cell-Based Therapies for Ischemic Stroke: Preclinical Results and the Potential of Imaging-Assisted Evaluation of Donor Cell Fate and Mechanisms of Brain Regeneration. Med Res Rev 2016; 36:1080-1126. [DOI: 10.1002/med.21400] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 05/27/2016] [Accepted: 06/17/2016] [Indexed: 12/15/2022]
Affiliation(s)
- Pascal Gervois
- Morphology Research Group, Biomedical Research Institute, Hasselt University; Campus Diepenbeek; Bioville Diepenbeek Belgium
| | - Esther Wolfs
- Morphology Research Group, Biomedical Research Institute, Hasselt University; Campus Diepenbeek; Bioville Diepenbeek Belgium
| | - Jessica Ratajczak
- Morphology Research Group, Biomedical Research Institute, Hasselt University; Campus Diepenbeek; Bioville Diepenbeek Belgium
| | - Yörg Dillen
- Morphology Research Group, Biomedical Research Institute, Hasselt University; Campus Diepenbeek; Bioville Diepenbeek Belgium
| | - Tim Vangansewinkel
- Morphology Research Group, Biomedical Research Institute, Hasselt University; Campus Diepenbeek; Bioville Diepenbeek Belgium
| | - Petra Hilkens
- Morphology Research Group, Biomedical Research Institute, Hasselt University; Campus Diepenbeek; Bioville Diepenbeek Belgium
| | - Annelies Bronckaers
- Morphology Research Group, Biomedical Research Institute, Hasselt University; Campus Diepenbeek; Bioville Diepenbeek Belgium
| | - Ivo Lambrichts
- Morphology Research Group, Biomedical Research Institute, Hasselt University; Campus Diepenbeek; Bioville Diepenbeek Belgium
| | - Tom Struys
- Morphology Research Group, Biomedical Research Institute, Hasselt University; Campus Diepenbeek; Bioville Diepenbeek Belgium
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Mitra SS, Feroze AH, Gholamin S, Richard C, Esparza R, Zhang M, Azad TD, Alrfaei B, Kahn SA, Hutter G, Guzman R, Creasey GH, Plant GW, Weissman IL, Edwards MSB, Cheshier S. Neural Placode Tissue Derived From Myelomeningocele Repair Serves as a Viable Source of Oligodendrocyte Progenitor Cells. Neurosurgery 2016. [PMID: 26225855 DOI: 10.1227/neu.0000000000000918] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND The presence, characteristics, and potential clinical relevance of neural progenitor populations within the neural placodes of myelomeningocele patients remain to be studied. Neural stem cells are known to reside adjacent to ependyma-lined surfaces along the central nervous system axis. OBJECTIVE Given such neuroanatomic correlation and regenerative capacity in fetal development, we assessed myelomeningocele-derived neural placode tissue as a potentially novel source of neural stem and progenitor cells. METHODS Nonfunctional neural placode tissue was harvested from infants during the surgical repair of myelomeningocele and subsequently further analyzed by in vitro studies, flow cytometry, and immunofluorescence. To assess lineage potential, neural placode-derived neurospheres were subjected to differential media conditions. Through assessment of platelet-derived growth factor receptor α (PDGFRα) and CD15 cell marker expression, Sox2+Olig2+ putative oligodendrocyte progenitor cells were successfully isolated. RESULTS PDGFRαCD15 cell populations demonstrated the highest rate of self-renewal capacity and multipotency of cell progeny. Immunofluorescence of neural placode-derived neurospheres demonstrated preferential expression of the oligodendrocyte progenitor marker, CNPase, whereas differentiation to neurons and astrocytes was also noted, albeit to a limited degree. CONCLUSION Neural placode tissue contains multipotent progenitors that are preferentially biased toward oligodendrocyte progenitor cell differentiation and presents a novel source of such cells for use in the treatment of a variety of pediatric and adult neurological disease, including spinal cord injury, multiple sclerosis, and metabolic leukoencephalopathies.
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Affiliation(s)
- Siddhartha S Mitra
- ‡Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California; §Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California; ¶Department of Neurosurgery, VA Palo Alto Health Care System, Stanford University School of Medicine, Palo Alto, California; ∥Department of Neurological Surgery, University of Washington, Seattle, Washington
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Doulames VM, Plant GW. Induced Pluripotent Stem Cell Therapies for Cervical Spinal Cord Injury. Int J Mol Sci 2016; 17:530. [PMID: 27070598 PMCID: PMC4848986 DOI: 10.3390/ijms17040530] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 03/17/2016] [Accepted: 03/28/2016] [Indexed: 02/07/2023] Open
Abstract
Cervical-level injuries account for the majority of presented spinal cord injuries (SCIs) to date. Despite the increase in survival rates due to emergency medicine improvements, overall quality of life remains poor, with patients facing variable deficits in respiratory and motor function. Therapies aiming to ameliorate symptoms and restore function, even partially, are urgently needed. Current therapeutic avenues in SCI seek to increase regenerative capacities through trophic and immunomodulatory factors, provide scaffolding to bridge the lesion site and promote regeneration of native axons, and to replace SCI-lost neurons and glia via intraspinal transplantation. Induced pluripotent stem cells (iPSCs) are a clinically viable means to accomplish this; they have no major ethical barriers, sources can be patient-matched and collected using non-invasive methods. In addition, the patient’s own cells can be used to establish a starter population capable of producing multiple cell types. To date, there is only a limited pool of research examining iPSC-derived transplants in SCI—even less research that is specific to cervical injury. The purpose of the review herein is to explore both preclinical and clinical recent advances in iPSC therapies with a detailed focus on cervical spinal cord injury.
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Affiliation(s)
- Vanessa M Doulames
- Stanford Partnership for Spinal Cord Injury and Repair, Department of Neurosurgery, Stanford University School of Medicine, 265 Campus Drive Stanford, California, CA 94305, USA.
| | - Giles W Plant
- Stanford Partnership for Spinal Cord Injury and Repair, Department of Neurosurgery, Stanford University School of Medicine, 265 Campus Drive Stanford, California, CA 94305, USA.
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Bianco J, De Berdt P, Deumens R, des Rieux A. Taking a bite out of spinal cord injury: do dental stem cells have the teeth for it? Cell Mol Life Sci 2016; 73:1413-37. [PMID: 26768693 PMCID: PMC11108394 DOI: 10.1007/s00018-015-2126-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 12/16/2015] [Accepted: 12/22/2015] [Indexed: 12/15/2022]
Abstract
Dental stem cells are an emerging star on a stage that is already quite populated. Recently, there has been a lot of hype concerning these cells in dental therapies, especially in regenerative endodontics. It is fitting that most research is concentrated on dental regeneration, although other uses for these cells need to be explored in more detail. Being a true mesenchymal stem cell, their capacities could also prove beneficial in areas outside their natural environment. One such field is the central nervous system, and in particular, repairing the injured spinal cord. One of the most formidable challenges in regenerative medicine is to restore function to the injured spinal cord, and as yet, a cure for paralysis remains to be discovered. A variety of approaches have already been tested, with graft-based strategies utilising cells harbouring appropriate properties for neural regeneration showing encouraging results. Here we present a review focusing on properties of dental stem cells that endorse their use in regenerative medicine, with particular emphasis on repairing the damaged spinal cord.
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Affiliation(s)
- John Bianco
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier, 73, B1 73.12, 1200, Brussels, Belgium.
- Integrated Center for Cell Therapy and Regenerative Medicine, International Clinical Research Center (FNUSA-ICRC), St. Anne's University Hospital Brno, Pekařská 53, 656 91, Brno, Czech Republic.
| | - Pauline De Berdt
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier, 73, B1 73.12, 1200, Brussels, Belgium
| | - Ronald Deumens
- Institute of Neuroscience, Université catholique de Louvain, Avenue Hippocrate B1.54.10, 1200, Brussels, Belgium
| | - Anne des Rieux
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier, 73, B1 73.12, 1200, Brussels, Belgium
- Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, 1348, Louvain-La-Neuve, Belgium
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Goel A. Stem cell therapy in spinal cord injury: Hollow promise or promising science? JOURNAL OF CRANIOVERTEBRAL JUNCTION AND SPINE 2016; 7:121-6. [PMID: 27217662 PMCID: PMC4872563 DOI: 10.4103/0974-8237.181880] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Spinal cord injury (SCI) remains one of the most physically, psychologically and socially debilitating conditions worldwide. While rehabilitation measures may help limit disability to some extent, there is no effective primary treatment yet available. The efficacy of stem cells as a primary therapeutic option in spinal cord injury is currently an area under much scrutiny and debate. Several laboratory and some primary clinical studies into the use of bone marrow mesenchymal stem cells or embryonic stem cell-derived oligodentrocyte precursor cells have shown some promising results in terms of remyelination and regeneration of damaged spinal nerve tracts. More recently,laboratory and early clinical experiments into the use of Olfactory Ensheathing Cells, a type of glial cell derived from olfactory bulb and mucosa have provided some phenomenal preliminary evidence as to their neuroregenerative and neural bridging capacity. This report compares and evaluates some current research into selected forms of embryonic and mesenchymal stem cell therapy as well as olfactory ensheathing cell therapy in SCI, and also highlights some legal and ethical issues surrounding their use. While early results shows promise, more rigorous large scaleclinical trials are needed to shed light on the safety, efficacy and long term viability of stem cell and cellular transplant techniques in SCI.
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Affiliation(s)
- Aimee Goel
- 4 year Medical Student, University College London, London, United Kingdom
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48
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Yang H, Qiu Y, Zeng X, Ding Y, Zeng J, Lu K, Li D. Effect of a feeder layer composed of mouse embryonic and human foreskin fibroblasts on the proliferation of human embryonic stem cells. Exp Ther Med 2016; 11:2321-2328. [PMID: 27313670 DOI: 10.3892/etm.2016.3204] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 10/29/2015] [Indexed: 12/14/2022] Open
Abstract
The aim of the present study was to investigate the effects of feeder layers composed of various ratios of mouse embryonic fibroblasts (MEFs) and human foreskin fibroblasts (hFFs) on the growth of human embryonic stem cells (hESCs). In addition, the secretion levels of basic fibroblast growth factor (bFGF) by the feeder layers was detected. MEFs and hFFs were treated with mitomycin C and seeded onto gelatin-coated plates at a density of 1×108 cells/l. The hFFs and MEFs were combined and plated at the following ratios: 0:1, 1:2, 1:1, 2:1 and 1:0. The secretion of bFGF by the various hFF/MEF ratio feeder layers was detected using an enzyme-linked immunosorbent assay. Subsequently, hESCs were cultured on top of the various feeder layers. The differences in the cellular morphology of the hESCs were observed using microscopy, and the expression levels alkaline phosphatase (AKP) and octamer-binding transcription factor 4 (OCT-4) were detected using immunohistochemical analysis as indicators of differentiation status. The results showed that the hFFs secreted substantial quantities of bFGF, while no bFGF was secreted by the MEFs. The clones of hESC growing on the feeder layer containing MEF or hFF alone were flat. By contrast, hESC clones grown on a mixed feeder layer containing hFFs + MEFs at a ratio of 1:1 exhibited an accumulated growth with a clear edge, as compared with the other ratios. In addition, hESCs growing on the feeder layer were positive for the expression of AKP and OCT-4. In summary, feeder layer hFFs secreted bFGF, while MEFs did not, indicating that bFGF is not the only factor that supports the growth and differentiation of hESCs. The optimal growth of hESCs was achieved using a mixed feeder layer composed of hFFs + MEFs at a ratio of 1:1.
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Affiliation(s)
- Hua Yang
- Reproductive Medical Center of Nanning Second People's Hospital, Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530031, P.R. China; State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Animal Reproduction Institute, Guangxi University, Nanning, Guangxi 530004, P.R. China
| | - Ying Qiu
- Reproductive Medical Center of Nanning Second People's Hospital, Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530031, P.R. China
| | - Xianghui Zeng
- Reproductive Medical Center of Nanning Second People's Hospital, Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530031, P.R. China
| | - Yan Ding
- Life Science Research Institute, Taihe Hospital, Shiyan, Hubei 442000, P.R. China
| | - Jianye Zeng
- Reproductive Medical Center of Nanning Second People's Hospital, Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530031, P.R. China
| | - Kehuan Lu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Animal Reproduction Institute, Guangxi University, Nanning, Guangxi 530004, P.R. China
| | - Dongsheng Li
- Life Science Research Institute, Taihe Hospital, Shiyan, Hubei 442000, P.R. China
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Ye JC, Qin Y, Wu YF, Wang P, Tang Y, Huang L, Ma MJ, Zeng YS, Shen HY. Using primate neural stem cells cultured in self-assembling peptide nanofiber scaffolds to repair injured spinal cords in rats. Spinal Cord 2016; 54:933-941. [PMID: 27001129 DOI: 10.1038/sc.2016.36] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 01/18/2016] [Accepted: 02/16/2016] [Indexed: 12/29/2022]
Abstract
STUDY DESIGN Transplanted primates' neural stem cells (NSCs) tissue engineering complex into spinal cord injury (SCI) model rats, analyze and evaluate the long-term effects of repairing. OBJECTIVES Primate NSCs were cultured in self-assembling peptide nanofiber scaffolds to repair SCI. SETTING Sun Yat-sen Memorial Hospital, Guangzhou, China. METHODS Primate NSCs were isolated and cultured in self-assembling peptide nanofiber scaffolds. T10 SCI model was established; the rats were randomly divided into four groups: NSC plus self-assembling peptide scaffold group; NSC group; self-assembling peptide scaffold group; and control group. Immunohistochemical staining and electronic microscope were used to investigate the growth and differentiation of transplanted NSCs. The motor function of the hind limbs of rats was evaluated (P<0.05 was considered as statistically significant). RESULTS NSCs and NSCs cultured in self-assembling peptide nanofiber scaffolds could be induced to differentiation into neurons, glial cells and oligodendrocytes in vitro. The primate NSC culture was established in self-assembling peptide scaffolds. No significant difference was seen in the differentiation rate between primate NSCs cultured in self-assembling peptide nanofiber scaffolds and primate NSCs cultured in regular medium. The motor function of the hind limbs in the NSC plus self-assembling peptide scaffold group was significantly better than that of the other three groups. In addition, the NSCs of the NSC group mainly differentiated into astrocytes. CONCLUSION Transplantation of primate NSCs cultured in self-assembling peptide scaffolds is efficient for repairing the injured spinal cord and for improving the motor function of spinal cord in rats. SPONSORSHIP The National Natural Science Foundation of China; Science and Technology Office of Guangdong Province.
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Affiliation(s)
- J-C Ye
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou China
| | - Y Qin
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou China.,Department of Orthopedics, Zhuhai People's Hospital, Zhuhai, China
| | - Y-F Wu
- Biotherapy Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - P Wang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou China
| | - Y Tang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou China
| | - L Huang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou China
| | - M-J Ma
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou China
| | - Y-S Zeng
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - H-Y Shen
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou China
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