|
1
|
Singh CSB, Johns KM, Kari S, Munro L, Mathews A, Fenninger F, Pfeifer CG, Jefferies WA. Conclusive demonstration of iatrogenic Alzheimer's disease transmission in a model of stem cell transplantation. Stem Cell Reports 2024; 19:456-468. [PMID: 38552634 PMCID: PMC11096610 DOI: 10.1016/j.stemcr.2024.02.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 02/27/2024] [Accepted: 02/28/2024] [Indexed: 04/12/2024] Open
Abstract
The risk of iatrogenic disease is often underestimated as a concern in contemporary medical procedures, encompassing tissue and organ transplantation, stem cell therapies, blood transfusions, and the administration of blood-derived products. In this context, despite the prevailing belief that Alzheimer's disease (AD) manifests primarily in familial and sporadic forms, our investigation reveals an unexpected transplantable variant of AD in a preclinical context, potentially indicating iatrogenic transmission in AD patients. Through adoptive transplantation of donor bone marrow stem cells carrying a mutant human amyloid precursor protein (APP) transgene into either APP-deficient knockout or normal recipient animals, we observed rapid development of AD pathological hallmarks. These pathological features were significantly accelerated and emerged within 6-9 months post transplantation and included compromised blood-brain barrier integrity, heightened cerebral vascular neoangiogenesis, elevated brain-associated β-amyloid levels, and cognitive impairment. Furthermore, our findings underscore the contribution of β-amyloid burden originating outside of the central nervous system to AD pathogenesis within the brain. We conclude that stem cell transplantation from donors harboring a pathogenic mutant allele can effectively transfer central nervous system diseases to healthy recipients, mirroring the pathogenesis observed in the donor. Consequently, our observations advocate for genomic sequencing of donor specimens prior to tissue, organ, or stem cell transplantation therapies, as well as blood transfusions and blood-derived product administration, to mitigate the risk of iatrogenic diseases.
Collapse
Affiliation(s)
- Chaahat S B Singh
- Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada; The Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada
| | - Kelly Marie Johns
- Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada; The Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada
| | - Suresh Kari
- Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada; The Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada
| | - Lonna Munro
- Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada; The Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z4, Canada
| | - Angela Mathews
- Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada; The Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada
| | - Franz Fenninger
- Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada; The Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada
| | - Cheryl G Pfeifer
- Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada; The Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z4, Canada
| | - Wilfred A Jefferies
- Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada; The Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; Department of Zoology, University of British Columbia, 6270 University Boulevard, Vancouver, BC V6T 1Z4, Canada; Department of Urologic Sciences, University of British Columbia, Level 6, 2775 Laurel Street, Vancouver, BC V5Z 1M9 Canada.
| |
Collapse
|
|
2
|
Daadi EW, Daadi ES, Oh T, Li M, Kim J, Daadi MM. Combining physical & cognitive training with iPSC-derived dopaminergic neuron transplantation promotes graft integration & better functional outcome in parkinsonian marmosets. Exp Neurol 2024; 374:114694. [PMID: 38272159 DOI: 10.1016/j.expneurol.2024.114694] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/09/2024] [Accepted: 01/15/2024] [Indexed: 01/27/2024]
Abstract
Parkinson's disease (PD) is a relentlessly progressive and currently incurable neurodegenerative disease with significant unmet medical needs. Since PD stems from the degeneration of midbrain dopaminergic (DA) neurons in a defined brain location, PD patients are considered optimal candidates for cell replacement therapy. Clinical trials for cell transplantation in PD are beginning to re-emerge worldwide with a new focus on induced pluripotent stem cells (iPSCs) as a source of DA neurons since they can be derived from adult somatic cells and produced in large quantities under current good manufacturing practices. However, for this therapeutic strategy to be realized as a viable clinical option, fundamental translational challenges need to be addressed including the manufacturing process, purity and efficacy of the cells, the method of delivery, the extent of host reinnervation and the impact of patient-centered adjunctive interventions. In this study we report on the impact of physical and cognitive training (PCT) on functional recovery in the nonhuman primate (NHP) model of PD after cell transplantation. We observed that at 6 months post-transplant, the PCT group returned to normal baseline in their daily activity measured by actigraphy, significantly improved in their sensorimotor and cognitive tasks, and showed enhanced synapse formation between grafted cells and host cells. We also describe a robust, simple, efficient, scalable, and cost-effective manufacturing process of engraftable DA neurons derived from iPSCs. This study suggests that integrating PCT with cell transplantation therapy could promote optimal graft functional integration and better outcome for patients with PD.
Collapse
Affiliation(s)
- Etienne W Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX 78227, USA
| | - Elyas S Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX 78227, USA
| | - Thomas Oh
- Southwest National Primate Research Center, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX 78227, USA
| | - Mingfeng Li
- Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
| | - Jeffrey Kim
- Southwest National Primate Research Center, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX 78227, USA; Department of Cell Systems & Anatomy, Long School of Medicine, University of Texas Health at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA
| | - Marcel M Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX 78227, USA; Department of Cell Systems & Anatomy, Long School of Medicine, University of Texas Health at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA; Department of Radiology, Long School of Medicine, University of Texas Health at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA.
| |
Collapse
|
|
3
|
Emborg ME, Gambardella JC, Zhang A, Federoff HJ. Autologous vs heterologous cell replacement strategies for Parkinson disease and other neurologic diseases. HANDBOOK OF CLINICAL NEUROLOGY 2024; 205:41-56. [PMID: 39341662 DOI: 10.1016/b978-0-323-90120-8.00010-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Successful cell replacement strategies for brain repair depend on graft integration into the neural network, which is affected by the immune response to the grafted cells. Using Parkinson disease as an example, in this chapter, we consider the immune system interaction and its role in autologous vs heterologous graft survival and integration, as well as past and emerging strategies to overcome the immunologic response. We also reflect on the role of nonhuman primate research to assess novel approaches and consider the role of different stakeholders on advancing the most promising new approaches into the clinic.
Collapse
Affiliation(s)
- Marina E Emborg
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, United States; Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, United States; Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, United States.
| | - Julia C Gambardella
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, United States; Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, United States
| | - Ai Zhang
- Aspen Neuroscience, San Diego, CA, United States
| | - Howard J Federoff
- Kenai Therapeutics, San Diego, CA, United States; Georgetown University Medical Center, Georgetown, Washington, DC, United States
| |
Collapse
|
|
4
|
Yeap YJ, Teddy TJW, Lee MJ, Goh M, Lim KL. From 2D to 3D: Development of Monolayer Dopaminergic Neuronal and Midbrain Organoid Cultures for Parkinson's Disease Modeling and Regenerative Therapy. Int J Mol Sci 2023; 24:ijms24032523. [PMID: 36768843 PMCID: PMC9917335 DOI: 10.3390/ijms24032523] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023] Open
Abstract
Parkinson's Disease (PD) is a prevalent neurodegenerative disorder that is characterized pathologically by the loss of A9-specific dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Despite intensive research, the etiology of PD is currently unresolved, and the disease remains incurable. This, in part, is due to the lack of an experimental disease model that could faithfully recapitulate the features of human PD. However, the recent advent of induced pluripotent stem cell (iPSC) technology has allowed PD models to be created from patient-derived cells. Indeed, DA neurons from PD patients are now routinely established in many laboratories as monolayers as well as 3D organoid cultures that serve as useful toolboxes for understanding the mechanism underlying PD and also for drug discovery. At the same time, the iPSC technology also provides unprecedented opportunity for autologous cell-based therapy for the PD patient to be performed using the patient's own cells as starting materials. In this review, we provide an update on the molecular processes underpinning the development and differentiation of human pluripotent stem cells (PSCs) into midbrain DA neurons in both 2D and 3D cultures, as well as the latest advancements in using these cells for drug discovery and regenerative medicine. For the novice entering the field, the cornucopia of differentiation protocols reported for the generation of midbrain DA neurons may seem daunting. Here, we have distilled the essence of the different approaches and summarized the main factors driving DA neuronal differentiation, with the view to provide a useful guide to newcomers who are interested in developing iPSC-based models of PD.
Collapse
Affiliation(s)
- Yee Jie Yeap
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
| | - Tng J. W. Teddy
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
- Interdisciplinary Graduate Programme (IGP-Neuroscience), Nanyang Technological University, Singapore 639798, Singapore
| | - Mok Jung Lee
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
| | - Micaela Goh
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
| | - Kah Leong Lim
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
- National Neuroscience Institute, Singapore 308433, Singapore
- Department of Brain Sciences, Imperial College London, London SW7 2AZ, UK
- Department of Anatomy, Shanxi Medical University, Taiyuan 030001, China
- Correspondence:
| |
Collapse
|
|
5
|
Pant T, Juric M, Bosnjak ZJ, Dhanasekaran A. Recent Insight on the Non-coding RNAs in Mesenchymal Stem Cell-Derived Exosomes: Regulatory and Therapeutic Role in Regenerative Medicine and Tissue Engineering. Front Cardiovasc Med 2021; 8:737512. [PMID: 34660740 PMCID: PMC8517144 DOI: 10.3389/fcvm.2021.737512] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 09/06/2021] [Indexed: 12/13/2022] Open
Abstract
Advances in the field of regenerative medicine and tissue engineering over the past few decades have paved the path for cell-free therapy. Numerous stem cell types, including mesenchymal stem cells (MSCs), have been reported to impart therapeutic effects via paracrine secretion of exosomes. The underlying factors and the associated mechanisms contributing to these MSC-derived exosomes' protective effects are, however, poorly understood, limiting their application in the clinic. The exosomes exhibit a diversified repertoire of functional non-coding RNAs (ncRNAs) and have the potential to transfer these biologically active transcripts to the recipient cells, where they are found to modulate a diverse array of functions. Altered expression of the ncRNAs in the exosomes has been linked with the regenerative potential and development of various diseases, including cardiac, neurological, skeletal, and cancer. Also, modulating the expression of ncRNAs in these exosomes has been found to improve their therapeutic impact. Moreover, many of these ncRNAs are expressed explicitly in the MSC-derived exosomes, making them ideal candidates for regenerative medicine, including tissue engineering research. In this review, we detail the recent advances in regenerative medicine and summarize the evidence supporting the altered expression of the ncRNA repertoire specific to MSCs under different degenerative diseases. We also discuss the therapeutic role of these ncRNA for the prevention of these various degenerative diseases and their future in translational medicine.
Collapse
Affiliation(s)
- Tarun Pant
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Matea Juric
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Zeljko J. Bosnjak
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States
| | | |
Collapse
|
|
6
|
Borlongan MC, Farooq J, Sadanandan N, Wang ZJ, Cozene B, Lee JY, Steinberg GK. Stem Cells for Aging-Related Disorders. Stem Cell Rev Rep 2021; 17:2054-2058. [PMID: 34374944 DOI: 10.1007/s12015-021-10222-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2021] [Indexed: 12/25/2022]
Abstract
This review captures recent advances in biological and translational research on stem cells. In particular, we discuss new discoveries and concepts regarding stem cell treatment of aging-related disorders. A myriad of stem cell sources exists, from hematopoietic to mesenchymal and neural cell lineages. We examine current applications of exogenous adult bone marrow-derived stem cells as an effective and safe transplantable cell source, as well as the use of electrical stimulation to promote endogenous neurogenesis for Parkinson's disease. We also explore the potential of transplanting exogenous umbilical cord blood cells and mobilizing host resident stem cells in vascular dementia and aging. In addition, we assess the ability of small molecules to recruit resident stem cells in Alzheimer's disease. Finally, we evaluate mechanisms of action recently implicated in stem cell therapy, such as the role of long non-coding RNAs, G-protein coupled receptor 5, and NeuroD1. Our goal is to provide a synopsis of recent milestones regarding the application of stem cells in aging.
Collapse
Affiliation(s)
- Mia C Borlongan
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA
| | - Jeffrey Farooq
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA
| | - Nadia Sadanandan
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA
| | - Zhen-Jie Wang
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA
| | - Blaise Cozene
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA
| | - Jea-Young Lee
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA
| | - Gary K Steinberg
- Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA, 94305, USA.
| |
Collapse
|
|
7
|
Aishwarya L, Arun D, Kannan S. Stem cells as a potential therapeutic option for treating neurodegenerative diseases. Curr Stem Cell Res Ther 2021; 17:590-605. [PMID: 35135464 DOI: 10.2174/1574888x16666210810105136] [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: 02/25/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 11/22/2022]
Abstract
In future, neurodegenerative diseases will take over cancer's place and become the major cause of death in the world, especially in developed countries. Advancements in the medical field and its facilities have led to an increase in the old age population, and thus contributing to the increase in number of people suffering from neurodegenerative diseases. Economically it is of a great burden to society and the affected family. No current treatment aims to replace, protect, and regenerate lost neurons; instead, it alleviates the symptoms, extends the life span by a few months and creates severe side effects. Moreover, people who are affected are physically dependent for performing their basic activities, which makes their life miserable. There is an urgent need for therapy that could be able to overcome the deficits of conventional therapy for neurodegenerative diseases. Stem cells, the unspecialized cells with the properties of self-renewing and potency to differentiate into various cells types can become a potent therapeutic option for neurodegenerative diseases. Stem cells have been widely used in clinical trials to evaluate their potential in curing different types of ailments. In this review, we discuss the various types of stem cells and their potential use in the treatment of neurodegenerative disease based on published preclinical and clinical studies.
Collapse
Affiliation(s)
- Aishwarya L
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Chennai-600 116. India
| | - Dharmarajan Arun
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Chennai-600 116. India
| | - Suresh Kannan
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Chennai-600 116. India
| |
Collapse
|
|
8
|
Ahani-Nahayati M, Shariati A, Mahmoodi M, Olegovna Zekiy A, Javidi K, Shamlou S, Mousakhani A, Zamani M, Hassanzadeh A. Stem cell in neurodegenerative disorders; an emerging strategy. Int J Dev Neurosci 2021; 81:291-311. [PMID: 33650716 DOI: 10.1002/jdn.10101] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/13/2021] [Accepted: 02/24/2021] [Indexed: 01/28/2023] Open
Abstract
Neurodegenerative disorders are a diversity of disorders, surrounding Alzheimer's (AD), Parkinson's (PD), Huntington's diseases (HD), and amyotrophic lateral sclerosis (ALS) accompanied by some other less common diseases generally characterized by either developed deterioration of central or peripheral nervous system structurally or functionally. Today, with the viewpoint of an increasingly aging society, the number of patients with neurodegenerative diseases and sociomedical burdens will spread intensely. During the last decade, stem cell technology has attracted great attention for treating neurodegenerative diseases worldwide because of its unique attributes. As acknowledged, there are several categories of stem cells being able to proliferate and differentiate into various cellular lineages, highlighting their significance in the context of regenerative medicine. In preclinical models, stem cell therapy using mesenchymal stem/stromal cells (MSCs), hematopoietic stem cells (HSCs), and neural progenitor or stem cells (NPCs or NSCs) along with pluripotent stem cells (PSCs)-derived neuronal cells could elicit desired therapeutic effects, enabling functional deficit rescue partially. Regardless of the noteworthy progress in our scientific awareness and understanding of stem cell biology, there still exist various challenges to defeat. In the present review, we provide a summary of the therapeutic potential of stem cells and discuss the current status and prospect of stem cell strategy in neurodegenerative diseases, in particular, AD, PD, ALS, and HD.
Collapse
Affiliation(s)
- Milad Ahani-Nahayati
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Ali Shariati
- Stem Cell Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Mahnaz Mahmoodi
- Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Angelina Olegovna Zekiy
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Kamran Javidi
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.,Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Shamlou
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Akbar Mousakhani
- Department of Plant Sciences, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Neurosciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
9
|
Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys. Nat Med 2021; 27:632-639. [PMID: 33649496 DOI: 10.1038/s41591-021-01257-1] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 01/21/2021] [Indexed: 12/11/2022]
Abstract
Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson's disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD1. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues1,2. Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.
Collapse
|
|
10
|
Hadi F, Akrami H, Totonchi M, Barzegar A, Nabavi SM, Shahpasand K. α-synuclein abnormalities trigger focal tau pathology, spreading to various brain areas in Parkinson disease. J Neurochem 2021; 157:727-751. [PMID: 33264426 DOI: 10.1111/jnc.15257] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 07/28/2020] [Accepted: 11/30/2020] [Indexed: 12/21/2022]
Abstract
Parkinson disease (PD) is the second most common neurodegenerative disorder, whose prevalence is 2~3% in the population over 65. α-Synuclein aggregation is the major pathological hallmark of PD. However, recent studies have demonstrated enhancing evidence of tau pathology in PD. Despite extensive considerations, thus far, the actual spreading mechanism of neurodegeneration has remained elusive in a PD brain. This study aimed to further investigate the development of α-synuclein and tau pathology. We employed various PD models, including cultured neurons treated with either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or with recombinant α-synuclein. Also, we studied dopaminergic neurons of cytokine Interferon-β knock-out. Moreover, we examined rats treated with 6-hydroxydopamine, Rhesus monkeys administrated with MPTP neurotoxin, and finally, human post-mortem brains. We found the α-synuclein phosphorylation triggers tau pathogenicity. Also, we observed more widespread phosphorylated tau than α-synuclein with prion-like nature in various brain areas. We optionally removed P-tau or P-α-synuclein from cytokine interferon-β knock out with respective monoclonal antibodies. We found that tau immunotherapy suppressed neurodegeneration more than α-synuclein elimination. Our findings indicate that the pathogenic tau could be one of the leading causes of comprehensive neurodegeneration triggered by PD. Thus, we can propose an efficient therapeutic target to fight the devastating disorder.
Collapse
Affiliation(s)
- Fatemeh Hadi
- Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran
| | - Hassan Akrami
- Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran
| | - Mehdi Totonchi
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute, ACECR, Tehran, Iran
| | | | - Seyed Massood Nabavi
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute, ACECR, Tehran, Iran
| | - Koorosh Shahpasand
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute, ACECR, Tehran, Iran
| |
Collapse
|
|
11
|
Domingues AV, Pereira IM, Vilaça-Faria H, Salgado AJ, Rodrigues AJ, Teixeira FG. Glial cells in Parkinson´s disease: protective or deleterious? Cell Mol Life Sci 2020; 77:5171-5188. [PMID: 32617639 PMCID: PMC11104819 DOI: 10.1007/s00018-020-03584-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 05/25/2020] [Accepted: 06/22/2020] [Indexed: 02/06/2023]
Abstract
Glial cells have been identified more than 100 years ago, and are known to play a key role in the central nervous system (CNS) function. A recent piece of evidence is emerging showing that in addition to the capacity of CNS modulation and homeostasis, glial cells are also being looked like as a promising cell source not only to study CNS pathologies initiation and progression but also to the establishment and development of new therapeutic strategies. Thus, in the present review, we will discuss the current evidence regarding glial cells' contribution to neurodegenerative diseases as Parkinson's disease, providing cellular, molecular, functional, and behavioral data supporting its active role in disease initiation, progression, and treatment. As so, considering their functional relevance, glial cells may be important to the understanding of the underlying mechanisms regarding neuronal-glial networks in neurodegeneration/regeneration processes, which may open new research opportunities for their future use as a target or treatment in human clinical trials.
Collapse
Affiliation(s)
- Ana V Domingues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Laboratory, Braga/Guimarães, Portugal
| | - Inês M Pereira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Laboratory, Braga/Guimarães, Portugal
| | - Helena Vilaça-Faria
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Laboratory, Braga/Guimarães, Portugal
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's Associate Lab, PT Government Associated Laboratory, Braga/Guimarães, Portugal
| | - Ana J Rodrigues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
- ICVS/3B's Associate Lab, PT Government Associated Laboratory, Braga/Guimarães, Portugal.
| | - Fábio G Teixeira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
- ICVS/3B's Associate Lab, PT Government Associated Laboratory, Braga/Guimarães, Portugal.
| |
Collapse
|
|
12
|
Zhao S, Duan K, Ai Z, Niu B, Chen Y, Kong R, Li T. Generation of cortical neurons through large-scale expanding neuroepithelial stem cell from human pluripotent stem cells. Stem Cell Res Ther 2020; 11:431. [PMID: 33008480 PMCID: PMC7532602 DOI: 10.1186/s13287-020-01939-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/22/2020] [Accepted: 09/17/2020] [Indexed: 02/08/2023] Open
Abstract
Background Considerable progress has been made in converting human pluripotent stem cells (hPSCs) into cortical neurons for disease modeling and regenerative medicine. However, these procedures are hard to provide sufficient cells for their applications. Using a combination of small-molecules and growth factors, we previously identified one condition which can rapidly induce hPSCs into neuroepithelial stem cells (NESCs). Here, we developed a scalable suspension culture system, which largely yields high-quality NESC-spheres and subsequent cortical neurons. Methods The NESC medium was first optimized, and the suspension culture system was then enlarged from plates to stirred bioreactors for large-scale production of NESC-spheres by a stirring speed of 60 rpm. During the expansion, the quality of NESC-spheres was evaluated. The differentiation potential of NESC-spheres into cortical neurons was demonstrated by removing bFGF and two pathway inhibitors from the NESC medium. Cellular immunofluorescence staining, global transcriptome, and single-cell RNA sequencing analysis were used to identify the characteristics, identities, purities, or homogeneities of NESC-spheres or their differentiated cells, respectively. Results The optimized culture system is more conducive to large-scale suspension production of NESCs. These largely expanded NESC-spheres maintain unlimited self-renewal ability and NESC state by retaining their uniform sizes, high cell vitalities, and robust expansion abilities. After long-term expansion, NESC-spheres preserve high purity, homogeneity, and normal diploid karyotype. These expanded NESC-spheres on a large scale have strong differentiation potential and effectively produce mature cortical neurons. Conclusions We developed a serum-free, defined, and low-cost culture system for large-scale expansion of NESCs in stirred suspension bioreactors. The stable and controllable 3D system supports long-term expansion of high-quality and homogeneous NESC-spheres. These NESC-spheres can be used to efficiently give rise to cortical neurons for cell therapy, disease modeling, and drug screening in future.
Collapse
Affiliation(s)
- Shumei Zhao
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
| | - Kui Duan
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
| | - Zongyong Ai
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
| | - Baohua Niu
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
| | - Yanying Chen
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
| | - Ruize Kong
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
| | - Tianqing Li
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China. .,Xi'an ChaoYue Stem Cell Co, Ltd, Xi'an, China.
| |
Collapse
|
|
13
|
Mateus JM, Ribeiro FF, Alonso-Gomes M, Rodrigues RS, Marques JM, Sebastião AM, Rodrigues RJ, Xapelli S. Neurogenesis and Gliogenesis: Relevance of Adenosine for Neuroregeneration in Brain Disorders. J Caffeine Adenosine Res 2019. [DOI: 10.1089/caff.2019.0010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Joana M. Mateus
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Filipa F. Ribeiro
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Marta Alonso-Gomes
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Rui S. Rodrigues
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Joana M. Marques
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
- Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Ana M. Sebastião
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Ricardo J. Rodrigues
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
- Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Sara Xapelli
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| |
Collapse
|
|
14
|
Cho IK, Hunter CE, Ye S, Pongos AL, Chan AWS. Combination of stem cell and gene therapy ameliorates symptoms in Huntington's disease mice. NPJ Regen Med 2019; 4:7. [PMID: 30937182 PMCID: PMC6435637 DOI: 10.1038/s41536-019-0066-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 01/09/2019] [Indexed: 12/18/2022] Open
Abstract
Huntington's disease (HD) is a dominantly inherited monogenetic disorder characterized by motor and cognitive dysfunction due to neurodegeneration. The disease is caused by the polyglutamine (polyQ) expansion at the 5' terminal of the exon 1 of the huntingtin (HTT) gene, IT15, which results in the accumulation of mutant HTT (mHTT) aggregates in neurons and cell death. The monogenetic cause and the loss of specific neural cell population make HD a suitable candidate for stem cell and gene therapy. In this study, we demonstrate the efficacy of the combination of stem cell and gene therapy in a transgenic HD mouse model (N171-82Q; HD mice) using rhesus monkey (Macaca mulatta) neural progenitor cells (NPCs). We have established monkey NPC cell lines from induced pluripotent stem cells (iPSCs) that can differentiate into GABAergic neurons in vitro as well as in mouse brains without tumor formation. Wild-type monkey NPCs (WT-NPCs), NPCs derived from a transgenic HD monkey (HD-NPCs), and genetically modified HD-NPCs with reduced mHTT levels by stable expression of small-hairpin RNA (HD-shHD-NPCs), were grafted into the striatum of WT and HD mice. Mice that received HD-shHD-NPC grafts showed a significant increase in lifespan compared to the sham injection group and HD mice. Both WT-NPC and HD-shHD-NPC grafts in HD mice showed significant improvement in motor functions assessed by rotarod and grip strength. Also, immunohistochemistry demonstrated the integration and differentiation. Our results suggest the combination of stem cell and gene therapy as a viable therapeutic option for HD treatment.
Collapse
Affiliation(s)
- In Ki Cho
- 1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA USA.,2Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA USA
| | - Carissa Emerson Hunter
- 2Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA USA
| | - Sarah Ye
- 2Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA USA
| | - Alvince Learnz Pongos
- 2Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA USA
| | - Anthony Wing Sang Chan
- 1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA USA.,2Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA USA
| |
Collapse
|
|
15
|
Chen W, Huang Q, Ma S, Li M. Progress in Dopaminergic Cell Replacement and Regenerative Strategies for Parkinson's Disease. ACS Chem Neurosci 2019; 10:839-851. [PMID: 30346716 DOI: 10.1021/acschemneuro.8b00389] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder symptomatically characterized by resting tremor, rigidity, bradykinesia, and gait impairment. These motor deficits suffered by PD patients primarily result from selective dysfunction or loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Most of the existing therapies for PD are based on the replacement of dopamine, which is symptomatically effective in the early stage but becomes increasingly less effective and is accompanied by serious side effects in the advanced stages of the disease. Currently, there are no strategies to slow neuronal degeneration or prevent the progression of PD. Thus, the prospect of regenerating functional dopaminergic neurons is very attractive. Over the last few decades, significant progress has been made in the development of dopaminergic regenerative strategies for curing PD. The most promising approach seems to be cell-replacement therapy (CRT) using human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs), which are unlimitedly available and have gained much success in preclinical trials. Despite the challenges, stem cell-based CRT will make significant steps toward the clinic in the coming decade. Alternatively, direct lineage reprogramming, especially in situ direct conversion of glia cells to induced neurons, which exhibits some advantages including no ethical concerns, no risk of tumor formation, and even no need for transplantation, has gained much attention recently. Evoking the endogenous regeneration ability of neural stem cells (NSCs) is an idyllic method of dopaminergic neuroregeneration which remains highly controversial. Here, we review many of these advances, highlighting areas and strategies that might be particularly suited to the development of regenerative approaches that restore dopaminergic function in PD.
Collapse
Affiliation(s)
- Weizhao Chen
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Road 2, Guangzhou 510080, China
| | - Qiaoying Huang
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Road 2, Guangzhou 510080, China
| | - Shanshan Ma
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Road 2, Guangzhou 510080, China
| | - Mingtao Li
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Road 2, Guangzhou 510080, China
| |
Collapse
|
|
16
|
Kane KIW, Moreno EL, Hachi S, Walter M, Jarazo J, Oliveira MAP, Hankemeier T, Vulto P, Schwamborn JC, Thoma M, Fleming RMT. Automated microfluidic cell culture of stem cell derived dopaminergic neurons. Sci Rep 2019; 9:1796. [PMID: 30741972 PMCID: PMC6370836 DOI: 10.1038/s41598-018-34828-3] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 10/12/2018] [Indexed: 12/22/2022] Open
Abstract
Parkinson’s disease is a slowly progressive neurodegenerative disease characterised by dysfunction and death of selectively vulnerable midbrain dopaminergic neurons and the development of human in vitro cellular models of the disease is a major challenge in Parkinson’s disease research. We constructed an automated cell culture platform optimised for long-term maintenance and monitoring of different cells in three dimensional microfluidic cell culture devices. The system can be flexibly adapted to various experimental protocols and features time-lapse imaging microscopy for quality control and electrophysiology monitoring to assess cellular activity. Using this system, we continuously monitored the differentiation of Parkinson’s disease patient derived human neuroepithelial stem cells into midbrain specific dopaminergic neurons. Calcium imaging confirmed the electrophysiological activity of differentiated neurons and immunostaining confirmed the efficiency of the differentiation protocol. This system is the first example of an automated Organ-on-a-Chip culture and has the potential to enable a versatile array of in vitro experiments for patient-specific disease modelling.
Collapse
Affiliation(s)
- Khalid I W Kane
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 avenue des Hauts-Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg
| | - Edinson Lucumi Moreno
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 avenue des Hauts-Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg.,Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands
| | - Siham Hachi
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 avenue des Hauts-Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg
| | - Moriz Walter
- Fraunhofer Institute for Manufacturing Engineering and Automation IPA, Stuttgart, Germany
| | - Javier Jarazo
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 avenue des Hauts-Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg
| | - Miguel A P Oliveira
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 avenue des Hauts-Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg
| | - Thomas Hankemeier
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands
| | - Paul Vulto
- Mimetas B.V, PO Box 11002, 2301EA, Leiden, The Netherlands
| | - Jens C Schwamborn
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 avenue des Hauts-Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg
| | - Martin Thoma
- Fraunhofer Institute for Manufacturing Engineering and Automation IPA, Stuttgart, Germany
| | - Ronan M T Fleming
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 avenue des Hauts-Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg. .,Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands.
| |
Collapse
|
|
17
|
Abstract
Genetic reporters offer attractive approaches to investigate gene expression, gene function, and spatiotemporal assessment in vitro and in vivo. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the biosynthesis of the dopamine neurotransmitter, and thus it has been used as a reliable marker for dopaminergic neurons in vitro and in vivo. Herein we describe a method for making iPSC lines with TH-green fluorescent protein reporter gene using CRISPR/Cas9 technique.
Collapse
Affiliation(s)
- Hyenjong Hong
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Marcel M Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, USA.
- Department of Radiology, Research Imaging Institute, Cell Systems and Anatomy, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
| |
Collapse
|
|
18
|
Daadi MM. Differentiation of Neural Stem Cells Derived from Induced Pluripotent Stem Cells into Dopaminergic Neurons. Methods Mol Biol 2019; 1919:89-96. [PMID: 30656623 DOI: 10.1007/978-1-4939-9007-8_7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Dopaminergic (DA) neurons are involved in many critical functions within the central nervous system (CNS), and dopamine neurotransmission impairment underlies a wide range of disorders from motor control deficiencies, such as Parkinson's disease (PD), to psychiatric disorders, such as alcoholism, drug addictions, bipolar disorders, schizophrenia and depression. Neural stem cell-based technology has potential to play an important role in developing efficacious biological and small molecule therapeutic products for disorders with dopamine dysregulation. Various methods of differentiating DA neurons from pluripotent stem cells have been reported. In this chapter, we describe a simple technique using dopamine-inducing factors (DIFs) to differentiate neural stem cells (NSCs), isolated from induced pluripotent stem cells (iPSCs) into DA neurons.
Collapse
Affiliation(s)
- Marcel M Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, USA.
- Department of Radiology, Research Imaging Institute, Cell Systems and Anatomy, Long School of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
| |
Collapse
|
|
19
|
Standards for Deriving Nonhuman Primate-Induced Pluripotent Stem Cells, Neural Stem Cells and Dopaminergic Lineage. Int J Mol Sci 2018; 19:ijms19092788. [PMID: 30227600 PMCID: PMC6164693 DOI: 10.3390/ijms19092788] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/11/2018] [Accepted: 09/13/2018] [Indexed: 01/09/2023] Open
Abstract
Humans and nonhuman primates (NHP) are similar in behavior and in physiology, specifically the structure, function, and complexity of the immune system. Thus, NHP models are desirable for pathophysiology and pharmacology/toxicology studies. Furthermore, NHP-derived induced pluripotent stem cells (iPSCs) may enable transformative developmental, translational, or evolutionary studies in a field of inquiry currently hampered by the limited availability of research specimens. NHP-iPSCs may address specific questions that can be studied back and forth between in vitro cellular assays and in vivo experimentations, an investigational process that in most cases cannot be performed on humans because of safety and ethical issues. The use of NHP model systems and cell specific in vitro models is evolving with iPSC-based three-dimensional (3D) cell culture systems and organoids, which may offer reliable in vitro models and reduce the number of animals used in experimental research. IPSCs have the potential to give rise to defined cell types of any organ of the body. However, standards for deriving defined and validated NHP iPSCs are missing. Standards for deriving high-quality iPSC cell lines promote rigorous and replicable scientific research and likewise, validated cell lines reduce variability and discrepancies in results between laboratories. We have derived and validated NHP iPSC lines by confirming their pluripotency and propensity to differentiate into all three germ layers (ectoderm, mesoderm, and endoderm) according to standards and measurable limits for a set of marker genes. The iPSC lines were characterized for their potential to generate neural stem cells and to differentiate into dopaminergic neurons. These iPSC lines are available to the scientific community. NHP-iPSCs fulfill a unique niche in comparative genomics to understand gene regulatory principles underlying emergence of human traits, in infectious disease pathogenesis, in vaccine development, and in immunological barriers in regenerative medicine.
Collapse
|
|
20
|
Nanobiosensing Platforms for Real-Time and Non-Invasive Monitoring of Stem Cell Pluripotency and Differentiation. SENSORS 2018; 18:s18092755. [PMID: 30134637 PMCID: PMC6163950 DOI: 10.3390/s18092755] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 08/17/2018] [Accepted: 08/17/2018] [Indexed: 01/05/2023]
Abstract
Breakthroughs in the biomedical and regenerative therapy fields have led to the influential ability of stem cells to differentiate into specific types of cells that enable the replacement of injured tissues/organs in the human body. Non-destructive identification of stem cell differentiation is highly necessary to avoid losses of differentiated cells, because most of the techniques generally used as confirmation tools for the successful differentiation of stem cells can result in valuable cells becoming irrecoverable. Regarding this issue, recent studies reported that both Raman spectroscopy and electrochemical sensing possess excellent characteristics for monitoring the behavior of stem cells, including differentiation. In this review, we focus on numerous studies that have investigated the detection of stem cell pluripotency and differentiation in non-invasive and non-destructive manner, mainly by using the Raman and electrochemical methods. Through this review, we present information that could provide scientific or technical motivation to employ or further develop these two techniques for stem cell research and its application.
Collapse
|
|
21
|
Zhu X, Zhou W, Jin H, Li T. Brn2 Alone Is Sufficient to Convert Astrocytes into Neural Progenitors and Neurons. Stem Cells Dev 2018; 27:736-744. [PMID: 29635978 DOI: 10.1089/scd.2017.0250] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Generating neurons or neural progenitor cells (NPCs) from astrocytes is a potential strategy for neurological repair by reprogramming. Previous study has showed that Brn2, by cooperating with other factors, participates in neurogenesis and neuronal reprogramming. However, it is still unclear whether the Brn2 alone can convert astrocytes into neurons or NPCs. Here, we explored the effect of Brn2 on reprogramming of astrocytes, and found that a single transcription factor Brn2 can convert mouse astrocytes into functional neurons. Furthermore, the Brn2-infected astrocytes can be induced into NPCs after changing culture condition. In addition, our study found that the reprogramming of astrocytes and the fate of transdifferentiated cells are closely associated with cell microenvironmental factors, such as the brain regions where the astrocytes come from, the proliferation ability of astrocytes, and culture condition of infected astrocytes. To sum up, for the first time, our results demonstrated that Brn2 alone is sufficient to convert astrocytes into neural progenitors and neurons, and the conversion is associated with cell microenvironments. This new conversion method will be a potential therapeutic approach to restore the injured diseased brain in regenerative medicine.
Collapse
Affiliation(s)
- Xiaoqing Zhu
- 1 Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology , Kunming, Yunnan, China .,2 Faculty of Environmental Science and Engineering, Kunming University of Science and Technology , Kunming, Yunnan, China .,3 Kunming Enovate Institute of Bioscience , Kunming, Yunnan, China
| | - Wenshu Zhou
- 1 Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology , Kunming, Yunnan, China .,3 Kunming Enovate Institute of Bioscience , Kunming, Yunnan, China
| | - Hua Jin
- 4 The First People's Hospital of Yunnan Province , Kunming, Yunnan, China
| | - Tianqing Li
- 1 Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology , Kunming, Yunnan, China .,3 Kunming Enovate Institute of Bioscience , Kunming, Yunnan, China
| |
Collapse
|
|
22
|
Bal-Price A, Hogberg HT, Crofton KM, Daneshian M, FitzGerald RE, Fritsche E, Heinonen T, Hougaard Bennekou S, Klima S, Piersma AH, Sachana M, Shafer TJ, Terron A, Monnet-Tschudi F, Viviani B, Waldmann T, Westerink RHS, Wilks MF, Witters H, Zurich MG, Leist M. Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity. ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION 2018; 35:306-352. [PMID: 29485663 DOI: 10.14573/altex.1712081] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 01/29/2018] [Indexed: 01/06/2023]
Abstract
Multiple non-animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs, to obtain initial information on potential hazards, and to allow prioritization for further testing. A background on the regulatory and scientific status of DNT testing is provided showing different types of test readiness levels, depending on the intended use of data from NAMs. Readiness criteria, compiled during a stakeholder workshop, uniting scientists from academia, industry and regulatory authorities are presented. An important step beyond the listing of criteria, was the suggestion for a preliminary scoring scheme. On this basis a (semi)-quantitative analysis process was assembled on test readiness of 17 NAMs with respect to various uses (e.g. prioritization/screening, risk assessment). The scoring results suggest that several assays are currently at high readiness levels. Therefore, suggestions are made on how DNT NAMs may be assembled into an integrated approach to testing and assessment (IATA). In parallel, the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision is presented on how further NAM development may be guided by knowledge of signaling pathways necessary for brain development, DNT pathophysiology, and relevant adverse outcome pathways (AOP).
Collapse
Affiliation(s)
- Anna Bal-Price
- European Commission, Joint Research Centre (EC JRC), Ispra (VA), Italy
| | - Helena T Hogberg
- Center for Alternatives to Animal Testing (CAAT), Johns Hopkins University, Baltimore, MD, USA
| | - Kevin M Crofton
- National Centre for Computational Toxicology, US EPA, RTP, Washington, NC, USA
| | - Mardas Daneshian
- Center for Alternatives to Animal Testing, CAAT-Europe, University of Konstanz, Konstanz, Germany
| | - Rex E FitzGerald
- Swiss Centre for Human Applied Toxicology, SCAHT, University of Basle, Switzerland
| | - Ellen Fritsche
- IUF - Leibniz Research Institute for Environmental Medicine & Heinrich-Heine-University, Düsseldorf, Germany
| | - Tuula Heinonen
- Finnish Centre for Alternative Methods (FICAM), University of Tampere, Tampere, Finland
| | | | - Stefanie Klima
- In vitro Toxicology and Biomedicine, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Aldert H Piersma
- RIVM, National Institute for Public Health and the Environment, Bilthoven, and Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
| | - Magdalini Sachana
- Organisation for Economic Co-operation and Development (OECD), Paris, France
| | - Timothy J Shafer
- National Centre for Computational Toxicology, US EPA, RTP, Washington, NC, USA
| | | | - Florianne Monnet-Tschudi
- Swiss Centre for Human Applied Toxicology, SCAHT, University of Basle, Switzerland.,Department of Physiology, University of Lausanne, Lausanne, Switzerland
| | - Barbara Viviani
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy
| | - Tanja Waldmann
- In vitro Toxicology and Biomedicine, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Remco H S Westerink
- Neurotoxicology Research Group, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Martin F Wilks
- Swiss Centre for Human Applied Toxicology, SCAHT, University of Basle, Switzerland
| | - Hilda Witters
- VITO, Flemish Institute for Technological Research, Unit Environmental Risk and Health, Mol, Belgium
| | - Marie-Gabrielle Zurich
- Swiss Centre for Human Applied Toxicology, SCAHT, University of Basle, Switzerland.,Department of Physiology, University of Lausanne, Lausanne, Switzerland
| | - Marcel Leist
- Center for Alternatives to Animal Testing, CAAT-Europe, University of Konstanz, Konstanz, Germany.,In vitro Toxicology and Biomedicine, Department of Biology, University of Konstanz, Konstanz, Germany
| |
Collapse
|
|
23
|
Srivastava RK, Bulte JWM, Walczak P, Janowski M. Migratory potential of transplanted glial progenitors as critical factor for successful translation of glia replacement therapy: The gap between mice and men. Glia 2017; 66:907-919. [PMID: 29266673 DOI: 10.1002/glia.23275] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 11/13/2017] [Accepted: 11/16/2017] [Indexed: 01/09/2023]
Abstract
Neurological disorders are a major threat to public health. Stem cell-based regenerative medicine is now a promising experimental paradigm for its treatment, as shown in pre-clinical animal studies. Initial attempts have been on the replacement of neuronal cells only, but glial progenitors (GPs) are now becoming strong alternative cellular therapeutic candidates to replace oligodendrocytes and astrocytes as knowledge accumulates about their important emerging role in various disease processes. There are many examples of successful therapeutic outcomes for transplanted GPs in small animal models, but clinical translation has proved to be challenging due to the 1,000-fold larger volume of the human brain compared to mice. Human GPs transplanted into the mouse brain migrate extensively and can induce global cell replacement, but a similar extent of migration in the human brain would only allow for local rather than global cell replacement. We review here the mechanisms that govern cell migration, which could potentially be exploited to enhance the migratory properties of GPs through cell engineering pre-transplantation. We furthermore discuss the (dis)advantages of the various cell delivery routes that are available, with particular emphasis on intra-arterial injection as the most suitable route for achieving global cell distribution in the larger brain. Now that therapeutic success has proven to be feasible in small animal models, future efforts will need to be directed to enhance global cell delivery and migration to make bench-to-bedside translation a reality.
Collapse
Affiliation(s)
- Rohit K Srivastava
- Division of MR Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jeff W M Bulte
- Division of MR Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Chemical & Biomolecular Engineering, The Johns Hopkins University Whiting School of Engineering, Baltimore, Maryland.,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Piotr Walczak
- Division of MR Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Neurology and Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland
| | - Miroslaw Janowski
- Division of MR Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of NeuroRepair, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| |
Collapse
|
|
24
|
Wianny F, Vezoli J. Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectives. Primate Biol 2017; 4:185-213. [PMID: 32110706 PMCID: PMC7041537 DOI: 10.5194/pb-4-185-2017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 08/31/2017] [Indexed: 12/22/2022] Open
Abstract
In order to calibrate stem cell exploitation for cellular therapy in neurodegenerative diseases, fundamental and preclinical research in NHP (nonhuman primate) models is crucial. Indeed, it is consensually recognized that it is not possible to directly extrapolate results obtained in rodent models to human patients. A large diversity of neurological pathologies should benefit from cellular therapy based on neural differentiation of stem cells. In the context of this special issue of Primate Biology on NHP stem cells, we describe past and recent advances on cell replacement in the NHP model of Parkinson's disease (PD). From the different grafting procedures to the various cell types transplanted, we review here diverse approaches for cell-replacement therapy and their related therapeutic potential on behavior and function in the NHP model of PD.
Collapse
Affiliation(s)
- Florence Wianny
- Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France
| | - Julien Vezoli
- Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, 60528 Frankfurt, Germany
| |
Collapse
|
|
25
|
Niu Y, Li T, Ji W. Paving the road for biomedicine: genome editing and stem cells in primates. Natl Sci Rev 2017. [DOI: 10.1093/nsr/nwx094] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Yuyu Niu
- Yunnan Key Laboratory of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China
| | - Tianqing Li
- Yunnan Key Laboratory of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China
| | - Weizhi Ji
- Yunnan Key Laboratory of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China
| |
Collapse
|
|
26
|
Fishman PS, Frenkel V. Treatment of Movement Disorders With Focused Ultrasound. J Cent Nerv Syst Dis 2017; 9:1179573517705670. [PMID: 28615985 PMCID: PMC5462491 DOI: 10.1177/1179573517705670] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 03/28/2017] [Indexed: 11/29/2022] Open
Abstract
Although the use of ultrasound as a potential therapeutic modality in the brain has been under study for several decades, relatively few neuroscientists or neurologists are familiar with this technology. Stereotactic brain lesioning had been widely used as a treatment for medically refractory patients with essential tremor (ET), Parkinson disease (PD), and dystonia but has been largely replaced by deep brain stimulation (DBS) surgery, with advantages both in safety and efficacy. However, DBS is associated with complications including intracerebral hemorrhage, infection, and hardware malfunction. The occurrence of these complications has spurred interest in less invasive stereotactic brain lesioning methods including magnetic resonance imaging–guided high intensity–focused ultrasound (FUS) surgery. Engineering advances now allow sound waves to be targeted noninvasively through the skull to a brain target. High intensities of sonic energy can create a coagulation lesion similar to that of older radiofrequency stereotactic methods, but without opening the skull, recent Food and Drug Administration approval of unilateral thalamotomy for treatment of ET. Clinical studies of stereotactic FUS for aspects of PD are underway. Moderate intensity, pulsed FUS has also demonstrated the potential to safely open the blood-brain barrier for localized delivery of therapeutics including proteins, genes, and cell-based therapy for PD and related disorders. The goal of this review is to provide basic and clinical neuroscientists with a level of understanding to interact with medical physicists, biomedical engineers, and radiologists to accelerate the application of this powerful technology to brain disease
Collapse
Affiliation(s)
- Paul S Fishman
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Victor Frenkel
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
27
|
Fishman PS, Frenkel V. Focused Ultrasound: An Emerging Therapeutic Modality for Neurologic Disease. Neurotherapeutics 2017; 14:393-404. [PMID: 28244011 PMCID: PMC5398988 DOI: 10.1007/s13311-017-0515-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Therapeutic ultrasound is only beginning to be applied to neurologic conditions, but the potential of this modality for a wide spectrum of brain applications is high. Engineering advances now allow sound waves to be targeted through the skull to a brain region selected with real time magnetic resonance imaging and thermography, using a commercial array of focused emitters. High intensities of sonic energy can create a coagulation lesion similar to that of older radiofrequency stereotactic methods, but without opening the skull. This has led to the recent Food and Drug Administration approval of focused ultrasound (FUS) thalamotomy for unilateral treatment of essential tremor. Clinical studies of stereotactic FUS for aspects of Parkinson's disease, chronic pain, and refractory psychiatric indications are underway, with promising results. Moderate-intensity FUS has the potential to safely open the blood-brain barrier for localized delivery of therapeutics, while low levels of sonic energy can be used as a form of neuromodulation.
Collapse
Affiliation(s)
- Paul S Fishman
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
| | - Victor Frenkel
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| |
Collapse
|
|
28
|
Vermilyea SC, Emborg ME. The role of nonhuman primate models in the development of cell-based therapies for Parkinson's disease. J Neural Transm (Vienna) 2017; 125:365-384. [PMID: 28326445 PMCID: PMC5847191 DOI: 10.1007/s00702-017-1708-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 03/12/2017] [Indexed: 12/23/2022]
Abstract
Through the course of over three decades, nonhuman primate (NHP) studies on cell-based therapies (CBTs) for Parkinson’s disease (PD) have provided insight into the feasibility, safety and efficacy of the approach, methods of cell collection and preparation, cell viability, as well as potential brain targets. Today, NHP research continues to be a vital source of information for improving cell grafts and analyzing how the host affects graft survival, integration and function. Overall, this article aims to discuss the role that NHP models of PD have played in CBT development and highlights specific issues that need to be considered to maximize the value of NHP studies for the successful clinical translation of CBTs.
Collapse
Affiliation(s)
- Scott C Vermilyea
- Neuroscience Training Program, University of Wisconsin, Madison, 1220 Capitol Court, Madison, WI, 53715, USA.,Wisconsin National Primate Research Center, University of Wisconsin, Madison, USA
| | - Marina E Emborg
- Neuroscience Training Program, University of Wisconsin, Madison, 1220 Capitol Court, Madison, WI, 53715, USA. .,Wisconsin National Primate Research Center, University of Wisconsin, Madison, USA. .,Department of Medical Physics, University of Wisconsin, Madison, USA.
| |
Collapse
|
|
29
|
Choudhury GR, Kim J, Frost PA, Bastarrachea RA, Daadi MM. Nonhuman primate model in clinical modeling of diseases for stem cell therapy. Brain Circ 2016; 2:141-145. [PMID: 30276291 PMCID: PMC6126269 DOI: 10.4103/2394-8108.192524] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 08/16/2016] [Accepted: 09/06/2016] [Indexed: 01/11/2023] Open
Abstract
Nonhuman primates (NHPs) are alike humans in size, behavior, physiology, biochemistry, and immunology. Given close similarities to humans, the NHP model offers exceptional opportunities to understand the biological mechanisms and translational applications with direct relevance to human conditions. Here, we evaluate the opportunities and limitations of NHPs as animal models for translational regenerative medicine. NHP models of human disease propose exceptional opportunities to advance stem cell-based therapy by addressing pertinent translational concerns related to this research. Nonetheless, the value of these primates must be carefully assessed, taking into account the expense of specialized equipment and requirement of highly specialized staff. Well-designed initial fundamental studies in small animal models are essential before translating research into NHP models and eventually into human trials. In addition, we suggest that applying a directed and collaborative approach, as seen in the evolution of stroke NHP models, will greatly benefit the translation of stem cell therapy in other NHP disease models.
Collapse
Affiliation(s)
- Gourav R Choudhury
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Jeffrey Kim
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Patrice A Frost
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Raul A Bastarrachea
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Marcel M Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.,Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, Texas, USA.,Department of Radiology, Medical School, UT Health Science Center, San Antonio, Texas, USA
| |
Collapse
|
|
30
|
Grow DA, Simmons DV, Gomez JA, Wanat MJ, McCarrey JR, Paladini CA, Navara CS. Differentiation and Characterization of Dopaminergic Neurons From Baboon Induced Pluripotent Stem Cells. Stem Cells Transl Med 2016; 5:1133-44. [PMID: 27343168 PMCID: PMC4996432 DOI: 10.5966/sctm.2015-0073] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 03/23/2016] [Indexed: 12/16/2022] Open
Abstract
UNLABELLED : The progressive death of dopamine producing neurons in the substantia nigra pars compacta is the principal cause of symptoms of Parkinson's disease (PD). Stem cells have potential therapeutic use in replacing these cells and restoring function. To facilitate development of this approach, we sought to establish a preclinical model based on a large nonhuman primate for testing the efficacy and safety of stem cell-based transplantation. To this end, we differentiated baboon fibroblast-derived induced pluripotent stem cells (biPSCs) into dopaminergic neurons with the application of specific morphogens and growth factors. We confirmed that biPSC-derived dopaminergic neurons resemble those found in the human midbrain based on cell type-specific expression of dopamine markers TH and GIRK2. Using the reverse transcriptase quantitative polymerase chain reaction, we also showed that biPSC-derived dopaminergic neurons express PAX6, FOXA2, LMX1A, NURR1, and TH genes characteristic of this cell type in vivo. We used perforated patch-clamp electrophysiology to demonstrate that biPSC-derived dopaminergic neurons fired spontaneous rhythmic action potentials and high-frequency action potentials with spike frequency adaption upon injection of depolarizing current. Finally, we showed that biPSC-derived neurons released catecholamines in response to electrical stimulation. These results demonstrate the utility of the baboon model for testing and optimizing the efficacy and safety of stem cell-based therapeutic approaches for the treatment of PD. SIGNIFICANCE Functional dopamine neurons were produced from baboon induced pluripotent stem cells, and their properties were compared to baboon midbrain cells in vivo. The baboon has advantages as a clinically relevant model in which to optimize the efficacy and safety of stem cell-based therapies for neurodegenerative diseases, such as Parkinson's disease. Baboons possess crucial neuroanatomical and immunological similarities to humans, and baboon pluripotent stem cells can be differentiated into functional neurons that mimic those in the human brain, thus laying the foundation for the utility of the baboon model for evaluating stem cell therapies.
Collapse
Affiliation(s)
- Douglas A Grow
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas, USA; San Antonio Cellular Therapeutics Institute, San Antonio, Texas, USA; University of Texas at San Antonio Neurosciences Institute, San Antonio, Texas, USA
| | - DeNard V Simmons
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas, USA; University of Texas at San Antonio Neurosciences Institute, San Antonio, Texas, USA
| | - Jorge A Gomez
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas, USA; University of Texas at San Antonio Neurosciences Institute, San Antonio, Texas, USA
| | - Matthew J Wanat
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas, USA; University of Texas at San Antonio Neurosciences Institute, San Antonio, Texas, USA
| | - John R McCarrey
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas, USA; San Antonio Cellular Therapeutics Institute, San Antonio, Texas, USA
| | - Carlos A Paladini
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas, USA; University of Texas at San Antonio Neurosciences Institute, San Antonio, Texas, USA
| | - Christopher S Navara
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas, USA; San Antonio Cellular Therapeutics Institute, San Antonio, Texas, USA;
| |
Collapse
|
|
31
|
Shen Y, Huang J, Liu L, Xu X, Han C, Zhang G, Jiang H, Li J, Lin Z, Xiong N, Wang T. A Compendium of Preparation and Application of Stem Cells in Parkinson's Disease: Current Status and Future Prospects. Front Aging Neurosci 2016; 8:117. [PMID: 27303288 PMCID: PMC4885841 DOI: 10.3389/fnagi.2016.00117] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 05/09/2016] [Indexed: 12/22/2022] Open
Abstract
Parkinson's Disease (PD) is a progressively neurodegenerative disorder, implicitly characterized by a stepwise loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and explicitly marked by bradykinesia, rigidity, resting tremor and postural instability. Currently, therapeutic approaches available are mainly palliative strategies, including L-3,4-dihydroxy-phenylalanine (L-DOPA) replacement therapy, DA receptor agonist and deep brain stimulation (DBS) procedures. As the disease proceeds, however, the pharmacotherapeutic efficacy is inevitably worn off, worse still, implicated by side effects of motor response oscillations as well as L-DOPA induced dyskinesia (LID). Therefore, the frustrating status above has propeled the shift to cell replacement therapy (CRT), a promising restorative therapy intending to secure a long-lasting relief of patients' symptoms. By far, stem cell lines of multifarious origins have been established, which can be further categorized into embryonic stem cells (ESCs), neural stem cells (NSCs), induced neural stem cells (iNSCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs). In this review, we intend to present a compendium of preparation and application of multifarious stem cells, especially in relation to PD research and therapy. In addition, the current status, potential challenges and future prospects for practical CRT in PD patients will be elaborated as well.
Collapse
Affiliation(s)
- Yan Shen
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Jinsha Huang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Ling Liu
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Xiaoyun Xu
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Chao Han
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Guoxin Zhang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Haiyang Jiang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Jie Li
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Zhicheng Lin
- Department of Psychiatry, Harvard Medical School, Division of Alcohol and Drug Abuse, and Mailman Neuroscience Research Center, McLean Hospital Belmont, MA, USA
| | - Nian Xiong
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Tao Wang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| |
Collapse
|
|
32
|
Shen T, Pu J, Si X, Ye R, Zhang B. An update on potential therapeutic strategies for Parkinson's disease based on pathogenic mechanisms. Expert Rev Neurother 2016; 16:711-22. [PMID: 27138872 DOI: 10.1080/14737175.2016.1179112] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Parkinson's disease is a common neurodegenerative disorder mainly caused by the loss of nigral dopaminergic neurons, of which the pathogenesis remains essentially unknown. Current therapeutic strategies help manage signs and symptoms but have no effect in disease modification. Over the past several decades, scientists have devoted a lot of effort to clarifying the pathological mechanism and searching for new targets for Parkinson's disease treatment. AREAS COVERED Treatment of Parkinson's disease. Expert Commentary: Illustrated in this review are newly found discoveries and evidence that contribute to the understanding of Parkinson's disease pathogenic mechanism. Also discussed are potential therapeutic strategies that are being studied, including disease-modifying and genetically mediated small molecule compounds, cell- and gene-based therapeutic strategies, immunization strategies and anti-diabetic therapy, which may be very promising therapeutic methods in the future.
Collapse
Affiliation(s)
- Ting Shen
- a Department of Neurology, Second Affiliated Hospital, School of Medicine , Zhejiang University , Hangzhou , China
| | - Jiali Pu
- a Department of Neurology, Second Affiliated Hospital, School of Medicine , Zhejiang University , Hangzhou , China
| | - Xiaoli Si
- a Department of Neurology, Second Affiliated Hospital, School of Medicine , Zhejiang University , Hangzhou , China
| | - Rong Ye
- a Department of Neurology, Second Affiliated Hospital, School of Medicine , Zhejiang University , Hangzhou , China
| | - Baorong Zhang
- a Department of Neurology, Second Affiliated Hospital, School of Medicine , Zhejiang University , Hangzhou , China
| |
Collapse
|
|
33
|
Yang H, Wang J, Wang F, Liu X, Chen H, Duan W, Qu T. Dopaminergic Neuronal Differentiation from the Forebrain-Derived Human Neural Stem Cells Induced in Cultures by Using a Combination of BMP-7 and Pramipexole with Growth Factors. Front Neural Circuits 2016; 10:29. [PMID: 27147976 PMCID: PMC4837145 DOI: 10.3389/fncir.2016.00029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 04/01/2016] [Indexed: 01/06/2023] Open
Abstract
Transplantation of dopaminergic (DA) neurons is considered to be the most promising therapeutic strategy for replacing degenerated dopamine cells in the midbrain of Parkinson's disease (PD), thereby restoring normal neural circuit function and slow clinical progression of the disease. Human neural stem cells (hNSCs) derived from fetal forebrain are thought to be the important cell sources for producing DA neurons because of their multipotency for differentiation and long-term expansion property in cultures. However, low DA differentiation of the forebrain-derived hNSCs limited their therapeutic potential in PD. In the current study, we explored a combined application of Pramipexole (PRX), bone morphogenetic proteins 7 (BMP-7), and growth factors, including acidic fibroblast factor (aFGF), forskolin, and phorbol-12-myristae-13-acetate (TPA), to induce differentiation of forebrain-derived hNSCs toward DA neurons in cultures. We found that DA neuron-associated genes, including Nurr1, Neurogenin2 (Ngn2), and tyrosine hydroxylase (TH) were significantly increased after 24 h of differentiation by RT-PCR analysis (p < 0.01). Fluorescent examination showed that about 25% of cells became TH-positive neurons at 24 h, about 5% of cells became VMAT2 (vascular monoamine transporter 2)-positive neurons, and less than 5% of cells became DAT (dopamine transporter)-positive neurons at 72 h following differentiation in cultures. Importantly, these TH-, VMAT2-, and DAT-expressing neurons were able to release dopamine into cultures under both of the basal and evoked conditions. Dopamine levels released by DA neurons produced using our protocol were significantly higher compared to the control groups (P < 0.01), as examined by ELISA. Our results demonstrated that the combination of PRX, BMP-7, and growth factors was able to greatly promote differentiation of the forebrain-derived hNSCs into DA-releasing neurons.
Collapse
Affiliation(s)
- HongNa Yang
- Department of Critical-Care Medicine, Qilu Hospital of Shandong University, Shandong UniversityJinan, China; Department of Psychiatry, College of Medicine, University of Illinois at ChicagoChicago, IL, USA
| | - Jing Wang
- Department of Critical-Care Medicine, Qilu Hospital of Shandong University, Shandong University Jinan, China
| | - Feng Wang
- Department of Psychiatry, College of Medicine, University of Illinois at Chicago Chicago, IL, USA
| | - XiaoDun Liu
- Department of Research and Development, Cell and Tissue Bank of Shandong Province Jinan, China
| | - Heng Chen
- Department of Research and Development, Cell and Tissue Bank of Shandong Province Jinan, China
| | - WeiMing Duan
- Department of Anatomy, Capital Medical University Beijing, China
| | - TingYu Qu
- Department of Psychiatry, College of Medicine, University of Illinois at Chicago Chicago, IL, USA
| |
Collapse
|
|
34
|
Liu P, Feng Y, Dong D, Liu X, Chen Y, Wang Y, Zhou Y. Enhanced renoprotective effect of IGF-1 modified human umbilical cord-derived mesenchymal stem cells on gentamicin-induced acute kidney injury. Sci Rep 2016; 6:20287. [PMID: 26830766 PMCID: PMC4735814 DOI: 10.1038/srep20287] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 12/30/2015] [Indexed: 02/07/2023] Open
Abstract
The therapeutic action of umbilical cord-derived mesenchymal stem cells (UC-MSCs) against acute kidney injury (AKI) has been demonstrated by several groups. However, how to further enhance the renoprotective effect of UC-MSCs and improve the therapy effect, are still unclear. In this study, we mainly investigated whether insulin-like growth factor-1 (IGF-1)-modified UC-MSCs hold an enhanced protective effect on gentamicin-induced AKI in vivo. Our results indicated that the IGF-1 overexpression could enhance the therapeutic action of human UC-MSCs, and the AKI rats treated with IGF-1-overexpressed UC-MSCs (UC-MSCs-IGF-1) showed better recovery of biochemical variables in serum or urine associated with renal function, histological injury and renal apoptosis, compared with AKI rats treated with normal UC-MSCs. RNA microarray analysis indicated that some key genes in the signal pathways associated with anti-oxidation, anti-inflammatory, and cell migratory capacity were up-regulated in UC-MSCs-IGF-1, and the results were further confirmed with qPCR. Furthermore, a series of detection in vitro and in vivo indicated that the UC-MSCs-IGF-1 hold better anti-oxidation, anti-inflammatory, and cell migratory capacity for IGF-1 overexpression. Thus, our study indicated that enhancement of UC-MSCs bioactivities with IGF-1 overexpression could increase the UC-MSCs therapeutic potential and further developed a new therapeutic strategy for the treatment of AKI.
Collapse
Affiliation(s)
- Pengfei Liu
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
- Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Yetong Feng
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, P.R. China
| | - Delu Dong
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
| | - Xiaobo Liu
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
- Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Yaoyu Chen
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
- Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Yi Wang
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
| | - Yulai Zhou
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China
| |
Collapse
|
|
35
|
Dynamic Trk and G Protein Signalings Regulate Dopaminergic Neurodifferentiation in Human Trophoblast Stem Cells. PLoS One 2015; 10:e0143852. [PMID: 26606046 PMCID: PMC4659658 DOI: 10.1371/journal.pone.0143852] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 11/09/2015] [Indexed: 12/18/2022] Open
Abstract
Understanding the mechanisms in the generation of neural stem cells from pluripotent stem cells is a fundamental step towards successful management of neurodegenerative diseases in translational medicine. Albeit all-trans retinoic acid (RA) has been associated with axon outgrowth and nerve regeneration, the maintenance of differentiated neurons, the association with degenerative disease like Parkinson's disease, and its regulatory molecular mechanism from pluripotent stem cells to neural stem cells remain fragmented. We have previously reported that RA is capable of differentiation of human trophoblast stem cells to dopamine (DA) committed progenitor cells. Intracranial implantation of such neural progenitor cells into the 6-OHDA-lesioned substantia nigra pars compacta successfully regenerates dopaminergic neurons and integrity of the nigrostriatal pathway, ameliorating the behavioral deficits in the Parkinson’s disease rat model. Here, we demonstrated a dynamic molecular network in systematic analysis by addressing spatiotemporal molecular expression, intracellular protein-protein interaction and inhibition, imaging study, and genetic expression to explore the regulatory mechanisms of RA induction in the differentiation of human trophoblast stem cells to DA committed progenitor cells. We focused on the tyrosine receptor kinase (Trk), G proteins, canonical Wnt2B/β-catenin, genomic and non-genomic RA signaling transductions with Tyrosine hydroxylase (TH) gene expression as the differentiation endpoint. We found that at the early stage, integration of TrkA and G protein signalings aims for axonogenesis and morphogenesis, involving the novel RXRα/Gαq/11 and RARβ/Gβ signaling pathways. While at the later stage, five distinct signaling pathways together with epigenetic histone modifications emerged to regulate expression of TH, a precursor of dopamine. RA induction generated DA committed progenitor cells in one day. Our results provided substantial mechanistic evidence that human trophoblast stem cell-derived neural stem cells can potentially be used for neurobiological study, drug discovery, and as an alternative source of cell-based therapy in neurodegenerative diseases like Parkinson’s disease.
Collapse
|
|
36
|
Current status of neuronal cell xenotransplantation. Int J Surg 2015; 23:267-272. [DOI: 10.1016/j.ijsu.2015.09.052] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 09/07/2015] [Accepted: 09/15/2015] [Indexed: 11/18/2022]
|
|
37
|
Oliveira Á, Illes P, Ulrich H. Purinergic receptors in embryonic and adult neurogenesis. Neuropharmacology 2015; 104:272-81. [PMID: 26456352 DOI: 10.1016/j.neuropharm.2015.10.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 10/01/2015] [Accepted: 10/04/2015] [Indexed: 01/14/2023]
Abstract
ATP (adenosine 5'-triphosphate), one of the most ancient neurotransmitters, exerts essential functions in the brain, including neurotransmission and modulation of synaptic activity. Moreover, this nucleotide has been attributed with trophic properties and experimental evidence points to the participation of ATP-activated P2X and P2Y purinergic receptors in embryonic brain development as well as in adult neurogenesis for maintenance of normal brain functions and neuroregeneration upon brain injury. We discuss here the available data on purinergic P2 receptor expression and function during brain development and in the neurogenic zones of the adult brain, as well as the insights based on the use of in vitro stem cell cultures. While several P2 receptor subtypes were shown to be expressed during in vitro and in vivo neurogenesis, specific functions have been proposed for P2Y1, P2Y2 metabotropic as well as P2X2 ionotropic receptors to promote neurogenesis. Further, the P2X7 receptor is suggested to function in the maintenance of pools of neural stem and progenitor cells through induction of proliferation or cell death, depending on the microenvironment. Pathophysiological actions have been proposed for this receptor in worsening damage in brain disease. The P2X7 receptor and possibly additional P2 receptor subtypes have been implicated in pathophysiology of neurological diseases including Parkinson's disease, Alzheimer's disease and epilepsy. New strategies in cell therapy could involve modulation of purinergic signaling, either in the achievement of more effective protocols to obtain viable and homogeneous cell populations or in the process of functional engraftment of transplanted cells into the damaged brain. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.
Collapse
Affiliation(s)
- Ágatha Oliveira
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508-900, Av. Prof. Lineu Prestes, 748, Brazil
| | - Peter Illes
- Rudolf-Boehm-Institut für Pharmakologie und Toxikologie der Universität Leipzig, Haertelstrasse 16-18, 04107 Leipzig, Germany.
| | - Henning Ulrich
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508-900, Av. Prof. Lineu Prestes, 748, Brazil.
| |
Collapse
|
|
38
|
Daadi MM, Barberi T, Shi Q, Lanford RE. Nonhuman primate models in translational regenerative medicine. Stem Cells Dev 2015; 23 Suppl 1:83-7. [PMID: 25457970 DOI: 10.1089/scd.2014.0374] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Humans and nonhuman primates (NHPs) are similar in size, behavior, physiology, biochemistry, structure and function of organs, and complexity of the immune system. Research on NHPs generates complementary data that bridge translational research from small animal models to humans. NHP models of human disease offer unique opportunities to develop stem cell-based therapeutic interventions that directly address relevant and challenging translational aspects of cell transplantation therapy. These include the use of autologous induced pluripotent stem cell-derived cellular products, issues related to the immune response in autologous and allogeneic setting, pros and cons of delivery techniques in a clinical setting, as well as the safety and efficacy of candidate cell lines. The NHP model allows the assessment of complex physiological, biochemical, behavioral, and imaging end points, with direct relevance to human conditions. At the same time, the value of using primates in scientific research must be carefully evaluated and timed due to expense and the necessity for specialized equipment and highly trained personnel. Often it is more efficient and useful to perform initial proof-of-concept studies for new therapeutics in rodents and/or other species before the pivotal studies in NHPs that may eventually lead to first-in-human trials. In this report, we present how the Southwest National Primate Research Center, one of seven NIH-funded National Primate Research Centers, may help the global community in translating promising technologies to the clinical arena.
Collapse
Affiliation(s)
- Marcel M Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute , San Antonio, Texas
| | | | | | | |
Collapse
|
|
39
|
Acton D, Miles GB. Stimulation of Glia Reveals Modulation of Mammalian Spinal Motor Networks by Adenosine. PLoS One 2015; 10:e0134488. [PMID: 26252389 PMCID: PMC4529192 DOI: 10.1371/journal.pone.0134488] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2015] [Accepted: 07/09/2015] [Indexed: 01/05/2023] Open
Abstract
Despite considerable evidence that glia can release modulators to influence the excitability of neighbouring neurons, the importance of gliotransmission for the operation of neural networks and in shaping behaviour remains controversial. Here we characterise the contribution of glia to the modulation of the mammalian spinal central pattern generator for locomotion, the output of which is directly relatable to a defined behaviour. Glia were stimulated by specific activation of protease-activated receptor-1 (PAR1), an endogenous G-protein coupled receptor preferentially expressed by spinal glia during ongoing activity of the spinal central pattern generator for locomotion. Selective activation of PAR1 by the agonist TFLLR resulted in a reversible reduction in the frequency of locomotor-related bursting recorded from ventral roots of spinal cord preparations isolated from neonatal mice. In the presence of the gliotoxins methionine sulfoximine or fluoroacetate, TFLLR had no effect, confirming the specificity of PAR1 activation to glia. The modulation of burst frequency upon PAR1 activation was blocked by the non-selective adenosine-receptor antagonist theophylline and by the A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, but not by the A2A-receptor antagonist SCH5826, indicating production of extracellular adenosine upon glial stimulation, followed by A1-receptor mediated inhibition of neuronal activity. Modulation of network output following glial stimulation was also blocked by the ectonucleotidase inhibitor ARL67156, indicating glial release of ATP and its subsequent degradation to adenosine rather than direct release of adenosine. Glial stimulation had no effect on rhythmic activity recorded following blockade of inhibitory transmission, suggesting that glial cell-derived adenosine acts via inhibitory circuit components to modulate locomotor-related output. Finally, the modulation of network output by endogenous adenosine was found to scale with the frequency of network activity, implying activity-dependent release of adenosine. Together, these data indicate that glia play an active role in the modulation of mammalian locomotor networks, providing negative feedback control that may stabilise network activity.
Collapse
Affiliation(s)
- David Acton
- School of Psychology and Neuroscience, University of St Andrews, Fife, United Kingdom
| | - Gareth B. Miles
- School of Psychology and Neuroscience, University of St Andrews, Fife, United Kingdom
- * E-mail:
| |
Collapse
|
|
40
|
Liu P, Zhang Y, Chen S, Cai J, Pei D. Application of iPS cells in dental bioengineering and beyond. Stem Cell Rev Rep 2015; 10:663-70. [PMID: 24917330 DOI: 10.1007/s12015-014-9531-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The stem-cell-based tissue-engineering approaches are widely applied in establishing functional organs and tissues for regenerative medicine. Successful generation of induced pluripotent stem cells (iPS cells) and rapid progress of related technical platform provide great promise in the development of regenerative medicine, including organ regeneration. We have previously reported that iPS cells could be an appealing stem cells source contributing to tooth regeneration. In the present paper, we mainly review the application of iPS technology in dental bioengineering and discuss the challenges for iPS cells in the whole tooth regeneration.
Collapse
Affiliation(s)
- Pengfei Liu
- CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell Biology and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kai Yuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China
| | | | | | | | | |
Collapse
|
|
41
|
Moreno EL, Hachi S, Hemmer K, Trietsch SJ, Baumuratov AS, Hankemeier T, Vulto P, Schwamborn JC, Fleming RMT. Differentiation of neuroepithelial stem cells into functional dopaminergic neurons in 3D microfluidic cell culture. LAB ON A CHIP 2015; 15:2419-2428. [PMID: 25902196 DOI: 10.1039/c5lc00180c] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
A hallmark of Parkinson's disease is the progressive loss of nigrostriatal dopaminergic neurons. We derived human neuroepithelial cells from induced pluripotent stem cells and successfully differentiated them into dopaminergic neurons within phase-guided, three-dimensional microfluidic cell culture bioreactors. After 30 days of differentiation within the microfluidic bioreactors, in situ morphological, immunocytochemical and calcium imaging confirmed the presence of dopaminergic neurons that were spontaneously electrophysiologically active, a characteristic feature of nigrostriatal dopaminergic neurons in vivo. Differentiation was as efficient as in macroscopic culture, with up to 19% of differentiated neurons immunoreactive for tyrosine hydroxylase, the penultimate enzyme in the synthesis of dopamine. This new microfluidic cell culture model integrates the latest innovations in developmental biology and microfluidic cell culture to generate a biologically realistic and economically efficient route to personalised drug discovery for Parkinson's disease.
Collapse
Affiliation(s)
- Edinson Lucumi Moreno
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 avenue des Hauts-Fourneaux, L-4362 Esch-sur-Alzette, Luxembourg.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Li Y, Zang D. The neuron regrowth is associated with the proliferation of neural precursor cells after leukemia inhibitory factor administration following spinal cord injury in mice. PLoS One 2014; 9:e116031. [PMID: 25542011 PMCID: PMC4277544 DOI: 10.1371/journal.pone.0116031] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 11/29/2014] [Indexed: 11/28/2022] Open
Abstract
Objectives To explore whether LIF could promote the proliferation of neural precursor cells (NPCs) and to analyze the correlation between increased NPCs and FluoroGold (FG) labeled neurons in mice after spinal cord injury (SCI). Methods Motor behavior was assessed using Rotarod and Platform Hang tests; neurons in the corticospinal and rubrospinal systems were labeled with FG, NPCs were immustained with nestin-FITC conjugate. The numbers of FG-labeled neurons and NPCs were estimated, and the correlation between FG-labeled neurons and NPCs was assessed. Results Mice in the SCI group showed negligible recovery of locomotor behavior; in contrast, mice in the LIF group showed a statically significant improvement. Both FG-labeled neurons and NPCs were significantly increased in the LIF group compared to the SCI group, and this increase in FG-labeled neurons and NPCs showed a clear association above the lesion level. Conclusions LIF could promote locomotive behaviors in mice post-SCI by encouraging the proliferation of NPCs; LIF may in fact be a potential cytokine for the induction of NPCs post-SCI.
Collapse
Affiliation(s)
- Yubo Li
- Capital Medical University, Beijing, 100069, China
| | - Dawei Zang
- Department of Neurology, Tianjin First Center Hospital, Tianjin Medical University, Tianjin, 300192, China
- * E-mail:
| |
Collapse
|
|
43
|
Nezakati T, Cousins BG, Seifalian AM. Toxicology of chemically modified graphene-based materials for medical application. Arch Toxicol 2014; 88:1987-2012. [PMID: 25234085 PMCID: PMC4201927 DOI: 10.1007/s00204-014-1361-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 09/03/2014] [Indexed: 12/12/2022]
Abstract
This review article aims to provide an overview of chemically modified graphene, and graphene oxide (GO), and their impact on toxicology when present in biological systems. Graphene is one of the most promising nanomaterials due to unique physicochemical properties including enhanced optical, thermal, and electrically conductive behavior in addition to mechanical strength and high surface-to-volume ratio. Graphene-based nanomaterials have received much attention over the last 5 years in the biomedical field ranging from their use as polymeric conduits for nerve regeneration, carriers for targeted drug delivery and in the treatment of cancer via photo-thermal therapy. Both in vitro and in vivo biological studies of graphene-based nanomaterials help understand their relative toxicity and biocompatibility when used for biomedical applications. Several studies investigating important material properties such as surface charge, concentration, shape, size, structural defects, and chemical functional groups relate to their safety profile and influence cyto- and geno-toxicology. In this review, we highlight the most recent studies of graphene-based nanomaterials and outline their unique properties, which determine their interactions under a range of environmental conditions. The advent of graphene technology has led to many promising new opportunities for future applications in the field of electronics, biotechnology, and nanomedicine to aid in the diagnosis and treatment of a variety of debilitating diseases.
Collapse
Affiliation(s)
- Toktam Nezakati
- UCL Centre for Nanotechnology and Regeneration Medicine, Division of Surgery and Interventional Science, University College London, London, UK
| | - Brian G. Cousins
- UCL Centre for Nanotechnology and Regeneration Medicine, Division of Surgery and Interventional Science, University College London, London, UK
| | - Alexander M. Seifalian
- UCL Centre for Nanotechnology and Regeneration Medicine, Division of Surgery and Interventional Science, University College London, London, UK
- Royal Free London NHS Foundation Trust, London, UK
| |
Collapse
|
|
44
|
Gnanasegaran N, Govindasamy V, Musa S, Abu Kasim NH. ReNCell VM conditioned medium enhances the induction of dental pulp stem cells into dopaminergic like cells. Cytotechnology 2014; 68:343-53. [PMID: 25322895 DOI: 10.1007/s10616-014-9787-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 09/13/2014] [Indexed: 12/21/2022] Open
Abstract
Among the debilitating diseases, neurological related diseases are the most challenging ones to be treated using cell replacement therapies. Recently, dental pulp stem cells (SHED) were found to be most suitable cell choice for neurological related diseases as evidenced with many preclinical studies. To enhance the neurological potential of SHED, we recapitulated one of the pharmacological therapeutic tools in cell replacement treatment, we pre-conditioned dental pulp stem cells (SHED) with culture medium of ReNCell VM, an immortalized neuron progenitor cell, prior to neurogenesis induction and investigated whether this practice enhances their neurogenesis potential especially towards dopaminergic neurons. We hypothesed that the integration of pharmacological practices such as co-administration of various drugs, a wide range of doses and duration as well as pre-conditioning into cell replacement may enhance the efficacy of stem cell therapy. In particular, pre-conditioning is shown to be involved in the protective effect from some membrano-tropic drugs, thereby improving the resistance of cell structures and homing capabilities. We found that cells pre-treated with ReNCell VM conditioned medium displayed bipolar structures with extensive branches resembling putative dopaminergic neurons as compared to non-treated cells. Furthermore, many neuronal related markers such as NES, NR4A2, MSI1, and TH were highly expressed (fold changes > 2; p < 0.05) in pre-treated cells. Similar observations were detected at the protein level. The results demonstrate for the first time that SHED pre-conditioning enhances neurological potential and we suggest that cells should be primed to their respective environment prior to transplantation.
Collapse
Affiliation(s)
- Nareshwaran Gnanasegaran
- cGMP-Compliant Stem Cell Laboratory, Hygieia Innovation Sdn. Bhd, Lot 1G-2G, Lanai Complex No. 2, Persiaran Seri Perdana, Precinct 10, 62250, Federal Territory of Putrajaya, Malaysia.,Department of Restorative Dentistry, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Vijayendran Govindasamy
- cGMP-Compliant Stem Cell Laboratory, Hygieia Innovation Sdn. Bhd, Lot 1G-2G, Lanai Complex No. 2, Persiaran Seri Perdana, Precinct 10, 62250, Federal Territory of Putrajaya, Malaysia.
| | - Sabri Musa
- Department of Paediatric Dentistry and Orthodontics, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Noor Hayaty Abu Kasim
- Department of Restorative Dentistry, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| |
Collapse
|
|
45
|
Liao MC, Diaconu M, Monecke S, Collombat P, Timaeus C, Kuhlmann T, Paulus W, Trenkwalder C, Dressel R, Mansouri A. Embryonic stem cell-derived neural progenitors as non-tumorigenic source for dopaminergic neurons. World J Stem Cells 2014; 6:248-255. [PMID: 24772251 PMCID: PMC3999782 DOI: 10.4252/wjsc.v6.i2.248] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 11/24/2013] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To find a safe source for dopaminergic neurons, we generated neural progenitor cell lines from human embryonic stem cells.
METHODS: The human embryonic stem (hES) cell line H9 was used to generate human neural progenitor (HNP) cell lines. The resulting HNP cell lines were differentiated into dopaminergic neurons and analyzed by quantitative real-time polymerase chain reaction and immunofluorescence for the expression of neuronal differentiation markers, including beta-III tubulin (TUJ1) and tyrosine hydroxylase (TH). To assess the risk of teratoma or other tumor formation, HNP cell lines and mouse neuronal progenitor (MNP) cell lines were injected subcutaneously into immunodeficient SCID/beige mice.
RESULTS: We developed a fairly simple and fast protocol to obtain HNP cell lines from hES cells. These cell lines, which can be stored in liquid nitrogen for several years, have the potential to differentiate in vitro into dopaminergic neurons. Following day 30 of differentiation culture, the majority of the cells analyzed expressed the neuronal marker TUJ1 and a high proportion of these cells were positive for TH, indicating differentiation into dopaminergic neurons. In contrast to H9 ES cells, the HNP cell lines did not form tumors in immunodeficient SCID/beige mice within 6 mo after subcutaneous injection. Similarly, no tumors developed after injection of MNP cells. Notably, mouse ES cells or neuronal cells directly differentiated from mouse ES cells formed teratomas in more than 90% of the recipients.
CONCLUSION: Our findings indicate that neural progenitor cell lines can differentiate into dopaminergic neurons and bear no risk of generating teratomas or other tumors in immunodeficient mice.
Collapse
|
|
46
|
Huang K, Liu P, Li X, Chen S, Wang L, Qin L, Su Z, Huang W, Liu J, Jia B, Liu J, Cai J, Pei D, Pan G. Neural progenitor cells from human induced pluripotent stem cells generated less autogenous immune response. SCIENCE CHINA-LIFE SCIENCES 2014; 57:162-70. [PMID: 24443177 DOI: 10.1007/s11427-013-4598-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Accepted: 09/20/2013] [Indexed: 11/28/2022]
Abstract
The breakthrough development of induced pluripotent stem cells (iPSCs) raises the prospect of patient-specific treatment for many diseases through the replacement of affected cells. However, whether iPSC-derived functional cell lineages generate a deleterious immune response upon auto-transplantation remains unclear. In this study, we differentiated five human iPSC lines from skin fibroblasts and urine cells into neural progenitor cells (NPCs) and analyzed their immunogenicity. Through co-culture with autogenous peripheral blood mononuclear cells (PBMCs), we showed that both somatic cells and iPSC-derived NPCs do not stimulate significant autogenous PBMC proliferation. However, a significant immune reaction was detected when these cells were co-cultured with allogenous PBMCs. Furthermore, no significant expression of perforin or granzyme B was detected following stimulation of autogenous immune effector cells (CD3(+)CD8(-) T cells, CD3(+)CD8(+) T cells or CD3(-)CD56(+) NK cells) by NPCs in both PBMC and T cell co-culture systems. These results suggest that human iPSC-derived NPCs may not initiate an immune response in autogenous transplants, and thus set a base for further preclinical evaluation of human iPSCs.
Collapse
Affiliation(s)
- Ke Huang
- Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Ji W, Hu S, Zhou J, Wang G, Wang K, Zhang Y. Tissue engineering is a promising method for the repair of spinal cord injuries (Review). Exp Ther Med 2013; 7:523-528. [PMID: 24520240 PMCID: PMC3919911 DOI: 10.3892/etm.2013.1454] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 12/10/2013] [Indexed: 12/23/2022] Open
Abstract
Spinal cord injury (SCI) may lead to a devastating and permanent loss of neurological function, which may place a great economic burden on the family of the patient and society. Methods for reducing the death of neuronal cells, inhibiting immune and inflammatory reactions, and promoting the growth of axons in order to build up synapses with the target cells are the focus of current research. Target cells are located in the damaged spinal cord which create a connect with the scaffold. As tissue engineering technology is developed for use in a variety of different areas, particularly the biomedical field, a clear understanding of the mechanisms of tissue engineering is important. This review establishes how this technology may be used in basic experiments with regard to SCI and considers its potential future clinical use.
Collapse
Affiliation(s)
- Wenchen Ji
- Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China ; Department of Physiology, College of Medicine, University of Sydney, Sydney 2006, Australia
| | - Shouye Hu
- Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jiao Zhou
- Department of Surgery, The Third Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710068, P.R. China
| | - Gang Wang
- Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Kunzheng Wang
- Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yuelin Zhang
- Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| |
Collapse
|
|
48
|
|
|
49
|
Characterization of induced neural progenitors from skin fibroblasts by a novel combination of defined factors. Sci Rep 2013; 3:1345. [PMID: 23439431 PMCID: PMC3581826 DOI: 10.1038/srep01345] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Accepted: 02/12/2013] [Indexed: 12/17/2022] Open
Abstract
Recent reports have demonstrated that somatic cells can be directly converted to other differentiated cell types through ectopic expression of sets of transcription factors, directly avoiding the transition through a pluripotent state. Our previous experiments generated induced neural progenitor-like cells (iNPCs) by a novel combination of five transcription factors (Sox2, Brn2, TLX, Bmi1 and c-Myc). Here we demonstrated that the iNPCs not only possess NPC-specific marker genes, but also have qualities of primary brain-derived NPCs (WT-NPCs), including tripotent differentiation potential, mature neuron differentiation capability and synapse formation. Importantly, the mature neurons derived from iNPCs exhibit significant physiological properties, such as potassium channel activity and generation of action potential-like spikes. These results suggest that directly reprogrammed iNPCs closely resemble WT-NPCs, which may suggest an alternative strategy to overcome the restricted proliferative and lineage potential of induced neurons (iNCs) and broaden applications of cell therapy in the treatment of neurodegenerative disorders.
Collapse
|
|
50
|
3D graphene oxide-encapsulated gold nanoparticles to detect neural stem cell differentiation. Biomaterials 2013; 34:8660-70. [PMID: 23937915 DOI: 10.1016/j.biomaterials.2013.07.101] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 07/28/2013] [Indexed: 11/21/2022]
Abstract
Monitoring of stem cell differentiation and pluripotency is an important step for the practical use of stem cells in the field of regenerative medicine. Hence, a new non-destructive detection tool capable of in situ monitoring of stem cell differentiation is highly needed. In this study, we report a 3D graphene oxide-encapsulated gold nanoparticle that is very effective for the detection of the differentiation potential of neural stem cells (NSCs) based on surface-enhanced Raman spectroscopy (SERS). A new material, 3D GO-encapsulated gold nanoparticle, is developed to induce the double enhancement effect of graphene oxide and gold nanoparticle on SERS signals which is only effective for undifferentiated NSCs. The Raman peaks achieved from undifferentiated NSCs on the graphene oxide (GO)-encapsulated gold nanoparticles were 3.5 times higher than peaks obtained from normal metal structures and were clearly distinguishable from those of differentiated cells. The number of CC bonds and the Raman intensity at 1656 cm(-1) was found to show a positive correlation, which matches the differentiation state of the NSCs. Moreover, the substrate composed of 3D GO-encapsulated gold nanoparticles was also effective at distinguishing the differentiation state of single NSC by using electrochemical and electrical techniques. Hence, the proposed technique can be used as a powerful non-destructive in situ monitoring tool for the identification of the differentiation potential of various kinds of stem cells (mesenchymal, hematopoietic, and neural stem cells).
Collapse
|