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Kelley KW, Revah O, Gore F, Kaganovsky K, Chen X, Deisseroth K, Pașca SP. Host circuit engagement of human cortical organoids transplanted in rodents. Nat Protoc 2024; 19:3542-3567. [PMID: 39075308 DOI: 10.1038/s41596-024-01029-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 05/22/2024] [Indexed: 07/31/2024]
Abstract
Human neural organoids represent promising models for studying neural function; however, organoids grown in vitro lack certain microenvironments and sensory inputs that are thought to be essential for maturation. The transplantation of patient-derived neural organoids into animal hosts helps overcome some of these limitations and offers an approach for neural organoid maturation and circuit integration. Here, we describe a method for transplanting human stem cell-derived cortical organoids (hCOs) into the somatosensory cortex of newborn rats. The differentiation of human induced pluripotent stem cells into hCOs occurs over 30-60 days, and the transplantation procedure itself requires ~0.5-1 hours per animal. The use of neonatal hosts provides a developmentally appropriate stage for circuit integration and allows the generation and experimental manipulation of a unit of human neural tissue within the cortex of a living animal host. After transplantation, animals can be maintained for hundreds of days, and transplanted hCO growth can be monitored by using brain magnetic resonance imaging. We describe the assessment of human neural circuit function in vivo by monitoring genetically encoded calcium responses and extracellular activity. To demonstrate human neuron-host functional integration, we also describe a procedure for engaging host neural circuits and for modulating animal behavior by using an optogenetic behavioral training paradigm. The transplanted human neurons can then undergo ex vivo characterization across modalities including dendritic morphology reconstruction, single-nucleus transcriptomics, optogenetic manipulation and electrophysiology. This approach may enable the discovery of cellular phenotypes from patient-derived cells and uncover mechanisms that contribute to human brain evolution from previously inaccessible developmental stages.
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Affiliation(s)
- Kevin W Kelley
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
| | - Omer Revah
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
| | - Felicity Gore
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Konstantin Kaganovsky
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
| | - Xiaoyu Chen
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
| | - Karl Deisseroth
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Sergiu P Pașca
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
- Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
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2
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Svendsen SP, Svendsen CN. Cell therapy for neurological disorders. Nat Med 2024; 30:2756-2770. [PMID: 39407034 DOI: 10.1038/s41591-024-03281-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/30/2024] [Indexed: 10/18/2024]
Abstract
Cell therapies for neurological disorders are entering the clinic and present unique challenges and opportunities compared with conventional medicines. They have the potential to replace damaged nervous tissue and integrate into the brain or spinal cord to produce functional effects for the lifetime of the patient, which could revolutionize the way clinicians treat debilitating neurological disorders. The major challenge has been cell sourcing, which historically relied mainly on fetal brain tissue. This has largely been overcome with the advent of pluripotent stem cell technology and the ability to make almost any cell of the nervous system at scale. Furthermore, advances in gene editing now allow the generation of genetically modified cells that could perform better and evade the immune system. With all the remarkable new approaches to treat neurological disorders, we take a critical look at the state of current clinical trials and how challenges may be overcome with the evolving technology and innovation occurring in the stem cell field.
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Affiliation(s)
- Soshana P Svendsen
- Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA
| | - Clive N Svendsen
- Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
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3
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Chang Z, Wang QY, Li LH, Jiang B, Zhou XM, Zhu H, Sun YP, Pan X, Tu XX, Wang W, Liu CY, Kuang HX. Potential Plausible Role of Stem Cell for Treating Depressive Disorder: a Retrospective Review. Mol Neurobiol 2024; 61:4454-4472. [PMID: 38097915 DOI: 10.1007/s12035-023-03843-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/29/2023] [Indexed: 07/11/2024]
Abstract
Depression poses a significant threat to global physical and mental health, impacting around 3.8% of the population with a rising incidence. Current treatment options primarily involve medication and psychological support, yet their effectiveness remains limited, contributing to high relapse rates. There is an urgent need for innovative and more efficacious treatment modalities. Stem cell therapy, a promising avenue in regenerative medicine for a spectrum of neurodegenerative conditions, has recently garnered attention for its potential application in depression. While much of this work remains preclinical, it has demonstrated considerable promise. Identified mechanisms underlying the antidepressant effects of stem cell therapy encompass the stimulation of neurotrophic factors, immune function modulation, and augmented monoamine levels. Nonetheless, these pathways and other undiscovered mechanisms necessitate further investigation. Depression fundamentally manifests as a neurodegenerative disorder. Given stem cell therapy's success in addressing a range of neurodegenerative pathologies, it opens the door to explore its application in depression treatment. This exploration may include repairing damaged nerves directly or indirectly and inhibiting neurotoxicity. Nevertheless, significant challenges must be overcome before stem cell therapies can be applied clinically. Successful resolution of these issues will ultimately determine the feasibility of incorporating stem cell therapies into the clinical landscape. This narrative review provides insights into the progress of research, potential avenues for exploration, and the prevailing challenges in the implementation of stem cell therapy for treatment of depression.
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Affiliation(s)
- Zhuo Chang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Qing-Yi Wang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Lu-Hao Li
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Bei Jiang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Xue-Ming Zhou
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Hui Zhu
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Yan-Ping Sun
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Xue Pan
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xu-Xu Tu
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Wei Wang
- First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Chen-Yue Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hai-Xue Kuang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China.
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4
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Pereira MF, Shyti R, Testa G. In and out: Benchmarking in vitro, in vivo, ex vivo, and xenografting approaches for an integrative brain disease modeling pipeline. Stem Cell Reports 2024; 19:767-795. [PMID: 38865969 PMCID: PMC11390705 DOI: 10.1016/j.stemcr.2024.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 05/09/2024] [Accepted: 05/11/2024] [Indexed: 06/14/2024] Open
Abstract
Human cellular models and their neuronal derivatives have afforded unprecedented advances in elucidating pathogenic mechanisms of neuropsychiatric diseases. Notwithstanding their indispensable contribution, animal models remain the benchmark in neurobiological research. In an attempt to harness the best of both worlds, researchers have increasingly relied on human/animal chimeras by xenografting human cells into the animal brain. Despite the unparalleled potential of xenografting approaches in the study of the human brain, literature resources that systematically examine their significance and advantages are surprisingly lacking. We fill this gap by providing a comprehensive account of brain diseases that were thus far subjected to all three modeling approaches (transgenic rodents, in vitro human lineages, human-animal xenografting) and provide a critical appraisal of the impact of xenografting approaches for advancing our understanding of those diseases and brain development. Next, we give our perspective on integrating xenografting modeling pipeline with recent cutting-edge technological advancements.
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Affiliation(s)
- Marlene F Pereira
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Via Santa Sofia 9, 20122 Milan, Italy; Neurogenomics Centre, Human Technopole, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy.
| | - Reinald Shyti
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy; Neurogenomics Centre, Human Technopole, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy.
| | - Giuseppe Testa
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Via Santa Sofia 9, 20122 Milan, Italy; Neurogenomics Centre, Human Technopole, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy.
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Lindvall O. History of cellular grafting for central nervous system repair-A clinical perspective. HANDBOOK OF CLINICAL NEUROLOGY 2024; 205:15-40. [PMID: 39341652 DOI: 10.1016/b978-0-323-90120-8.00011-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
As late as in the 1970s, the evidence supporting that brain function might be restored by replacing dead cells by transplantation of new healthy cells was scarce in experimental animals and lacking in humans. Repairing the human brain was regarded as completely unrealistic by clinicians. Fifty years later, the situation is very different, and cellular grafting has reached patient application in several conditions affecting the CNS. The clinical studies performed so far have shown that cellular grafts can survive, grow, and function also in the diseased adult human brain. However, no proven treatment based on cell transplantation is currently available for any brain disorder. Here, the history of cellular grafting is described from a clinical perspective, including some of the preclinical work that has formed the basis for its translation to patient application. The focus is on cell transplantation for Parkinson disease, which in many ways is paving the way for this field of research. The chapter gives an account of the scientific milestones, the ups and downs, as well as the positive and negative reactions from the scientific and clinical community, and how this research field despite many obstacles has continued to move forward over more than four decades.
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Affiliation(s)
- Olle Lindvall
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden; Division of Neurology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
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Harary PM, Jgamadze D, Kim J, Wolf JA, Song H, Ming GL, Cullen DK, Chen HI. Cell Replacement Therapy for Brain Repair: Recent Progress and Remaining Challenges for Treating Parkinson's Disease and Cortical Injury. Brain Sci 2023; 13:1654. [PMID: 38137103 PMCID: PMC10741697 DOI: 10.3390/brainsci13121654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/16/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
Neural transplantation represents a promising approach to repairing damaged brain circuitry. Cellular grafts have been shown to promote functional recovery through "bystander effects" and other indirect mechanisms. However, extensive brain lesions may require direct neuronal replacement to achieve meaningful restoration of function. While fetal cortical grafts have been shown to integrate with the host brain and appear to develop appropriate functional attributes, the significant ethical concerns and limited availability of this tissue severely hamper clinical translation. Induced pluripotent stem cell-derived cells and tissues represent a more readily scalable alternative. Significant progress has recently been made in developing protocols for generating a wide range of neural cell types in vitro. Here, we discuss recent progress in neural transplantation approaches for two conditions with distinct design needs: Parkinson's disease and cortical injury. We discuss the current status and future application of injections of dopaminergic cells for the treatment of Parkinson's disease as well as the use of structured grafts such as brain organoids for cortical repair.
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Affiliation(s)
- Paul M. Harary
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
| | - Dennis Jgamadze
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
| | - Jaeha Kim
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
| | - John A. Wolf
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA
| | - Hongjun Song
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Guo-li Ming
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - D. Kacy Cullen
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - H. Isaac Chen
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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7
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Oz T, Kaushik A, Kujawska M. Neural stem cells for Parkinson's disease management: Challenges, nanobased support, and prospects. World J Stem Cells 2023; 15:687-700. [PMID: 37545757 PMCID: PMC10401423 DOI: 10.4252/wjsc.v15.i7.687] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/27/2023] [Accepted: 05/16/2023] [Indexed: 07/25/2023] Open
Abstract
Parkinson's disease (PD), characterized by loss of nigrostriatal dopaminergic neurons, is one of the most predominant neurodegenerative diseases affecting the elderly population worldwide. The concept of stem cell therapy in managing neurodegenerative diseases has evolved over the years and has recently rapidly progressed. Neural stem cells (NSCs) have a few key features, including self-renewal, proliferation, and multipotency, which make them a promising agent targeting neurodegeneration. It is generally agreed that challenges for NSC-based therapy are present at every stage of the transplantation process, including preoperative cell preparation and quality control, perioperative procedures, and postoperative graft preservation, adherence, and overall therapy success. In this review, we provided a comprehensive, careful, and critical discussion of experimental and clinical data alongside the pros and cons of NSC-based therapy in PD. Given the state-of-the-art accomplishments of stem cell therapy, gene therapy, and nanotechnology, we shed light on the perspective of complementing the advantages of each process by developing nano-stem cell therapy, which is currently a research hotspot. Although various obstacles and challenges remain, nano-stem cell therapy holds promise to cure PD, however, continuous improvement and development from the stage of laboratory experiments to the clinical application are necessary.
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Affiliation(s)
- Tuba Oz
- Department of Toxicology, Poznan University of Medical Sciences, Poznan 60-631, Poland
| | - Ajeet Kaushik
- NanoBioTech Laboratory, Health System Engineering, Department of Environmental Engineering, Florida Polytechnic University, Lakeland, FL 33805, United States
- School of Engineering, University of Petroleum and Energy Studies, Dehradun 248007, India
| | - Małgorzata Kujawska
- Department of Toxicology, Poznan University of Medical Sciences, Poznan 60-631, Poland.
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Nakamura R, Nonaka R, Oyama G, Jo T, Kamo H, Nuermaimaiti M, Akamatsu W, Ishikawa KI, Hattori N. A defined method for differentiating human iPSCs into midbrain dopaminergic progenitors that safely restore motor deficits in Parkinson's disease. Front Neurosci 2023; 17:1202027. [PMID: 37502682 PMCID: PMC10368972 DOI: 10.3389/fnins.2023.1202027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 06/20/2023] [Indexed: 07/29/2023] Open
Abstract
Background Parkinson's disease (PD) is a progressive neurodegenerative condition that primarily affects motor functions; it is caused by the loss of midbrain dopaminergic (mDA) neurons. The therapeutic effects of transplanting human-induced pluripotent stem cell (iPSC)-derived mDA neural progenitor cells in animal PD models are known and are being evaluated in an ongoing clinical trial. However, However, improvements in the safety and efficiency of differentiation-inducing methods are crucial for providing a larger scale of cell therapy studies. This study aimed to investigate the usefulness of dopaminergic progenitor cells derived from human iPSCs by our previously reported method, which promotes differentiation and neuronal maturation by treating iPSCs with three inhibitors at the start of induction. Methods Healthy subject-derived iPS cells were induced into mDA progenitor cells by the CTraS-mediated method we previously reported, and their proprieties and dopaminergic differentiation efficiency were examined in vitro. Then, the induced mDA progenitors were transplanted into 6-hydroxydopamine-lesioned PD model mice, and their efficacy in improving motor function, cell viability, and differentiation ability in vivo was evaluated for 16 weeks. Results Approximately ≥80% of cells induced by this method without sorting expressed mDA progenitor markers and differentiated primarily into A9 dopaminergic neurons in vitro. After transplantation in 6-hydroxydopamine-lesioned PD model mice, more than 90% of the engrafted cells differentiated into the lineage of mDA neurons, and approximately 15% developed into mature mDA neurons without tumour formation. The grafted PD model mice also demonstrated significantly improved motor functions. Conclusion This study suggests that the differentiation protocol for the preparation of mDA progenitors is a promising option for cell therapy in patients with PD.
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Affiliation(s)
- Ryota Nakamura
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
| | - Risa Nonaka
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
- Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Medicine, Juntendo University, Tokyo, Japan
- Department of Clinical Data of Parkinson’s Disease, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Genko Oyama
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
| | - Takayuki Jo
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
| | - Hikaru Kamo
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
| | - Maierdanjiang Nuermaimaiti
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
- Department of Clinical Data of Parkinson’s Disease, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Wado Akamatsu
- Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Kei-ichi Ishikawa
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
- Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan
- Department of Research and Development for Organoids, School of Medicine, Juntendo University, Tokyo, Japan
| | - Nobutaka Hattori
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
- Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Medicine, Juntendo University, Tokyo, Japan
- Department of Clinical Data of Parkinson’s Disease, Graduate School of Medicine, Juntendo University, Tokyo, Japan
- Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan
- Department of Research and Development for Organoids, School of Medicine, Juntendo University, Tokyo, Japan
- Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, Saitama, Japan
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Rodríguez-Pallares J, Labandeira-García J, García-Garrote M, Parga J. Combined cell-based therapy strategies for the treatment of Parkinson’s disease: focus on mesenchymal stromal cells. Neural Regen Res 2023; 18:478-484. [DOI: 10.4103/1673-5374.350193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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10
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Xue J, Wu Y, Bao Y, Zhao M, Li F, Sun J, Sun Y, Wang J, Chen L, Mao Y, Schweitzer JS, Song B. Clinical considerations in Parkinson's disease cell therapy. Ageing Res Rev 2023; 83:101792. [PMID: 36402405 DOI: 10.1016/j.arr.2022.101792] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 11/13/2022] [Accepted: 11/13/2022] [Indexed: 11/18/2022]
Abstract
Cell replacement therapy is an area of increasing interest for treating Parkinson's disease (PD). However, to become a clinically practical option for PD patients, it must first overcome significant barriers, including establishment of safe and standardized surgical procedures, determination of appropriate perioperative medication regimens, demonstration of long-term graft survival and incorporation, and standardized, clinically meaningful follow-up measures. In this review, we will describe the current status of cell therapy for PD with special attention to these critical requirements, to define guideposts on the road to bring the benefit of this therapy to the Parkinson's clinic.
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Affiliation(s)
- Jun Xue
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
| | - Yifan Wu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
| | - Yuting Bao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
| | - Minglai Zhao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
| | - Fangzhou Li
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
| | - Jing Sun
- Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China
| | - Yimin Sun
- Institute of Neurology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jian Wang
- Institute of Neurology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Liang Chen
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China.
| | - Jeffrey S Schweitzer
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
| | - Bin Song
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China.
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11
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Zhang L, Zhang X, Ji R, Ji Y, Wu Y, Ding X, Shang Z, Liu X, Li W, Guo J, Wang J, Cheng X, Qin J, Tian M, Jin G, Zhang X. Lama2 And Samsn1 Mediate the Effects of Brn4 on Hippocampal Neural Stem Cell Proliferation and Differentiation. Stem Cells Int 2023; 2023:7284986. [PMID: 37091532 PMCID: PMC10118897 DOI: 10.1155/2023/7284986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 01/14/2023] [Accepted: 03/20/2023] [Indexed: 04/25/2023] Open
Abstract
The transcription factor Brn4 exhibits vital roles in the embryonic development of the neural tube, inner ear, pancreas islet, and neural stem cell differentiation. Our previous studies have shown that Brn4 promotes neuronal differentiation of hippocampal neural stem cells (NSCs). However, its mechanism is still unclear. Here, starting from the overlapping genes between RNA-seq and ChIP-seq results, we explored the downstream target genes that mediate Brn4-induced hippocampal neurogenesis. There were 16 genes at the intersection of RNA-seq and ChIP-seq, among which the Lama2 and Samsn1 levels can be upregulated by Brn4, and the combination between their promoters and Brn4 was further determined using ChIP and dual luciferase reporter gene assays. EdU incorporation, cell cycle analysis, and CCK-8 assay indicated that Lama2 and Samsn1 mediated the inhibitory effect of Brn4 on the proliferation of hippocampal NSCs. Immunofluorescence staining, RT-qPCR, and Western blot suggested that Lama2 and Samsn1 mediated the promoting effect of Brn4 on the differentiation of hippocampal NSCs into neurons. In conclusion, our study demonstrates that Brn4 binds to the promoters of Lama2 and Samsn1, and they partially mediate the regulation of Brn4 on the proliferation inhibition and neuronal differentiation promotion of hippocampal NSCs.
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Affiliation(s)
- Lei Zhang
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Xunrui Zhang
- Faculty of Medicine, Xinglin College, Nantong University, Nantong, China
| | - Ruijie Ji
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Yaya Ji
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Yuhang Wu
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Xiuyu Ding
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Zhiying Shang
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Xueyuan Liu
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Wen Li
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Jingjing Guo
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Jue Wang
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Xiang Cheng
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Jianbing Qin
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Meiling Tian
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Guohua Jin
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Xinhua Zhang
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
- Central Lab, Yancheng Third People's Hospital, The Sixth Affiliated Hospital of Nantong University, Yancheng 224002, China
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12
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Behl T, Kaur I, Sehgal A, Singh S, Sharma N, Chigurupati S, Felemban SG, Alsubayiel AM, Iqbal MS, Bhatia S, Al-Harrasi A, Bungau S, Mostafavi E. "Cutting the Mustard" with Induced Pluripotent Stem Cells: An Overview and Applications in Healthcare Paradigm. Stem Cell Rev Rep 2022; 18:2757-2780. [PMID: 35793037 DOI: 10.1007/s12015-022-10390-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2022] [Indexed: 12/09/2022]
Abstract
Treatment of numerous ailments has been made accessible by the advent of genetic engineering, where the self-renewal property has unfolded the mysteries of regeneration, i.e., stem cells. This is narrowed down to pluripotency, the cell property of differentiating into other adult cells. The generation of induced pluripotent stem cells (iPSCs) was a major breakthrough in 2006, which was generated by a cocktail of 4 Yamanaka Factors, following which significant advancements have been reported in medical science and therapeutics. The iPSCs are reprogrammed from somatic cells, and the fascinating results focused on developing authentic techniques for their generation via molecular reprogramming mechanisms, with a plethora of molecules, like NANOG, miRNAs, and DNA modifying agents, etc. The iPSCs have exhibited reliable results in assessing the etiology and molecular mechanisms of diseases, followed by the development of possible treatments and the elimination of risks of immune rejection. The authors formulate a comprehensive review to develop a clear understanding of iPSC generation, their advantages and limitations, with potential challenges associated with their medical utility. In addition, a wide compendium of applications of iPSCs in regenerative medicine and disease modeling has been discussed, alongside bioengineering technologies for iPSC reprogramming, expansion, isolation, and differentiation. The manuscript aims to provide a holistic picture of the booming advancement of iPSC therapy, to attract the attention of global researchers, to investigate this versatile approach in treatment of multiple disorders, subsequently overcoming the challenges, in order to effectively expand its therapeutic window.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
| | - Ishnoor Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Sridevi Chigurupati
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah, Kingdom of Saudi Arabia
| | - Shatha Ghazi Felemban
- Department of Medical Laboratory Science, Fakeeh College for Medical Sciences, Jeddah, Kingdom of Saudi Arabia
| | - Amal M Alsubayiel
- Department of Pharmaceutics, College of Pharmacy, Qassim University, Buraydah, Kingdom of Saudi Arabia
| | - Muhammad Shahid Iqbal
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
- School of Health Science, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
| | - Ebrahim Mostafavi
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
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13
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Zayed MA, Sultan S, Alsaab HO, Yousof SM, Alrefaei GI, Alsubhi NH, Alkarim S, Al Ghamdi KS, Bagabir SA, Jana A, Alghamdi BS, Atta HM, Ashraf GM. Stem-Cell-Based Therapy: The Celestial Weapon against Neurological Disorders. Cells 2022; 11:3476. [PMID: 36359871 PMCID: PMC9655836 DOI: 10.3390/cells11213476] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/15/2022] [Accepted: 10/24/2022] [Indexed: 09/01/2023] Open
Abstract
Stem cells are a versatile source for cell therapy. Their use is particularly significant for the treatment of neurological disorders for which no definitive conventional medical treatment is available. Neurological disorders are of diverse etiology and pathogenesis. Alzheimer's disease (AD) is caused by abnormal protein deposits, leading to progressive dementia. Parkinson's disease (PD) is due to the specific degeneration of the dopaminergic neurons causing motor and sensory impairment. Huntington's disease (HD) includes a transmittable gene mutation, and any treatment should involve gene modulation of the transplanted cells. Multiple sclerosis (MS) is an autoimmune disorder affecting multiple neurons sporadically but induces progressive neuronal dysfunction. Amyotrophic lateral sclerosis (ALS) impacts upper and lower motor neurons, leading to progressive muscle degeneration. This shows the need to try to tailor different types of cells to repair the specific defect characteristic of each disease. In recent years, several types of stem cells were used in different animal models, including transgenic animals of various neurologic disorders. Based on some of the successful animal studies, some clinical trials were designed and approved. Some studies were successful, others were terminated and, still, a few are ongoing. In this manuscript, we aim to review the current information on both the experimental and clinical trials of stem cell therapy in neurological disorders of various disease mechanisms. The different types of cells used, their mode of transplantation and the molecular and physiologic effects are discussed. Recommendations for future use and hopes are highlighted.
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Affiliation(s)
- Mohamed A. Zayed
- Physiology Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Physiology Department, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
| | - Samar Sultan
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Regenerative Medicine Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Hashem O. Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Shimaa Mohammad Yousof
- Physiology Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Medical Physiology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Ghadeer I. Alrefaei
- Department of Biology, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia
| | - Nouf H. Alsubhi
- Department of Biological Sciences, College of Science & Arts, King Abdulaziz University, Rabigh 21911, Saudi Arabia
| | - Saleh Alkarim
- Embryonic and Cancer Stem Cell Research Group, King Fahad Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Biology Department, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Embryonic Stem Cells Research Unit, Biology Department, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Kholoud S. Al Ghamdi
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Sali Abubaker Bagabir
- Genetic Unit, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Ankit Jana
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Campus-11, Patia, Bhubaneswar 751024, Odisha, India
| | - Badrah S. Alghamdi
- Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Hazem M. Atta
- Clinical Biochemistry Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
| | - Ghulam Md Ashraf
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, University City, Sharjah 27272, United Arab Emirates
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14
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Montemurro N, Aliaga N, Graff P, Escribano A, Lizana J. New Targets and New Technologies in the Treatment of Parkinson's Disease: A Narrative Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:8799. [PMID: 35886651 PMCID: PMC9321220 DOI: 10.3390/ijerph19148799] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/16/2022] [Accepted: 07/18/2022] [Indexed: 02/06/2023]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disease, whose main neuropathological finding is pars compacta degeneration due to the accumulation of Lewy bodies and Lewy neurites, and subsequent dopamine depletion. This leads to an increase in the activity of the subthalamic nucleus (STN) and the internal globus pallidus (GPi). Understanding functional anatomy is the key to understanding and developing new targets and new technologies that could potentially improve motor and non-motor symptoms in PD. Currently, the classical targets are insufficient to improve the entire wide spectrum of symptoms in PD (especially non-dopaminergic ones) and none are free of the side effects which are not only associated with the procedure, but with the targets themselves. The objective of this narrative review is to show new targets in DBS surgery as well as new technologies that are under study and have shown promising results to date. The aim is to give an overview of these new targets, as well as their limitations, and describe the current studies in this research field in order to review ongoing research that will probably become effective and routine treatments for PD in the near future.
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Affiliation(s)
- Nicola Montemurro
- Department of Neurosurgery, Azienda Ospedaliera Universitaria Pisana (AOUP), University of Pisa, 56100 Pisa, Italy
| | - Nelida Aliaga
- Medicine Faculty, Austral University, Buenos Aires B1406, Argentina; (N.A.); (A.E.)
| | - Pablo Graff
- Functional Neurosurgery Program, Department of Neurosurgery, San Miguel Arcángel Hospital, Buenos Aires B1406, Argentina;
| | - Amanda Escribano
- Medicine Faculty, Austral University, Buenos Aires B1406, Argentina; (N.A.); (A.E.)
| | - Jafeth Lizana
- Department of Neurosurgery, Hospital Nacional Guillermo Almenara Irigoyen, Lima 07035, Peru;
- Medicine Faculty, Universidad Nacional Mayor de San Marcos, Lima 07035, Peru
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15
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Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson's disease. NPJ Regen Med 2022; 7:24. [PMID: 35449132 PMCID: PMC9023503 DOI: 10.1038/s41536-022-00221-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 03/22/2022] [Indexed: 12/25/2022] Open
Abstract
In pursuit of treating Parkinson’s disease with cell replacement therapy, differentiated induced pluripotent stem cells (iPSC) are an ideal source of midbrain dopaminergic (mDA) cells. We previously established a protocol for differentiating iPSC-derived post-mitotic mDA neurons capable of reversing 6-hydroxydopamine-induced hemiparkinsonism in rats. In the present study, we transitioned the iPSC starting material and defined an adapted differentiation protocol for further translation into a clinical cell transplantation therapy. We examined the effects of cellular maturity on survival and efficacy of the transplants by engrafting mDA progenitors (cryopreserved at 17 days of differentiation, D17), immature neurons (D24), and post-mitotic neurons (D37) into immunocompromised hemiparkinsonian rats. We found that D17 progenitors were markedly superior to immature D24 or mature D37 neurons in terms of survival, fiber outgrowth and effects on motor deficits. Intranigral engraftment to the ventral midbrain demonstrated that D17 cells had a greater capacity than D24 cells to innervate over long distance to forebrain structures, including the striatum. When D17 cells were assessed across a wide dose range (7,500-450,000 injected cells per striatum), there was a clear dose response with regards to numbers of surviving neurons, innervation, and functional recovery. Importantly, although these grafts were derived from iPSCs, we did not observe teratoma formation or significant outgrowth of other cells in any animal. These data support the concept that human iPSC-derived D17 mDA progenitors are suitable for clinical development with the aim of transplantation trials in patients with Parkinson’s disease.
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16
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Li JY, Li W. Postmortem Studies of Fetal Grafts in Parkinson's Disease: What Lessons Have We Learned? Front Cell Dev Biol 2021; 9:666675. [PMID: 34055800 PMCID: PMC8155361 DOI: 10.3389/fcell.2021.666675] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/06/2021] [Indexed: 12/28/2022] Open
Abstract
Neural transplantation is a potential therapeutic method for Parkinson’s disease (PD). Fetal dopaminergic (DA) neurons have been important transplantation cell sources in the history of replacement therapy for PD. Several decades of preclinical animal experiments and clinical trials using fetal DA neuron transplantation in PD therapy have shown not only promising results but also problems. In order to reveal possible factors influencing the clinical outcomes, we reviewed fetal DA neuron transplantation therapies from 1970s to present, with a special focus on postmortem studies. Firstly, we gave a general description of the clinical outcomes and neuroanatomy of grafted cases; secondly, we summarized the main available postmortem studies, including the cell survival, reinnervation, and pathology development. In the end, we further discussed the link between function and structure of the grafts, seeking for the possible factors contributing to a functional graft. With our review, we hope to provide references for future transplantation trials from a histological point of view.
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Affiliation(s)
- Jia-Yi Li
- Laboratory of Neurodegenerative Diseases and Repair, Institute of Health Sciences, China Medical University, Shenyang, China.,Neural Plasticity and Repair Unit, Wallenberg Neuroscience Centre, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Wen Li
- Laboratory of Neurodegenerative Diseases and Repair, Institute of Health Sciences, China Medical University, Shenyang, China.,Neural Plasticity and Repair Unit, Wallenberg Neuroscience Centre, Department of Experimental Medical Science, Lund University, Lund, Sweden
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17
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Barbuti PA, Barker RA, Brundin P, Przedborski S, Papa SM, Kalia LV, Mochizuki H. Recent Advances in the Development of Stem-Cell-Derived Dopaminergic Neuronal Transplant Therapies for Parkinson's Disease. Mov Disord 2021; 36:1772-1780. [PMID: 33963552 DOI: 10.1002/mds.28628] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 12/16/2022] Open
Abstract
The last decade has seen exciting advances in the development of potential stem cell-based therapies for Parkinson's disease (PD), which have used different types of stem cells as starting material. These cells have been developed primarily to replace dopamine-producing neurons in the substantia nigra that are progressively lost in the disease process. The aim is to largely restore lost motor functions, whilst not ever being curative. We discuss cell-based strategies that will have to fulfill important criteria to become effective and competitive therapies for PD. These criteria include reproducibly producing sufficient numbers of cells with an authentic substantia nigra dopamine neuron A9 phenotype, which can integrate into the host brain after transplantation and form synapses (considered crucial for long-term functional benefits). Furthermore, it is essential that transplanted cells exhibit no, or only very low levels of, proliferation without tumor formation at the site of grafting. Cumulative research has shown that stem cell-based approaches continue to have great potential in PD, but key questions remain to be answered. Here, we review the most recent progress in research on stem cell-based dopamine neuron replacement therapy for PD and briefly discuss what the immediate future might hold. © 2021 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Peter A Barbuti
- Departments of Neurology, Pathology and Cell Biology, and Neuroscience, Columbia University, New York, New York, USA
| | - Roger A Barker
- Department of Clinical Neuroscience and WT-MRC Cambridge Stem Cell Institute, University of Cambridge and Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Patrik Brundin
- Van Andel Institute, Center for Parkinson's Disease, Department of Neurodegenerative Science, Grand Rapids, Michigan, USA
| | - Serge Przedborski
- Departments of Neurology, Pathology and Cell Biology, and Neuroscience, Columbia University, New York, New York, USA
| | - Stella M Papa
- Yerkes National Primate Research Center and Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Lorraine V Kalia
- Division of Neurology, Department of Medicine, Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Hideki Mochizuki
- Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan
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18
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Neuromodulation-Based Stem Cell Therapy in Brain Repair: Recent Advances and Future Perspectives. Neurosci Bull 2021; 37:735-745. [PMID: 33871821 DOI: 10.1007/s12264-021-00667-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/28/2020] [Indexed: 02/07/2023] Open
Abstract
Stem cell transplantation holds a promising future for central nervous system repair. Current challenges, however, include spatially and temporally defined cell differentiation and maturation, plus the integration of transplanted neural cells into host circuits. Here we discuss the potential advantages of neuromodulation-based stem cell therapy, which can improve the viability and proliferation of stem cells, guide migration to the repair site, orchestrate the differentiation process, and promote the integration of neural circuitry for functional rehabilitation. All these advantages of neuromodulation make it one potentially valuable tool for further improving the efficiency of stem cell transplantation.
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19
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Aldewachi H, Al-Zidan RN, Conner MT, Salman MM. High-Throughput Screening Platforms in the Discovery of Novel Drugs for Neurodegenerative Diseases. Bioengineering (Basel) 2021; 8:30. [PMID: 33672148 PMCID: PMC7926814 DOI: 10.3390/bioengineering8020030] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/05/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative diseases (NDDs) are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells in the central nervous system (CNS). Identification of viable therapeutic targets and new treatments for CNS disorders and in particular, for NDDs is a major challenge in the field of drug discovery. These difficulties can be attributed to the diversity of cells involved, extreme complexity of the neural circuits, the limited capacity for tissue regeneration, and our incomplete understanding of the underlying pathological processes. Drug discovery is a complex and multidisciplinary process. The screening attrition rate in current drug discovery protocols mean that only one viable drug may arise from millions of screened compounds resulting in the need to improve discovery technologies and protocols to address the multiple causes of attrition. This has identified the need to screen larger libraries where the use of efficient high-throughput screening (HTS) becomes key in the discovery process. HTS can investigate hundreds of thousands of compounds per day. However, if fewer compounds could be screened without compromising the probability of success, the cost and time would be largely reduced. To that end, recent advances in computer-aided design, in silico libraries, and molecular docking software combined with the upscaling of cell-based platforms have evolved to improve screening efficiency with higher predictability and clinical applicability. We review, here, the increasing role of HTS in contemporary drug discovery processes, in particular for NDDs, and evaluate the criteria underlying its successful application. We also discuss the requirement of HTS for novel NDD therapies and examine the major current challenges in validating new drug targets and developing new treatments for NDDs.
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Affiliation(s)
- Hasan Aldewachi
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK;
- College of Pharmacy, Nineveh University, Mosul 41002, Iraq
| | - Radhwan N. Al-Zidan
- College of Pharmacy, University of Mosul, Mosul 41002, Iraq;
- School of Applied Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK
| | - Matthew T. Conner
- School of Sciences, Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton WV1 1LY, UK;
| | - Mootaz M. Salman
- College of Pharmacy, University of Mosul, Mosul 41002, Iraq;
- Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
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20
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Katolikova NV, Malashicheva AB, Gainetdinov RR. Cell Replacement Therapy in Parkinson’s Disease—History of Development and Prospects for Use in Clinical Practice. Mol Biol 2021. [DOI: 10.1134/s0026893320060060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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21
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Modelling Neuromuscular Diseases in the Age of Precision Medicine. J Pers Med 2020; 10:jpm10040178. [PMID: 33080928 PMCID: PMC7712305 DOI: 10.3390/jpm10040178] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 12/20/2022] Open
Abstract
Advances in knowledge resulting from the sequencing of the human genome, coupled with technological developments and a deeper understanding of disease mechanisms of pathogenesis are paving the way for a growing role of precision medicine in the treatment of a number of human conditions. The goal of precision medicine is to identify and deliver effective therapeutic approaches based on patients’ genetic, environmental, and lifestyle factors. With the exception of cancer, neurological diseases provide the most promising opportunity to achieve treatment personalisation, mainly because of accelerated progress in gene discovery, deep clinical phenotyping, and biomarker availability. Developing reproducible, predictable and reliable disease models will be key to the rapid delivery of the anticipated benefits of precision medicine. Here we summarize the current state of the art of preclinical models for neuromuscular diseases, with particular focus on their use and limitations to predict safety and efficacy treatment outcomes in clinical trials.
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22
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Jang SE, Qiu L, Chan LL, Tan EK, Zeng L. Current Status of Stem Cell-Derived Therapies for Parkinson's Disease: From Cell Assessment and Imaging Modalities to Clinical Trials. Front Neurosci 2020; 14:558532. [PMID: 33177975 PMCID: PMC7596695 DOI: 10.3389/fnins.2020.558532] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 09/17/2020] [Indexed: 12/23/2022] Open
Abstract
Curative therapies or treatments reversing the progression of Parkinson’s disease (PD) have attracted considerable interest in the last few decades. PD is characterized by the gradual loss of dopaminergic (DA) neurons and decreased striatal dopamine levels. Current challenges include optimizing neuroprotective strategies, developing personalized drug therapy, and minimizing side effects from the long-term prescription of pharmacological drugs used to relieve short-term motor symptoms. Transplantation of DA cells into PD patients’ brains to replace degenerated DA has the potential to change the treatment paradigm. Herein, we provide updates on current progress in stem cell-derived DA neuron transplantation as a therapeutic alternative for PD. We briefly highlight cell sources for transplantation and focus on cell assessment methods such as identification of genetic markers, single-cell sequencing, and imaging modalities used to access cell survival and function. More importantly, we summarize clinical reports of patients who have undergone cell-derived transplantation in PD to better perceive lessons that can be drawn from past and present clinical outcomes. Modifying factors include (1) source of the stem cells, (2) quality of the stem cells, (3) age of the patient, (4) stage of disease progression at the time of cell therapy, (5) surgical technique/practices, and (6) the use of immunosuppression. We await the outcomes of joint efforts in clinical trials around the world such as NYSTEM and CiRA to further guide us in the selection of the most suitable parameters for cell-based neurotransplantation in PD.
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Affiliation(s)
- Se Eun Jang
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore, Singapore
| | - Lifeng Qiu
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore, Singapore
| | - Ling Ling Chan
- Department of Diagnostic Radiology, Singapore General Hospital, Singapore, Singapore.,Neuroscience & Behavioral Disorders Program, Duke University and National University of Singapore (DUKE-NUS), Graduate Medical School, Singapore, Singapore
| | - Eng-King Tan
- Neuroscience & Behavioral Disorders Program, Duke University and National University of Singapore (DUKE-NUS), Graduate Medical School, Singapore, Singapore.,Department of Neurology, National Neuroscience Institute, Singapore General Hospital Campus, Singapore, Singapore
| | - Li Zeng
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore, Singapore.,Neuroscience & Behavioral Disorders Program, Duke University and National University of Singapore (DUKE-NUS), Graduate Medical School, Singapore, Singapore.,Lee Kong Chian School of Medicine, Nanyang Technological University, Novena Campus, Singapore, Singapore
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23
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Chung YG, Seay M, Elsworth JD, Redmond DE. Generation of Pluripotent Stem Cells Using Somatic Cell Nuclear Transfer and Induced Pluripotent Somatic Cells from African Green Monkeys. Stem Cells Dev 2020; 29:1294-1307. [PMID: 32715987 DOI: 10.1089/scd.2020.0059] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Patient-specific stem cells derived from somatic cell nuclear transfer (SCNT) embryos or from induced pluripotent stem cells (iPSCs) could be used to treat various diseases with minimal immune rejection. Many studies using these cells have been conducted in rats and mice; however, there exist numerous dissimilarities between the rodents and humans limiting the clinical predictive power and experimental utility of rodent experiments alone. Nonhuman primates (NHPs) share greater homology to human than rodents in all respects, including genomics, physiology, biochemistry, and the immune system. Thus, experimental data obtained from monkey studies would be more predictive for designing an effective cell replacement therapy in humans. Unfortunately, there are few iPSC lines and even fewer SCNT lines that have been derived in NHPs, hampering broader studies in regenerative medicine. One promising potential therapy would be the replacement of dopamine neurons that are lost in Parkinson's disease. After dopamine depletion by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the African green monkey (Chlorocebus sabaeus) shows the most complete model of Parkinsonism compared with other species and brain pathology and behavioral changes are almost identical to those in humans after accidental exposure to MPTP. Therefore, we have developed a SCNT procedure to generate multiple pluripotent stem cell lines in this species for studies of possible treatment of Parkinsonism and for comparing with cells derived from iPSCs. Using 24 female monkeys as egg donors and 7 somatic cell donor monkeys, we have derived 11 SCNT embryonic stem cell lines that expressed typical stemness genes and formed all three germ layer derivatives. We also derived two iPSC lines using an episome-mediated reprogramming factor delivery system. This report describes the process for deriving these cell lines and proving their pluripotency for differentiation into various potentially therapeutic cells.
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Affiliation(s)
- Young Gie Chung
- Enolc, Inc., Farmington, Connecticut, USA.,Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA.,Some of these data were presented in Poster 132.05 at the Society for Neuroscience, Chicago, Illinois, USA, 2019
| | - Montrell Seay
- Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA.,Some of these data were presented in Poster 132.05 at the Society for Neuroscience, Chicago, Illinois, USA, 2019
| | - John D Elsworth
- Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA.,Some of these data were presented in Poster 132.05 at the Society for Neuroscience, Chicago, Illinois, USA, 2019
| | - D Eugene Redmond
- Research Department, Axion Research Foundation, Hamden, Connecticut, USA.,Some of these data were presented in Poster 132.05 at the Society for Neuroscience, Chicago, Illinois, USA, 2019
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24
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Henchcliffe C, Sarva H. Restoring Function to Dopaminergic Neurons: Progress in the Development of Cell-Based Therapies for Parkinson's Disease. CNS Drugs 2020; 34:559-577. [PMID: 32472450 DOI: 10.1007/s40263-020-00727-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
There is escalating interest in cell-based therapies to restore lost dopamine inputs in Parkinson's disease. This is based upon the rationale that implanting dopamine progenitors into the striatum can potentially improve dopamine-responsive motor symptoms. A rich body of data describing clinical trials of previous cell transplantation exists. These have included multiple cell sources for transplantation including allogeneic (human embryonic mesencephalic tissue, retinal pigment epithelial cells) and autologous (carotid body, adrenal medullary tissue) cells, as well as xenotransplantation. However, there are multiple limitations related to these cell sources, including availability of adequate numbers of cells for transplant, heterogeneity within cells transplanted, imprecisely defined mechanisms of action, and poor cell survival after transplantation in some cases. Nonetheless, evidence has accrued from a subset of trials to support the rationale for such a regenerative approach. Recent rapid advances in stem cell technology may now overcome these prior limitations. For example, dopamine neuron precursor cells for transplant can be generated from induced pluripotent cells and human embryonic stem cells. The benefits of these innovative approaches include: the possibility of scalability; a high degree of quality control; and improved understanding of mechanisms of action with rigorous preclinical testing. In this review, we focus on the potential for cell-based therapies in Parkinson's disease to restore the function of dopaminergic neurons, we critically review previous attempts to harness such strategies, we discuss potential benefits and predicted limitations, and we address how previous roadblocks may be overcome to bring a cell-based approach to the clinic.
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Affiliation(s)
- Claire Henchcliffe
- Department of Neurology, Weill Medical College of Cornell University, 428 East 72nd Street, Suite 400, New York, NY, 10021, USA.
| | - Harini Sarva
- Department of Neurology, Weill Medical College of Cornell University, 428 East 72nd Street, Suite 400, New York, NY, 10021, USA
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25
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Singh MS, Park SS, Albini TA, Canto-Soler MV, Klassen H, MacLaren RE, Takahashi M, Nagiel A, Schwartz SD, Bharti K. Retinal stem cell transplantation: Balancing safety and potential. Prog Retin Eye Res 2020; 75:100779. [PMID: 31494256 PMCID: PMC7056514 DOI: 10.1016/j.preteyeres.2019.100779] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 08/29/2019] [Accepted: 09/02/2019] [Indexed: 12/14/2022]
Abstract
Stem cell transplantation holds great promise as a potential treatment for currently incurable retinal degenerative diseases that cause poor vision and blindness. Recently, safety data have emerged from several Phase I/II clinical trials of retinal stem cell transplantation. These clinical trials, usually run in partnership with academic institutions, are based on sound preclinical studies and are focused on patient safety. However, reports of serious adverse events arising from cell therapy in other poorly regulated centers have now emerged in the lay and scientific press. While progress in stem cell research for blindness has been greeted with great enthusiasm by patients, scientists, doctors and industry alike, these adverse events have raised concerns about the safety of retinal stem cell transplantation and whether patients are truly protected from undue harm. The aim of this review is to summarize and appraise the safety of human retinal stem cell transplantation in the context of its potential to be developed into an effective treatment for retinal degenerative diseases.
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Affiliation(s)
- Mandeep S Singh
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
| | - Susanna S Park
- Department of Ophthalmology & Vision Science, University of California-Davis Eye Center, Sacramento, CA, 95817, USA
| | - Thomas A Albini
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - M Valeria Canto-Soler
- CellSight Ocular Stem Cell and Regeneration Research Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Henry Klassen
- Gavin Herbert Eye Institute and Stem Cell Research Center, Irvine, CA, 92697, USA
| | - Robert E MacLaren
- Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford and Oxford University Eye Hospital, NHS Foundation Trust, NIHR Biomedical Research Centre, Oxford, OX3 9DU, UK
| | - Masayo Takahashi
- Laboratory for Retinal Regeneration, Center for Biosystems Dynamics Research, RIKEN, Kobe, Hyogo, 650-0047, Japan
| | - Aaron Nagiel
- The Vision Center, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA; USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90007, USA
| | - Steven D Schwartz
- Stein Eye Institute, University of California Los Angeles Geffen School of Medicine, Los Angeles, CA, 90095, USA; Edythe and Eli Broad Stem Cell Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Kapil Bharti
- National Eye Institute, National Institutes of Health, Bethesda, MD, 90892, USA
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26
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Harris JP, Burrell JC, Struzyna LA, Chen HI, Serruya MD, Wolf JA, Duda JE, Cullen DK. Emerging regenerative medicine and tissue engineering strategies for Parkinson's disease. NPJ Parkinsons Dis 2020; 6:4. [PMID: 31934611 PMCID: PMC6949278 DOI: 10.1038/s41531-019-0105-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 11/25/2019] [Indexed: 02/07/2023] Open
Abstract
Parkinson's disease (PD) is the second most common progressive neurodegenerative disease, affecting 1-2% of people over 65. The classic motor symptoms of PD result from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a loss of their long axonal projections to the striatum. Current treatment strategies such as dopamine replacement and deep brain stimulation (DBS) can only minimize the symptoms of nigrostriatal degeneration, not directly replace the lost pathway. Regenerative medicine-based solutions are being aggressively pursued with the goal of restoring dopamine levels in the striatum, with several emerging techniques attempting to reconstruct the entire nigrostriatal pathway-a key goal to recreate feedback pathways to ensure proper dopamine regulation. Although many pharmacological, genetic, and optogenetic treatments are being developed, this article focuses on the evolution of transplant therapies for the treatment of PD, including fetal grafts, cell-based implants, and more recent tissue-engineered constructs. Attention is given to cell/tissue sources, efficacy to date, and future challenges that must be overcome to enable robust translation into clinical use. Emerging regenerative medicine therapies are being developed using neurons derived from autologous stem cells, enabling the construction of patient-specific constructs tailored to their particular extent of degeneration. In the upcoming era of restorative neurosurgery, such constructs may directly replace SNpc neurons, restore axon-based dopaminergic inputs to the striatum, and ameliorate motor deficits. These solutions may provide a transformative and scalable solution to permanently replace lost neuroanatomy and improve the lives of millions of people afflicted by PD.
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Affiliation(s)
- James P. Harris
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
| | - Justin C. Burrell
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA USA
| | - Laura A. Struzyna
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA USA
| | - H. Isaac Chen
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
| | - Mijail D. Serruya
- Department of Neurology, Thomas Jefferson University, Philadelphia, PA USA
| | - John A. Wolf
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
| | - John E. Duda
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Parkinson’s Disease Research, Education, and Clinical Center (PADRECC), Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
| | - D. Kacy Cullen
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA USA
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27
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Nair RR, Corrochano S, Gasco S, Tibbit C, Thompson D, Maduro C, Ali Z, Fratta P, Arozena AA, Cunningham TJ, Fisher EMC. Uses for humanised mouse models in precision medicine for neurodegenerative disease. Mamm Genome 2019; 30:173-191. [PMID: 31203387 PMCID: PMC6759662 DOI: 10.1007/s00335-019-09807-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 05/11/2019] [Indexed: 12/11/2022]
Abstract
Neurodegenerative disease encompasses a wide range of disorders afflicting the central and peripheral nervous systems and is a major unmet biomedical need of our time. There are very limited treatments, and no cures, for most of these diseases, including Alzheimer's Disease, Parkinson's Disease, Huntington Disease, and Motor Neuron Diseases. Mouse and other animal models provide hope by analysing them to understand pathogenic mechanisms, to identify drug targets, and to develop gene therapies and stem cell therapies. However, despite many decades of research, virtually no new treatments have reached the clinic. Increasingly, it is apparent that human heterogeneity within clinically defined neurodegenerative disorders, and between patients with the same genetic mutations, significantly impacts disease presentation and, potentially, therapeutic efficacy. Therefore, stratifying patients according to genetics, lifestyle, disease presentation, ethnicity, and other parameters may hold the key to bringing effective therapies from the bench to the clinic. Here, we discuss genetic and cellular humanised mouse models, and how they help in defining the genetic and environmental parameters associated with neurodegenerative disease, and so help in developing effective precision medicine strategies for future healthcare.
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Affiliation(s)
- Remya R Nair
- Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, OX11 0RD, UK
| | - Silvia Corrochano
- Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, OX11 0RD, UK
| | - Samanta Gasco
- Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, OX11 0RD, UK
| | - Charlotte Tibbit
- Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, OX11 0RD, UK
| | - David Thompson
- Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, OX11 0RD, UK
| | - Cheryl Maduro
- Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Zeinab Ali
- Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, OX11 0RD, UK
| | - Pietro Fratta
- Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Abraham Acevedo Arozena
- Unidad de Investigación Hospital Universitario de Canarias, FUNCANIS, Instituto de Tecnologías Biomédicas ULL, and CIBERNED, La Laguna, 38320, Tenerife, Spain
| | | | - Elizabeth M C Fisher
- Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, OX11 0RD, UK.
- Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, WC1N 3BG, UK.
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28
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Crane AT, Voth JP, Shen FX, Low WC. Concise Review: Human-Animal Neurological Chimeras: Humanized Animals or Human Cells in an Animal? Stem Cells 2019; 37:444-452. [PMID: 30629789 DOI: 10.1002/stem.2971] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/16/2018] [Accepted: 12/03/2018] [Indexed: 12/24/2022]
Abstract
Blastocyst complementation is an emerging methodology in which human stem cells are transferred into genetically engineered preimplantation animal embryos eventually giving rise to fully developed human tissues and organs within the animal host for use in regenerative medicine. The ethical issues surrounding this method have caused the National Institutes of Health to issue a moratorium on funding for blastocyst complementation citing the potential for human cells to substantially contribute to the brain of the chimeric animal. To address this concern, we performed an in-depth review of the neural transplantation literature to determine how the integration of human cells into the nonhuman neural circuitry has altered the behavior of the host. Despite reports of widespread integration of human cell transplants, our review of 150 transplantation studies found no evidence suggestive of humanization of the animal host, and we thus conclude that, at present, concerns over humanization should not prevent research on blastocyst complementation to continue. We suggest proceeding in a controlled and transparent manner, however, and include recommendations for future research with careful consideration for how human cells may contribute to the animal host nervous system. Stem Cells 2019;37:444-452.
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Affiliation(s)
- Andrew T Crane
- Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.,Minnesota Craniofacial Research Training Program, University of Minnesota, Minneapolis, Minnesota, USA
| | - Joseph P Voth
- Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.,Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Francis X Shen
- University of Minnesota Law School, Minneapolis, Minnesota, USA.,Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA
| | - Walter C Low
- Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.,Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA.,Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA
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29
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de Natale ER, Wilson H, Pagano G, Politis M. Imaging Transplantation in Movement Disorders. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2018; 143:213-263. [PMID: 30473196 DOI: 10.1016/bs.irn.2018.10.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cell replacement therapy with graft transplantation has been tested as a disease-modifying treatment in neurodegenerative diseases characterized by the damage of a predominant cell type, such as substantia nigra dopaminergic neurons in Parkinson's disease (PD) or striatal medium spiny projection neurons in Huntington's disease (HD). The results of these trials are mixed with success in preclinical and pilot open-label trials, which were not consistently reproduced in randomized controlled trials. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) molecular imaging and functional magnetic resonance imaging allow the graft survival, and its relationship with the host tissues to be studied in vivo. In PD, PET with [18F]DOPA showed that graft survival does not necessarily correlate with the clinical improvement and PD patients with worse outcome had lower binding in the ventral striatum and a high serotonin ([11C]DASB PET) to dopamine ([18F]DOPA PET) ratio in the grafted neurons. In HD, PET with [11C]PK11195 showed the graft survival and the clinical responses may be related to the reactive activation of the host inflammatory/immune system. Findings from these studies have been used to refine study protocols and patient selection in current clinical trials, which includes identifying suitable candidates for transplantation using imaging markers and employing multiple and/or novel PET tracers to better assess graft functions and inflammatory responses to grafts.
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Affiliation(s)
- Edoardo Rosario de Natale
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom
| | - Heather Wilson
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom
| | - Gennaro Pagano
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom
| | - Marios Politis
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.
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30
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Cardoso T, Adler AF, Mattsson B, Hoban DB, Nolbrant S, Wahlestedt JN, Kirkeby A, Grealish S, Björklund A, Parmar M. Target-specific forebrain projections and appropriate synaptic inputs of hESC-derived dopamine neurons grafted to the midbrain of parkinsonian rats. J Comp Neurol 2018; 526:2133-2146. [PMID: 30007046 PMCID: PMC6175216 DOI: 10.1002/cne.24500] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 06/11/2018] [Accepted: 06/19/2018] [Indexed: 12/25/2022]
Abstract
Dopamine (DA) neurons derived from human embryonic stem cells (hESCs) are a promising unlimited source of cells for cell replacement therapy in Parkinson's disease (PD). A number of studies have demonstrated functionality of DA neurons originating from hESCs when grafted to the striatum of rodent and non‐human primate models of PD. However, several questions remain in regard to their axonal outgrowth potential and capacity to integrate into host circuitry. Here, ventral midbrain (VM) patterned hESC‐derived progenitors were grafted into the midbrain of 6‐hydroxydopamine‐lesioned rats, and analyzed at 6, 18, and 24 weeks for a time‐course evaluation of specificity and extent of graft‐derived fiber outgrowth as well as potential for functional recovery. To investigate synaptic integration of the transplanted cells, we used rabies‐based monosynaptic tracing to reveal the origin and extent of host presynaptic inputs to grafts at 6 weeks. The results reveal the capacity of grafted neurons to extend axonal projections toward appropriate forebrain target structures progressively over 24 weeks. The timing and extent of graft‐derived dopaminergic fibers innervating the dorsolateral striatum matched reduction in amphetamine‐induced rotational asymmetry in the animals where recovery could be observed. Monosynaptic tracing demonstrated that grafted cells integrate with host circuitry 6 weeks after transplantation, in a manner that is comparable with endogenous midbrain connectivity. Thus, we demonstrate that VM patterned hESC‐derived progenitors grafted to midbrain have the capacity to extensively innervate appropriate forebrain targets, integrate into the host circuitry and that functional recovery can be achieved when grafting fetal or hESC‐derived DA neurons to the midbrain.
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Affiliation(s)
- Tiago Cardoso
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Andrew F Adler
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Bengt Mattsson
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Deirdre B Hoban
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Sara Nolbrant
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Jenny Nelander Wahlestedt
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Agnete Kirkeby
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Danish Stem Cell Center (DanStem), University of Copenhagen, Copenhagen, Denmark
| | - Shane Grealish
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Anders Björklund
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Malin Parmar
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
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31
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Stern JH, Tian Y, Funderburgh J, Pellegrini G, Zhang K, Goldberg JL, Ali RR, Young M, Xie Y, Temple S. Regenerating Eye Tissues to Preserve and Restore Vision. Cell Stem Cell 2018; 22:834-849. [PMID: 29859174 PMCID: PMC6492284 DOI: 10.1016/j.stem.2018.05.013] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ocular regenerative therapies are on track to revolutionize treatment of numerous blinding disorders, including corneal disease, cataract, glaucoma, retinitis pigmentosa, and age-related macular degeneration. A variety of transplantable products, delivered as cell suspensions or as preformed 3D structures combining cells and natural or artificial substrates, are in the pipeline. Here we review the status of clinical and preclinical studies for stem cell-based repair, covering key eye tissues from front to back, from cornea to retina, and including bioengineering approaches that advance cell product manufacturing. While recognizing the challenges, we look forward to a deep portfolio of sight-restoring, stem cell-based medicine. VIDEO ABSTRACT.
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Affiliation(s)
- Jeffrey H Stern
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA; Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA
| | - Yangzi Tian
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA
| | - James Funderburgh
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Graziella Pellegrini
- Centre for Regenerative Medicine, University of Modena and Reggio Emilia, via G.Gottardi 100, 41125 Modena, Italy
| | - Kang Zhang
- Shiley Eye Institute and Institute for Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University and Guangzhou Regenerative Medicine and Health Laboratory, Guangzhou 510060, China
| | - Jeffrey L Goldberg
- Byers Eye Institute at Stanford University, 2452 Watson Court, Palo Alto, CA 94303, USA
| | - Robin R Ali
- Department of Genetics, University College London Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, City Road, London EC1V 2PD, UK; Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA
| | - Michael Young
- The Schepens Eye Research Institute, Massachusetts Eye and Ear, an affiliate of Harvard Medical School, Boston, MA 02114, USA
| | - Yubing Xie
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA
| | - Sally Temple
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA; Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA.
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32
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Nickerson PEB, Ortin-Martinez A, Wallace VA. Material Exchange in Photoreceptor Transplantation: Updating Our Understanding of Donor/Host Communication and the Future of Cell Engraftment Science. Front Neural Circuits 2018; 12:17. [PMID: 29559897 PMCID: PMC5845679 DOI: 10.3389/fncir.2018.00017] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 02/09/2018] [Indexed: 12/23/2022] Open
Abstract
Considerable research effort has been invested into the transplantation of mammalian photoreceptors into healthy and degenerating mouse eyes. Several platforms of rod and cone fluorescent reporting have been central to refining the isolation, purification and transplantation of photoreceptors. The tracking of engrafted cells, including identifying the position, morphology and degree of donor cell integration post-transplant is highly dependent on the use of fluorescent protein reporters. Improvements in imaging and analysis of transplant recipients have revealed that donor cell fluorescent reporters can transfer into host tissue though a process termed material exchange (ME). This recent discovery has chaperoned a new era of interpretation when reviewing the field’s use of dissociated donor cell preparations, and has prompted scientists to re-examine how we use and interpret the information derived from fluorescence-based tracking tools. In this review, we describe the status of our understanding of ME in photoreceptor transplantation. In addition, we discuss the impact of this discovery on several aspects of historical rod and cone transplantation data, and provide insight into future standards and approaches to advance the field of cell engraftment.
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Affiliation(s)
- Philip E B Nickerson
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Arturo Ortin-Martinez
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Valerie A Wallace
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada
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33
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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.
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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
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Tom CM, Younesi S, Meer E, Bresee C, Godoy M, Mattis VB. Survival of iPSC-derived grafts within the striatum of immunodeficient mice: Importance of developmental stage of both transplant and host recipient. Exp Neurol 2017; 297:118-128. [PMID: 28760579 DOI: 10.1016/j.expneurol.2017.07.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 06/29/2017] [Accepted: 07/26/2017] [Indexed: 01/04/2023]
Abstract
Degeneration of the striatum can occur in multiple disorders with devastating consequences for the patients. Infantile infections with streptococcus, measles, or herpes can cause striatal necrosis associated with dystonia or dyskinesia; and in patients with Huntington's disease the striatum undergoes massive degeneration, leading to behavioral, psychological and movement issues, ultimately resulting in death. Currently, only supportive therapies are available for striatal degeneration. Clinical trials have shown some efficacy using transplantation of fetal-derived primary striatal progenitors. Large banks of fetal progenitors that give rise to medium spiny neurons (MSNs), the primary neuron of the striatum, are needed to make transplantation therapy a reality. However, fetal tissue is of limited supply, has ethical concerns, and is at risk of graft immunorejection. An alternative potential source of MSNs is induced pluripotent stem cells (iPSCs), adult somatic tissues reprogrammed back to a stem cell fate. Multiple publications have demonstrated the ability to differentiate striatal MSNs from iPSCs. Previous publications have demonstrated that the efficacy of fetal progenitor transplants is critically dependent upon the age of the donor embryo/fetus as well as the age of the transplant recipient. With the advent of iPSC technology, a question that remains unanswered concerns the graft's "age," which is crucial since transplanting pluripotent cells has an inherent risk of over proliferation and teratoma formation. Therefore, in order to also determine the effect of transplant recipient age on the graft, iPSCs were differentiated to three stages along a striatal differentiation paradigm and transplanted into the striatum of both neonatal and adult immunodeficient mice. This study demonstrated that increased murine transplant-recipient age (adult vs neonate) resulted in decreased graft survival and volume/rostro-caudal spread after six weeks in vivo, regardless of "age" of the cells transplanted. Importantly, this study implicates that the in vivo setting may provide a better neurogenic niche for iPSC-based modeling as compared to the in vitro setting. Together, these results recapitulate findings from fetal striatal progenitor transplantation studies and further demonstrate the influence of the host environment on cellular survival and maturation.
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Affiliation(s)
- Colton M Tom
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Shahab Younesi
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Elana Meer
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Catherine Bresee
- Biostatistics & Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Marlesa Godoy
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Virginia B Mattis
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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Davis RJ, Alam NM, Zhao C, Müller C, Saini JS, Blenkinsop TA, Mazzoni F, Campbell M, Borden SM, Charniga CJ, Lederman PL, Aguilar V, Naimark M, Fiske M, Boles N, Temple S, Finnemann SC, Prusky GT, Stern JH. The Developmental Stage of Adult Human Stem Cell-Derived Retinal Pigment Epithelium Cells Influences Transplant Efficacy for Vision Rescue. Stem Cell Reports 2017; 9:42-49. [PMID: 28625537 PMCID: PMC5511099 DOI: 10.1016/j.stemcr.2017.05.016] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 05/15/2017] [Accepted: 05/15/2017] [Indexed: 02/06/2023] Open
Abstract
Age-related macular degeneration (AMD) is a common cause of central visual loss in the elderly. Retinal pigment epithelial (RPE) cell loss occurs early in the course of AMD and RPE cell transplantation holds promise to slow disease progression. We report that subretinal transplantation of RPE stem cell (RPESC)-derived RPE cells (RPESC-RPE) preserved vision in a rat model of RPE cell dysfunction. Importantly, the stage of differentiation that RPESC-RPE acquired prior to transplantation influenced the efficacy of vision rescue. Whereas cells at all stages of differentiation tested rescued photoreceptor layer morphology, an intermediate stage of RPESC-RPE differentiation obtained after 4 weeks of culture was more consistent at vision rescue than progeny that were differentiated for 2 weeks or 8 weeks of culture. Our results indicate that the developmental stage of RPESC-RPE significantly influences the efficacy of RPE cell replacement, which affects the therapeutic application of these cells for AMD.
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Affiliation(s)
- Richard J Davis
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Nazia M Alam
- Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10605, USA; Center for Visual Restoration, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA
| | - Cuiping Zhao
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Claudia Müller
- Department of Biological Sciences, Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University, Bronx, NY 10458, USA
| | - Janmeet S Saini
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Timothy A Blenkinsop
- Cell, Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Francesca Mazzoni
- Department of Biological Sciences, Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University, Bronx, NY 10458, USA
| | - Melissa Campbell
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Susan M Borden
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Carol J Charniga
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Patty L Lederman
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Vanessa Aguilar
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Michael Naimark
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Michael Fiske
- Upstate Stem Cell cGMP Facility, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Nathan Boles
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Sally Temple
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Silvia C Finnemann
- Department of Biological Sciences, Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University, Bronx, NY 10458, USA
| | - Glen T Prusky
- Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10605, USA; Center for Visual Restoration, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA
| | - Jeffrey H Stern
- Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY 12144, USA.
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Freeman TB, Sanberg PR, Nauert GM, Boss BD, Spector D, Olanow CW, Kordower JH. The Influence of Donor Age on the Survival of Solid and Suspension Intraparenchymal Human Embryonic Nigral Grafts. Cell Transplant 2017; 4:141-54. [PMID: 7728329 DOI: 10.1177/096368979500400118] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
In many species, graft survival and graft-derived behavioral recovery are affected by the embryonic donor age. We compared the ability of solid and suspension grafts of human embryonic mesencephalic dopaminergic (DA) neurons at different embryonic stages to survive intra-parenchymal transplantation into 6-OHDA lesioned immunosuppressed rats. Suspension grafts survived best when donor age was between postconception (PC) days 34 and 56. Transplants displayed numerous healthy tyrosine hydroxylase immunoreactive (TH-IR) neurons which sent extensive neuritic processes into the host striatum. Suspension grafts survived poorly when donor age was greater than 65 days. Solid implants displayed comparable viability of TH-IR neurons when donor age was between 44 and 65 days. No solid grafts contained TH-IR cells when donor tissue was older than 72 days. The suspension and solid methods of transplantation resulted in comparable survival of robust grafts, but solid grafts resulted in more intergraft variability than suspension grafts, particularly among the more marginal implants. Our results demonstrate that the upper limit for survival of human embryonic DA suspension grafts correlates well with the period of development of the human nigrostriatal pathway. The “window” for donor age of solid human embryonic DA grafts appears to be extended by about 9 days in comparison to suspension grafts. These data suggest that the upper age limit for grafting human mesencephalic DA neurons should be PC day 56 for suspension grafts, and PC day 65 for solid implants. Older donors are likely to produce grafts with fewer surviving DA neurons.
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Affiliation(s)
- T B Freeman
- Division of Neurosurgery, University of South Florida, Tampa 33606, USA
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Boronat-García A, Guerra-Crespo M, Drucker-Colín R. Historical perspective of cell transplantation in Parkinson’s disease. World J Transplant 2017; 7:179-192. [PMID: 28698835 PMCID: PMC5487308 DOI: 10.5500/wjt.v7.i3.179] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 04/27/2017] [Accepted: 05/15/2017] [Indexed: 02/05/2023] Open
Abstract
Cell grafting has been considered a therapeutic approach for Parkinson’s disease (PD) since the 1980s. The classical motor symptoms of PD are caused by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrement in dopamine release in the striatum. Consequently, the therapy of cell-transplantation for PD consists in grafting dopamine-producing cells directly into the brain to reestablish dopamine levels. Different cell sources have been shown to induce functional benefits on both animal models of PD and human patients. However, the observed motor improvements are highly variable between individual subjects, and the sources of this variability are not fully understood. The purpose of this review is to provide a general overview of the pioneering studies done in animal models of PD that established the basis for the first clinical trials in humans, and compare these with the latest findings to identify the most relevant aspects that remain unanswered to date. The main focus of the discussions presented here will be on the mechanisms associated with the survival and functionality of the transplants. These include the role of the dopamine released by the grafts and the capacity of the grafted cells to extend fibers and to integrate into the motor circuit. The complete understanding of these aspects will require extensive research on basic aspects of molecular and cellular physiology, together with neuronal network function, in order to uncover the real potential of cell grafting for treating PD.
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Abstract
Neural transplantation has been extensively applied in Parkinson's disease, including numerous clinical studies, studies in animal models, and related basic research on cell biology. There is evidence that the clinical trials of both adrenal medulla transplantation and fetal substantia nigra transplantation have produced a detectable clinical effect, although it is not yet clear whether the clinical benefit is sufficient to justify a more widespread application of these procedures. Studies of long-term outcome and quantitative tests are important in assaying the degree of benefit produced by transplantation procedures in Parkinson's disease and for developing improved and refined procedures. Other disease-related applications of neural transplantation are beginning to be developed. These include Huntington's disease, chronic pain, epilepsy, spinal cord injury, and perhaps even demyelinating diseases and cortical ischemic injury. Although most of these applications lie in the future, it is not too soon to begin to consider the scientific justification that should be required for initiation of human clinical trials.
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Affiliation(s)
- William J. Freed
- Preclinical Neurosciences Section, Neuropsychiatry Branch, NIMH Neuroscience Center at St. Elizabeths, 2700 Martin Luther King Ave., Washington, DC 20032, USA
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40
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Annett LE, Torres EM, Clarke DJ, Ishida Y, Barker RA, Ridley RM, Baker HF, Dunnett SB. Survival of Nigral Grafts within the Striatum of Marmosets with 6-Ohda Lesions Depends Critically on Donor Embryo Age. Cell Transplant 2017; 6:557-69. [PMID: 9440865 DOI: 10.1177/096368979700600606] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The study examined the importance of embryonic donor age for the survival of nigral grafts in 6-OHDA–lesioned marmosets. The issue as to whether donor age is critical for the survival of nigral grafts in primates is controversial, because several early reports suggested that relatively old tissue could survive transplantation and produce functional benefits in monkeys, in contrast to the restrictive time dependence observed in rodents. Embryonic marmoset donors embryos of three different ages were employed: 1) E74 (Carnegie stage 18-19); 2) E83-84 (Carnegie stage 23+); 3) E92-93 (foetal period). The nigral neurons derived from the ventral mesencephalon in the two older donor age groups did not survive well when grafted to the striatum of adult marmosets with unilateral 6-OHDA lesions. Although a few tyrosine hydroxylase (TH+) neurons could be identified by immunohistochemistry at graft sites in all recipients in older donor age groups, the numbers of surviving neurons in these were small, on average typically less than 100 TH+ cells. These small grafts were not sufficient to affect amphetamine-induced rotation. In contrast, many more TH+ cells typically survived transplantation in the recipients; of graft tissue derived from the youngest donors and amphetamine-induced rotation was significantly reduced in this group alone. The time course and extent of the reduction in rotation was remarkably similar to that observed in previous marmoset nigral graft studies, confirming the utility of amphetamine-induced rotation as a sensitive and reliable indicator of nigral graft function in this species. Considering these results and other recent evidence from monkey to monkey, human to rat, and human to human graft studies, the survival of embryonic nigral tissues derived from primate donors transplanted into the striatum does appear to be critically dependent on the age of the donor tissue.
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Affiliation(s)
- L E Annett
- Department of Experimental Psychology, University of Cambridge, UK
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41
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Giovanini MA, Reier PJ, Eskin TA, Anderson DK. Map2 Expression in the Developing Human Fetal Spinal Cord and following Xenotransplantation. Cell Transplant 2017; 6:339-46. [PMID: 9171166 DOI: 10.1177/096368979700600316] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Human fetal spinal cord (FSC) tissue was obtained from elective abortions at 6-14 wk gestational age (GA). The specimens were then either immediately processed for immunohistochemical analysis or xenotransplantation. In the latter case, donor tissue was prepared as a dissociated cell suspension and then introduced either sub-pially or intraspinally into contusion lesions of the adult rat midthoracic spinal cord. The xenografts were subsequently examined by conventional histological and immunohistochemical methods at 2-3 mo postgrafting. Immunostaining showed that MAP2 was expressed heavily in cells residing in the mantle layer of the human fetal spinal cord in situ as early as 6 wk GA. Subpial and intraparenchymal xenografts also were intensely immunoreactive for MAP2, but no staining of surrounding host neural tissue was detected. We conclude that the differential expression of MAP2 can be used to distinguish human graft tissue from the surrounding rat spinal cord in this xenograft paradigm. Under appropriate staining conditions, MAP2 can thus serve to facilitate analyses of host-graft integration, donor cell migration, and neuritic outgrowth.
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Affiliation(s)
- M A Giovanini
- Department of Neurological Surgery, Gainesville Veterans Affairs Medical Center, University of Florida College of Medicine, 32610, USA
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Saporta S, Borlongan C, Moore J, Mejia-Millan E, Jones SL, Bonness P, Randall TS, Allen RC, Freeman TB, Sanberg PR. Microcarrier Enhanced Survival of Human and Rat Fetal Ventral Mesencephalon Cells Implanted in the Rat Striatum. Cell Transplant 2017; 6:579-84. [PMID: 9440867 DOI: 10.1177/096368979700600608] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The transplantation of tissue containing dopamine-producing cells into the mammalian central nervous system is an emerging treatment for Parkinson's disease, despite relatively poor survival of implanted tissue. Recent evidence has suggested that Cytodex microcarriers enhance the survival of dopaminergic rat chromaffin cells transplanted into the rat striatum in the absence of immunosuppression. The current study was undertaken to evaluate the survival of rat and human fetal ventral mesencephalic neurons (VM) implanted alone or after attachment to microcarriers in the striatum of rats without immunosuppression. Rat fetal VM neurons demonstrated enhanced survival in the rat striatum when transplanted on microcarriers, compared to their transplantation alone during the 3-mo period examined in the present study. Transplants of human fetal VM neurons on microcarriers also survived remarkably well in the rat striatum without systemic immunosuppression. In contrast, human fetal VM cells transplanted alone into the rat striatum did not survive without systemic immunosuppression. There was no evidence of TH fiber sprouting in the vicinity of any transplant site. These data indicated that Cytodex microcarriers provide enhanced survival of both rat allograft and human xenograft fetal mesencephalic cells in the rat striatum without the necessity of systemic immunosuppression, perhaps by inducing a unique neuron–glia environment.
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Affiliation(s)
- S Saporta
- Department of Anatomy, University of South Florida College of Medicine, Tampa 33612-4799, USA
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Evtouchenko L, Studer L, Spenger C, Dreher E, Seiler RW. A Mathematical Model for the Estimation of Human Embryonic and Fetal Age. Cell Transplant 2017; 5:453-64. [PMID: 8800513 DOI: 10.1177/096368979600500404] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Precise determination of donor age in human embryonic and fetal tissue is crucial for cell transplantation due to the existence of distinct time windows within which successful grafting is possible. This study demonstrates that between 4-12 wk postconception embryonic and fetal age can be estimated based on various morphometric parameters measured on a routine basis in suction abortion material. The greatest length, the neck-rump length, the foot length, and the proximal and distal arm and leg length were correlated with the anamnestic and ultra-sonographically estimated age. Multivariate regression analyses showed a linear correlation between age and the logarithmic value of the various morphometric parameters. The best correlation was found for a mathematical model combining the limb parameters (r = 0.904; p < 0.001; n −37). A prospective follow-up study (n = 40) was carried out to test the validity of the mathematical model. A high correlation was found between the calculated age and the estimated age based on anamnestic data (r = 0.749, p < 0.001). Outliers due to errors in the anamnestic data were readily identified by comparing anamnestic with calculated age. This method allows determination of embryonic and fetal age within and beyond the age group of the Carnegie classification and may, therefore, be useful for the needs of experimental and clinical cell transplantation.
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Affiliation(s)
- L Evtouchenko
- Department of Neurosurgery, University of Bern, Inselspital, Switzerland
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44
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Abstract
The MIB-1 antibody against a nuclear protein Ki-67 was used to study the proliferation of cells in the rabbit retinal transplants. Fragmented pieces of embryonic day 15 rabbit retinas were transplanted into the subretinal space of adult rabbits and allowed to survive for different times. Fragmented donor tissue starts organizing in rosettes 1 day after transplantation. The transplanted cells continue to proliferate in the host eye and their pattern of proliferation resembles that of normal developing retina, suggesting that the factors responsible for the proliferation pattern are preserved after transplantation. The dividing cells in metaphase line up in the luminal layers of the rosettes. Certain cells become postmitotic in the regions corresponding to the inner retina first, followed by the cells in the luminal layers of rosettes. Cells in the regions between the rosettes, corresponding to the inner nuclear layer, presumably the Müller cells, proliferate significantly for the equivalent age of postnatal day 2. Few cells in these regions proliferate for at least the equivalent age of postnatal day 11 in transplants. There is a layer of nonproliferating, degenerating cells in the transplant situated close to the host retina. However, some cells in this layer, situated at the host-graft interface, proliferate. These cells proliferate for a long time possibly indicating gliosis.
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Affiliation(s)
- R K Sharma
- Department of Ophthalmology, University of Lund, Sweden
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45
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Strömberg I, Björklund L, Förander P. The Age of Striatum Determines the Pattern and Extent of Dopaminergic Innervation: a Nigrostriatal Double Graft Study. Cell Transplant 2017; 6:287-96. [PMID: 9171161 DOI: 10.1177/096368979700600311] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
In animal models of Parkinson's disease, transplanted fetal mesencephalic dopaminergic neurons can innervate the dopamine-depleted host brain, but it is unclear why large portions of the host striatum are left uninnervated. During normal development, the dopaminergic innervation first occurs in the form of a dense patchy pattern in the striatum, followed by a widespread nerve fiber network. Using intraocular double grafts we have investigated dopaminergic growth patterns initiated when ventral mesencephalic grafts innervate striatal targets. The fetal lateral ganglionic eminence was implanted into the anterior eye chamber. After maturation in oculo, fetal ventral mesencephalon was implanted and placed in contact with the first graft. In other animals the two pieces of tissue were implanted simultaneously. Tyrosine hydroxylase (TH) immunohistochemistry revealed a pattern of dense TH-positive patches throughout the total volume of the striatal grafts in simultaneously transplanted cografts, while a widespread, less dense, pattern was found when mature striatal transplants were innervated by fetal dopaminergic grafts. To investigate which type or types of growth patterns that developed after grafting to striatum in situ of an adult host, fetal ventral mesencephalic tissue was implanted into the lateral ventricle adjacent to the dopamine-lesioned striatum. After maturation of the mesencephalic graft, the fetal lateral ganglionic eminence was implanted into the reinnervated part of the host striatum. TH immunohistochemistry revealed a few nerve fibers within the striatal graft and the growth pattern was of the widespread type. In conclusion, grafted dopaminergic neurons preferably innervate mature striatum with a widespread sparse nerve fiber network, while the innervation of the immature striatum occurs in the form of dense patches. Furthermore, when the patchy pattern is formed, the total volume of the striatal target is innervated while growth of the widespread type terminates prior to reaching distal striatal parts. Thus, the growth pattern seems essential to the final volume that is innervated. Once the widespread growth pattern is initiated, the presence of immature striatum does not change the dopaminergic growth pattern.
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Affiliation(s)
- I Strömberg
- Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
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46
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Natalwala A, Kunath T. Preparation, characterization, and banking of clinical-grade cells for neural transplantation: Scale up, fingerprinting, and genomic stability of stem cell lines. PROGRESS IN BRAIN RESEARCH 2017; 230:133-150. [PMID: 28552226 DOI: 10.1016/bs.pbr.2017.02.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Parkinson's disease is a complex and progressive neurodegenerative condition that is characterized by the severe loss of midbrain dopaminergic (mDA) neurons, which innervate the striatum. Cell transplantation therapies to rebuild this dopaminergic network have been attempted for over 30 years. The most promising outcomes were observed when human fetal mesencephalic tissue was used as the source of cells for transplantation. However, reliance on terminations for a Parkinson's therapy presents significant logistical and ethical hurdles. An alternative source of transplantable mDA neurons is urgently needed, and the solution may come from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). Protocols to differentiate hESCs/iPSCs toward mDA neurons are now robust and efficient, and upon grafting the cells rescue preclinical animal models of Parkinson's disease. The challenge now is to apply Good Manufacturing Practice (GMP) to the academic discoveries and protocols to produce clinical-grade transplantable mDA cells. Major technical and logistical considerations include (i) source of hESC or iPSC line, (ii) GMP compliance of the differentiation protocol and all reagents, (iii) characterization of the cell product in terms of identity, safety, and efficacy, (iv) characterization of genomic state and stability, and (v) banking of a transplantation-ready cell product. Approaches and solutions to these challenges are reviewed here.
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Affiliation(s)
- Ammar Natalwala
- MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom; Translational Neurosurgery Group, Western General Hospital, Crewe Road South, Edinburgh, United Kingdom
| | - Tilo Kunath
- MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom.
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47
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Björklund A, Lindvall O. Replacing Dopamine Neurons in Parkinson's Disease: How did it happen? JOURNAL OF PARKINSON'S DISEASE 2017; 7:S21-S31. [PMID: 28282811 PMCID: PMC5345652 DOI: 10.3233/jpd-179002] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The efforts to develop a dopamine cell replacement therapy for Parkinson's disease have spanned over more than three decades. Based on almost 10 years of transplantation studies in animal models, the first patients receiving grafts of fetal-derived dopamine neuroblasts were operated in Lund in 1987. Over the following two decades, a total of 18 patients were transplanted and followed closely by our team with mixed but also very encouraging results. In this article we tell the story of how the preclinical and clinical transplantation program in Lund evolved. We recall the excitement when we obtained the first evidence for survival and function of transplanted neurons in the diseased human brain. We also remember the setbacks that we have experienced during these 30 years and discuss the very interesting developments that are now taking place in this exciting field.
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Affiliation(s)
- Anders Björklund
- Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund, Sweden
| | - Olle Lindvall
- Department of Clinical Sciences, and Lund Stem Cell Center, Division of Neurology, University Hospital, Lund, Sweden
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48
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Towns CR. The science and ethics of cell-based therapies for Parkinson's disease. Parkinsonism Relat Disord 2016; 34:1-6. [PMID: 28341222 DOI: 10.1016/j.parkreldis.2016.10.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 10/18/2016] [Accepted: 10/18/2016] [Indexed: 12/22/2022]
Abstract
Parkinson's Disease (PD) is an age-related, disabling neurodegenerative disorder. Although sufferers usually respond to dopamine agonists for extended periods, the disease remains progressive and adverse drug effects can compromise effective long term treatment. Cell-based therapies have been the subject of much hype and optimism with regard to PD. Proof of principle was provided in the 1980s with fetal tissue transplantation trials demonstrating successful graft survival. Embryonic stem cells and reprogrammed or transdifferentiated somatic cells may provide alternative sources of tissue with the potential to overcome the material shortages and technical difficulties that have hindered fetal neural transplants. This article will review the state of the science for cell based therapies and examine the ethical issues that societies must negotiate regarding their clinical use.
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Affiliation(s)
- C R Towns
- Department of General Medicine, Wellington Hospital, New Zealand; Bioethics Centre, University of Otago, Dunedin, New Zealand.
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Moon J, Schwarz SC, Lee H, Kang JM, Lee Y, Kim B, Sung M, Höglinger G, Wegner F, Kim JS, Chung H, Chang SW, Cha KY, Kim K, Schwarz J. Preclinical Analysis of Fetal Human Mesencephalic Neural Progenitor Cell Lines: Characterization and Safety In Vitro and In Vivo. Stem Cells Transl Med 2016; 6:576-588. [PMID: 28191758 PMCID: PMC5442800 DOI: 10.5966/sctm.2015-0228] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 05/16/2016] [Indexed: 12/21/2022] Open
Abstract
We have developed a good manufacturing practice for long‐term cultivation of fetal human midbrain‐derived neural progenitor cells. The generation of human dopaminergic neurons may serve as a tool of either restorative cell therapies or cellular models, particularly as a reference for phenotyping region‐specific human neural stem cell lines such as human embryonic stem cells and human inducible pluripotent stem cells. We cultivated 3 different midbrain neural progenitor lines at 10, 12, and 14 weeks of gestation for more than a year and characterized them in great detail, as well as in comparison with Lund mesencephalic cells. The whole cultivation process of tissue preparation, cultivation, and cryopreservation was developed using strict serum‐free conditions and standardized operating protocols under clean‐room conditions. Long‐term‐cultivated midbrain‐derived neural progenitor cells retained stemness, midbrain fate specificity, and floorplate markers. The potential to differentiate into authentic A9‐specific dopaminergic neurons was markedly elevated after prolonged expansion, resulting in large quantities of functional dopaminergic neurons without genetic modification. In restorative cell therapeutic approaches, midbrain‐derived neural progenitor cells reversed impaired motor function in rodents, survived well, and did not exhibit tumor formation in immunodeficient nude mice in the short or long term (8 and 30 weeks, respectively). We conclude that midbrain‐derived neural progenitor cells are a promising source for human dopaminergic neurons and suitable for long‐term expansion under good manufacturing practice, thus opening the avenue for restorative clinical applications or robust cellular models such as high‐content or high‐throughput screening. Stem Cells Translational Medicine2017;6:576–588
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Affiliation(s)
- Jisook Moon
- Department of Biotechnology, College of Life Science, CHA University, Seongnam‐si, Gyeonggi‐do, Korea
- General Research Division, Korea Research‐Driven Hospital, Bundang CHA Medical Center, CHA University, Seongnam‐si, Gyeonggi‐do, Korea
| | - Sigrid C. Schwarz
- German Center for Neurodegenerative Diseases, Technical University Munich, Munich, Germany
| | - Hyun‐Seob Lee
- General Research Division, Korea Research‐Driven Hospital, Bundang CHA Medical Center, CHA University, Seongnam‐si, Gyeonggi‐do, Korea
| | - Jun Mo Kang
- General Research Division, Korea Research‐Driven Hospital, Bundang CHA Medical Center, CHA University, Seongnam‐si, Gyeonggi‐do, Korea
| | - Young‐Eun Lee
- General Research Division, Korea Research‐Driven Hospital, Bundang CHA Medical Center, CHA University, Seongnam‐si, Gyeonggi‐do, Korea
| | - Bona Kim
- Development Division, CHA Biotech, Seongnam‐si, Gyeonggi‐do, Korea
| | - Mi‐Young Sung
- Development Division, CHA Biotech, Seongnam‐si, Gyeonggi‐do, Korea
| | - Günter Höglinger
- German Center for Neurodegenerative Diseases, Technical University Munich, Munich, Germany
| | - Florian Wegner
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Jin Su Kim
- Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hyung‐Min Chung
- Department of Stem Cell Biology, Graduate School of Medicine, Konkuk University, Gwangjin‐gu, Seoul, Korea
| | - Sung Woon Chang
- Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam‐si, Gyeonggi‐do, Korea
| | - Kwang Yul Cha
- General Research Division, Korea Research‐Driven Hospital, Bundang CHA Medical Center, CHA University, Seongnam‐si, Gyeonggi‐do, Korea
| | - Kwang‐Soo Kim
- Molecular Neurobiology Laboratory, Department of Psychiatry, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA
| | - Johannes Schwarz
- German Center for Neurodegenerative Diseases, Technical University Munich, Munich, Germany
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Lelos MJ, Morgan RJ, Kelly CM, Torres EM, Rosser AE, Dunnett SB. Amelioration of non-motor dysfunctions after transplantation of human dopamine neurons in a model of Parkinson's disease. Exp Neurol 2016; 278:54-61. [PMID: 26851542 PMCID: PMC4801014 DOI: 10.1016/j.expneurol.2016.02.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Revised: 01/25/2016] [Accepted: 02/02/2016] [Indexed: 11/29/2022]
Abstract
Background Patients suffering from Parkinson's disease (PD) display cognitive and neuropsychiatric dysfunctions, especially with disease progression. Although these impairments have been reported to impact more heavily upon a patient's quality of life than any motor dysfunctions, there are currently no interventions capable of adequately targeting these non-motor deficits. Objectives Utilizing a rodent model of PD, we investigated whether cell replacement therapy, using intrastriatal transplants of human-derived ventral mesencephalic (hVM) grafts, could alleviate cognitive and neuropsychiatric, as well as motor, dysfunctions. Methods Rats with unilateral 6-hydroxydopamine lesions to the medial forebrain bundle were tested on a complex operant task that dissociates motivational, visuospatial and motor impairments sensitive to the loss of dopamine. A subset of lesioned rats received intrastriatal hVM grafts of ~ 9 weeks gestation. Post-graft, rats underwent repeated drug-induced rotation tests and were tested on two versions of the complex operant task, before post-mortem analysis of the hVM tissue grafts. Results Post-graft behavioural testing revealed that hVM grafts improved non-motor aspects of task performance, specifically visuospatial function and motivational processing, as well as alleviating motor dysfunctions. Conclusions We report the first evidence of human VM cell grafts alleviating both non-motor and motor dysfunctions in an animal model of PD. This intervention, therefore, is the first to improve cognitive and neuropsychiatric symptoms long-term in a model of PD.
Non-motor dysfunctions affect quality of life in Parkinson's disease. We tested whether human-derived foetal dopamine cells could improve these deficits. Human dopamine cells improved rotational bias and movement impairments in a rat model. Non-motor dysfunctions, specifically visuospatial and motivational deficits, improved. This is the first evidence of improved non-motor deficits from human dopamine cells.
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Affiliation(s)
- M J Lelos
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales CF10 3AX, UK.
| | - R J Morgan
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales CF10 3AX, UK
| | - C M Kelly
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales CF10 3AX, UK
| | - E M Torres
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales CF10 3AX, UK
| | - A E Rosser
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales CF10 3AX, UK
| | - S B Dunnett
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales CF10 3AX, UK
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