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Begh MZA, Zehravi M, Bhuiyan MAK, Molla MR, Raman K, Emran TB, Ullah MH, Ahmad I, Osman H, Khandaker MU. Recent advances in stem cell approaches to neurodegeneration: A comprehensive review with mechanistic insight. Pathol Res Pract 2025; 271:156013. [PMID: 40381433 DOI: 10.1016/j.prp.2025.156013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2025] [Revised: 05/10/2025] [Accepted: 05/12/2025] [Indexed: 05/20/2025]
Abstract
The progressive nature of neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, presents substantial problems because current treatments are still obscure. Stem cell-based treatments are emerging as a viable solution to address the significant gaps in treating these severe diseases. This study provides a comprehensive analysis of the latest advancements in stem cell research, focusing on the treatment of NDs. Various types of stem cells, such as adult, induced pluripotent, and embryonic stem cells, and their potential applications in immunomodulation, neurotrophic factor release, and neuronal development are also discussed. Recent clinical studies reveal outcomes, challenges, and solutions, with advancements in disease-specific neural cell production, gene editing, and improved stem cell transplantation transport strategies. The review discussed future perspectives on developing more effective stem cell-based interventions. Biomaterials are being used for cell distribution and personalized medicine techniques to improve treatment outcomes, while exploring stem cell treatments for NDs and identifying areas for further research.
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Affiliation(s)
- Md Zamshed Alam Begh
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka 1216, Bangladesh.
| | - Mehrukh Zehravi
- Department of Clinical Pharmacy, College of Dentistry & Pharmacy, Buraydah Private Colleges, Buraydah 51418, Saudi Arabia.
| | | | - M Raju Molla
- Department of Pharmacy, Atish Dipankar University of Science and Technology, Dhaka 1230, Bangladesh
| | - Kannan Raman
- Department of Pharmacology, St. John's College of Pharmaceutical Sciences & Research, Kattappana, Idukki, Kerala, India
| | - Talha Bin Emran
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka 1216, Bangladesh
| | - Md Habib Ullah
- Department of Physics, American International University-Bangladesh (AIUB), 408/1, Kuratoli, Khilkhet, Dhaka 1229, Bangladesh
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Hamid Osman
- Department of Radiological Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
| | - Mayeen Uddin Khandaker
- Applied Physics and Radiation Technologies Group, CCDCU, Faculty of Engineering and Technology, Sunway University, Bandar Sunway, 47500 Selangor, Malaysia; Department of Physics, College of Science, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
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2
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Deng Q, Parker E, Duan R, Yang L. Preconditioning and Posttreatment Strategies in Neonatal Hypoxic-Ischemic Encephalopathy: Recent Advances and Clinical Challenges. Mol Neurobiol 2025:10.1007/s12035-025-04896-4. [PMID: 40178781 DOI: 10.1007/s12035-025-04896-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Accepted: 03/24/2025] [Indexed: 04/05/2025]
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe neurological disorder caused by impaired cerebral blood flow and brain hypoxia, resulting in high morbidity and mortality rates. While therapeutic hypothermia remains the standard treatment and has been shown to reduce mortality to some extent, its therapeutic efficacy is limited, and it applies only to a select group of neonates who meet stringent inclusion criteria. Advances in our understanding of the pathophysiology of HIE have led to the identification of several promising neuroprotective strategies designed to mitigate or prevent the neurological damage induced by hypoxia-ischemia. Among these, preconditioning has emerged as a potent neuroprotective approach, enhancing cellular resilience to subsequent injury and potentially reducing treatment complexity and healthcare costs. Preconditioning/pretreatment and posttreatment offer significant promise in attenuating the neurological damage associated with HIE. Thus, exploring early intervention strategies for neonatal HIE, focusing on the comparative mechanisms and therapeutic targets of preconditioning and postconditioning, is critical to developing more effective treatment modalities. This review summarizes the current understanding of the pathophysiological mechanisms underlying neonatal HIE and its prevention and treatment strategies, providing new perspectives and a theoretical foundation for future neuroprotective interventions.
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Affiliation(s)
- Qianting Deng
- Laboratory of Exercise and Neurobiology, College of Physical Education and Sport Science, South China Normal University, Guangzhou, 510006, GD, China
| | - Emily Parker
- Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Rui Duan
- Lab of Regenerative Medicine in Sports Science, School of Physical Education and Sports Science, South China Normal University, Guangzhou, China.
| | - Luodan Yang
- Laboratory of Exercise and Neurobiology, College of Physical Education and Sport Science, South China Normal University, Guangzhou, 510006, GD, China.
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3
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Tieu K, Salehe SS, Brown HJ. Toxin-Induced Animal Models of Parkinson's Disease. Cold Spring Harb Perspect Med 2025; 15:a041643. [PMID: 38951030 PMCID: PMC11875089 DOI: 10.1101/cshperspect.a041643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
The debilitating motor symptoms of Parkinson's disease (PD) result primarily from the degenerative nigrostriatal dopaminergic pathway. To elucidate pathogenic mechanisms and evaluate therapeutic strategies for PD, numerous animal models have been developed. Understanding the strengths and limitations of these models can significantly impact the choice of model, experimental design, and data interpretation. Herein, we systematically review the literature over the past decade. Some models no longer serve the purpose of PD models. The primary objectives of this review are: First, to assist new investigators in navigating through available animal models and making appropriate selections based on the objective of the study. Emphasis will be placed on common toxin-induced murine models. And second, to provide an overview of basic technical requirements for assessing the nigrostriatal pathway's pathology, structure, and function.
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Affiliation(s)
- Kim Tieu
- Department of Environmental Health Sciences, Florida International University, Miami, Florida 33199, USA
- Biomolecular Sciences Institute, Florida International University, Miami, Florida 33199, USA
| | - Said S Salehe
- Department of Environmental Health Sciences, Florida International University, Miami, Florida 33199, USA
| | - Harry J Brown
- Department of Environmental Health Sciences, Florida International University, Miami, Florida 33199, USA
- Biomolecular Sciences Institute, Florida International University, Miami, Florida 33199, USA
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Ore A, Angelastro JM, Giulivi C. Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases. Brain Sci 2024; 14:899. [PMID: 39335395 PMCID: PMC11429837 DOI: 10.3390/brainsci14090899] [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: 08/08/2024] [Revised: 08/31/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell-derived secretions, and extracellular vesicles. Mesenchymal stem cell-mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues.
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Affiliation(s)
- Adaleiz Ore
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
- Department of Chemical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - James M. Angelastro
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
| | - Cecilia Giulivi
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
- University of California Medical Investigations of Neurodevelopmental Disorders Institute (MIND Institute), University of California Health, Sacramento, CA 95817, USA
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5
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Yong SH, Kim SM, Kong GW, Ko SH, Lee EH, Oh Y, Park CH. ASCL1-mediated direct reprogramming: converting ventral midbrain astrocytes into dopaminergic neurons for Parkinson's disease therapy. BMB Rep 2024; 57:363-368. [PMID: 38649147 PMCID: PMC11362138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/12/2023] [Accepted: 01/23/2024] [Indexed: 04/25/2024] Open
Abstract
Parkinson's disease (PD), characterized by dopaminergic neuron degeneration in the substantia nigra, is caused by various genetic and environmental factors. Current treatment methods are medication and surgery; however, a primary therapy has not yet been proposed. In this study, we aimed to develop a new treatment for PD that induces direct reprogramming of dopaminergic neurons (iDAN). Achaete-scute family bHLH transcription factor 1 (ASCL1) is a primary factor that initiates and regulates central nervous system development and induces neurogenesis. In addition, it interacts with BRN2 and MYT1L, which are crucial transcription factors for the direct conversion of fibroblasts into neurons. Overexpression of ASCL1 along with the transcription factors NURR1 and LMX1A can directly reprogram iDANs. Using a retrovirus, GFP-tagged ASCL1 was overexpressed in astrocytes. One week of culture in iDAN convertsion medium reprogrammed the astrocytes into iDANs. After 7 days of differentiation, TH+/TUJ1+ cells emerged. After 2 weeks, the number of mature TH+/TUJ1+ dopaminergic neurons increased. Only ventral midbrain (VM) astrocytes exhibited these results, not cortical astrocytes. Thus, VM astrocytes can undergo direct iDAN reprogramming with ASCL1 alone, in the absence of transcription factors that stimulate dopaminergic neurons development. [BMB Reports 2024; 57(8): 363-368].
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Affiliation(s)
- Sang Hui Yong
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Sang-Mi Kim
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea
- Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam 13488, Korea, Seoul 04763, Korea
| | - Gyeong Woon Kong
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Seung Hwan Ko
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Eun-Hye Lee
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, Korea
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, Seoul 04763, Korea
| | - Yohan Oh
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 04763, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Korea
- Hanyang Institute of Advanced BioConvergence, Hanyang University, Seoul 04763, Korea
| | - Chang-Hwan Park
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea
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López-Ornelas A, Escobedo-Avila I, Ramírez-García G, Lara-Rodarte R, Meléndez-Ramírez C, Urrieta-Chávez B, Barrios-García T, Cáceres-Chávez VA, Flores-Ponce X, Carmona F, Reynoso CA, Aguilar C, Kerik NE, Rocha L, Verdugo-Díaz L, Treviño V, Bargas J, Ramos-Mejía V, Fernández-Ruiz J, Campos-Romo A, Velasco I. Human Embryonic Stem Cell-Derived Immature Midbrain Dopaminergic Neurons Transplanted in Parkinsonian Monkeys. Cells 2023; 12:2738. [PMID: 38067166 PMCID: PMC10706241 DOI: 10.3390/cells12232738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 11/20/2023] [Accepted: 11/23/2023] [Indexed: 12/18/2023] Open
Abstract
Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DANs), and Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinson's disease (PD) patients. Here, we obtained well-characterized DANs from hESCs and transplanted them into two parkinsonian monkeys to assess their behavioral and imaging changes. DANs from hESCs expressed dopaminergic markers, generated action potentials, and released dopamine (DA) in vitro. These neurons were transplanted bilaterally into the putamen of parkinsonian NHPs, and using magnetic resonance imaging techniques, we calculated the fractional anisotropy (FA) and mean diffusivity (MD), both employed for the first time for these purposes, to detect in vivo axonal and cellular density changes in the brain. Likewise, positron-emission tomography scans were performed to evaluate grafted DANs. Histological analyses identified grafted DANs, which were quantified stereologically. After grafting, animals showed signs of partially improved motor behavior in some of the HALLWAY motor tasks. Improvement in motor evaluations was inversely correlated with increases in bilateral FA. MD did not correlate with behavior but presented a negative correlation with FA. We also found higher 11C-DTBZ binding in positron-emission tomography scans associated with grafts. Higher DA levels measured by microdialysis after stimulation with a high-potassium solution or amphetamine were present in grafted animals after ten months, which has not been previously reported. Postmortem analysis of NHP brains showed that transplanted DANs survived in the putamen long-term, without developing tumors, in immunosuppressed animals. Although these results need to be confirmed with larger groups of NHPs, our molecular, behavioral, biochemical, and imaging findings support the integration and survival of human DANs in this pre-clinical PD model.
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Affiliation(s)
- Adolfo López-Ornelas
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (A.L.-O.); (I.E.-A.); (R.L.-R.); (C.M.-R.); (B.U.-C.); (V.A.C.-C.); (X.F.-P.); (J.B.)
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico
- División de Investigación, Hospital Juárez de México, Mexico City 07760, Mexico
| | - Itzel Escobedo-Avila
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (A.L.-O.); (I.E.-A.); (R.L.-R.); (C.M.-R.); (B.U.-C.); (V.A.C.-C.); (X.F.-P.); (J.B.)
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico
- Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (L.V.-D.); (J.F.-R.)
- Unidad Periférica de Neurociencias, Facultad de Medicina, Universidad Nacional Autónoma de México, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico;
| | - Gabriel Ramírez-García
- Unidad Periférica de Neurociencias, Facultad de Medicina, Universidad Nacional Autónoma de México, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico;
| | - Rolando Lara-Rodarte
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (A.L.-O.); (I.E.-A.); (R.L.-R.); (C.M.-R.); (B.U.-C.); (V.A.C.-C.); (X.F.-P.); (J.B.)
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico
| | - César Meléndez-Ramírez
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (A.L.-O.); (I.E.-A.); (R.L.-R.); (C.M.-R.); (B.U.-C.); (V.A.C.-C.); (X.F.-P.); (J.B.)
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico
| | - Beetsi Urrieta-Chávez
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (A.L.-O.); (I.E.-A.); (R.L.-R.); (C.M.-R.); (B.U.-C.); (V.A.C.-C.); (X.F.-P.); (J.B.)
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico
| | - Tonatiuh Barrios-García
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Monterrey 64710, Mexico; (T.B.-G.); (V.T.)
| | - Verónica A. Cáceres-Chávez
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (A.L.-O.); (I.E.-A.); (R.L.-R.); (C.M.-R.); (B.U.-C.); (V.A.C.-C.); (X.F.-P.); (J.B.)
| | - Xóchitl Flores-Ponce
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (A.L.-O.); (I.E.-A.); (R.L.-R.); (C.M.-R.); (B.U.-C.); (V.A.C.-C.); (X.F.-P.); (J.B.)
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico
| | - Francia Carmona
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN (Cinvestav), Mexico City 07360, Mexico; (F.C.); (L.R.)
| | - Carlos Alberto Reynoso
- Molecular Imaging PET-CT Unit, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico; (C.A.R.); (C.A.); (N.E.K.)
| | - Carlos Aguilar
- Molecular Imaging PET-CT Unit, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico; (C.A.R.); (C.A.); (N.E.K.)
| | - Nora E. Kerik
- Molecular Imaging PET-CT Unit, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico; (C.A.R.); (C.A.); (N.E.K.)
| | - Luisa Rocha
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN (Cinvestav), Mexico City 07360, Mexico; (F.C.); (L.R.)
| | - Leticia Verdugo-Díaz
- Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (L.V.-D.); (J.F.-R.)
| | - Víctor Treviño
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Monterrey 64710, Mexico; (T.B.-G.); (V.T.)
| | - José Bargas
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (A.L.-O.); (I.E.-A.); (R.L.-R.); (C.M.-R.); (B.U.-C.); (V.A.C.-C.); (X.F.-P.); (J.B.)
| | - Verónica Ramos-Mejía
- Gene Regulation, Stem Cells, and Development Group, GENYO-Centre for Genomics and Oncological Research Pfizer, University of Granada, Andalusian Regional Government, PTS, 18016 Granada, Spain;
| | - Juan Fernández-Ruiz
- Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (L.V.-D.); (J.F.-R.)
| | - Aurelio Campos-Romo
- Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (L.V.-D.); (J.F.-R.)
- Unidad Periférica de Neurociencias, Facultad de Medicina, Universidad Nacional Autónoma de México, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico;
| | - Iván Velasco
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (A.L.-O.); (I.E.-A.); (R.L.-R.); (C.M.-R.); (B.U.-C.); (V.A.C.-C.); (X.F.-P.); (J.B.)
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico
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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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8
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Arderiu G, Civit-Urgell A, Badimon L. Adipose-Derived Stem Cells to Treat Ischemic Diseases: The Case of Peripheral Artery Disease. Int J Mol Sci 2023; 24:16752. [PMID: 38069074 PMCID: PMC10706341 DOI: 10.3390/ijms242316752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 11/21/2023] [Accepted: 11/23/2023] [Indexed: 12/18/2023] Open
Abstract
Critical limb ischemia incidence and prevalence have increased over the years. However, there are no successful treatments to improve quality of life and to reduce the risk of cardiovascular and limb events in these patients. Advanced regenerative therapies have focused their interest on the generation of new blood vessels to repair tissue damage through the use of stem cells. One of the most promising sources of stem cells with high potential in cell-based therapy is adipose-derived stem cells (ASCs). ASCs are adult mesenchymal stem cells that are relatively abundant and ubiquitous and are characterized by a multilineage capacity and low immunogenicity. The proangiogenic benefits of ASCs may be ascribed to: (a) paracrine secretion of proangiogenic molecules that may stimulate angiogenesis; (b) secretion of microvesicles/exosomes that are also considered as a novel therapeutic prospect for treating ischemic diseases; and (c) their differentiation capability toward endothelial cells (ECs). Although we know the proangiogenic effects of ASCs, the therapeutic efficacy of ASCs after transplantation in peripheral artery diseases patients is still relatively low. In this review, we evidence the potential therapeutic use of ASCs in ischemic regenerative medicine. We also highlight the main challenges in the differentiation of these cells into functional ECs. However, significant efforts are still needed to ascertain relevant transcription factors, intracellular signaling and interlinking pathways in endothelial differentiation.
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Affiliation(s)
- Gemma Arderiu
- Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau Barcelona, 08041 Barcelona, Spain; (A.C.-U.); (L.B.)
- Ciber CV, Instituto Carlos III, 28029 Madrid, Spain
| | - Anna Civit-Urgell
- Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau Barcelona, 08041 Barcelona, Spain; (A.C.-U.); (L.B.)
- Facultat de Medicina i Ciències de la Salut—Campus Clínic, Universitat de Barcelona, 08007 Barcelona, Spain
| | - Lina Badimon
- Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau Barcelona, 08041 Barcelona, Spain; (A.C.-U.); (L.B.)
- Ciber CV, Instituto Carlos III, 28029 Madrid, Spain
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9
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Han X, Zhang Q, He H, Zhao Q, Li G. Reflow-molded deep concave microwell arrays for robust and large-scale production of embryoid bodies. LAB ON A CHIP 2023; 23:4378-4389. [PMID: 37695312 DOI: 10.1039/d3lc00504f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Embryonic stem cell (ESC)-derived aggregates, called embryoid bodies (EBs), are powerful in vitro models used to study human development and disease. However, the cost-effective and large-scale production of homogeneous EBs still remains a challenge. Here, we report a rapid, straightforward method for fabricating closely arrayed deep concave microwells, enabling the mass production of uniform EBs from single cell suspensions. By simply combining micromilling, caramel replica molding, and thermal reflow, we generate convex micromolds with high aspect ratios and excellent surface smoothness. Benefitting from the nature of reflow, this method can produce rounded bottom polydimethylsiloxane (PDMS) microwells, which are not easily achieved with standard soft lithography techniques but critical to producing spherical EBs. To achieve optimal concave microwells, we investigated the effect of thermal reflow temperature and time on the surface smoothness and roundness of the finished microwells. In addition, to further improve the utility of this method, we also investigated the effect of microwell aspect ratio (AR) on the loss of EBs during medium manipulation. The capability of this deep concave microwell system was validated by rapidly generating a large number of human embryonic stem cell (hESC)-derived EBs and then efficiently differentiating them into a cardiac lineage. The proposed fabrication method and deep concave microwell platform are highly practical, and thus will benefit the mass production of EBs for potential tissue regeneration and cell therapy applications.
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Affiliation(s)
- Xue Han
- Key Laboratory of Optoelectronic Technology and Systems, Ministry of Education, Defense Key Disciplines Lab of Novel Micro-Nano Devices and System Technology, Chongqing University, Chongqing 400044, China.
| | - Qi Zhang
- Key Laboratory of Optoelectronic Technology and Systems, Ministry of Education, Defense Key Disciplines Lab of Novel Micro-Nano Devices and System Technology, Chongqing University, Chongqing 400044, China.
| | - Hui He
- Institute of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Qiang Zhao
- Key Laboratory of Optoelectronic Technology and Systems, Ministry of Education, Defense Key Disciplines Lab of Novel Micro-Nano Devices and System Technology, Chongqing University, Chongqing 400044, China.
| | - Gang Li
- Key Laboratory of Optoelectronic Technology and Systems, Ministry of Education, Defense Key Disciplines Lab of Novel Micro-Nano Devices and System Technology, Chongqing University, Chongqing 400044, China.
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10
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Pinjala P, Tryphena KP, Prasad R, Khatri DK, Sun W, Singh SB, Gugulothu D, Srivastava S, Vora L. CRISPR/Cas9 assisted stem cell therapy in Parkinson's disease. Biomater Res 2023; 27:46. [PMID: 37194005 PMCID: PMC10190035 DOI: 10.1186/s40824-023-00381-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 04/16/2023] [Indexed: 05/18/2023] Open
Abstract
Since its discovery in 2012, CRISPR Cas9 has been tried as a direct treatment approach to correct the causative gene mutation and establish animal models in neurodegenerative disorders. Since no strategy developed until now could completely cure Parkinson's disease (PD), neuroscientists aspire to use gene editing technology, especially CRISPR/Cas9, to induce a permanent correction in genetic PD patients expressing mutated genes. Over the years, our understanding of stem cell biology has improved. Scientists have developed personalized cell therapy using CRISPR/Cas9 to edit embryonic and patient-derived stem cells ex-vivo. This review details the importance of CRISPR/Cas9-based stem cell therapy in Parkinson's disease in developing PD disease models and developing therapeutic strategies after elucidating the possible pathophysiological mechanisms.
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Affiliation(s)
- Poojitha Pinjala
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana-500037, Hyderabad, India
| | - Kamatham Pushpa Tryphena
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana-500037, Hyderabad, India
| | - Renuka Prasad
- Department of Anatomy, Korea University College of Medicine, Moonsuk Medical Research Building, 73 Inchon-Ro, Seongbuk-Gu, Seoul, 12841, Republic of Korea
| | - Dharmendra Kumar Khatri
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana-500037, Hyderabad, India.
| | - Woong Sun
- Department of Anatomy, Korea University College of Medicine, Moonsuk Medical Research Building, 73 Inchon-Ro, Seongbuk-Gu, Seoul, 12841, Republic of Korea
| | - Shashi Bala Singh
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana-500037, Hyderabad, India
| | - Dalapathi Gugulothu
- Department of Pharmaceutics, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, 110017, India
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana-500037, Hyderabad, India
| | - Lalitkumar Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.
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11
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Perez SM, Boley AM, McCoy AM, Lodge DJ. Aberrant Dopamine System Function in the Ferrous Amyloid Buthionine (FAB) Rat Model of Alzheimer's Disease. Int J Mol Sci 2023; 24:7196. [PMID: 37108357 PMCID: PMC10138591 DOI: 10.3390/ijms24087196] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/06/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
Antipsychotics increase the risk of death in elderly patients with Alzheimer's disease (AD). Thus, there is an immediate need for novel therapies to treat comorbid psychosis in AD. Psychosis has been attributed to a dysregulation of the dopamine system and is associated with aberrant regulation by the hippocampus. Given that the hippocampus is a key site of pathology in AD, we posit that aberrant regulation of the dopamine system may contribute to comorbid psychosis in AD. A ferrous amyloid buthionine (FAB) rodent model was used to model a sporadic form of AD. FAB rats displayed functional hippocampal alterations, which were accompanied by decreases in spontaneous, low-frequency oscillations and increases in the firing rates of putative pyramidal neurons. Additionally, FAB rats exhibited increases in dopamine neuron population activity and augmented responses to the locomotor-inducing effects of MK-801, as is consistent with rodent models of psychosis-like symptomatology. Further, working memory deficits in the Y-maze, consistent with an AD-like phenotype, were observed in FAB rats. These data suggest that the aberrant hippocampal activity observed in AD may contribute to dopamine-dependent psychosis, and that the FAB model may be useful for the investigation of comorbid psychosis related to AD. Understanding the pathophysiology that leads to comorbid psychosis in AD will ultimately lead to the discovery of novel targets for the treatment of this disease.
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Affiliation(s)
- Stephanie M. Perez
- Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, TX 78229, USA; (A.M.B.); (D.J.L.)
- South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX 78229, USA
| | - Angela M. Boley
- Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, TX 78229, USA; (A.M.B.); (D.J.L.)
- South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX 78229, USA
| | - Alexandra M. McCoy
- Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, TX 78229, USA; (A.M.B.); (D.J.L.)
- South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX 78229, USA
| | - Daniel J. Lodge
- Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, TX 78229, USA; (A.M.B.); (D.J.L.)
- South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX 78229, USA
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12
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Huang J, Yi L, Yang X, Zheng Q, Zhong J, Ye S, Li X, Li H, Chen D, Li C. Neural stem cells transplantation combined with ethyl stearate improve PD rats motor behavior by promoting NSCs migration and differentiation. CNS Neurosci Ther 2023; 29:1571-1584. [PMID: 36924304 PMCID: PMC10173712 DOI: 10.1111/cns.14119] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 01/28/2023] [Accepted: 01/31/2023] [Indexed: 03/18/2023] Open
Abstract
BACKGROUND In recent years, the ability of neural stem cells (NSCs) transplantation to treat Parkinson's disease (PD) has attracted attention. However, it is still a challenge to promote the migration of NSCs to the lesion site and their directional differentiation into dopaminergic neurons in PD. C-C motif chemokine ligand 5 (CCL5) and C-C motif chemokine receptor 5 (CCR5) are expressed in the brain and are important regulators of cell migration. It has been reported that ethyl stearate (PubChem CID: 8122) has a protective effect in 6-OHDA-induced PD rats. METHODS Parkinson's disease rats were injected with 6-hydroxydopamine (6-OHDA) into the right substantia nigra, and striatum followed by 8 μL of an NSC cell suspension containing 100 μM ethyl stearate and 8 × 105 cells in the right striatum. The effect of transplantation NSCs combined with ethyl stearate was assessed by evaluating apomorphine (APO)-induced turning behavior and performance in the pole test. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR), Western blotting (WB), and immunofluorescence staining were also performed. RESULTS NSCs transplantation combined with ethyl stearate ameliorated the behavioral deficits of PD rats. PD rats that received transplantation NSCs combined with ethyl stearate exhibited increased expression of tyrosine hydroxylase (TH) and an increased number of green fluorescent protein (GFP)-positive cells. Furthermore, GFP-positive cells migrated into the substantia nigra and differentiated into dopaminergic neurons. The expression of CCL5 and CCR5 was significantly increased after transplantation NSCs combined with ethyl stearate. CONCLUSIONS These findings suggest that NSCs transplantation combined with ethyl stearate can improve the motor behavioral performance of PD rats by promoting NSCs migration from the striatum to the substantia nigra via CCL5/CCR5 and promoting the differentiation of NSCs into dopaminergic neurons.
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Affiliation(s)
- Jiapei Huang
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.,Research Center of Integrative Medicine (Key Laboratory of Chinese Medicine Pathogenesis and Therapy Research), School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Lan Yi
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.,Research Center of Integrative Medicine (Key Laboratory of Chinese Medicine Pathogenesis and Therapy Research), School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xiaoxiao Yang
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.,Research Center of Integrative Medicine (Key Laboratory of Chinese Medicine Pathogenesis and Therapy Research), School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Qi Zheng
- School of Information Science and Technology, Guangdong University of Foreign Studies, Guangzhou, Guangdong, China
| | - Jun Zhong
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.,Research Center of Integrative Medicine (Key Laboratory of Chinese Medicine Pathogenesis and Therapy Research), School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Sen Ye
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.,Research Center of Integrative Medicine (Key Laboratory of Chinese Medicine Pathogenesis and Therapy Research), School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xican Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Hui Li
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Dongfeng Chen
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Caixia Li
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.,Research Center of Integrative Medicine (Key Laboratory of Chinese Medicine Pathogenesis and Therapy Research), School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
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13
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Anderson KA, Whitehead BJ, Petersen ED, Kemme MR, Wedster A, Hochgeschwender U, Sandstrom MI. Behavioral context improves optogenetic stimulation of transplanted dopaminergic cells in unilateral 6-OHDA rats. Behav Brain Res 2023; 441:114279. [PMID: 36586489 DOI: 10.1016/j.bbr.2022.114279] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 12/20/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022]
Abstract
Stem cell therapy has long been a popular method of treatment for Parkinson's disease currently being researched in both preclinical and clinical settings. While early clinical results are based upon fetal tissue transplants rather than stem cell transplants, the lack of successful integration in some patients and gradual loss of effect in others suggests a more robust protocol is needed. We propose a two-front approach, one where transplants are directly stimulated in coordination with host activity elicited by behavioral tasks, which we refer to as behavioral context. After a pilot with unilateral 6-OHDA rats transplanted with dopaminergic cells differentiated from mesenchymal stem cells that were optogenetically stimulated during a swim task, we discovered that early stimulation predicted lasting reduction of motor deficits, even in the absence of later stimulation. This led to a follow-up with n = 21 rats split into three groups: one stimulated while performing a swim task (Stim-Swim; St-Sw), one not stimulated while swimming (NoStim-Swim; NSt-Sw), and one stimulated while stationary in a bowl (Stim-NoSwim; St-NSw). After initial stimulation (or lack thereof), all rats were retested two and seven days later with the swim task in the absence of stimulation. The St-Sw group gradually achieved and maintained symmetrical limb use, whereas the NSt-Sw group showed persistent asymmetry and the St-NSw group showed mixed results. This supports the notion that stem cell therapy should integrate targeted stimulation of the transplant with behavioral stimulation of the host tissue to encourage proper functional integration of the graft.
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Affiliation(s)
- Kevin A Anderson
- Central Michigan University, Department of Psychology, Mt. Pleasant, MI, USA
| | - Bailey J Whitehead
- Central Michigan University, Department of Psychology, Mt. Pleasant, MI, USA; West Virginia University, Rockefeller Neuroscience Institute, College of Medicine, Morgantown, WV, USA
| | - Eric D Petersen
- Central Michigan University, Program in Neuroscience, Mt. Pleasant, MI, USA; Central Michigan University, College of Medicine, Mt. Pleasant, MI, USA; Central Michigan University, Biochemistry, Cell, and Molecular Biology Program, Mt. Pleasant, MI, USA
| | - Madison R Kemme
- Central Michigan University, Department of Psychology, Mt. Pleasant, MI, USA; Michigan State University, College of Human Medicine, East Lansing, MI, USA
| | - Anna Wedster
- Central Michigan University, Program in Neuroscience, Mt. Pleasant, MI, USA
| | - Ute Hochgeschwender
- Central Michigan University, Program in Neuroscience, Mt. Pleasant, MI, USA; Central Michigan University, College of Medicine, Mt. Pleasant, MI, USA; Central Michigan University, Biochemistry, Cell, and Molecular Biology Program, Mt. Pleasant, MI, USA
| | - Michael I Sandstrom
- Central Michigan University, Department of Psychology, Mt. Pleasant, MI, USA; Central Michigan University, Program in Neuroscience, Mt. Pleasant, MI, USA.
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14
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Embryoid Body Cells from Human Embryonic Stem Cells Overexpressing Dopaminergic Transcription Factors Survive and Initiate Neurogenesis via Neural Rosettes in the Substantia Nigra. Brain Sci 2023; 13:brainsci13020329. [PMID: 36831872 PMCID: PMC9954545 DOI: 10.3390/brainsci13020329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/06/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Transplantation of immature dopaminergic neurons or neural precursors derived from embryonic stem cells (ESCs) into the substantia nigra pars compacta (SNpc) is a potential therapeutic approach for functional restitution of the nigrostriatal pathway in Parkinson's disease (PD). However, further studies are needed to understand the effects of the local microenvironment on the transplanted cells to improve survival and specific differentiation in situ. We have previously reported that the adult SNpc sustains a neurogenic microenvironment. Non-neuralized embryoid body cells (EBCs) from mouse ESCs (mESCs) overexpressing the dopaminergic transcription factor Lmx1a gave rise to many tyrosine hydroxylase (Th+) cells in the intact and damaged adult SNpc, although only for a short-term period. Here, we extended our study by transplanting EBCs from genetically engineered naive human ESC (hESC), overexpressing the dopaminergic transcription factors LMX1A, FOXA2, and OTX2 (hESC-LFO), in the SNpc. Unexpectedly, no graft survival was observed in wild-type hESC EBCs transplants, whereas hESC-LFO EBCs showed viability in the SNpc. Interestingly, neural rosettes, a developmental hallmark of neuroepithelial tissue, emerged at 7- and 15-days post-transplantation (dpt) from the hESC-LFO EBCs. Neural rosettes expressed specification dopaminergic markers (Lmx1a, Otx2), which gave rise to several Th+ cells at 30 dpt. Our results suggest that the SNpc enables the robust initiation of neural differentiation of transplanted human EBCs prompted to differentiate toward the midbrain dopaminergic phenotype.
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15
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Lane EL, Lelos MJ. Defining the unknowns for cell therapies in Parkinson's disease. Dis Model Mech 2022; 15:dmm049543. [PMID: 36165848 PMCID: PMC9555765 DOI: 10.1242/dmm.049543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
First-in-human clinical trials have commenced to test the safety and efficacy of cell therapies for people with Parkinson's disease (PD). Proof of concept that this neural repair strategy is efficacious is based on decades of preclinical studies and clinical trials using primary foetal cells, as well as a significant literature exploring more novel stem cell-derived products. Although several measures of efficacy have been explored, including the successful in vitro differentiation of stem cells to dopamine neurons and consistent alleviation of motor dysfunction in rodent models, many unknowns still remain regarding the long-term clinical implications of this treatment strategy. Here, we consider some of these outstanding questions, including our understanding of the interaction between anti-Parkinsonian medication and the neural transplant, the impact of the cell therapy on cognitive or neuropsychiatric symptoms of PD, the role of neuroinflammation in the therapeutic process and the development of graft-induced dyskinesias. We identify questions that are currently pertinent to the field that require further exploration, and pave the way for a more holistic understanding of this neural repair strategy for treatment of PD.
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Affiliation(s)
- Emma L. Lane
- Cardiff School of Pharmacy and Pharmaceutical Sciences, King Edward VII Avenue, Cardiff University, Cardiff CF10 3NB, UK
| | - Mariah J. Lelos
- School of Biosciences, Museum Avenue, Cardiff University, Cardiff CF10 3AX, UK
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16
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Vasudevan S, Dotti A, Kajtez J, Martínez-Serrano A, Gundlach C, Campos Maçãs S, Lauschke K, Vinngaard AM, García López S, Pereira M, Heiskanen A, Keller SS, Emnéus J. OMNIDIRECTIONAL LEAKY OPTO-ELECTRICAL FIBER FOR OPTOGENETIC CONTROL OF NEURONS IN CELL REPLACEMENT THERAPY. Bioelectrochemistry 2022; 149:108306. [DOI: 10.1016/j.bioelechem.2022.108306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 10/05/2022] [Accepted: 10/11/2022] [Indexed: 11/29/2022]
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17
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Li F, Zhang A, Li M, Wang X, Wang X, Guan Y, An J, Han D, Zhang YA, Chen Z. Induced neural stem cells from Macaca fascicularis show potential of dopaminergic neuron specification and efficacy in a mouse Parkinson's disease model. Acta Histochem 2022; 124:151927. [DOI: 10.1016/j.acthis.2022.151927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 11/01/2022]
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18
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Oxidative Stress in Ageing and Chronic Degenerative Pathologies: Molecular Mechanisms Involved in Counteracting Oxidative Stress and Chronic Inflammation. Int J Mol Sci 2022; 23:ijms23137273. [PMID: 35806275 PMCID: PMC9266760 DOI: 10.3390/ijms23137273] [Citation(s) in RCA: 148] [Impact Index Per Article: 49.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/24/2022] [Accepted: 06/24/2022] [Indexed: 12/17/2022] Open
Abstract
Ageing and chronic degenerative pathologies demonstrate the shared characteristics of high bioavailability of reactive oxygen species (ROS) and oxidative stress, chronic/persistent inflammation, glycation, and mitochondrial abnormalities. Excessive ROS production results in nucleic acid and protein destruction, thereby altering the cellular structure and functional outcome. To stabilise increased ROS production and modulate oxidative stress, the human body produces antioxidants, “free radical scavengers”, that inhibit or delay cell damage. Reinforcing the antioxidant defence system and/or counteracting the deleterious repercussions of immoderate reactive oxygen and nitrogen species (RONS) is critical and may curb the progression of ageing and chronic degenerative syndromes. Various therapeutic methods for ROS and oxidative stress reduction have been developed. However, scientific investigations are required to assess their efficacy. In this review, we summarise the interconnected mechanism of oxidative stress and chronic inflammation that contributes to ageing and chronic degenerative pathologies, including neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), cardiovascular diseases CVD, diabetes mellitus (DM), and chronic kidney disease (CKD). We also highlight potential counteractive measures to combat ageing and chronic degenerative diseases.
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19
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Zheng Y, Zhou J, Wang Y, Fan F, Liu S, Wang Y. Neural Stem/Progenitor Cell Transplantation in Parkinson's Rodent Animals: A Meta-Analysis and Systematic Review. Stem Cells Transl Med 2022; 11:383-393. [PMID: 35325234 PMCID: PMC9052406 DOI: 10.1093/stcltm/szac006] [Citation(s) in RCA: 3] [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: 01/29/2020] [Accepted: 01/08/2022] [Indexed: 12/02/2022] Open
Abstract
The effects of neural stem/progenitor cells (NSPCs) have been extensively evaluated by multiple studies in animal models of Parkinson's disease (PD), but the therapeutic efficacy was inconsistent. Here, we searched 4 databases (PubMed, Embase, Scopus, and Web of Science) and performed a meta-analysis to estimate the therapeutic effects of unmodified NSPCs on neurological deficits in rodent animal models of PD. Data on study quality score, behavioral outcomes (apomorphine or amphetamine-induced rotation and limb function), histological outcome (densitometry of TH+ staining in the SNpc), and cell therapy-related severe adverse events were extracted for meta-analysis and systematic review. Twenty-one studies with a median quality score of 6 (range from 4 to 9) in 11 were examined. Significant improvement was observed in the overall pooled standardized mean difference (SMD) between animals transplanted with NSPCs and with control medium (1.22 for apomorphine-induced rotation, P < .001; 1.50 for amphetamine-induced rotation, P < .001; 0.86 for limb function, P < .001; and -1.96 for the densitometry of TH+ staining, P < .001). Further subgroup analysis, animal gender, NSPCs source, NSPCs dosage, and pretreatment behavioral assessment were closely correlated with apomorphine-induced rotation and amphetamine-induced rotation. In conclusion, unmodified NSPCs therapy attenuated behavioral deficits and increased dopaminergic neurons in rodent PD models, supporting the consideration of early-stage clinical trial of NSPCs in patients with PD.
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Affiliation(s)
- Yifeng Zheng
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Jun Zhou
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Yisai Wang
- Department of Electrical and Computer Engineering, Rutgers University-New Brunswick, New Jersey, USA
| | - Fanfan Fan
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Shengwen Liu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Yu Wang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
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20
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Striatal glutamatergic hyperactivity in Parkinson's disease. Neurobiol Dis 2022; 168:105697. [DOI: 10.1016/j.nbd.2022.105697] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 12/21/2022] Open
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21
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Rahman MM, Islam MR, Islam MT, Harun-Or-Rashid M, Islam M, Abdullah S, Uddin MB, Das S, Rahaman MS, Ahmed M, Alhumaydhi FA, Emran TB, Mohamed AAR, Faruque MRI, Khandaker MU, Mostafa-Hedeab G. Stem Cell Transplantation Therapy and Neurological Disorders: Current Status and Future Perspectives. BIOLOGY 2022; 11:147. [PMID: 35053145 PMCID: PMC8772847 DOI: 10.3390/biology11010147] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/26/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023]
Abstract
Neurodegenerative diseases are a global health issue with inadequate therapeutic options and an inability to restore the damaged nervous system. With advances in technology, health scientists continue to identify new approaches to the treatment of neurodegenerative diseases. Lost or injured neurons and glial cells can lead to the development of several neurological diseases, including Parkinson's disease, stroke, and multiple sclerosis. In recent years, neurons and glial cells have successfully been generated from stem cells in the laboratory utilizing cell culture technologies, fueling efforts to develop stem cell-based transplantation therapies for human patients. When a stem cell divides, each new cell has the potential to either remain a stem cell or differentiate into a germ cell with specialized characteristics, such as muscle cells, red blood cells, or brain cells. Although several obstacles remain before stem cells can be used for clinical applications, including some potential disadvantages that must be overcome, this cellular development represents a potential pathway through which patients may eventually achieve the ability to live more normal lives. In this review, we summarize the stem cell-based therapies that have been explored for various neurological disorders, discuss the potential advantages and drawbacks of these therapies, and examine future directions for this field.
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Affiliation(s)
- Mohammad Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Touhidul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Harun-Or-Rashid
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mahfuzul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Sabirin Abdullah
- Space Science Center, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia;
| | - Mohammad Borhan Uddin
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Sumit Das
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Saidur Rahaman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Muniruddin Ahmed
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Fahad A. Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia;
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | | | | | - Mayeen Uddin Khandaker
- Centre for Applied Physics and Radiation Technologies, School of Engineering and Technology, Sunway University, Bandar Sunway 47500, Selangor, Malaysia;
| | - Gomaa Mostafa-Hedeab
- Pharmacology Department & Health Sciences Research Unit, Medical College, Jouf University, Sakaka 72446, Saudi Arabia;
- Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef 62521, Egypt
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22
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Goyal S, Seth B, Chaturvedi RK. Polyphenols and Stem Cells for Neuroregeneration in Parkinson's Disease and Amyotrophic Lateral Sclerosis. Curr Pharm Des 2021; 28:806-828. [PMID: 34781865 DOI: 10.2174/1381612827666211115154450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 11/02/2021] [Indexed: 11/22/2022]
Abstract
Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS) are neurological disorders, pathologically characterized by chronic degeneration of dopaminergic neurons and motor neurons respectively. There is still no cure or effective treatment against the disease progression and most of the treatments are symptomatic. The present review offers an overview of the different factors involved in the pathogenesis of these diseases. Subsequently, we focused on the recent advanced studies of dietary polyphenols and stem cell therapies, which have made it possible to slow down the progression of neurodegeneration. To date, stem cells and different polyphenols have been used for the directional induction of neural stem cells into dopaminergic neurons and motor neurons. We have also discussed their involvement in the modulation of different signal transduction pathways and growth factor levels in various in vivo and in vitro studies. Likewise stem cells, polyphenols also exhibit the potential of neuroprotection by their anti-apoptotic, anti-inflammatory, anti-oxidant properties regulating the growth factors levels and molecular signaling events. Overall this review provides a detailed insight into recent strategies that promise the use of polyphenol with stem cell therapy for the possible treatment of PD and ALS.
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Affiliation(s)
- Shweta Goyal
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001. India
| | - Brashket Seth
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001. India
| | - Rajnish Kumar Chaturvedi
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001. India
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23
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Kim IK, Park JH, Kim B, Hwang KC, Song BW. Recent advances in stem cell therapy for neurodegenerative disease: Three dimensional tracing and its emerging use. World J Stem Cells 2021; 13:1215-1230. [PMID: 34630859 PMCID: PMC8474717 DOI: 10.4252/wjsc.v13.i9.1215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/20/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative disease is a brain disorder caused by the loss of structure and function of neurons that lowers the quality of human life. Apart from the limited potential for endogenous regeneration, stem cell-based therapies hold considerable promise for maintaining homeostatic tissue regeneration and enhancing plasticity. Despite many studies, there remains insufficient evidence for stem cell tracing and its correlation with endogenous neural cells in brain tissue with three-dimensional structures. Recent advancements in tissue optical clearing techniques have been developed to overcome the existing shortcomings of cross-sectional tissue analysis in thick and complex tissues. This review focuses on recent progress of stem cell treatments to improve neurodegenerative disease, and introduces tissue optical clearing techniques that can implement a three-dimensional image as a proof of concept. This review provides a more comprehensive understanding of stem cell tracing that will play an important role in evaluating therapeutic efficacy and cellular interrelationship for regeneration in neurodegenerative diseases.
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Affiliation(s)
- Il-Kwon Kim
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea
| | - Jun-Hee Park
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
| | - Bomi Kim
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea.
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24
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Nair S, Rocha‐Ferreira E, Fleiss B, Nijboer CH, Gressens P, Mallard C, Hagberg H. Neuroprotection offered by mesenchymal stem cells in perinatal brain injury: Role of mitochondria, inflammation, and reactive oxygen species. J Neurochem 2021; 158:59-73. [PMID: 33314066 PMCID: PMC8359360 DOI: 10.1111/jnc.15267] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 12/03/2020] [Accepted: 12/03/2020] [Indexed: 12/11/2022]
Abstract
Preclinical studies have shown that mesenchymal stem cells have a positive effect in perinatal brain injury models. The mechanisms that cause these neurotherapeutic effects are not entirely intelligible. Mitochondrial damage, inflammation, and reactive oxygen species are considered to be critically involved in the development of injury. Mesenchymal stem cells have immunomodulatory action and exert mitoprotective effects which attenuate production of reactive oxygen species and promote restoration of tissue function and metabolism after perinatal insults. This review summarizes the present state, the underlying causes, challenges and possibilities for effective clinical translation of mesenchymal stem cell therapy.
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Affiliation(s)
- Syam Nair
- Centre of Perinatal Medicine and Health, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Institute of Neuroscience and PhysiologySahlgrenska Academy, University of GothenburgGothenburgSweden
- Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
| | - Eridan Rocha‐Ferreira
- Centre of Perinatal Medicine and Health, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Institute of Neuroscience and PhysiologySahlgrenska Academy, University of GothenburgGothenburgSweden
- Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
| | - Bobbi Fleiss
- School of Health and Biomedical SciencesRMIT UniversityBundooraVictoriaAustralia
- Université de Paris, NeuroDiderotParisFrance
| | - Cora H Nijboer
- Department for Developmental Origins of DiseaseUniversity Medical Center Utrecht Brain Center and Wilhelmina Children’s Hospital, Utrecht UniversityUtrechtNetherlands
| | | | - Carina Mallard
- Centre of Perinatal Medicine and Health, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Institute of Neuroscience and PhysiologySahlgrenska Academy, University of GothenburgGothenburgSweden
| | - Henrik Hagberg
- Centre of Perinatal Medicine and Health, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
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25
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Sharma Y, Shobha K, Sundeep M, Pinnelli VB, Parveen S, Dhanushkodi A. Neural Basis of Dental Pulp Stem Cells and its Potential Application in Parkinson's disease. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 21:62-76. [PMID: 33719979 DOI: 10.2174/1871527320666210311122921] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 01/16/2021] [Accepted: 01/29/2021] [Indexed: 11/22/2022]
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Though significant insights into the molecular-biochemical-cellular-behavioral basis of PD have been understood, there is no appreciable treatment available till date. Current therapies provide symptomatic relief without any influence on the progression of the disease. Stem cell therapy has been vigorously explored to treat PD. In this comprehensive review, we analyze various stem cell candidates for treating PD and discuss the possible mechanisms. We advocate the advantage of using neural crest originated dental pulp stem cells (DPSC) due to their predisposition towards neural differentiation and their potential to regenerate neurons far better than commonly used bone marrow derived mesenchymal stem cells (BM-MSCs). Eventually, we highlight the current challenges in the field and the strategies which may be used for overcoming the impediments.
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Affiliation(s)
- Yogita Sharma
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka. India
| | - Shobha K
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka. India
| | - Mata Sundeep
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka. India
| | | | - Shagufta Parveen
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka. India
| | - Anandh Dhanushkodi
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka. India
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26
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Li H, Kang A, An B, Chou LY, Shieh FK, Tsung CK, Zhong C. Encapsulation of bacterial cells in cytoprotective ZIF-90 crystals as living composites. Mater Today Bio 2021; 10:100097. [PMID: 33733083 PMCID: PMC7937694 DOI: 10.1016/j.mtbio.2021.100097] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 12/19/2022] Open
Abstract
Exploiting metal-organic frameworks (MOFs) as selectively permeable shelters for encapsulating engineered cells to form hybrid living materials has attracted increasing attention in recent years. Optimizing the synthesis process to improve encapsulation efficiency (EE) is critical for further technological development and applications. Here, using ZIF-90 and genetically engineered Escherichia coli (E. coli) as a demo, we fabricated E. coli@ZIF-90 living composites in which E. coli cells were encapsulated in ZIF-90 crystals. We illustrated that ZIF-90 could serve as a protective porous cage for cells to shield against toxic bactericides including benzaldehyde, cinnamaldehyde, and kanamycin. Notably, the E. coli cells remained alive and could self-reproduce after removing the ZIF-90 crystal cages in ethylenediaminetetraacetic acid, suggesting a feasible route for protecting and prolonging the lifespan of bacterial cells. Moreover, an aqueous multiple-step deposition approach was developed to improve EE of the E. coli@ZIF-90 composites: the EE increased to 61.9 ± 5.2%, in contrast with the efficiency of the traditional method (21.3 ± 4.4%) prepared with PBS buffer. In short, we develop a simple yet viable strategy to manufacture MOF-based living hybrid materials that promise new applications across diverse fields.
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Affiliation(s)
- H. Li
- Materials and Physical Biology Division, School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - A. Kang
- Materials and Physical Biology Division, School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - B. An
- Materials and Physical Biology Division, School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - L.-Y. Chou
- Materials and Physical Biology Division, School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - F.-K. Shieh
- Department of Chemistry, National Central University, Taoyuan 32001, Taiwan
| | - C.-K. Tsung
- Boston College Chemistry Department, Merkert Chemistry Center, 2609 Beacon St, Chestnut Hill, MA 02467, USA
| | - C. Zhong
- Materials and Physical Biology Division, School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
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27
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Jarrin S, Cabré S, Dowd E. The potential of biomaterials for central nervous system cellular repair. Neurochem Int 2021; 144:104971. [PMID: 33515647 DOI: 10.1016/j.neuint.2021.104971] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 01/01/2023]
Abstract
The central nervous system (CNS) can be injured or damaged through a variety of insults including traumatic injury, stroke, and neurodegenerative or demyelinating diseases, including Alzheimer's disease, Parkinson's disease and multiple sclerosis. Existing pharmacological and other therapeutics strategies are limited in their ability to repair or regenerate damaged CNS tissue meaning there are significant unmet clinical needs facing patients suffering CNS damage and/or degeneration. Through a variety of mechanisms including neuronal replacement, secretion of therapeutic factors, and stimulation of host brain plasticity, cell-based repair offers a potential mechanism to repair and heal the damaged CNS. However, over the decades of its evolution as a therapeutic strategy, cell-based CNS repair has faced significant hurdles that have prevented its translation to widespread clinical practice. In recent years, advances in cell technologies combined with advances in biomaterial-based regenerative medicine and tissue engineering have meant there is very real potential for many of these hurdles to be overcome. This review will provide an overview of the main CNS conditions that lend themselves to cellular repair and will then outline the potential of biomaterial-based approaches for improving the outcome of cellular repair in these conditions.
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Affiliation(s)
- Sarah Jarrin
- Pharmacology & Therapeutics and Galway Neuroscience Centre, National University of Ireland, Galway, Ireland
| | - Sílvia Cabré
- Pharmacology & Therapeutics and Galway Neuroscience Centre, National University of Ireland, Galway, Ireland; APC Microbiome Ireland, University College Cork, Ireland
| | - Eilís Dowd
- Pharmacology & Therapeutics and Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
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28
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Simorgh S, Alizadeh R, Shabani R, Karimzadeh F, Seidkhani E, Majidpoor J, Moradi F, Kasbiyan H. Olfactory mucosa stem cells delivery via nasal route: a simple way for the treatment of Parkinson disease. Neurotox Res 2021; 39:598-608. [PMID: 33433781 DOI: 10.1007/s12640-020-00290-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 09/17/2020] [Accepted: 09/20/2020] [Indexed: 12/11/2022]
Abstract
Finding a simple and effective way for transferring cells to the brain lesion site with minimum side effects mounts a challenge in cell therapy. Cell delivery via nasal route using the bypassing the blood-brain barrier (BBB) property is a simple and non-invasive strategy without serious complications such as trauma. Therefore, it is a suitable technique to treat neurodegenerative disorders like Parkinson's disease (PD). Olfactory ectomesenchymal stem cells (OE-MSCs) located in the lamina propria of olfactory mucosa could be differentiated into dopaminergic neurons under in vitro and in vivo conditions. Thus, OE-MSCs represent a good source of Parkinson's stem cell-based therapy. In this research, we studied thirty male rats (n = 10 in each group) in three control (Ctl), lesion (LE), and intranasal administration (INA) groups to investigate the therapeutic effect of intranasal injection of OE-MSCs in the Parkinson's animal models. To do so, we examined the homing variation of OE-MSCs in different brain regions such as olfactory bulb (OB), cortex, striatum (Str), hippocampus (HPC), and substantia nigra (SN). The results of real-time PCR and immunohistochemistry (IHC) analysis showed the expression of dopaminergic neuron markers such as PITX3, PAX2, PAX5 (as dopaminergic neurons markers), tyrosine hydroxylase (TH), and dopamine transporter (DAT) 2 months after INA of 1 × 106 OE-MSCs. The results confirmed that IN OE-MSCs delivery into the central nervous system (CNS) was powerful enough to improve the behavioral functions in the animal models of PD.
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Affiliation(s)
- Sara Simorgh
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rafieh Alizadeh
- ENT and Head & Neck Research Center and Department, The Five Senses Institute, HazratRasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Ronk Shabani
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Fariba Karimzadeh
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Elham Seidkhani
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Jamal Majidpoor
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Moradi
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. .,Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamidreza Kasbiyan
- Department of chemical engineering, Universitat Politècnica de Catalunya, Barcelona, Spain.
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29
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Xiao Z, Lei T, Liu Y, Yang Y, Bi W, Du H. The potential therapy with dental tissue-derived mesenchymal stem cells in Parkinson's disease. Stem Cell Res Ther 2021; 12:5. [PMID: 33407864 PMCID: PMC7789713 DOI: 10.1186/s13287-020-01957-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/27/2020] [Indexed: 12/19/2022] Open
Abstract
Parkinson’s disease (PD), the second most common neurodegenerative disease worldwide, is caused by the loss of dopaminergic (DAergic) neurons in the substantia nigra resulting in a series of motor or non-motor disorders. Current treatment methods are unable to stop the progression of PD and may bring certain side effects. Cell replacement therapy has brought new hope for the treatment of PD. Recently, human dental tissue-derived mesenchymal stem cells have received extensive attention. Currently, dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) are considered to have strong potential for the treatment of these neurodegenerative diseases. These cells are considered to be ideal cell sources for the treatment of PD on account of their unique characteristics, such as neural crest origin, immune rejection, and lack of ethical issues. In this review, we briefly describe the research investigating cell therapy for PD and discuss the application and progress of DPSCs and SHED in the treatment of PD. This review offers significant and comprehensive guidance for further clinical research on PD.
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Affiliation(s)
- Zhuangzhuang Xiao
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Tong Lei
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Yanyan Liu
- Kangyanbao (Beijing) Stem Cell Technology Co., Ltd, Beijing, 102600, China
| | - Yanjie Yang
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Wangyu Bi
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Hongwu Du
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China.
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30
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Carelli S, Giallongo T, Rey F, Barzaghini B, Zandrini T, Pulcinelli A, Nardomarino R, Cerullo G, Osellame R, Cereda C, Zuccotti GV, Raimondi MT. Neural precursors cells expanded in a 3D micro-engineered niche present enhanced therapeutic efficacy in vivo. Nanotheranostics 2021; 5:8-26. [PMID: 33391972 PMCID: PMC7738947 DOI: 10.7150/ntno.50633] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/04/2020] [Indexed: 12/13/2022] Open
Abstract
Rationale: Stem Cells (SCs) show a great potential in therapeutics for restoring and regenerating native tissues. The clinical translation of SCs therapies is currently hindered by the inability to expand SCs in vitro in large therapeutic dosages, while maintaining their safety and potency. The use of biomaterials allows for the generation of active biophysical signals for directing SCs fate through 3D micro-scaffolds, such as the one named “Nichoid”, fabricated with two-photon laser polymerization with a spatial resolution of 100 nm. The aims of this study were: i) to investigate the proliferation, differentiation and stemness properties of neural precursor cells (NPCs) following their cultivation inside the Nichoid micro-scaffold; ii) to assess the therapeutic effect and safety in vivo of NPCs cultivated in the Nichoid in a preclinical experimental model of Parkinson's Disease (PD). Methods: Nichoids were fabricated by two photon laser polymerization onto circular glass coverslips using a home-made SZ2080 photoresist. NPCs were grown inside the Nichoid for 7 days, counted and characterized with RNA-Seq, Real Time PCR analysis, immunofluorescence and Western Blot. Then, NPCs were transplanted in a murine experimental model of PD, in which parkinsonism was induced by the intraperitoneal administration of the neurotoxin MPTP in C57/bl mice. The efficacy of engrafted Nichoid-expanded NPCs was evaluated by means of specific behavioral tests and, after animal sacrifice, with immunohistochemical studies in brain slices. Results: NPCs grown inside the Nichoid show a significantly higher cell viability and proliferation than in standard culture conditions in suspension. Furthermore, we report the mechanical conditioning of NPCs in 3D micro-scaffolds, showing a significant increase in the expression of pluripotency genes. We also report that such mechanical reprogramming of NPCs produces an enhanced therapeutic effect in the in vivo model of PD. Recovery of PD symptoms was significantly increased when animals were treated with Nichoid-grown NPCs, and this is accompanied by the recovery of dopaminergic markers expression in the striatum of PD affected mice. Conclusion: SCs demonstrated an increase in pluripotency potential when expanded inside the Nichoid, without the need of any genetic modification of cells, showing great promise for large-scale production of safe and functional cell therapies to be used in multiple clinical applications.
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Affiliation(s)
- Stephana Carelli
- Pediatric Clinical Research Center "Romeo and Enrica Invernizzi", L. Sacco Department of Biomedical and Clinical Sciences, University of Milano, Milano, 20157, Italy
| | - Toniella Giallongo
- Pediatric Clinical Research Center "Romeo and Enrica Invernizzi", L. Sacco Department of Biomedical and Clinical Sciences, University of Milano, Milano, 20157, Italy
| | - Federica Rey
- Pediatric Clinical Research Center "Romeo and Enrica Invernizzi", L. Sacco Department of Biomedical and Clinical Sciences, University of Milano, Milano, 20157, Italy
| | - Bianca Barzaghini
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milano, 20133, Italy
| | - Tommaso Zandrini
- Istituto di Fotonica e Nanotecnologie (IFN)-CNR and Department of Physics, Politecnico di Milano, Milano, 20133, Italy
| | - Andrea Pulcinelli
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milano, 20133, Italy
| | - Riccardo Nardomarino
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milano, 20133, Italy
| | - Giulio Cerullo
- Istituto di Fotonica e Nanotecnologie (IFN)-CNR and Department of Physics, Politecnico di Milano, Milano, 20133, Italy
| | - Roberto Osellame
- Istituto di Fotonica e Nanotecnologie (IFN)-CNR and Department of Physics, Politecnico di Milano, Milano, 20133, Italy
| | - Cristina Cereda
- Genomic and Postgenomic Lab, IRCCS Mondino Foundation, Pavia, 27100, Italy
| | - Gian Vincenzo Zuccotti
- Pediatric Clinical Research Center "Romeo and Enrica Invernizzi", L. Sacco Department of Biomedical and Clinical Sciences, University of Milano, Milano, 20157, Italy
| | - Manuela Teresa Raimondi
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milano, 20133, Italy
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31
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Frajewicki A, Laštůvka Z, Borbélyová V, Khan S, Jandová K, Janišová K, Otáhal J, Mysliveček J, Riljak V. Perinatal hypoxic-ischemic damage: review of the current treatment possibilities. Physiol Res 2020; 69:S379-S401. [PMID: 33464921 DOI: 10.33549/physiolres.934595] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Neonatal hypoxic-ischemic encephalopathy is a disorder with heterogeneous manifestation due to asphyxia during perinatal period. It affects approximately 3-12 children per 1000 live births and cause death of 1 million neonates worldwide per year. Besides, motor disabilities, seizures, impaired muscle tone and epilepsy are few of the consequences of hypoxic-ischemic encephalopathy. Despite an extensive research effort regarding various treatment strategies, therapeutic hypothermia with intensive care unit supportive treatment remains the only approved method for neonates who have suffered from moderate to severe hypoxic-ischemic encephalopathy. However, these protocols are only partially effective given that many infants still suffer from severe brain damage. Thus, further research to systematically test promising neuroprotective treatments in combination with hypothermia is essential. In this review, we discussed the pathophysiology of hypoxic-ischemic encephalopathy and delved into different promising treatment modalities, such as melatonin and erythropoietin. However, preclinical studies and clinical trials are still needed to further elucidate the mechanisms of action of these modalities.
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Affiliation(s)
- A Frajewicki
- Institute of Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
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D'Elia A, Schiavi S, Soluri A, Massari R, Soluri A, Trezza V. Role of Nuclear Imaging to Understand the Neural Substrates of Brain Disorders in Laboratory Animals: Current Status and Future Prospects. Front Behav Neurosci 2020; 14:596509. [PMID: 33362486 PMCID: PMC7759612 DOI: 10.3389/fnbeh.2020.596509] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/23/2020] [Indexed: 12/18/2022] Open
Abstract
Molecular imaging, which allows the real-time visualization, characterization and measurement of biological processes, is becoming increasingly used in neuroscience research. Scintigraphy techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) provide qualitative and quantitative measurement of brain activity in both physiological and pathological states. Laboratory animals, and rodents in particular, are essential in neuroscience research, providing plenty of models of brain disorders. The development of innovative high-resolution small animal imaging systems together with their radiotracers pave the way to the study of brain functioning and neurotransmitter release during behavioral tasks in rodents. The assessment of local changes in the release of neurotransmitters associated with the performance of a given behavioral task is a turning point for the development of new potential drugs for psychiatric and neurological disorders. This review addresses the role of SPECT and PET small animal imaging systems for a better understanding of brain functioning in health and disease states. Brain imaging in rodent models faces a series of challenges since it acts within the boundaries of current imaging in terms of sensitivity and spatial resolution. Several topics are discussed, including technical considerations regarding the strengths and weaknesses of both technologies. Moreover, the application of some of the radioligands developed for small animal nuclear imaging studies is discussed. Then, we examine the changes in metabolic and neurotransmitter activity in various brain areas during task-induced neural activation with special regard to the imaging of opioid, dopaminergic and cannabinoid receptors. Finally, we discuss the current status providing future perspectives on the most innovative imaging techniques in small laboratory animals. The challenges and solutions discussed here might be useful to better understand brain functioning allowing the translation of preclinical results into clinical applications.
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Affiliation(s)
- Annunziata D'Elia
- Institute of Biochemistry and Cell Biology, National Research Council of Italy (CNR), Rome, Italy
- Section of Biomedical Sciences and Technologies, Department of Science, University “Roma Tre”, Rome, Italy
| | - Sara Schiavi
- Section of Biomedical Sciences and Technologies, Department of Science, University “Roma Tre”, Rome, Italy
| | - Andrea Soluri
- Institute of Biochemistry and Cell Biology, National Research Council of Italy (CNR), Rome, Italy
| | - Roberto Massari
- Institute of Biochemistry and Cell Biology, National Research Council of Italy (CNR), Rome, Italy
| | - Alessandro Soluri
- Institute of Biochemistry and Cell Biology, National Research Council of Italy (CNR), Rome, Italy
| | - Viviana Trezza
- Section of Biomedical Sciences and Technologies, Department of Science, University “Roma Tre”, Rome, Italy
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Qiu H, Qian T, Wu T, Wang X, Zhu C, Chen C, Wang L. Umbilical cord blood cells for the treatment of preterm white matter injury: Potential effects and treatment options. J Neurosci Res 2020; 99:778-792. [PMID: 33207392 DOI: 10.1002/jnr.24751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/31/2022]
Abstract
Preterm birth is a global public health problem. A large number of preterm infants survive with preterm white matter injury (PWMI), which leads to neurological deficits, and has multifaceted etiology, clinical course, monitoring, and outcomes. The principal upstream insults leading to PWMI initiation are hypoxia-ischemia and infection and/or inflammation and the key target cells are late oligodendrocyte precursor cells. Current PWMI treatments are mainly supportive, and thus have little effect in terms of protecting the immature brain or repairing injury to improve long-term outcomes. Umbilical cord blood (UCB) cells comprise abundant immunomodulatory and stem cells, which have the potential to reduce brain injury, mainly due to anti-inflammatory and immunomodulatory mechanisms, and also through their release of neurotrophic or growth factors to promote endogenous neurogenesis. In this review, we briefly summarize PWMI pathogenesis and pathophysiology, and the specific properties of different cell types in UCB. We further explore the potential mechanism by which UCB can be used to treat PWMI, and discuss the advantages of and potential issues related to UCB cell therapy. Finally, we suggest potential future studies of UCB cell therapy in preterm infants.
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Affiliation(s)
- Han Qiu
- Key Laboratory of Neonatal Diseases of Health Commission of the People's Republic of China, Shanghai, China.,Department of Neonatology, National Children's Medical Center/Children's Hospital of Fudan University, Shanghai, China
| | - Tianyang Qian
- Key Laboratory of Neonatal Diseases of Health Commission of the People's Republic of China, Shanghai, China.,Department of Neonatology, National Children's Medical Center/Children's Hospital of Fudan University, Shanghai, China
| | - Tong Wu
- Key Laboratory of Neonatal Diseases of Health Commission of the People's Republic of China, Shanghai, China.,Department of Neonatology, National Children's Medical Center/Children's Hospital of Fudan University, Shanghai, China
| | - Xiaoyang Wang
- Center of Perinatal Medicine and Health, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Changlian Zhu
- Center of Perinatal Medicine and Health, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Chao Chen
- Key Laboratory of Neonatal Diseases of Health Commission of the People's Republic of China, Shanghai, China.,Department of Neonatology, National Children's Medical Center/Children's Hospital of Fudan University, Shanghai, China
| | - Laishuan Wang
- Key Laboratory of Neonatal Diseases of Health Commission of the People's Republic of China, Shanghai, China.,Department of Neonatology, National Children's Medical Center/Children's Hospital of Fudan University, Shanghai, China
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Goggi JL, Qiu L, Liao MC, Khanapur S, Jiang L, Boominathan R, Hartimath SV, Cheng P, Yong FF, Soh V, Deng X, Lin YM, Haslop A, Tan PW, Zeng X, Lee JWL, Zhang Z, Sadasivam P, Tan EK, Luthra SK, Shingleton WD, Oh SKW, Zeng L, Robins EG. Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson's disease. Stem Cell Res Ther 2020; 11:347. [PMID: 32771055 PMCID: PMC7414543 DOI: 10.1186/s13287-020-01868-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 06/30/2020] [Accepted: 07/31/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Significant developments in stem cell therapy for Parkinson's disease (PD) have already been achieved; however, methods for reliable assessment of dopamine neuron maturation in vivo are lacking. Establishing the efficacy of new cellular therapies using non-invasive methodologies will be critical for future regulatory approval and application. The current study examines the utility of neuroimaging to characterise the in vivo maturation, innervation and functional dopamine release of transplanted human embryonic stem cell-derived midbrain dopaminergic neurons (hESC-mDAs) in a preclinical model of PD. METHODS Female NIH RNu rats received a unilateral stereotaxic injection of 6-OHDA into the left medial forebrain bundle to create the PD lesion. hESC-mDA cell and sham transplantations were carried out 1 month post-lesion, with treated animals receiving approximately 4 × 105 cells per transplantation. Behavioural analysis, [18F]FBCTT and [18F]fallypride microPET/CT, was conducted at 1, 3 and 6 months post-transplantation and compared with histological characterisation at 6 months. RESULTS PET imaging revealed transplant survival and maturation into functional dopaminergic neurons. [18F]FBCTT-PET/CT dopamine transporter (DAT) imaging demonstrated pre-synaptic restoration and [18F]fallypride-PET/CT indicated functional dopamine release, whilst amphetamine-induced rotation showed significant behavioural recovery. Moreover, histology revealed that the grafted cells matured differently in vivo producing high- and low-tyrosine hydroxylase (TH) expressing cohorts, and only [18F]FBCTT uptake was well correlated with differentiation. CONCLUSIONS This study provides further evidence for the value of in vivo functional imaging for the assessment of cell therapies and highlights the utility of DAT imaging for the determination of early post-transplant cell maturation and differentiation of hESC-mDAs.
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Affiliation(s)
- Julian L Goggi
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Lifeng Qiu
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore
| | - Mei Chih Liao
- Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Shivashankar Khanapur
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Lingfan Jiang
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Ramasamy Boominathan
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Siddesh V Hartimath
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Peter Cheng
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Fui Fong Yong
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Vanessa Soh
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Xiaozhou Deng
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Youshan Melissa Lin
- Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Anna Haslop
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Peng Wen Tan
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Xiaoxia Zeng
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore
| | - Jolene W L Lee
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore
| | - Zhiwei Zhang
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore
| | - Pragalath Sadasivam
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore
| | - Eng King Tan
- Research Department, National Neuroscience Institute, SGH Campus, Singapore, 169856, Singapore.,Department of Neurology, National Neuroscience Institute, SGH Campus, Singapore, 169856, Singapore.,Neuroscience & Behavioural Disorders Program, DUKE-NUS Graduate Medical School, Singapore, 169857, Singapore
| | - Sajinder K Luthra
- GE Healthcare Life Sciences, White Lion Rd., Little Chalfont, Amersham, HP7 9LL, UK
| | - William D Shingleton
- GE Healthcare Life Sciences, White Lion Rd., Little Chalfont, Amersham, HP7 9LL, UK
| | - Steve K W Oh
- Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Li Zeng
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore. .,Neuroscience & Behavioural Disorders Program, DUKE-NUS Graduate Medical School, Singapore, 169857, Singapore. .,Lee Kong Chian School of Medicine, Novena Campus, 11 Mandalay Road, Singapore, 308232, Singapore.
| | - Edward G Robins
- Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, #01-02 HELIOS, Singapore, 138667, Singapore. .,Clinical Imaging Research Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
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Ebrahimi V, Eskandarian Boroujeni M, Aliaghaei A, Abdollahifar MA, Piryaei A, Haghir H, Sadeghi Y. Functional dopaminergic neurons derived from human chorionic mesenchymal stem cells ameliorate striatal atrophy and improve behavioral deficits in Parkinsonian rat model. Anat Rec (Hoboken) 2020; 303:2274-2289. [PMID: 31642188 DOI: 10.1002/ar.24301] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 08/17/2019] [Accepted: 09/22/2019] [Indexed: 12/15/2022]
Abstract
Human chorionic mesenchymal stem cells (HCMSCs) have been recognized as a desirable choice for cell therapy in neurological disorders such as Parkinson's disease (PD). Due to invaluable features of HCMSCs including their immunomodulatory and immunosuppressive properties, easily accessible and less differentiated compared to other types of MSCs, HCMSCs provide a great hope for regenerative medicine. Thus, the purpose of this study was to determine the in vitro and in vivo efficacy of HCMSCs-derived dopaminergic (DA) neuron-like cells with regard to PD. Initially, HCMSCs were isolated and underwent a 2-week DA differentiation, followed by in vitro assessments, using quantitative real-time polymerase chain reaction, immunocytochemistry, patch clamp recording, and high-performance liquid chromatography. In addition, the effects of implanted HCMSCs-derived DA neuron-like cells on the motor coordination along with stereological alterations in the striatum of rat models of PD were investigated. Our results showed that under neuronal induction, HCMSCs revealed neuron-like morphology, and expressed neuronal and DA-specific genes, together with DA release. Furthermore, transplantation of HCMSCs-derived DA neurons into the striatum of rat models of PD, augmented performance. Besides, it prevented reduction of striatal volume, dendritic length, and the total number of neurons, coupled with a diminished level of cleaved caspase-3. Altogether, these findings suggest that HCMSCs could be considered as an attractive strategy for cell-based therapies in PD.
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Affiliation(s)
- Vahid Ebrahimi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Eskandarian Boroujeni
- Department of Stem Cells and Regenerative Medicine, Faculty of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Abbas Aliaghaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Abdollahifar
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Haghir
- Department of Anatomy, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetic Research Center (MGRC), Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yousef Sadeghi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Xu R, Wu J, Lang L, Hu J, Tang H, Xu J, Sun B. Implantation of glial cell line-derived neurotrophic factor-expressing adipose tissue-derived stromal cells in a rat Parkinson's disease model. Neurol Res 2020; 42:712-720. [PMID: 32567526 DOI: 10.1080/01616412.2020.1783473] [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: 10/24/2022]
Abstract
In previous studies, the effects of glial cell line-derived neurotrophic factor (GDNF) expressing adipose tissue-derived stromal cells (ADSCs) on Parkinson's disease (PD) models have been studied but have not been elucidated. The present study aims to investigate this phenomenon and trace their differentiation in vivo. In our study, ADSCs were harvested from adult Sprague-Dawley rats, then genetically modified into GDNF-expressing system by lentivirus. The secretion of GDNF from the transduced cells was titrated by enzyme-linked immunosorbent assay (ELISA). Cellular differentiation in vitro was observed after induction. To examine survival and differentiation in vivo, they were injected into the striatum of 6-hydroxydopamine-lesioned rats, whose apomorphine-induced rotations were examined 2, 7, 14 and 21d after grafting. It's found that GDNF-expressing ADSCs can differentiate into neuron-like cells in vitro. Moreover, engrafted GDNF-expressing ADSCs survived at least 90 days post-grafting and differentiated into dopaminergic neuron-like cells. Most importantly, these cells drastically improved the clinical symptoms of PD rats. In conclusion, ADSCs can be efficiently engineered by lentivirus system and deliver a therapeutic level of the transgene to target tissues. GDNF-ADSCs can improve behavior phenotype in the rat PD model. Moreover, ADSCs is a more readily available source of dopaminergic neurons, though a more effective procedure needs to be developed to enrich the number of differentiation.
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Affiliation(s)
- Rong Xu
- Department of Neurosurgery, Huashan Hospital, Fudan University , Shanghai, China
| | - Julei Wu
- Department of Nursing, Huashan Hospital North, Fudan University , Shanghai, China
| | - Liqin Lang
- Department of Neurosurgery, Huashan Hospital, Fudan University , Shanghai, China
| | - Jie Hu
- Department of Neurosurgery, Huashan Hospital, Fudan University , Shanghai, China
| | - Hailiang Tang
- Department of Neurosurgery, Huashan Hospital, Fudan University , Shanghai, China
| | - Juefeng Xu
- Department of Nursing, Huashan Hospital North, Fudan University , Shanghai, China
| | - Bing Sun
- Department of Neurosurgery, Huashan Hospital, Fudan University , Shanghai, China
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Thompson C, Otero P, Srinageshwar B, Petersen RB, Dunbar GL, Rossignol J. Possible roles of epigenetics in stem cell therapy for Parkinson's disease. Epigenomics 2020; 12:647-656. [PMID: 32396465 DOI: 10.2217/epi-2019-0347] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease with loss of dopaminergic neurons. PD has genetic and epigenetic influences that determine specific changes in the brain. Epigenetic changes result in defective methylation of genes leading to differential gene-expression causing PD. This review provides an overview of stem cell transplantations as potential therapies for PD, with a focus on the epigenetic changes, prior or following transplantation. To date, no reports have addressed epigenetic alterations following stem cell transplantation into the PD brain. Given the potential for affecting the efficacy of stem cell therapy, increased attention needs to be given to the epigenetic processes that occur during stem cell culture and transplantation to maximize the therapeutic potential of stem cells to PD.
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Affiliation(s)
- Cassandra Thompson
- Field Neurosciences Institute laboratory for Restorative Neurology, Central Michigan University, Mt. Pleasant, MI 48859, USA.,Program in Neuroscience, Central Michigan University, Mt. Pleasant, MI 48859, USA
| | - Paulina Otero
- Field Neurosciences Institute laboratory for Restorative Neurology, Central Michigan University, Mt. Pleasant, MI 48859, USA.,Program in Neuroscience, Central Michigan University, Mt. Pleasant, MI 48859, USA
| | - Bhairavi Srinageshwar
- Field Neurosciences Institute laboratory for Restorative Neurology, Central Michigan University, Mt. Pleasant, MI 48859, USA.,Program in Neuroscience, Central Michigan University, Mt. Pleasant, MI 48859, USA.,College of Medicine, Central Michigan University, Mt. Pleasant, MI 48859, USA
| | - Robert B Petersen
- College of Medicine, Central Michigan University, Mt. Pleasant, MI 48859, USA
| | - Gary L Dunbar
- Field Neurosciences Institute laboratory for Restorative Neurology, Central Michigan University, Mt. Pleasant, MI 48859, USA.,Program in Neuroscience, Central Michigan University, Mt. Pleasant, MI 48859, USA.,College of Medicine, Central Michigan University, Mt. Pleasant, MI 48859, USA.,Department of Psychology, Central Michigan University, Mt. Pleasant, MI 48859, USA.,Field Neurosciences Institute, St. Mary's of Michigan, Saginaw, MI 48604, USA
| | - Julien Rossignol
- Field Neurosciences Institute laboratory for Restorative Neurology, Central Michigan University, Mt. Pleasant, MI 48859, USA.,Program in Neuroscience, Central Michigan University, Mt. Pleasant, MI 48859, USA.,College of Medicine, Central Michigan University, Mt. Pleasant, MI 48859, USA
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Mesenchymal and Induced Pluripotent Stem Cells-Derived Extracellular Vesicles: The New Frontier for Regenerative Medicine? Cells 2020; 9:cells9051163. [PMID: 32397132 PMCID: PMC7290733 DOI: 10.3390/cells9051163] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/02/2020] [Accepted: 05/04/2020] [Indexed: 12/13/2022] Open
Abstract
Regenerative medicine aims to repair damaged, tissues or organs for the treatment of various diseases, which have been poorly managed with conventional drugs and medical procedures. To date, multimodal regenerative methods include transplant of healthy organs, tissues, or cells, body stimulation to activate a self-healing response in damaged tissues, as well as the combined use of cells and bio-degradable scaffold to obtain functional tissues. Certainly, stem cells are promising tools in regenerative medicine due to their ability to induce de novo tissue formation and/or promote organ repair and regeneration. Currently, several studies have shown that the beneficial stem cell effects, especially for mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) in damaged tissue restore are not dependent on their engraftment and differentiation on the injury site, but rather to their paracrine activity. It is now well known that paracrine action of stem cells is due to their ability to release extracellular vesicles (EVs). EVs play a fundamental role in cell-to-cell communication and are directly involved in tissue regeneration. In the present review, we tried to summarize the molecular mechanisms through which MSCs and iPSCs-derived EVs carry out their therapeutic action and their possible application for the treatment of several diseases.
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Histopathological and Behavioral Assessments of Aging Effects on Stem Cell Transplants in an Experimental Traumatic Brain Injury. Methods Mol Biol 2020; 2045:299-310. [PMID: 29445958 DOI: 10.1007/7651_2018_121] [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: 05/02/2023]
Abstract
Traumatic brain injury (TBI) displays cognitive and motor symptoms following the initial injury which can be exacerbated by secondary cell death. Aging contributes significantly to the morbidity of TBI, with higher rates of negative neurological and behaviors outcomes. In the recent study, young and aged animals were injected intravenously with human adipose-derived mesenchymal stem cells (hADSCs) (Tx), conditioned media (CM), or vehicle (unconditioned media) following TBI. The beneficial effects of hADSCs were analyzed using various molecular and behavioral techniques. More specially, DiR-labeled hADSCs were used to observe the biodistribution of the transplanted cells. In addition, a battery of behavior tests was conducted to evaluate the neuromotor function for each treatment group and various regions of the brain were analyzed utilizing Nissl, hematoxylin and eosin (H&E), and human nuclei (HuNu) staining. Finally, flow cytometry was also performed to determine the levels of various proteins in the spleen. Here, we discuss the protocols for characterizing the histopathological and behavioral effects of transplanted stem cells in an animal model of TBI, with an emphasis on the role of aging in the therapeutic outcomes.
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Osborn TM, Hallett PJ, Schumacher JM, Isacson O. Advantages and Recent Developments of Autologous Cell Therapy for Parkinson's Disease Patients. Front Cell Neurosci 2020; 14:58. [PMID: 32317934 PMCID: PMC7147334 DOI: 10.3389/fncel.2020.00058] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 02/27/2020] [Indexed: 12/14/2022] Open
Abstract
Parkinson’s Disease (PD) is a progressive degenerative disease characterized by tremor, bradykinesia, rigidity and postural instability. There are approximately 7–10 million PD patients worldwide. Currently, there are no biomarkers available or pharmaceuticals that can halt the dopaminergic neuron degeneration. At the time of diagnosis about 60% of the midbrain dopamine (mDA) neurons have already degenerated, resulting in a depletion of roughly 70% of striatal dopamine (DA) levels and synapses. Symptomatic treatment (e.g., with L-dopa) can initially restore DA levels and motor function, but with time often lead to side-effects like dyskinesia. Deep-brain-stimulation can alleviate these side-effects and some of the motor symptoms but requires repeat procedures and adds limitations for the patients. Restoration of dopaminergic synapses using neuronal cell replacement therapy has shown benefit in clinical studies using cells from fetal ventral midbrain. This approach, if done correctly, increases DA levels and restores synapses, allowing biofeedback regulation between the grafted cells and the host brain. Drawbacks are that it is not scalable for a large patient population and the patients require immunosuppression. Stem cells differentiated in vitro to mDA neurons or progenitors have shown promise in animal studies and is a scalable approach that allows for cryopreservation of transplantable cells and rigorous quality control prior to transplantation. However, all allogeneic grafts require immunosuppression. HLA-donor-matching, reduces, but does not completely eliminate, the need for immunosuppression, and is currently investigated in a clinical trial for PD in Japan. Since immune compatibility is very important in all areas of transplantation, these approaches may ultimately be of less benefit to the patients than an autologous approach. By using the patient’s own somatic cells, reprogrammed to induced pluripotent stem cells (iPSCs) and differentiated to mDA neurons immunosuppression is not required, and may also present with several biological and functional advantages in the patients, as described in this article. The proof-of-principle of autologous iPSC mDA restoration of function has been shown in parkinsonian non-human primates (NHPs), and this can now be investigated in clinical trials in addition to the allogeneic and HLA-matched approaches. In this review, we focus on the autologous approach of cell therapy for PD.
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Affiliation(s)
- Teresia M Osborn
- Neuroregeneration Research Institute, McLean Hospital/Harvard Medical School, Belmont, MA, United States
| | - Penelope J Hallett
- Neuroregeneration Research Institute, McLean Hospital/Harvard Medical School, Belmont, MA, United States
| | - James M Schumacher
- Neuroregeneration Research Institute, McLean Hospital/Harvard Medical School, Belmont, MA, United States
| | - Ole Isacson
- Neuroregeneration Research Institute, McLean Hospital/Harvard Medical School, Belmont, MA, United States
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Moayeri A, Darvishi M, Amraei M. Homing of Super Paramagnetic Iron Oxide Nanoparticles (SPIONs) Labeled Adipose-Derived Stem Cells by Magnetic Attraction in a Rat Model of Parkinson's Disease. Int J Nanomedicine 2020; 15:1297-1308. [PMID: 32161459 PMCID: PMC7049746 DOI: 10.2147/ijn.s238266] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 02/07/2020] [Indexed: 12/11/2022] Open
Abstract
Introduction Stem cell therapies for neurodegenerative diseases such as Parkinson’s disease (PD) are intended to replace lost dopaminergic neurons. The basis of this treatment is to guide the migration of transplanted cells into the target tissue or injury site. The aim of this study is an evaluation of the homing of superparamagnetic iron oxide nanoparticles (SPIONs) labeled adipose-derived stem cells (ADSC) by an external magnetic field in a rat model of PD. Methods ADSCs were obtained from perinephric regions of male adult rats and cultured in a DMEM medium. ADSC markers were assessed by immunostaining with CD90, CD105, CD49d, and CD45. The SPION was coated using poly-L-lysine hydrobromide and transfection was determined in rat ADSC using the GFP reporter gene. For this in vivo study, rats with PD were divided into five groups: a positive control group, a control group with PD (lesion with 6-HD injection), and three treatment groups: the PD/ADSC group (PD transplant with ADSCs transfected by BrdU), PD/ADSC/SPION group (PD transplant with ADSCs labeled with SPION and transfected by GFP), and the PD/ADSC/SPION/EM group (PD transplant with ADSCs labeled with SPION and transfected by GFP induced with external magnet). Results ADSCs were immunoreactive to fat markers CD90 (90.73±1.7), CD105 (87.4±2.9) and CD49d (79.6±2.6), with negative immunostaining at the hematopoietic stem cell marker (CD45: 1.4±0.4). The efficiency of cells with SPION/PLL was about 96% of ADSC. The highest number of GFP-positive cells was in the ADSC/SPION/EM group (54.5±1.3), which was significantly different from that in ADSC/SPION group (30.83±3 and P<0.01). Conclusion Transfection of ADSC by SPION/PLL is an appropriate protocol for cell therapy. External magnets can be used for the delivery and homing of transplanted stem cells in the target tissue.
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Affiliation(s)
- Ardeshir Moayeri
- Department of Anatomy, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Marzieh Darvishi
- Department of Anatomy, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran.,Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran
| | - Mansour Amraei
- Department of Physiology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
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Curcumin-Activated Mesenchymal Stem Cells Derived from Human Umbilical Cord and Their Effects on MPTP-Mouse Model of Parkinson's Disease: A New Biological Therapy for Parkinson's Disease. Stem Cells Int 2020; 2020:4636397. [PMID: 32148518 PMCID: PMC7048946 DOI: 10.1155/2020/4636397] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Accepted: 01/23/2020] [Indexed: 02/07/2023] Open
Abstract
Background The aim of this study was to investigate the effects of human umbilical cord mesenchymal stem cell activated by curcumin (hUC-MSCs-CUR) on Parkinson's disease (PD). hUC-MSCs can differentiate into many types of adult tissue cells including dopaminergic (DA) neurons. CUR could protect DA neurons from apoptosis induced by 6-hydroxydopamine (6-OHDA). Therefore, we used the hUC-MSCs activated by CUR for the treatment of PD in an animal model. Methods The hUC-MSCs-CUR was transplanted into the MPTP-induced PD mouse models via the tail vein. We found that hUC-MSCs-CUR significantly improved the motor ability, increased the tyrosine hydroxylase (TH), dopamine (DA), and Bcl-2 levels, and reduced nitric oxide synthase, Bax, and cleaved caspase 3 expression in PD mice. The supernatant of hUC-MSCs-CUR (CM-CUR) was used to stimulate the SH-SY5Y cellular model of PD; cell proliferation, differentiation, TH, and neuronal-specific marker microtubular-associated protein 2 (MAP2) expressions were examined. Results Our data showed that CM-CUR significantly promoted cell proliferation and gradually increased TH and MAP2 expression in SH-SY5Y PD cells. The beneficial effects could be associated with significant increase of rough endoplasmic reticulum in the hUC-MSCs-CUR, which secretes many cytokines and growth factors beneficial for PD treatment. Conclusions Transplantation of hUC-MSCs-CUR could show promise for improving the motor recovery of PD.
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Cendelin J, Buffo A, Hirai H, Magrassi L, Mitoma H, Sherrard R, Vozeh F, Manto M. Task Force Paper On Cerebellar Transplantation: Are We Ready to Treat Cerebellar Disorders with Cell Therapy? THE CEREBELLUM 2019; 18:575-592. [PMID: 30607797 DOI: 10.1007/s12311-018-0999-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Restoration of damaged central nervous system structures, functional recovery, and prevention of neuronal loss during neurodegenerative diseases are major objectives in cerebellar research. The highly organized anatomical structure of the cerebellum with numerous inputs/outputs, the complexity of cerebellar functions, and the large spectrum of cerebellar ataxias render therapies of cerebellar disorders highly challenging. There are currently several therapeutic approaches including motor rehabilitation, neuroprotective drugs, non-invasive cerebellar stimulation, molecularly based therapy targeting pathogenesis of the disease, and neurotransplantation. We discuss the goals and possible beneficial mechanisms of transplantation therapy for cerebellar damage and its limitations and factors determining outcome.
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Affiliation(s)
- Jan Cendelin
- Department of Pathophysiology, Faculty of Medicine in Pilsen, Charles University, alej Svobody 1655/76, 323 00, Plzen, Czech Republic
- Laboratory of Neurodegenerative Disorders, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, alej Svobody 1655/76, 323 00, Plzen, Czech Republic
| | - Annalisa Buffo
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi, Orbassano, 10043, Turin, Italy
| | - Hirokazu Hirai
- Department of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, 3-39-22, Maebashi, Gunma, 371-8511, Japan
| | - Lorenzo Magrassi
- Neurosurgery, Dipartimento di Scienze Clinico-Chirurgiche Diagnostiche e Pediatriche, Fondazione IRCCS Policlinico S. Matteo, Università degli Studi di Pavia, 27100, Pavia, Italy
- Istituto di Genetica Molecolare - CNR, 27100, Pavia, Italy
| | - Hiroshi Mitoma
- Medical Education Promotion Center, Tokyo Medical University, Tokyo, Japan
| | - Rachel Sherrard
- IBPS, UMR8256 Biological Adaptation and Ageing, Sorbonne Université and CNRS, Paris, France
| | - Frantisek Vozeh
- Department of Pathophysiology, Faculty of Medicine in Pilsen, Charles University, alej Svobody 1655/76, 323 00, Plzen, Czech Republic
- Laboratory of Neurodegenerative Disorders, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, alej Svobody 1655/76, 323 00, Plzen, Czech Republic
| | - Mario Manto
- Department of Neurology, CHU-Charleroi, 6000, Charleroi, Belgium.
- Service des Neurosciences, Université de Mons, 7000, Mons, Belgium.
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44
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Henriques D, Moreira R, Schwamborn J, Pereira de Almeida L, Mendonça LS. Successes and Hurdles in Stem Cells Application and Production for Brain Transplantation. Front Neurosci 2019; 13:1194. [PMID: 31802998 PMCID: PMC6877657 DOI: 10.3389/fnins.2019.01194] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/21/2019] [Indexed: 12/18/2022] Open
Abstract
Brain regenerative strategies through the transplantation of stem cells hold the potential to promote functional rescue of brain lesions caused either by trauma or neurodegenerative diseases. Most of the positive modulations fostered by stem cells are fueled by bystander effects, namely increase of neurotrophic factors levels and reduction of neuroinflammation. Nevertheless, the ultimate goal of cell therapies is to promote cell replacement. Therefore, the ability of stem cells to migrate and differentiate into neurons that later become integrated into the host neuronal network replacing the lost neurons has also been largely explored. However, as most of the preclinical studies demonstrate, there is a small functional integration of graft-derived neurons into host neuronal circuits. Thus, it is mandatory to better study the whole brain cell therapy approach in order to understand what should be better comprehended concerning graft-derived neuronal and glial cells migration and integration before we can expect these therapies to be ready as a viable solution for brain disorder treatment. Therefore, this review discusses the positive mechanisms triggered by cell transplantation into the brain, the limitations of adult brain plasticity that might interfere with the neuroregeneration process, as well as some strategies tested to overcome some of these limitations. It also considers the efforts that have been made by the regulatory authorities to lead to better standardization of preclinical and clinical studies in this field in order to reduce the heterogeneity of the obtained results.
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Affiliation(s)
- Daniel Henriques
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Ricardo Moreira
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Jens Schwamborn
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Luís Pereira de Almeida
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Liliana S Mendonça
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
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45
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Yang C, Wang X, Tang X, Wang R, Bao X. Stem-Cell Research of Parkinson Disease: Bibliometric Analysis of Research Productivity from 1999 to 2018. World Neurosurg 2019; 134:e405-e411. [PMID: 31655231 DOI: 10.1016/j.wneu.2019.10.087] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 10/13/2019] [Accepted: 10/14/2019] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Although the overall publication trends in Parkinson disease (PD) and characteristics of top-cited articles have been reported, there was only 1 literature analysis published in 2012 with a special focus on stem cells. It is necessary to evaluate and update the global publication trends in stem cell research of PD. METHODS We identified the publications designated as "article" about stem-cell research of PD between 1999 and 2018 in the Web of Science Core Collection. We used HistCite to analyze annual outputs, journals, countries/regions, and institutions every 5 years and visualized global collaborations between publications by VOSviewer. Moreover, to track the growing hotspots, MeSH terms of each publication were obtained by Medical Text Indexer according to the title and abstract. RESULTS We described the publication trends and topic hotspots of stem-cell research of PD by bibliometric analysis of 1709 papers. Researchers showed growing interest in publishing relevant scientific literature in journals associated with stem cells or multidisciplinary science. Stem cell research of PD was more common in developed countries and regions. The United States of America was the most contributive country throughout, accounting for 33% of total publications and ranking first in all 5-year periods. Harvard University was the most productive institution in this area, ranking first during 1999-2003, 2004-2008, and 2009-2013. The application of induced pluripotent stem cells was at the forefront of cell therapies for PD. CONCLUSIONS These bibliometric findings suggest that stem cell research consistently promotes the understanding and treatment of PD.
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Affiliation(s)
- Chengxian Yang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Xue Wang
- Institute of Medical Information and Library, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoli Tang
- Institute of Medical Information and Library, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Renzhi Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Xinjie Bao
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.
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46
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Bojnordi MN, Ebrahimi-Barough S, Vojoudi E, Hamidabadi HG. Silk nanofibrous electrospun scaffold enhances differentiation of embryonic stem like cells derived from testis in to mature neuron. J Biomed Mater Res A 2019; 106:2662-2669. [PMID: 29901281 DOI: 10.1002/jbm.a.36463] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/06/2018] [Accepted: 05/16/2018] [Indexed: 01/05/2023]
Abstract
The scaffolds accompanied with stem cells have great potential for applications in neural tissue engineering. Fabrication of nanofibrous scaffold similar to extracellular matrix is one of the applicable methods in neural tissue regeneration. The aim of this study was the fabrication of a silk nanofibrous scaffold as a microenvironment for neural guiding differentiation of embryonic stem like cells (ES Like cells) derived from testis toward neuron-like cells. ES Like derived from culturing of testicular cells in vitro, were seeded on silk scaffolds and induced to neuronal phenotype using 4-/4± RA technique following culturing the cells in the neurobasal medium supplemented with 20 ng/mL bFGF,10 ng/mL EGF, B27, and N2 for 8-12 days. The neural differentiation was confirmed via the evaluation of specific neural markers; Nestin, NF68, MAP2 and β tubulin using immunocytochemistry and real-time polymerase chain reaction. Our results showed that silk scaffold support the attachment and proliferation of ES Like cells. The expression of Nestin, NF68, Map2, and ß tubulin markers were higher in cells grown on silk scaffold in compare to monolayer group. This study suggests electrospun silk nanofibrous scaffold as an appropriate substrate for neural induction of stem cells that is applicable for repairmen of damaged neural tissues. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2662-2669, 2018.
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Affiliation(s)
- Maryam Nazm Bojnordi
- Immunogenetic Research Center, Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, P.O. Box, Sari, 48471-91971, Iran
| | - Somayeh Ebrahimi-Barough
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Vojoudi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hatef Ghasemi Hamidabadi
- Immunogenetic Research Center, Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, P.O. Box, Sari, 48471-91971, Iran
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47
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Yang X, Wang R, Wang X, Cai G, Qian Y, Feng S, Tan F, Chen K, Tang K, Huang X, Jing N, Qiao Y. TGFβ signaling hyperactivation-induced tumorigenicity during the derivation of neural progenitors from mouse ESCs. J Mol Cell Biol 2019; 10:216-228. [PMID: 29481611 DOI: 10.1093/jmcb/mjy013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 02/20/2018] [Indexed: 02/06/2023] Open
Abstract
Clinical therapies of pluripotent stem cells (PSCs)-based transplantation have been hindered by frequent development of teratomas or tumors in animal models and clinical patients. Therefore, clarifying the mechanism of carcinogenesis in stem cell therapy is of great importance for reducing the risk of tumorigenicity. Here we differentiate Oct4-GFP mouse embryonic stem cells (mESCs) into neural progenitor cells (NPCs) and find that a minority of Oct4+ cells are continuously sustained at Oct4+ state. These cells can be enriched and proliferated in a standard ESC medium. Interestingly, the differentiation potential of these enriched cells is tightly restricted with much higher tumorigenic activity, which are thus defined as differentiation-resistant ESCs (DR-ESCs). Transcriptomic and epigenomic analyses show that DR-ESCs are characterized by primordial germ cell-like gene signatures (Dazl, Rec8, Stra8, Blimp1, etc.) and specific epigenetic patterns distinct from mESCs. Moreover, the DR-ESCs possess germ cell potential to generate Sycp3+ haploid cells and are able to reside in sperm-free spermaduct induced by busulfan. Finally, we find that TGFβ signaling is overactivated in DR-ESCs, and inhibition of TGFβ signaling eliminates the tumorigenicity of mESC-derived NPCs by inducing the full differentiation of DR-ESCs. These data demonstrate that these TGFβ-hyperactivated germ cell-like DR-ESCs are the main contributor for the tumorigenicity of ESCs-derived target cell therapy and that inhibition of TGFβ signaling in ESC-derived NPC transplantation could drastically reduce the risk of tumor development.
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Affiliation(s)
- Xianfa Yang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Ran Wang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China
| | - Xiongjun Wang
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Guoqing Cai
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China
| | - Yun Qian
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China
| | - Su Feng
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China
| | - Fangzhi Tan
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Kun Chen
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Ke Tang
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Xingxu Huang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Naihe Jing
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Yunbo Qiao
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
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48
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Reversal of neurobehavioral teratogenicity in animal models and human: Three decades of progress. Brain Res Bull 2019; 150:328-342. [DOI: 10.1016/j.brainresbull.2019.06.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/09/2019] [Accepted: 06/12/2019] [Indexed: 12/13/2022]
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49
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Simorgh S, Alizadeh R, Eftekharzadeh M, Haramshahi SMA, Milan PB, Doshmanziari M, Ramezanpour F, Gholipourmalekabadi M, Seifi M, Moradi F. Olfactory mucosa stem cells: An available candidate for the treatment of the Parkinson's disease. J Cell Physiol 2019; 234:23763-23773. [PMID: 31173364 DOI: 10.1002/jcp.28944] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 05/22/2019] [Accepted: 05/23/2019] [Indexed: 01/01/2023]
Abstract
Olfactory ectomesenchymal stem cells (OE-MSCs) possess the immunosuppressive activity and regeneration capacity and hold a lot of promises for neurodegenerative disorders treatment. This study aimed to determine OE-MSCs which are able to augment and differentiate into functional neurons and regenerate the CNS and also examine whether the implantation of OE-MSCs in the pars compacta of the substantia nigra (SNpc) can improve Parkinson's symptoms in a rat model-induced with 6-hydroxydopamine. We isolated OE-MSCs from lamina propria in olfactory mucosa and characterized them using flow cytometry and immunocytochemistry. The therapeutic potential of OE-MSCs was evaluated by the transplantation of isolated cells using a rat model of acute SN injury as a Parkinson's disease. Significant behavioral improvement in Parkinsonian rats was elicited by the OE-MSCs. The results demonstrate that the expression of PAX2, PAX5, PITX3, dopamine transporter, and tyrosine hydroxylase was increased by OE-MSCs compared to the control group which is analyzed with real-time polymerase chain reaction technique and immunohistochemical staining. In the outcome, the transplantation of 1,1'-dioctadecyl-3,3,3'3'-tetramethyl indocarbocyanine perchlorate labeled OE-MSCs that were fully differentiated to dopaminergic neurons contribute to a substantial improvement in patients with Parkinson's. Together, our results provide that using OE-MSCs in neurodegenerative disorders might lead to better neural regeneration.
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Affiliation(s)
- Sara Simorgh
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rafieh Alizadeh
- ENT and Head & Neck Research Center and Department, The Five Senses Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mina Eftekharzadeh
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Amin Haramshahi
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Peiman Brouki Milan
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Doshmanziari
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farnaz Ramezanpour
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Morteza Seifi
- Departments of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Fatemeh Moradi
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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50
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Zhang J, Yang C, Chen J, Luo M, Qu Y, Mu D, Chen Q. Umbilical cord mesenchymal stem cells and umbilical cord blood mononuclear cells improve neonatal rat memory after hypoxia-ischemia. Behav Brain Res 2019; 362:56-63. [PMID: 30639506 DOI: 10.1016/j.bbr.2019.01.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/06/2019] [Accepted: 01/08/2019] [Indexed: 12/26/2022]
Abstract
Current treatment options for hypoxic-ischemic encephalopathy (HIE) are limited. Human umbilical cord mesenchymal stem cells (UC-MSCs) and cord blood mononuclear cells (CB-MNCs) offer great potential for the treatment of many neurological diseases. The aim of the present study was to identify which cell type is more effective for the treatment of HIE. PKH26-labeled UC-MSCs and CB-MNCs were transplanted into rats with hypoxia-ischemia (HI)-induced brain damage. Apoptotic cell numbers in the brain, as labeled by TUNEL, were assessed. Myelination and gliosis were investigated using myelin basic protein and glial fibrillary acidic protein immunohistochemistry, respectively. The Morris water maze was used to assess animal learning abilities. Our data show that transplantation of UC-MSCs or CB-MNCs after HI reduced astrogliosis, prevented neuronal loss in the striatum, and markedly improved functional brain outcomes after a 28-day recovery period. Moreover, treatment with CB-MNCs increased the proportion of mature oligodendrocytes and improved myelination in cortical areas. Both UC-MSCs and CB-MNCs may result in the recovery of neurological function in HI rats. Based on our data, UC-MSCs and UCB-MNCs may be particularly effective stem cell subsets for treatment of neonatal HIE.
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Affiliation(s)
- Jie Zhang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Chao Yang
- Stem Cells and Regenerative Medicine Research Center, Sichuan Cord Blood Bank/Sichuan Neo-Life Stem Cell Biotech Inc., Chengdu, 610037, Sichuan, China
| | - Juan Chen
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Maowen Luo
- Stem Cells and Regenerative Medicine Research Center, Sichuan Cord Blood Bank/Sichuan Neo-Life Stem Cell Biotech Inc., Chengdu, 610037, Sichuan, China
| | - Yi Qu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of the Ministry of Education, Sichuan University, Chengdu, 610041, China
| | - Dezhi Mu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of the Ministry of Education, Sichuan University, Chengdu, 610041, China
| | - Qiang Chen
- Stem Cells and Regenerative Medicine Research Center, Sichuan Cord Blood Bank/Sichuan Neo-Life Stem Cell Biotech Inc., Chengdu, 610037, Sichuan, China
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