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1
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Bello AB, Canlas KKV, Kim D, Park H, Lee SH. Stepwise dual-release microparticles of BMP-4 and SCF in induced pluripotent stem cell spheroids enhance differentiation into hematopoietic stem cells. J Control Release 2024; 371:386-405. [PMID: 38844177 DOI: 10.1016/j.jconrel.2024.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 06/03/2024] [Accepted: 06/03/2024] [Indexed: 06/11/2024]
Abstract
Recently, the formation of three-dimensional (3D) cell aggregates known as embryoid bodies (EBs) grown in media supplemented with HSC-specific morphogens has been utilized for the directed differentiation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), into clinically relevant hematopoietic stem cells (HSCs). However, delivering growth factors and nutrients have become ineffective in inducing synchronous differentiation of cells due to their 3D conformation. Moreover, irregularly sized EBs often lead to the formation of necrotic cores in larger EBs, impairing differentiation. Here, we developed two gelatin microparticles (GelMPs) with different release patterns and two HSC-related growth factors conjugated to them. Slow and fast releasing GelMPs were conjugated with bone morphogenic factor-4 (BMP-4) and stem cell factor (SCF), respectively. The sequential presentation of BMP-4 and SCF in GelMPs resulted in efficient and effective hematopoietic differentiation, shown by the enhanced gene and protein expression of several mesoderm and HSC-related markers, and the increased concentration of released HSC-related cytokines. In the present study, we were able to generate CD34+, CD133+, and FLT3+ cells with similar cellular and molecular morphology as the naïve HSCs that can produce colony units of different blood cells, in vitro.
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Affiliation(s)
- Alvin Bacero Bello
- Department of Biomedical Engineering, Dongguk University, Seoul 04620, Republic of Korea; School of Integrative Engineering, Chung-Ang University, Seoul 06911, Republic of Korea
| | | | - Deogil Kim
- Department of Biomedical Engineering, Dongguk University, Seoul 04620, Republic of Korea
| | - Hansoo Park
- School of Integrative Engineering, Chung-Ang University, Seoul 06911, Republic of Korea.
| | - Soo-Hong Lee
- Department of Biomedical Engineering, Dongguk University, Seoul 04620, Republic of Korea.
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2
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Raghunathan N, Sankaran S, Miteu GD. A comprehensive review of iPS cell line-based disease modelling of the polyglutamine spinocerebellar ataxias 2 and 3: a focus on the research outcomes. Ann Med Surg (Lond) 2024; 86:3487-3498. [PMID: 38846892 PMCID: PMC11152827 DOI: 10.1097/ms9.0000000000001984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 03/07/2024] [Indexed: 06/09/2024] Open
Abstract
Spinocerebellar ataxias (SCAs) are a rare autosomal dominant neurodegenerative disorder. To date, approximately 50 different subtypes of SCAs have been characterized. The prevalent types of SCAs are usually of PolyQ origin, wherein the disease pathology is a consequence of multiple glutamine residues being encoded onto the disease proteins, causing expansions. SCAs 2 and 3 are the most frequently diagnosed subtypes, wherein affected patients exhibit certain characteristic physiological manifestations, such as gait ataxia and dysarthria. Nevertheless, other clinical signs were exclusive to these subtypes. Recently, multiple molecular diagnostic methods have been developed to identify and characterize these subtypes. Despite these advancements, the molecular pathology of SCAs remains unknown. To further understand the mechanisms involved in neurodegenerative SCAs 2 and 3, patient-derived induced pluripotent stem cell (iPSC)-based modelling is a compelling avenue to pursue. We cover the present state of iPSC-based in-vitro illness modelling of SCA subtypes 2 and 3 below, along with a list of cell lines created, and the relevance of research outcomes to personalized autologous therapy.
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Affiliation(s)
| | | | - Goshen D. Miteu
- School of Biosciences, Biotechnology, University of Nottingham, England, UK
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA
- Department of Biochemistry, Caleb University, Lagos, Nigeria
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3
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Brandão-Teles C, Zuccoli GS, de Moraes Vrechi TA, Ramos-da-Silva L, Santos AVS, Crunfli F, Martins-de-Souza D. Induced-pluripotent stem cells and neuroproteomics as tools for studying neurodegeneration. Biochem Soc Trans 2024; 52:163-176. [PMID: 38288874 DOI: 10.1042/bst20230341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/05/2024] [Accepted: 01/08/2024] [Indexed: 02/29/2024]
Abstract
The investigation of neurodegenerative diseases advanced significantly with the advent of cell-reprogramming technology, leading to the creation of new models of human illness. These models, derived from induced pluripotent stem cells (iPSCs), facilitate the study of sporadic as well as hereditary diseases and provide a comprehensive understanding of the molecular mechanisms involved with neurodegeneration. Through proteomics, a quantitative tool capable of identifying thousands of proteins from small sample volumes, researchers have attempted to identify disease mechanisms by detecting differentially expressed proteins and proteoforms in disease models, biofluids, and postmortem brain tissue. The integration of these two technologies allows for the identification of novel pathological targets within the realm of neurodegenerative diseases. Here, we highlight studies from the past 5 years on the contributions of iPSCs within neuroproteomic investigations, which uncover the molecular mechanisms behind these illnesses.
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Affiliation(s)
- Caroline Brandão-Teles
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Giuliana S Zuccoli
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Talita Aparecida de Moraes Vrechi
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Lívia Ramos-da-Silva
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Aline Valéria Sousa Santos
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Fernanda Crunfli
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Daniel Martins-de-Souza
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil
- Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas 13083-862, SP, Brazil
- Instituto Nacional de Biomarcadores em Neuropsiquiatria, Conselho Nacional de Desenvolvimento Científico e Tecnológico, São Paulo, Brazil
- INCT in Modelling Human Complex Diseases with 3D Platforms (Model3D)
- D'Or Institute for Research and Education (IDOR), São Paulo, Brazil
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4
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Yuan H, Chen L, Zhang LC, Shi LL, Han XF, Liu S, Xiong LL, Wang TH. Microarray analysis of lncRNAs and mRNAs in spinal cord contusion rats with iPSC-derived A2B5 + oligodendrocyte precursor cells transplantation. Heliyon 2024; 10:e22808. [PMID: 38169755 PMCID: PMC10758718 DOI: 10.1016/j.heliyon.2023.e22808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/12/2023] [Accepted: 11/20/2023] [Indexed: 01/05/2024] Open
Abstract
Spinal cord injury (SCI) is a severe complication of spinal trauma with high disability and mortality rates. Effective therapeutic methods to alleviate neurobehavioural deficits in patients with SCI are still lacking. In this study, we established a spinal cord contusion (SCC) model in adult Sprague Dawley rats. Induced pluripotent stem cell-derived A2B5+ oligodendrocyte precursor cells (iP-A2B5+OPCs) were obtained from mouse embryonic fibroblasts and injected into the lesion sites of SCC rats. Serological testing and magnetic resonance imaging were employed to determine the effect of iP-A2B5+OPCs cell therapy. The Basso-Beattie-Bresnahan score and inclined plane test were performed on days 1, 3, 7, and 14 after cell transplantation, respectively. Differentially expressed long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) were detected by microarray analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to analyse the biological functions of these lncRNAs and mRNAs. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to verify variations in the expression of crucial target genes. The results demonstrated that induced pluripotent stem cells exhibited embryonic stem cell-like morphology and could differentiate into diverse neural cells dominated by oligodendrocytes. The neurobehavioural performance of rats treated with iP-A2B5+OPCs transplantation was better than that of rats with SCC without cell transplantation. Notably, we found that 22 lncRNAs and 42 mRNAs were concurrently altered after cell transplantation, and the key lncRNA (NR_037671) and target gene (Cntnap5a) were identified in the iP-A2B5+OPCs group. Moreover, RT-qPCR revealed that iP-A2B5+OPCs transplantation reversed the downregulation of NR_037671 induced by SCC. Our findings indicated that iP-A2B5+OPCs transplantation effectively improves neurological function recovery after SCC, and the mechanism might be related to alterations in the expression of lncRNAs and mRNAs, such as NR_037671 and Cntnap5a.
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Affiliation(s)
- Hao Yuan
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Institute of Neuroscience, Kunming Medical University, Kunming, 650031, Yunnan, China
- Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Li Chen
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Institute of Neurological Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Lan-Chun Zhang
- Institute of Neuroscience, Kunming Medical University, Kunming, 650031, Yunnan, China
| | - Lan-Lan Shi
- Institute of Neuroscience, Kunming Medical University, Kunming, 650031, Yunnan, China
| | - Xue-Fei Han
- Institute of Neuroscience, Kunming Medical University, Kunming, 650031, Yunnan, China
| | - Su Liu
- Internal Center of Spinal Cord Injury, Johns Hopkins School of Medicine, Baltimore, 21250, Maryland, USA
- Hugo W. Moser Research Institute at Kennedy Krieger Inc., Baltimore, 21250, Maryland, USA
| | - Liu-Lin Xiong
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Ting-Hua Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Institute of Neuroscience, Kunming Medical University, Kunming, 650031, Yunnan, China
- Institute of Neurological Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
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Lockard G, Gordon J, Schimmel S, El Sayed B, Monsour M, Garbuzova‐Davis S, Borlongan CV. Attenuation of amyotrophic lateral sclerosis via stem cell and extracellular vesicle therapy: An updated review. NEUROPROTECTION 2023; 1:130-138. [PMID: 38188233 PMCID: PMC10766415 DOI: 10.1002/nep3.26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 09/06/2023] [Accepted: 09/16/2023] [Indexed: 01/09/2024]
Abstract
Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurological disease characterized by upper and lower motor neuron degeneration. Though typically idiopathic, familial forms of ALS are commonly comprised of a superoxide dismutase 1 (SOD1) mutation. Basic science frequently utilizes SOD1 models in vitro and in vivo to replicate ALS conditions. Therapies are sparse; those that exist on the market extend life minimally, thus driving the demand for research to identify novel therapeutics. Transplantation of stem cells is a promising approach for many diseases and has shown efficacy in SOD1 models and clinical trials. The underlying mechanism for stem cell therapy presents an exciting venue for research investigations. Most notably, the paracrine actions of stem cell-derived extracellular vesicles (EVs) have been suggested as a potent mitigating factor. This literature review focuses on the most recent preclinical research investigating cell-free methods for treating ALS. Various avenues are being explored, differing on the EV contents (protein, microRNA, etc.) and on the cell target (astrocyte, endothelial cell, motor neuron-like cells, etc.), and both molecular and behavioral outcomes are being examined. Unfortunately, EVs may also play a role in propagating ALS pathology. Nonetheless, the overarching goal remains clear; to identify efficient cell-free techniques to attenuate the deadly consequences of ALS.
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Affiliation(s)
- Gavin Lockard
- University of South Florida Morsani College of MedicineTampaFloridaUSA
| | - Jonah Gordon
- University of South Florida Morsani College of MedicineTampaFloridaUSA
| | - Samantha Schimmel
- University of South Florida Morsani College of MedicineTampaFloridaUSA
| | - Bassel El Sayed
- University of South Florida Morsani College of MedicineTampaFloridaUSA
| | - Molly Monsour
- University of South Florida Morsani College of MedicineTampaFloridaUSA
| | - Svitlana Garbuzova‐Davis
- Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain RepairUniversity of South Florida Morsani College of MedicineTampaFloridaUSA
| | - Cesar V. Borlongan
- Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain RepairUniversity of South Florida Morsani College of MedicineTampaFloridaUSA
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Menduti G, Boido M. Recent Advances in High-Content Imaging and Analysis in iPSC-Based Modelling of Neurodegenerative Diseases. Int J Mol Sci 2023; 24:14689. [PMID: 37834135 PMCID: PMC10572296 DOI: 10.3390/ijms241914689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 09/24/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
In the field of neurodegenerative pathologies, the platforms for disease modelling based on patient-derived induced pluripotent stem cells (iPSCs) represent a valuable molecular diagnostic/prognostic tool. Indeed, they paved the way for the in vitro recapitulation of the pathological mechanisms underlying neurodegeneration and for characterizing the molecular heterogeneity of disease manifestations, also enabling drug screening approaches for new therapeutic candidates. A major challenge is related to the choice and optimization of the morpho-functional study designs in human iPSC-derived neurons to deeply detail the cell phenotypes as markers of neurodegeneration. In recent years, the specific combination of high-throughput screening with subcellular resolution microscopy for cell-based high-content imaging (HCI) screening allowed in-depth analyses of cell morphology and neurite trafficking in iPSC-derived neuronal cells by using specific cutting-edge microscopes and automated computational assays. The present work aims to describe the main recent protocols and advances achieved with the HCI analysis in iPSC-based modelling of neurodegenerative diseases, highlighting technical and bioinformatics tips and tricks for further uses and research. To this end, microscopy requirements and the latest computational pipelines to analyze imaging data will be explored, while also providing an overview of the available open-source high-throughput automated platforms.
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Affiliation(s)
- Giovanna Menduti
- Department of Neuroscience “Rita Levi Montalcini”, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Regione Gonzole 10, Orbassano, 10043 Turin, TO, Italy;
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7
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Maheshwari S, Vilema-Enríquez G, Wade-Martins R. Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application. Transl Neurodegener 2023; 12:45. [PMID: 37726850 PMCID: PMC10510273 DOI: 10.1186/s40035-023-00376-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/28/2023] [Indexed: 09/21/2023] Open
Abstract
Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease. The recent discovery and subsequent development of induced pluripotent stem cell (iPSC) technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases. Utilising iPSCs, researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA. These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research.
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Affiliation(s)
- Saumya Maheshwari
- Department of Physiology, Anatomy and Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
| | - Gabriela Vilema-Enríquez
- Department of Physiology, Anatomy and Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
| | - Richard Wade-Martins
- Department of Physiology, Anatomy and Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
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8
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Timalsina B, Choi HJ, Moon IS. N-Acetylglucosamine Kinase-Small Nuclear Ribonucleoprotein Polypeptide N Interaction Promotes Axodendritic Branching in Neurons via Dynein-Mediated Microtubule Transport. Int J Mol Sci 2023; 24:11672. [PMID: 37511433 PMCID: PMC10380243 DOI: 10.3390/ijms241411672] [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: 06/27/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
N-acetylglucosamine kinase (NAGK) has been identified as an anchor protein that facilitates neurodevelopment with its non-canonical structural role. Similarly, small nuclear ribonucleoprotein polypeptide N (SNRPN) regulates neurodevelopment and cognitive ability. In our previous study, we revealed the interaction between NAGK and SNRPN in the neuron. However, the precise role in neurodevelopment is elusive. In this study, we investigate the role of NAGK and SNRPN in the axodendritic development of neurons. NAGK and SNRPN interaction is significantly increased in neurons at the crucial stages of neurodevelopment. Furthermore, overexpression of the NAGK and SNRPN proteins increases axodendritic branching and neuronal complexity, whereas the knockdown inhibits neurodevelopment. We also observe the interaction of NAGK and SNRPN with the dynein light-chain roadblock type 1 (DYNLRB1) protein variably during neurodevelopment, revealing the microtubule-associated delivery of the complex. Interestingly, NAGK and SNRPN proteins rescued impaired axodendritic development in an SNRPN depletion model of Prader-Willi syndrome (PWS) patient-derived induced pluripotent stem cell neurons. Taken together, these findings are crucial in developing therapeutic approaches for neurodegenerative diseases.
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Affiliation(s)
- Binod Timalsina
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
| | - Ho Jin Choi
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
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Marsool MDM, Prajjwal P, Reddy YB, Marsool ADM, Lam JR, Nandwana V. Newer modalities in the management of Alzheimer's dementia along with the role of aducanumab and lecanemab in the treatment of its refractory cases. Dis Mon 2023; 69:101547. [PMID: 36931947 DOI: 10.1016/j.disamonth.2023.101547] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
Abstract
Alzheimer's disease (AD) is a common neurological condition characterized by a gradual and progressive decline in memory, language, emotion, and cognition. It mainly affects elderly people. Due to the effects of AD, pharmaceutical medications and anticholinesterases have been vigorously promoted and approved by the FDA as a form of AD therapy. However, it was progressively found that these drugs did not address the underlying causes of AD pathogenesis; rather, they focused on the symptoms in order to enhance patients' cognitive outcomes. Consequently, a hunt for superior disease-modifying options is launched. Designing new therapeutic agents requires a thorough understanding of the neuroprotective processes and varied functions carried out by certain genes, and antibodies. In this comprehensive review article, we give an overview of the history of Alzheimer's disease, the significance of the blood-brain barrier in determining the scope of treatment options, as well as the advantages and disadvantages of the current therapeutic treatment options for stem cell therapy, immunotherapy, regenerative therapy, and improved Alzheimer's disease care and diagnosis. We have also included a discussion on the potential role of aducanumab and Lecanemab as a cutting-edge therapy in refractory Alzheimer's disease patients. Lecanemab has been recently approved by the FDA for the treatment of Alzheimer's disease.
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Affiliation(s)
| | | | | | | | - Justin Riley Lam
- Internal Medicine, Cebu Institute of Medicine, Cebu, Philippines
| | - Varsha Nandwana
- Neurology, Virginia Tech Carilion School of Medicine, Virginia, USA
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10
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Elzayat EM, Shahien SA, El-Sherif AA, Hosney M. miRNAs and Stem Cells as Promising Diagnostic and Therapeutic Targets for Alzheimer's Disease. J Alzheimers Dis 2023; 94:S203-S225. [PMID: 37212107 PMCID: PMC10473110 DOI: 10.3233/jad-221298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2023] [Indexed: 05/23/2023]
Abstract
Alzheimer's disease (AD) is a cumulative progressive neurodegenerative disease characterized mainly by impairment in cognitive functions accompanied by memory loss, disturbance in behavior and personality, and difficulties in learning. Although the main causes of AD pathogenesis are not fully understood yet, amyloid-β peptides and tau proteins are supposed to be responsible for AD onset and pathogenesis. Various demographic, genetic, and environmental risk factors are involved in AD onset and pathogenesis such as age, gender, several genes, lipids, malnutrition, and poor diet. Significant changes were observed in microRNA (miRNA) levels between normal and AD cases giving hope for a diagnostic procedure for AD through a simple blood test. As yet, only two classes of AD therapeutic drugs are approved by FDA. They are classified as acetylcholinesterase inhibitors and N-methyl-D-aspartate antagonists (NMDA). Unfortunately, they can only treat the symptoms but cannot cure AD or stop its progression. New therapeutic approaches were developed for AD treatment including acitretin due to its ability to cross blood-brain barrier in the brain of rats and mice and induce the expression of ADAM 10 gene, the α-secretase of human amyloid-β protein precursor, stimulating the non-amyloidogenic pathway for amyloid-β protein precursor processing resulting in amyloid-β reduction. Also stem cells may have a crucial role in AD treatment as they can improve cognitive functions and memory in AD rats through regeneration of damaged neurons. This review spotlights on promising diagnostic techniques such as miRNAs and therapeutic approaches such as acitretin and/or stem cells keeping in consideration AD pathogenesis, stages, symptoms, and risk factors.
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Affiliation(s)
- Emad M. Elzayat
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Sherif A. Shahien
- Biotechnology/Bimolecular Chemistry Program, Faculty of Science, Helwan University, Cairo, Egypt
| | - Ahmed A. El-Sherif
- Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
| | - Mohamed Hosney
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt
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11
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Kim J, Daadi EW, Oh T, Daadi ES, Daadi MM. Human Induced Pluripotent Stem Cell Phenotyping and Preclinical Modeling of Familial Parkinson's Disease. Genes (Basel) 2022; 13:1937. [PMID: 36360174 PMCID: PMC9689743 DOI: 10.3390/genes13111937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 10/13/2022] [Accepted: 10/18/2022] [Indexed: 12/05/2022] Open
Abstract
Parkinson's disease (PD) is primarily idiopathic and a highly heterogenous neurodegenerative disease with patients experiencing a wide array of motor and non-motor symptoms. A major challenge for understanding susceptibility to PD is to determine the genetic and environmental factors that influence the mechanisms underlying the variations in disease-associated traits. The pathological hallmark of PD is the degeneration of dopaminergic neurons in the substantia nigra pars compacta region of the brain and post-mortem Lewy pathology, which leads to the loss of projecting axons innervating the striatum and to impaired motor and cognitive functions. While the cause of PD is still largely unknown, genome-wide association studies provide evidence that numerous polymorphic variants in various genes contribute to sporadic PD, and 10 to 15% of all cases are linked to some form of hereditary mutations, either autosomal dominant or recessive. Among the most common mutations observed in PD patients are in the genes LRRK2, SNCA, GBA1, PINK1, PRKN, and PARK7/DJ-1. In this review, we cover these PD-related mutations, the use of induced pluripotent stem cells as a disease in a dish model, and genetic animal models to better understand the diversity in the pathogenesis and long-term outcomes seen in PD patients.
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Affiliation(s)
- Jeffrey Kim
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
- Cell Systems and Anatomy, San Antonio, TX 78229, USA
| | - Etienne W. Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
| | - Thomas Oh
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
| | - Elyas S. Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
| | - Marcel M. Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
- Cell Systems and Anatomy, San Antonio, TX 78229, USA
- Department of Radiology, Long School of Medicine, University of Texas Health at San Antonio, San Antonio, TX 78229, USA
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12
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Akimov SS, Jiang M, Kedaigle AJ, Arbez N, Marque LO, Eddings CR, Ranum PT, Whelan E, Tang A, Wang R, DeVine LR, Talbot CC, Cole RN, Ratovitski T, Davidson BL, Fraenkel E, Ross CA. Immortalized striatal precursor neurons from Huntington's disease patient-derived iPS cells as a platform for target identification and screening for experimental therapeutics. Hum Mol Genet 2021; 30:2469-2487. [PMID: 34296279 PMCID: PMC8643509 DOI: 10.1093/hmg/ddab200] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 11/12/2022] Open
Abstract
We have previously established induced pluripotent stem cell (iPSC) models of Huntington's disease (HD), demonstrating CAG-repeat-expansion-dependent cell biological changes and toxicity. However, the current differentiation protocols are cumbersome and time consuming, making preparation of large quantities of cells for biochemical or screening assays difficult. Here, we report the generation of immortalized striatal precursor neurons (ISPNs) with normal (33) and expanded (180) CAG repeats from HD iPSCs, differentiated to a phenotype resembling medium spiny neurons (MSN), as a proof of principle for a more tractable patient-derived cell model. For immortalization, we used co-expression of the enzymatic component of telomerase hTERT and conditional expression of c-Myc. ISPNs can be propagated as stable adherent cell lines, and rapidly differentiated into highly homogeneous MSN-like cultures within 2 weeks, as demonstrated by immunocytochemical criteria. Differentiated ISPNs recapitulate major HD-related phenotypes of the parental iPSC model, including brain-derived neurotrophic factor (BDNF)-withdrawal-induced cell death that can be rescued by small molecules previously validated in the parental iPSC model. Proteome and RNA-seq analyses demonstrate separation of HD versus control samples by principal component analysis. We identified several networks, pathways, and upstream regulators, also found altered in HD iPSCs, other HD models, and HD patient samples. HD ISPN lines may be useful for studying HD-related cellular pathogenesis, and for use as a platform for HD target identification and screening experimental therapeutics. The described approach for generation of ISPNs from differentiated patient-derived iPSCs could be applied to a larger allelic series of HD cell lines, and to comparable modeling of other genetic disorders.
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Affiliation(s)
- Sergey S Akimov
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Mali Jiang
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Amanda J Kedaigle
- Department of Biological Engineering, Computational and Systems Biology Graduate Program, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Nicolas Arbez
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Leonard O Marque
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Chelsy R Eddings
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Paul T Ranum
- The Department of Pathology and Laboratory Medicine, The University of Pennsylvania, The Raymond G Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Emma Whelan
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Anthony Tang
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Ronald Wang
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Lauren R DeVine
- Mass Spectrometry and Proteomics Facility, Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Conover C Talbot
- The Johns Hopkins School of Medicine, Institute for Basic Biomedical Sciences, Baltimore, MD 21205, USA
| | - Robert N Cole
- Mass Spectrometry and Proteomics Facility, Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Tamara Ratovitski
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Beverly L Davidson
- The Department of Pathology and Laboratory Medicine, The University of Pennsylvania, The Raymond G Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- The Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ernest Fraenkel
- Department of Biological Engineering, Computational and Systems Biology Graduate Program, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Christopher A Ross
- Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Neurology, Neuroscience and Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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13
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Pansri P, Phanthong P, Suthprasertporn N, Kitiyanant Y, Tubsuwan A, Dinnyes A, Kobolak J, Kitiyanant N. Brain-derived neurotrophic factor increases cell number of neural progenitor cells derived from human induced pluripotent stem cells. PeerJ 2021; 9:e11388. [PMID: 34026357 PMCID: PMC8123227 DOI: 10.7717/peerj.11388] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 04/10/2021] [Indexed: 12/23/2022] Open
Abstract
Background Several pieces of evidence from in vitro studies showed that brain-derived neurotrophic factor (BDNF) promotes proliferation and differentiation of neural stem/progenitor cells (NSCs) into neurons. Moreover, the JAK2 pathway was proposed to be associated with mouse NSC proliferation. BDNF could activate the STAT-3 pathway and induce proliferation in mouse NSCs. However, its effects on proliferation are not fully understood and JAK/STAT pathway was proposed to play a role in this activity. Methods In the present study, the effects of BDNF on cell proliferation and neurite outgrowth of Alzheimer’s disease (AD) induced pluripotent stem cells (iPSCs)-derived human neural progenitor cells (hNPCs) were examined. Moreover, a specific signal transduction pathway important in cell proliferation was investigated using a JAK2 inhibitor (AG490) to clarify the role of that pathway. Results The proliferative effect of BDNF was remarkably observed as an increase in Ki-67 positive cells. The cell number of hNPCs was significantly increased after BDNF treatment represented by cellular metabolic activity of the cells measured by MTT assay. This noticeable effect was statistically shown at 20 ng/ml of BDNF treatment. BDNF, however, did not promote neurite outgrowth but increased neuronal cell number. It was found that AG490 suppressed hNPCs proliferation. However, this inhibitor partially decreased BDNF-induced hNPCs proliferation. These results demonstrated the potential role of BDNF for the amelioration of AD through the increase of AD-derived hNPCs number.
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Affiliation(s)
- Panetha Pansri
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand.,BioTalentum Ltd., Gödöllö, Hungary
| | - Phetcharat Phanthong
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Nopparat Suthprasertporn
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Yindee Kitiyanant
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Alisa Tubsuwan
- Molecular Medical Biosciences Cluster, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Andras Dinnyes
- BioTalentum Ltd., Gödöllö, Hungary.,HCEMM-USZ StemCell Research Group, University of Szeged, Szeged, Hungary.,Department of Physiology and Animal Health, Hungarian University of Agriculture and Life Sciences, Gödöllö, Hungary
| | | | - Narisorn Kitiyanant
- Molecular Medical Biosciences Cluster, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
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14
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Ahani-Nahayati M, Shariati A, Mahmoodi M, Olegovna Zekiy A, Javidi K, Shamlou S, Mousakhani A, Zamani M, Hassanzadeh A. Stem cell in neurodegenerative disorders; an emerging strategy. Int J Dev Neurosci 2021; 81:291-311. [PMID: 33650716 DOI: 10.1002/jdn.10101] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/13/2021] [Accepted: 02/24/2021] [Indexed: 01/28/2023] Open
Abstract
Neurodegenerative disorders are a diversity of disorders, surrounding Alzheimer's (AD), Parkinson's (PD), Huntington's diseases (HD), and amyotrophic lateral sclerosis (ALS) accompanied by some other less common diseases generally characterized by either developed deterioration of central or peripheral nervous system structurally or functionally. Today, with the viewpoint of an increasingly aging society, the number of patients with neurodegenerative diseases and sociomedical burdens will spread intensely. During the last decade, stem cell technology has attracted great attention for treating neurodegenerative diseases worldwide because of its unique attributes. As acknowledged, there are several categories of stem cells being able to proliferate and differentiate into various cellular lineages, highlighting their significance in the context of regenerative medicine. In preclinical models, stem cell therapy using mesenchymal stem/stromal cells (MSCs), hematopoietic stem cells (HSCs), and neural progenitor or stem cells (NPCs or NSCs) along with pluripotent stem cells (PSCs)-derived neuronal cells could elicit desired therapeutic effects, enabling functional deficit rescue partially. Regardless of the noteworthy progress in our scientific awareness and understanding of stem cell biology, there still exist various challenges to defeat. In the present review, we provide a summary of the therapeutic potential of stem cells and discuss the current status and prospect of stem cell strategy in neurodegenerative diseases, in particular, AD, PD, ALS, and HD.
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Affiliation(s)
- Milad Ahani-Nahayati
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Ali Shariati
- Stem Cell Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Mahnaz Mahmoodi
- Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Angelina Olegovna Zekiy
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Kamran Javidi
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.,Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Shamlou
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Akbar Mousakhani
- Department of Plant Sciences, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Neurosciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
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15
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Robin G, Evans JC, Hauser DN, Wren P, Zembrzycki A. Longitudinal Characterization of Transcriptomic, Functional, and Morphological Features in Human iPSC-Derived Neurons and Their Application to Investigate Translational Progranulin Disease Biology. Front Aging Neurosci 2020; 12:576678. [PMID: 33281596 PMCID: PMC7689020 DOI: 10.3389/fnagi.2020.576678] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 10/07/2020] [Indexed: 01/19/2023] Open
Abstract
The disease biology of frontotemporal lobe dementia (FTD) is complex and not fully understood, with limited translational value appreciated from animal models to date. Human cellular systems that can recapitulate phenotypic features of disease offer promise as translational tools to not only increase our understanding of disease processes but also increase the probability of success of translating novel treatment options to patients. However not all researchers may necessarily have access to well-characterized induced pluripotent stem cell (iPSC)-derived human neurons. As an example, we therefore comprehensively profiled phenotypic features over time in one commercially-available IPSC-derived human neuron cell line. This included systems-level assessments of neurite outgrowth dynamics, neuronal network function, and genome-wide gene expression. By investigating progranulin biology as an example we then demonstrated the utility of these cells as a tool to investigate human disease biology. For example, by using the siRNA-mediated knockdown of the progranulin (GRN) gene, we demonstrated the establishment of an isogenic human cellular model to facilitate translational FTD research. We reproduced findings from rodent neurons by demonstrating that recombinant progranulin (rPGRN) mediated neuroprotection. Contrary to previous rodent data, in our human cellular models, growth factor treatment showed no consistent sensitivity to modulate neurite outgrowth dynamics. Our study further provides the first evidence that rRPGRN modulated neuronal firing and synchrony in human neurons. Taken together, our datasets are a valuable systems-level resource demonstrating the utility of the tested commercially-available human iPSC neurons for investigating basic human neurobiology, translational neuroscience, and drug discovery applications in neurodegenerative and other CNS diseases.
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Affiliation(s)
- Gaëlle Robin
- SBP-GSK Center for Translational Neuroscience, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - J Corey Evans
- SBP-GSK Center for Translational Neuroscience, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - David N Hauser
- SBP-GSK Center for Translational Neuroscience, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Paul Wren
- GSK, Neuroscience Discovery, Collegeville, PA, United States
| | - Andreas Zembrzycki
- SBP-GSK Center for Translational Neuroscience, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
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16
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Yde Ohki CM, Grossmann L, Alber E, Dwivedi T, Berger G, Werling AM, Walitza S, Grünblatt E. The stress-Wnt-signaling axis: a hypothesis for attention-deficit hyperactivity disorder and therapy approaches. Transl Psychiatry 2020; 10:315. [PMID: 32948744 PMCID: PMC7501308 DOI: 10.1038/s41398-020-00999-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 12/27/2022] Open
Abstract
Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric neurodevelopmental disorders in children and adolescents. Although ADHD has been studied for nearly a century, the cause and pathophysiology of ADHD is yet largely unknown. However, findings from previous studies have resulted in the formation of a new hypothesis: Apart from the well-known multifactorial etiology of ADHD, recent evidence suggests that the interaction between genetic and environmental factors and especially Wnt- and mTOR-signaling pathways might have an important role in the pathophysiology of ADHD. The Wnt-signaling pathway is known to orchestrate cellular proliferation, polarity, and differentiation, and the mTOR pathway is involved in several significant processes of neurodevelopment and synaptic plasticity. As a result, dysregulations of these pathways in a time-dependent manner could lead to neurodevelopmental delays, resulting in ADHD phenotype. This review presents further evidence supporting our hypothesis by combining results from studies on ADHD and Wnt- or mTOR-signaling and the influence of genetics, methylphenidate treatment, Omega-3 supplementation, and stress.
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Affiliation(s)
- Cristine Marie Yde Ohki
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry, University of Zurich, Zürich, Switzerland
| | - Leoni Grossmann
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry, University of Zurich, Zürich, Switzerland
| | - Emma Alber
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry, University of Zurich, Zürich, Switzerland
| | - Tanushree Dwivedi
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry, University of Zurich, Zürich, Switzerland
| | - Gregor Berger
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry, University of Zurich, Zürich, Switzerland
| | - Anna Maria Werling
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry, University of Zurich, Zürich, Switzerland
| | - Susanne Walitza
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry, University of Zurich, Zürich, Switzerland
- Neuroscience Center Zurich, University of Zurich and the ETH Zurich, Zürich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zürich, Switzerland
| | - Edna Grünblatt
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry, University of Zurich, Zürich, Switzerland.
- Neuroscience Center Zurich, University of Zurich and the ETH Zurich, Zürich, Switzerland.
- Zurich Center for Integrative Human Physiology, University of Zurich, Zürich, Switzerland.
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17
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Enhanced integrin affinity and neural differentiation of induced pluripotent stem cells using Ln5-P4-grafted amphiphilic solid lipid nanoparticles. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 118:111339. [PMID: 33254967 DOI: 10.1016/j.msec.2020.111339] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 03/11/2020] [Accepted: 07/20/2020] [Indexed: 12/29/2022]
Abstract
Amphiphilic solid lipid nanoparticles (ASLNs) with surface PPFLMLLKGSTR peptide (Ln5-P4) (Ln5-P4/ASLNs) were prepared to load nerve growth factor (NGF) and retinoic acid (RA) and to guide the differentiation of induced pluripotent stem cells (iPSCs) toward neurons. Beeswax (BW) and lecithin played predominant roles in microemulsion and in the average diameter, zeta potential, encapsulation efficiency of NGF and RA and release kinetics of NGF- and RA-loaded Ln5-P4/ASLNs (Ln5-P4/NGF-RA-ASLNs). An increasing BW weight percentage from 0% to 75% decreased the particle size and zeta potential along with improved encapsulation efficiency of RA and NGF with enhanced positive expression of β-tubulin III to 93.72% in cultured cells. Strong affinity of Ln5-P4/NGF-RA-ASLNs to α3β1 integrin expressed on iPSCs facilitated internalization of Ln5-P4/NGF-RA-ASLNs. The capability of Ln5-P4/NGF-RA-ASLNs to induce neuronal differentiation was much higher than that of free NGF-ASLNs and RA-ASLNs, as visualized using immunochemical staining. Flow cytometry analysis indicated that Ln5-P4 on NGF-RA-ASLNs promoted the uptake of NGF and RA by iPSCs and accelerated neuronal production. Ln5-P4/NGF-RA-ASLNs are a promising colloidal delivery system to generate mature neurons from iPSCs and can be potential for treating neurodegenerative disease and nerve injury in regeneration medicine.
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18
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Modeling Brain Disorders Using Induced Pluripotent Stem Cells. Cold Spring Harb Perspect Biol 2020; 12:cshperspect.a035659. [PMID: 31767646 DOI: 10.1101/cshperspect.a035659] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Brain disorders, from neurodegenerative to psychiatric disorders, are among the most challenging conditions to study because of the intricate nature of the human brain and the limitations of existing model systems in recapitulating all these intricacies. However, innovations in stem cell technologies now allow us to reprogram patient somatic cells to induced pluripotent stem cells (iPSCs), which can then be differentiated to disease-relevant neural and glial cells. iPSCs are a valuable tool to model brain disorders, as they can be derived from patients with known symptom histories, genetics, and drug-response profiles. Here, we discuss the premise and validity of the iPSC-based in vitro model system and highlight key findings from the most commonly studied neurodegenerative and psychiatric disorders.
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19
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Yousefi N, Abdollahii S, Kouhbanani MAJ, Hassanzadeh A. Induced pluripotent stem cells (iPSCs) as game-changing tools in the treatment of neurodegenerative disease: Mirage or reality? J Cell Physiol 2020; 235:9166-9184. [PMID: 32437029 DOI: 10.1002/jcp.29800] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/02/2020] [Accepted: 05/02/2020] [Indexed: 12/14/2022]
Abstract
Based on investigations, there exist tight correlations between neurodegenerative diseases' incidence and progression and aberrant protein aggregreferates in nervous tissue. However, the pathology of these diseases is not well known, leading to an inability to find an appropriate therapeutic approach to delay occurrence or slow many neurodegenerative diseases' development. The accessibility of induced pluripotent stem cells (iPSCs) in mimicking the phenotypes of various late-onset neurodegenerative diseases presents a novel strategy for in vitro disease modeling. The iPSCs provide a valuable and well-identified resource to clarify neurodegenerative disease mechanisms, as well as prepare a promising human stem cell platform for drug screening. Undoubtedly, neurodegenerative disease modeling using iPSCs has established innovative opportunities for both mechanistic types of research and recognition of novel disease treatments. Most important, the iPSCs have been considered as a novel autologous cell origin for cell-based therapy of neurodegenerative diseases following differentiation to varied types of neural lineage cells (e.g. GABAergic neurons, dopamine neurons, cortical neurons, and motor neurons). In this review, we summarize iPSC-based disease modeling in neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Moreover, we discuss the efficacy of cell-replacement therapies for neurodegenerative disease.
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Affiliation(s)
- Niloufar Yousefi
- Department of Physiology and Pharmacology, Pasteur Instittableute of Iran, Tehran, Iran.,Stem Cell and Regenerative Medicine Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahla Abdollahii
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mohammad Amin Jadidi Kouhbanani
- Stem Cell and Regenerative Medicine Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hassanzadeh
- Stem Cell and Regenerative Medicine Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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20
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Lopatkina ME, Lebedev IN. Transcriptome Analysis as a Tool for Investigation of Pathogenesis of Chromosomal Diseases. RUSS J GENET+ 2020. [DOI: 10.1134/s1022795420050099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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21
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Sabogal-Guáqueta AM, Marmolejo-Garza A, de Pádua VP, Eggen B, Boddeke E, Dolga AM. Microglia alterations in neurodegenerative diseases and their modeling with human induced pluripotent stem cell and other platforms. Prog Neurobiol 2020; 190:101805. [PMID: 32335273 DOI: 10.1016/j.pneurobio.2020.101805] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/16/2020] [Accepted: 04/09/2020] [Indexed: 12/13/2022]
Abstract
Microglia are the main innate immune cells of the central nervous system (CNS). Unlike neurons and glial cells, which derive from ectoderm, microglia migrate early during embryo development from the yolk-sac, a mesodermal-derived structure. Microglia regulate synaptic pruning during development and induce or modulate inflammation during aging and chronic diseases. Microglia are sensitive to brain injuries and threats, altering their phenotype and function to adopt a so-called immune-activated state in response to any perceived threat to the CNS integrity. Here, we present a short overview on the role of microglia in human neurodegenerative diseases and provide an update on the current model systems to study microglia, including cell lines, iPSC-derived microglia with an emphasis in their transcriptomic profile and integration into 3D brain organoids. We present various strategies to model and study their role in neurodegeneration providing a relevant platform for the development of novel and more effective therapies.
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Affiliation(s)
- Angélica María Sabogal-Guáqueta
- Department of Molecular Pharmacology, Faculty of Science and Engineering, Groningen Research Institute of Pharmacy, Behavioral and Cognitive Neurosciences (BCN), University of Groningen, Groningen, The Netherlands; Department of Biomedical Sciences of Cells & Systems, section Molecular Neurobiology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Neuroscience Group of Antioquia, Cellular and Molecular Neurobiology Area-School of Medicine, SIU, University of Antioquia, Medellín, Colombia
| | - Alejandro Marmolejo-Garza
- Department of Molecular Pharmacology, Faculty of Science and Engineering, Groningen Research Institute of Pharmacy, Behavioral and Cognitive Neurosciences (BCN), University of Groningen, Groningen, The Netherlands; Department of Biomedical Sciences of Cells & Systems, section Molecular Neurobiology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Vítor Passos de Pádua
- Department of Molecular Pharmacology, Faculty of Science and Engineering, Groningen Research Institute of Pharmacy, Behavioral and Cognitive Neurosciences (BCN), University of Groningen, Groningen, The Netherlands; Neurology Department, Medical School, University of São Paulo (USP), São Paulo, SP, Brazil
| | - Bart Eggen
- Department of Biomedical Sciences of Cells & Systems, section Molecular Neurobiology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Erik Boddeke
- Department of Biomedical Sciences of Cells & Systems, section Molecular Neurobiology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Amalia M Dolga
- Department of Molecular Pharmacology, Faculty of Science and Engineering, Groningen Research Institute of Pharmacy, Behavioral and Cognitive Neurosciences (BCN), University of Groningen, Groningen, The Netherlands.
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22
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Bobkova NV, Poltavtseva RA, Leonov SV, Sukhikh GT. Neuroregeneration: Regulation in Neurodegenerative Diseases and Aging. BIOCHEMISTRY (MOSCOW) 2020; 85:S108-S130. [PMID: 32087056 DOI: 10.1134/s0006297920140060] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
It had been commonly believed for a long time, that once established, degeneration of the central nervous system (CNS) is irreparable, and that adult person merely cannot restore dead or injured neurons. The existence of stem cells (SCs) in the mature brain, an organ with minimal regenerative ability, had been ignored for many years. Currently accepted that specific structures of the adult brain contain neural SCs (NSCs) that can self-renew and generate terminally differentiated brain cells, including neurons and glia. However, their contribution to the regulation of brain activity and brain regeneration in natural aging and pathology is still a subject of ongoing studies. Since the 1970s, when Fuad Lechin suggested the existence of repair mechanisms in the brain, new exhilarating data from scientists around the world have expanded our knowledge on the mechanisms implicated in the generation of various cell phenotypes supporting the brain, regulation of brain activity by these newly generated cells, and participation of SCs in brain homeostasis and regeneration. The prospects of the SC research are truthfully infinite and hitherto challenging to forecast. Once researchers resolve the issues regarding SC expansion and maintenance, the implementation of the SC-based platform could help to treat tissues and organs impaired or damaged in many devastating human diseases. Over the past 10 years, the number of studies on SCs has increased exponentially, and we have already become witnesses of crucial discoveries in SC biology. Comprehension of the mechanisms of neurogenesis regulation is essential for the development of new therapeutic approaches for currently incurable neurodegenerative diseases and neuroblastomas. In this review, we present the latest achievements in this fast-moving field and discuss essential aspects of NSC biology, including SC regulation by hormones, neurotransmitters, and transcription factors, along with the achievements of genetic and chemical reprogramming for the safe use of SCs in vitro and in vivo.
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Affiliation(s)
- N V Bobkova
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia.
| | - R A Poltavtseva
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia. .,National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov, Ministry of Healthcare of Russian Federation, Moscow, 117997, Russia
| | - S V Leonov
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia. .,Moscow Institute of Physics and Technology (National Research University), The Phystech School of Biological and Medical Physics, Dolgoprudny, Moscow Region, 141700, Russia
| | - G T Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov, Ministry of Healthcare of Russian Federation, Moscow, 117997, Russia.
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23
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Tabassum R, Jeong NY, Jung J. Therapeutic importance of hydrogen sulfide in age-associated neurodegenerative diseases. Neural Regen Res 2020; 15:653-662. [PMID: 31638087 PMCID: PMC6975154 DOI: 10.4103/1673-5374.266911] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 04/27/2019] [Accepted: 08/01/2019] [Indexed: 02/06/2023] Open
Abstract
Hydrogen sulfide (H2S) is a gasotransmitter that acts as an antioxidant and exhibits a wide variety of cytoprotective and physiological functions in age-associated diseases. One of the major causes of age-related diseases is oxidative stress. In recent years, the importance of H2S has become clear, although its antioxidant function has not yet been fully explored. The enzymes cystathionine β-synthase, cystathionine γ-lya-se, and 3-mercaptopyruvate sulfurtransferase are involved in the enzymatic production of H2S. Previously, H2S was considered a neuromodulator, given its role in long-term hippocampal potentiation, but it is now also recognized as an antioxidant in age-related neurodegeneration. Due to aerobic metabolism, the central nervous system is vulnerable to oxidative stress in brain aging, resulting in age-associated degenerative diseases. H2S exerts its antioxidant effect by limiting free radical reactions through the activation of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase, which protect against the effects of aging by regulating apoptosis-related genes, including p53, Bax, and Bcl-2. This review explores the implications and mechanisms of H2S as an antioxidant in age-associated neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Down syndrome.
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Affiliation(s)
- Rubaiya Tabassum
- Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan, Korea
- Department of Medicine, Graduate School, Dong-A University, Busan, Korea
| | - Na Young Jeong
- Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan, Korea
- Department of Medicine, Graduate School, Dong-A University, Busan, Korea
| | - Junyang Jung
- Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul, Korea
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Sato M, Takizawa H, Nakamura A, Turner BJ, Shabanpoor F, Aoki Y. Application of Urine-Derived Stem Cells to Cellular Modeling in Neuromuscular and Neurodegenerative Diseases. Front Mol Neurosci 2019; 12:297. [PMID: 31920531 PMCID: PMC6915080 DOI: 10.3389/fnmol.2019.00297] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 11/20/2019] [Indexed: 12/11/2022] Open
Abstract
Neuromuscular and neurodegenerative diseases are mostly modeled using genetically modified animals such as mice. However, animal models do not recapitulate all the phenotypes that are specific to human disease. This is mainly due to the genetic, anatomical and physiological difference in the neuromuscular systems of animals and humans. The emergence of direct and indirect human somatic cell reprogramming technologies may overcome this limitation because they enable the use of disease and patient-specific cellular models as enhanced platforms for drug discovery and autologous cell-based therapy. Induced pluripotent stem cells (iPSCs) and urine-derived stem cells (USCs) are increasingly employed to recapitulate the pathophysiology of various human diseases. Recent cell-based modeling approaches utilize highly complex differentiation systems that faithfully mimic human tissue- and organ-level dysfunctions. In this review, we discuss promising cellular models, such as USC- and iPSC-based approaches, that are currently being used to model human neuromuscular and neurodegenerative diseases.
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Affiliation(s)
- Mitsuto Sato
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.,Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan
| | - Hotake Takizawa
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
| | - Akinori Nakamura
- Department of Clinical Research, National Hospital Organization Matsumoto Medical Center, Matsumoto, Japan
| | - Bradley J Turner
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
| | - Fazel Shabanpoor
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
| | - Yoshitsugu Aoki
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
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Neurodegeneration and Neuro-Regeneration-Alzheimer's Disease and Stem Cell Therapy. Int J Mol Sci 2019; 20:ijms20174272. [PMID: 31480448 PMCID: PMC6747457 DOI: 10.3390/ijms20174272] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/27/2019] [Accepted: 08/28/2019] [Indexed: 12/17/2022] Open
Abstract
Aging causes many changes in the human body, and is a high risk for various diseases. Dementia, a common age-related disease, is a clinical disorder triggered by neurodegeneration. Brain damage caused by neuronal death leads to cognitive decline, memory loss, learning inabilities and mood changes. Numerous disease conditions may cause dementia; however, the most common one is Alzheimer’s disease (AD), a futile and yet untreatable illness. Adult neurogenesis carries the potential of brain self-repair by an endogenous formation of newly-born neurons in the adult brain; however it also declines with age. Strategies to improve the symptoms of aging and age-related diseases have included different means to stimulate neurogenesis, both pharmacologically and naturally. Finally, the regulatory mechanisms of stem cells neurogenesis or a functional integration of newborn neurons have been explored to provide the basis for grafted stem cell therapy. This review aims to provide an overview of AD pathology of different neural and glial cell types and summarizes current strategies of experimental stem cell treatments and their putative future use in clinical settings.
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Koseoglu E. New treatment modalities in Alzheimer's disease. World J Clin Cases 2019; 7:1764-1774. [PMID: 31417922 PMCID: PMC6692264 DOI: 10.12998/wjcc.v7.i14.1764] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/18/2019] [Accepted: 06/10/2019] [Indexed: 02/05/2023] Open
Abstract
Alzheimer’s disease (AD) is still a major public health challenge without an effective treatment to prevent or stop it. Routinely used acetylcholinesterase inhibitors and memantine seem to slow disease progression only to a limited extend. Therefore, many investigations on new drugs and other treatment modalities are ongoing in close association with increasing knowledge of the pathophysiology of the disease. Here, we review the studies about the new treatment modalities in AD with a classification based on their main targets, specifically pathologic structures of the disease, amyloid and tau, neural network dysfunction with special interest to the regulation of gamma oscillations, and attempts for the restoration of neural tissue via regenerative medicine. Additionally, we describe the evolving modalities related to gut microbiota, modulation, microglial function, and glucose metabolism.
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Affiliation(s)
- Emel Koseoglu
- Department of Neurology, Faculty of Medicine, Erciyes University, Kayseri 38039, Turkey
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27
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Kandasamy M, Yesudhas A, Poornimai Abirami GP, Radhakrishnan RK, Roshan SA, Johnson E, Ravichandran VR, Biswas A, Shanmugaapriya S, Anusuyadevi M, Aigner L. Genetic reprogramming of somatic cells into neuroblasts through a co-induction of the doublecortin gene along the Yamanaka factors: A promising approach to model neuroregenerative disorders. Med Hypotheses 2019; 127:105-111. [PMID: 31088631 DOI: 10.1016/j.mehy.2019.04.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/28/2019] [Accepted: 04/11/2019] [Indexed: 12/25/2022]
Abstract
Neural stem cell (NSC) mediated adult neurogenesis represents the regenerative plasticity of the brain. The functionality of the neurogenic process appears to be operated by neuroblasts, the multipotent immature neuronal population of the adult brain. While neuroblasts have been realized to play a major role in synaptic remodeling and immunogenicity, neurodegenerative disorders have been characterized by failure in the terminal differentiation, maturation, integration and survival of newborn neuroblasts. Advancement in understanding the impaired neuroregenerative process along the neuropathological conditions has currently been limited by lack of an appropriate experimental model of neuroblasts. The genetic reprogramming of somatic cells into pluripotent state offers a potential strategy for the experimental modeling of brain disorders. Thus, the induced pluripotent stem cell (iPSC) based direct reprogramming of somatic cells into neuroblasts would represent a potential tool to understand the regenerative biology of the adult brain. Therefore, this concise article discusses the significance of iPSCs, the functional roles of neuroblasts in the adult brain and provides a research hypothesis for the direct reprogramming of somatic cells into neuroblasts through the co-induction of a potential proneurogenic marker, the doublecortin (DCX) gene along with the Yamanaka factors. The proposed cellular model of adult neurogenesis may provide us with further insights into neuropathogenesis of many neurodegenerative disorders and will provide a potential experimental platform for diagnostic, drug discovery and regenerative therapeutic strategies.
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Affiliation(s)
- Mahesh Kandasamy
- Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India; School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India; UGC-Faculty Recharge Programme (UGC-FRP), University Grants Commission, New Delhi, India.
| | - Ajisha Yesudhas
- Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - G P Poornimai Abirami
- School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Risna Kanjirassery Radhakrishnan
- Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Syed Aasish Roshan
- Molecular Gerontology Laboratory, Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Esther Johnson
- Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Vijaya Roobini Ravichandran
- Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Abir Biswas
- Molecular Gerontology Laboratory, Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | | | - Muthuswamy Anusuyadevi
- School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India; Molecular Gerontology Laboratory, Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Ludwig Aigner
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center, Salzburg, Paracelsus Medical University, Salzburg, Austria.
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Buijsen RAM, Toonen LJA, Gardiner SL, van Roon-Mom WMC. Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias. Neurotherapeutics 2019; 16:263-286. [PMID: 30607747 PMCID: PMC6554265 DOI: 10.1007/s13311-018-00696-y] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs have progressive ataxia as their main clinical feature, frequently accompanied by dysarthria and oculomotor deficits. The most common spinocerebellar ataxias (SCAs) are 6 polyglutamine (polyQ) SCAs. These diseases are all caused by a CAG repeat expansion in the coding region of a gene. Currently, no curative treatment is available for any of the polyQ SCAs, but increasing knowledge on the genetics and the pathological mechanisms of these polyQ SCAs has provided promising therapeutic targets to potentially slow disease progression. Potential treatments can be divided into pharmacological and gene therapies that target the toxic downstream effects, gene therapies that target the polyQ SCA genes, and stem cell replacement therapies. Here, we will provide a review on the genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias.
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Affiliation(s)
- Ronald A M Buijsen
- Department of Human Genetics, LUMC, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
| | - Lodewijk J A Toonen
- Department of Human Genetics, LUMC, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
| | - Sarah L Gardiner
- Department of Human Genetics, LUMC, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
- Department of Neurology, LUMC, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
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Dong Y, Peng T, Wu W, Tan D, Liu X, Xie D. Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using CRISPR/Cas9 and single-stranded donor oligonucleotides. J Int Med Res 2019; 47:1717-1730. [PMID: 30819013 PMCID: PMC6460615 DOI: 10.1177/0300060519829990] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 01/17/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Heterozygous purinergic receptor p2x gene ( P2RX2) c.178G>T (p.V60L) mutations can lead to progressive hearing loss (HL) and increased susceptibility to noise. However, the underlying mechanisms remain unclear. A combination of human induced pluripotent stem cell (hiPSC) technology with clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9-mediated gene editing may provide a promising tool to study gene function and treat hereditary deafness in humans. METHODS hiPSC technology and CRISPR/Cas9-mediated gene editing were used to generate heterozygous and homozygous P2RX2 c.178G>T (p.V60L) cell models. RESULTS We generated non-integrative hiPSCs from urine samples derived from three members of a large Chinese family carrying heterozygous P2RX2 c.178G>T mutations (designated P2RX2+/-) as a model to study P2RX2-mediated hereditary HL. Furthermore, we used CRISPR/Cas9 and single-stranded donor oligonucleotides to genetically establish homozygous P2RX2 c.178G>T hiPSCs (designated P2RX2-/-) from heterozygous patient-specific hiPSCs as a control to further study the pathological gene function. CONCLUSIONS Heterozygous and homozygous P2RX2-mutated hiPSC lines are good models to investigate the pathological mechanisms of P2RX2 mutations in HL pathogenesis. Our findings confirmed our hypothesis that it is feasible and convenient to introduce precise point mutations into genomic loci of interest to generate gene-mutated hiPSC models.
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Affiliation(s)
- Yunpeng Dong
- Department of Otolaryngology Head and Neck Surgery, Institute of Otology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Departments of Otolaryngology and Head and Neck Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA
| | - Tao Peng
- Department of Otolaryngology Head and Neck Surgery, Institute of Otology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Weijing Wu
- Department of Otolaryngology Head and Neck Surgery, Institute of Otology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Donghui Tan
- Department of Otolaryngology Head and Neck Surgery, the Affiliated Hospital of Xiangnan College, Chenzhou, Hunan, China
| | - Xuezhong Liu
- Department of Otolaryngology Head and Neck Surgery, Institute of Otology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Departments of Otolaryngology and Head and Neck Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA
| | - Dinghua Xie
- Department of Otolaryngology Head and Neck Surgery, Institute of Otology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Ştefănescu R, Stanciu GD, Luca A, Caba IC, Tamba BI, Mihai CT. Contributions of Mass Spectrometry to the Identification of Low Molecular Weight Molecules Able to Reduce the Toxicity of Amyloid-β Peptide to Cell Cultures and Transgenic Mouse Models of Alzheimer's Disease. Molecules 2019; 24:E1167. [PMID: 30909659 PMCID: PMC6471768 DOI: 10.3390/molecules24061167] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 03/22/2019] [Accepted: 03/22/2019] [Indexed: 11/16/2022] Open
Abstract
Alzheimer's Disease affects approximately 33 million people worldwide and is characterized by progressive loss of memory at the cognitive level. The formation of toxic amyloid oligomers, extracellular amyloid plaques and amyloid angiopathy in brain by amyloid beta peptides are considered a part of the identified mechanism involved in disease pathogenesis. The optimal treatment approach leads toward finding a chemical compound able to form a noncovalent complex with the amyloid peptide thus blocking the process of amyloid aggregation. This direction gained an increasing interest lately, many studies demonstrating that mass spectrometry is a valuable method useful for the identification and characterization of such molecules able to interact with amyloid peptides. In the present review we aim to identify in the scientific literature low molecular weight chemical compounds for which there is mass spectrometric evidence of noncovalent complex formation with amyloid peptides and also there are toxicity reduction results which verify the effects of these compounds on amyloid beta toxicity towards cell cultures and transgenic mouse models developing Alzheimer's Disease.
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Affiliation(s)
- Raluca Ştefănescu
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universității Street, 700115 Iaşi, Romania.
| | - Gabriela Dumitriṭa Stanciu
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universității Street, 700115 Iaşi, Romania.
| | - Andrei Luca
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universității Street, 700115 Iaşi, Romania.
| | - Ioana Cezara Caba
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universității Street, 700115 Iaşi, Romania.
- Faculty of Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universităṭii Street, 700115 Iaşi, Romania.
| | - Bogdan Ionel Tamba
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universității Street, 700115 Iaşi, Romania.
| | - Cosmin Teodor Mihai
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universității Street, 700115 Iaşi, Romania.
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31
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Saha SK, Saikot FK, Rahman MS, Jamal MAHM, Rahman SMK, Islam SMR, Kim KH. Programmable Molecular Scissors: Applications of a New Tool for Genome Editing in Biotech. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 14:212-238. [PMID: 30641475 PMCID: PMC6330515 DOI: 10.1016/j.omtn.2018.11.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 11/23/2018] [Accepted: 11/23/2018] [Indexed: 01/04/2023]
Abstract
Targeted genome editing is an advanced technique that enables precise modification of the nucleic acid sequences in a genome. Genome editing is typically performed using tools, such as molecular scissors, to cut a defined location in a specific gene. Genome editing has impacted various fields of biotechnology, such as agriculture; biopharmaceutical production; studies on the structure, regulation, and function of the genome; and the creation of transgenic organisms and cell lines. Although genome editing is used frequently, it has several limitations. Here, we provide an overview of well-studied genome-editing nucleases, including single-stranded oligodeoxynucleotides (ssODNs), transcription activator-like effector nucleases (TALENs), zinc-finger nucleases (ZFNs), and CRISPR-Cas9 RNA-guided nucleases (CRISPR-Cas9). To this end, we describe the progress toward editable nuclease-based therapies and discuss the minimization of off-target mutagenesis. Future prospects of this challenging scientific field are also discussed.
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Affiliation(s)
- Subbroto Kumar Saha
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, 120 Neungdong-Ro, Seoul 05029, Republic of Korea.
| | - Forhad Karim Saikot
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore 7408, Bangladesh
| | - Md Shahedur Rahman
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore 7408, Bangladesh
| | | | - S M Khaledur Rahman
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore 7408, Bangladesh
| | - S M Riazul Islam
- Department of Computer Science and Engineering, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul 05006, South Korea
| | - Ki-Hyun Kim
- Department of Civil & Environmental Engineering, Hanyang University, 222 Wangsimni-Ro, Seoul 04763, Republic of Korea.
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Rai SN, Dilnashin H, Birla H, Singh SS, Zahra W, Rathore AS, Singh BK, Singh SP. The Role of PI3K/Akt and ERK in Neurodegenerative Disorders. Neurotox Res 2019; 35:775-795. [PMID: 30707354 DOI: 10.1007/s12640-019-0003-y] [Citation(s) in RCA: 305] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 01/05/2019] [Accepted: 01/15/2019] [Indexed: 12/27/2022]
Abstract
Disruption of Akt and Erk-mediated signal transduction significantly contributes in the pathogenesis of various neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's diseases, Huntington's disease, and many others. These regulatory proteins serve as the regulator of cell survival, motility, transcription, metabolism, and progression of the cell cycle. Therefore, targeting Akt and Erk pathway has been proposed as a reasonable approach to suppress ND progression. This review has emphasized on involvement of Akt/Erk cascade in the neurodegeneration. Akt has been reported to regulate neuronal toxicity through its various substrates like FOXos, GSK3β, and caspase-9 etc. Akt is also involved with PI3K in signaling pathway to mediate neuronal survival. ERK is another kinase which also regulates proliferation, differentiation, and survival of the neural cell. There has also been much progress in developing a therapeutic molecule targeting Akt and Erk signaling. Therefore, improved understanding of the molecular mechanism behind the regulatory aspect of Akt and Erk networks can make strong impact on exploration of the neurodegenerative disease pathogenesis.
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Key Words
- 6-OHDA, 6-hydroxydopamine
- BDNF, brain-derived neurotrophic factor
- HD, Huntington disease
- MAPK, mitogen-activated protein-extracellular kinase
- MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- NDs, neurodegenerative disorders
- Nrf2, nuclear factor erythroid 2 p45-related factor 2
- PD, Parkinson’s disease
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Affiliation(s)
- Sachchida Nand Rai
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Hagera Dilnashin
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Hareram Birla
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Saumitra Sen Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Walia Zahra
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Aaina Singh Rathore
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Brijesh Kumar Singh
- Department of Pathology and Cell Biology, Columbia University Medical Centre, Columbia University, New York, NY, 10032, USA
| | - Surya Pratap Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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Keller JM, Frega M. Past, Present, and Future of Neuronal Models In Vitro. ADVANCES IN NEUROBIOLOGY 2019; 22:3-17. [PMID: 31073930 DOI: 10.1007/978-3-030-11135-9_1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Over the past century, robust methods were developed that enable the isolation, culture, and dynamic observation of mammalian neuronal networks in vitro. But even if neuronal culture cannot yet fully recapitulate the normal brain, the knowledge that has been acquired from these surrogate in vitro models is invaluable. Indeed, neuronal culture has continued to propel basic neuroscience research, proving that in vitro systems have legitimacy when it comes to studying either the healthy or diseased human brain. Furthermore, scientific advancement typically parallels technical refinements in the field. A pertinent example is that a collective drive in the field of neuroscience to better understand the development, organization, and emergent properties of neuronal networks is being facilitated by progressive advances in micro-electrode array (MEA) technology. In this chapter, we briefly review the emergence of neuronal cell culture as a technique, the current trends in human stem cell-based modeling, and the technologies used to monitor neuronal communication. We conclude by highlighting future prospects that are evolving specifically out of the combination of human neuronal models and MEA technology.
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Affiliation(s)
- Jason M Keller
- Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, The Netherlands
| | - Monica Frega
- Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, The Netherlands. .,Department of Clinical Neurophysiology, University of Twente, Enschede, The Netherlands.
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Alipour M, Nabavi SM, Arab L, Vosough M, Pakdaman H, Ehsani E, Shahpasand K. Stem cell therapy in Alzheimer's disease: possible benefits and limiting drawbacks. Mol Biol Rep 2018; 46:1425-1446. [PMID: 30565076 DOI: 10.1007/s11033-018-4499-7] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 11/13/2018] [Indexed: 02/06/2023]
Abstract
Alzheimer's disease (AD) is the sixth leading cause of death globally and the main reason for dementia in elderly people. AD is a long-term and progressive neurodegenerative disorder that steadily worsens memory and communicating skills eventually leads to a disabled person of performing simple daily tasks. Unfortunately, numerous clinical trials exploring new therapeutic drugs have encountered disappointing outcomes in terms of improved cognitive performance since they are not capable of halting or stimulating the regeneration of already-damaged neural cells, and merely provide symptomatic relief. Therefore, a deeper understanding of the mechanism of action of stem cell may contribute to the development of novel and effective therapies. The revolutionary discovery of stem cells has cast a new hope for the development of disease-modifying treatments for AD, in terms of their potency in the replenishment of lost cells via differentiating towards specific lineages, stimulating in situ neurogenesis, and delivering the therapeutic agents to the brain. Herein, firstly, we explore the pathophysiology of AD. Next, we summarize the most recent preclinical stem cell reports designed for AD treatment, their benefits and outcomes according to cell type. We briefly review relevant clinical trials and their potential clinical applications in order to find a unique solution to effectively relieve the patients' pain.
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Affiliation(s)
- Masoume Alipour
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat highway, P.O. Box 19395-4644, Tehran, Iran
| | - Seyed Massood Nabavi
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat highway, P.O. Box 19395-4644, Tehran, Iran
| | - Leila Arab
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat highway, P.O. Box 19395-4644, Tehran, Iran
| | - Massoud Vosough
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hossein Pakdaman
- Department of Neurology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ehsan Ehsani
- Department of Biology, Roudehen Branch, Islamic Azad University, Roudehen, Iran
| | - Koorosh Shahpasand
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat highway, P.O. Box 19395-4644, Tehran, Iran.
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Monzio Compagnoni G, Kleiner G, Samarani M, Aureli M, Faustini G, Bellucci A, Ronchi D, Bordoni A, Garbellini M, Salani S, Fortunato F, Frattini E, Abati E, Bergamini C, Fato R, Tabano S, Miozzo M, Serratto G, Passafaro M, Deleidi M, Silipigni R, Nizzardo M, Bresolin N, Comi GP, Corti S, Quinzii CM, Di Fonzo A. Mitochondrial Dysregulation and Impaired Autophagy in iPSC-Derived Dopaminergic Neurons of Multiple System Atrophy. Stem Cell Reports 2018; 11:1185-1198. [PMID: 30344007 PMCID: PMC6234905 DOI: 10.1016/j.stemcr.2018.09.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 09/18/2018] [Accepted: 09/19/2018] [Indexed: 12/27/2022] Open
Abstract
Multiple system atrophy (MSA) is a progressive neurodegenerative disease that affects several areas of the CNS, whose pathogenesis is still widely unclear and for which an effective treatment is lacking. We have generated induced pluripotent stem cell-derived dopaminergic neurons from four MSA patients and four healthy controls and from two monozygotic twins discordant for the disease. In this model, we have demonstrated an aberrant autophagic flow and a mitochondrial dysregulation involving respiratory chain activity, mitochondrial content, and CoQ10 biosynthesis. These defective mechanisms may contribute to the onset of the disease, representing potential therapeutic targets.
An iPSC-based neuronal model of MSA is described Mitochondria are dysfunctional in MSA neurons Autophagic machinery is impaired in MSA neurons
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Affiliation(s)
- Giacomo Monzio Compagnoni
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Giulio Kleiner
- Department of Neurology, Columbia University, New York, NY 10032, USA
| | - Maura Samarani
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan 20090, Italy
| | - Massimo Aureli
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan 20090, Italy
| | - Gaia Faustini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy
| | - Arianna Bellucci
- Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy
| | - Dario Ronchi
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Andreina Bordoni
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Manuela Garbellini
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Sabrina Salani
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Francesco Fortunato
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Emanuele Frattini
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Elena Abati
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Christian Bergamini
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna 40126, Italy
| | - Romana Fato
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna 40126, Italy
| | - Silvia Tabano
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy; Division of Pathology, IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan 20122, Italy
| | - Monica Miozzo
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy; Division of Pathology, IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan 20122, Italy
| | - Giulia Serratto
- CNR Institute of Neuroscience, Department BIOMETRA, Università degli Studi di Milano, Milan 20129, Italy
| | - Maria Passafaro
- CNR Institute of Neuroscience, Department BIOMETRA, Università degli Studi di Milano, Milan 20129, Italy
| | - Michela Deleidi
- German Center for Neurodegenerative Diseases (DZNE), Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller Straße 23, Tübingen 72076, Germany
| | - Rosamaria Silipigni
- Laboratory of Medical Genetics, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
| | - Monica Nizzardo
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Nereo Bresolin
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Giacomo P Comi
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Stefania Corti
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | | | - Alessio Di Fonzo
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy.
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Stem Cells as Potential Targets of Polyphenols in Multiple Sclerosis and Alzheimer's Disease. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1483791. [PMID: 30112360 PMCID: PMC6077677 DOI: 10.1155/2018/1483791] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 06/19/2018] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease (AD) and multiple sclerosis are major neurodegenerative diseases, which are characterized by the accumulation of abnormal pathogenic proteins due to oxidative stress, mitochondrial dysfunction, impaired autophagy, and pathogens, leading to neurodegeneration and behavioral deficits. Herein, we reviewed the utility of plant polyphenols in regulating proliferation and differentiation of stem cells for inducing brain self-repair in AD and multiple sclerosis. Firstly, we discussed the genetic, physiological, and environmental factors involved in the pathophysiology of both the disorders. Next, we reviewed various stem cell therapies available and how they have proved useful in animal models of AD and multiple sclerosis. Lastly, we discussed how polyphenols utilize the potential of stem cells, either complementing their therapeutic effects or stimulating endogenous and exogenous neurogenesis, against these diseases. We suggest that polyphenols could be a potential candidate for stem cell therapy against neurodegenerative disorders.
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Deming Y, Li Z, Benitez BA, Cruchaga C. Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease? Expert Opin Ther Targets 2018; 22:587-598. [PMID: 29889572 DOI: 10.1080/14728222.2018.1486823] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
INTRODUCTION There are currently no effective therapeutics for Alzheimer disease (AD). Clinical trials targeting amyloid beta thus far have shown very little benefit and only in the earliest stages of disease. These limitations have driven research to identify alternative therapeutic targets, one of the most promising is the triggering receptor expressed on myeloid cells 2 (TREM2). Areas covered: Here, we review the literature to-date and discuss the potentials and pitfalls for targeting TREM2 as a potential therapeutic for AD. We focus on research in animal and cell models for AD and central nervous system injury models which may help in understanding the role of TREM2 in disease. Expert opinion: Studies suggest TREM2 plays a key role in AD pathology; however, results have been conflicting about whether TREM2 is beneficial or harmful. More research is necessary before designing TREM2-targeting therapies. Successful therapeutics will most likely be administered early in disease.
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Affiliation(s)
- Yuetiva Deming
- a Department of Psychiatry , Washington University School of Medicine , St Louis , MO , USA
| | - Zeran Li
- a Department of Psychiatry , Washington University School of Medicine , St Louis , MO , USA
| | - Bruno A Benitez
- b Department of Medicine , Washington University School of Medicine , St Louis , MO , USA
| | - Carlos Cruchaga
- a Department of Psychiatry , Washington University School of Medicine , St Louis , MO , USA.,c Department of Developmental Biology , Washington University School of Medicine , St Louis , MO , USA.,d Knight Alzheimer's Disease Research Center , Washington University School of Medicine , St Louis , MO , USA.,e Hope Center for Neurological Disorders , Washington University School of Medicine , St Louis , MO , USA
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Efficient production of erythroid, megakaryocytic and myeloid cells, using single cell-derived iPSC colony differentiation. Stem Cell Res 2018; 29:232-244. [PMID: 29751281 DOI: 10.1016/j.scr.2018.04.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 04/10/2018] [Accepted: 04/26/2018] [Indexed: 12/16/2022] Open
Abstract
Hematopoietic differentiation of human induced pluripotent stem cells (iPSCs) provide opportunities not only for fundamental research and disease modelling/drug testing but also for large-scale production of blood effector cells for future clinical application. Although there are multiple ways to differentiate human iPSCs towards hematopoietic lineages, there is a need to develop reproducible and robust protocols. Here we introduce an efficient way to produce three major blood cell types using a standardized differentiation protocol that starts with a single hematopoietic initiation step. This system is feeder-free, avoids EB-formation, starts with a hematopoietic initiation step based on a novel single cell-derived iPSC colony differentiation and produces multi-potential progenitors within 8-10 days. Followed by lineage-specific growth factor supplementation these cells can be matured into well characterized erythroid, megakaryocytic and myeloid cells with high-purity, without transcription factor overexpression or any kind of pre-purification step. This standardized differentiation system provides a simple platform to produce specific blood cells in a reproducible manner for hematopoietic development studies, disease modelling, drug testing and the potential for future therapeutic applications.
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Gong L, Cao L, Shen Z, Shao L, Gao S, Zhang C, Lu J, Li W. Materials for Neural Differentiation, Trans-Differentiation, and Modeling of Neurological Disease. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2018; 30:e1705684. [PMID: 29573284 DOI: 10.1002/adma.201705684] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 12/04/2017] [Indexed: 05/02/2023]
Abstract
Neuron regeneration from pluripotent stem cells (PSCs) differentiation or somatic cells trans-differentiation is a promising approach for cell replacement in neurodegenerative diseases and provides a powerful tool for investigating neural development, modeling neurological diseases, and uncovering the mechanisms that underlie diseases. Advancing the materials that are applied in neural differentiation and trans-differentiation promotes the safety, efficiency, and efficacy of neuron regeneration. In the neural differentiation process, matrix materials, either natural or synthetic, not only provide a structural and biochemical support for the monolayer or three-dimensional (3D) cultured cells but also assist in cell adhesion and cell-to-cell communication. They play important roles in directing the differentiation of PSCs into neural cells and modeling neurological diseases. For the trans-differentiation of neural cells, several materials have been used to make the conversion feasible for future therapy. Here, the most current applications of materials for neural differentiation for PSCs, neuronal trans-differentiation, and neurological disease modeling is summarized and discussed.
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Affiliation(s)
- Lulu Gong
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Lining Cao
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Zhenmin Shen
- The VIP Department, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Li Shao
- The VIP Department, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Shaorong Gao
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Chao Zhang
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Jianfeng Lu
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Weida Li
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
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40
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Zink A, Priller J, Prigione A. Pluripotent Stem Cells for Uncovering the Role of Mitochondria in Human Brain Function and Dysfunction. J Mol Biol 2018; 430:891-903. [PMID: 29458125 DOI: 10.1016/j.jmb.2018.02.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 02/09/2018] [Accepted: 02/09/2018] [Indexed: 02/06/2023]
Abstract
Mitochondrial dysfunctions are a known pathogenetic mechanism of a number of neurological and psychiatric disorders. At the same time, mutations in genes encoding for components of the mitochondrial respiratory chain cause mitochondrial diseases, which commonly exhibit neurological symptoms. Mitochondria are therefore critical for the functionality of the human nervous system. The importance of mitochondria stems from their key roles in cellular metabolism, calcium handling, redox and protein homeostasis, and overall cellular homeostasis through their dynamic network. Here, we describe how the use of pluripotent stem cells (PSCs) may help in addressing the physiological and pathological relevance of mitochondria for the human nervous system. PSCs allow the generation of patient-derived neurons and glia and the identification of gene-specific and mutation-specific cellular phenotypes via genome engineering approaches. We discuss the recent advances in PSC-based modeling of brain diseases and the current challenges of the field. We anticipate that the careful use of PSCs will improve our understanding of the impact of mitochondria in neurological and psychiatric disorders and the search for effective therapeutic avenues.
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Affiliation(s)
- Annika Zink
- Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany; Department of Neuropsychiatry, Charité-Universitätsmedizin, 10117 Berlin, Germany
| | - Josef Priller
- Department of Neuropsychiatry, Charité-Universitätsmedizin, 10117 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany; Cluster of Excellence NeuroCure and German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany; UK Dementia Research Institute and University of Edinburgh, Edinburgh EH16 4SB, UK
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41
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Pihlstrøm L, Wiethoff S, Houlden H. Genetics of neurodegenerative diseases: an overview. HANDBOOK OF CLINICAL NEUROLOGY 2018; 145:309-323. [PMID: 28987179 DOI: 10.1016/b978-0-12-802395-2.00022-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Genetic factors are central to the etiology of neurodegeneration, both as monogenic causes of heritable disease and as modifiers of susceptibility to complex, sporadic disorders. Over the last two decades, the identification of disease genes and risk loci has led to some of the greatest advances in medicine and invaluable insights into pathogenic mechanisms and disease pathways. Large-scale research efforts, novel study designs, and advances in methodology are rapidly expanding our understanding of the genome and the genetic architecture of neurodegenerative disease. Here, we review major developments in the field to date, highlighting overarching historic trends and general insights. Monogenic neurodegenerative diseases are discussed from the perspectives of both rare Mendelian forms of common disorders, such as Alzheimer disease and Parkinson disease, and heterogeneous heritable conditions, including ataxias and spastic paraplegias. Next, we summarize the experiences from investigations of complex neurodegenerative disorders, including genomewide association studies. In the final section, we reflect upon the limitations of current findings and outline important future directions. Genetics plays an essential role in translational research, ultimately aiming to develop novel disease-modifying therapies for neurodegenerative disorders. We anticipate that individual genetic profiling will also be increasingly relevant in a clinical context, with implications for patient care in line with the proposed ideal of personalized medicine.
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Affiliation(s)
- Lasse Pihlstrøm
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, United Kingdom
| | - Sarah Wiethoff
- UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, United Kingdom; Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany
| | - Henry Houlden
- UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
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Freitas BC, Mei A, Mendes APD, Beltrão-Braga PCB, Marchetto MC. Modeling Inflammation in Autism Spectrum Disorders Using Stem Cells. Front Pediatr 2018; 6:394. [PMID: 30619789 PMCID: PMC6299043 DOI: 10.3389/fped.2018.00394] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 11/29/2018] [Indexed: 12/11/2022] Open
Abstract
Recent reports show an increase in the incidence of Autism Spectrum Disorders (ASD) to 1 in every 59 children up to 8 years old in 11 states in North America. Induced pluripotent stem cell (iPSC) technology offers a groundbreaking platform for the study of polygenic neurodevelopmental disorders in live cells. Robust inflammation states and immune system dysfunctions are associated with ASD and several cell types participate on triggering and sustaining these processes. In this review, we will examine the contribution of neuroinflammation to the development of autistic features and discuss potential therapeutic approaches. We will review the available tools, emphasizing stem cell modeling as a technology to investigate the various molecular pathways and different cell types involved in the process of neuroinflammation in ASD.
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Affiliation(s)
- Beatriz C Freitas
- Laboratory of Disease Modeling, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Arianna Mei
- Laboratory of Genetics, The Salk Institute, La Jolla, CA, United States
| | | | - Patricia C B Beltrão-Braga
- Laboratory of Disease Modeling, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.,School of Arts, Sciences and Humanities, University of São Paulo, São Paulo, Brazil
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Phosphorylation of huntingtin at residue T3 is decreased in Huntington's disease and modulates mutant huntingtin protein conformation. Proc Natl Acad Sci U S A 2017; 114:E10809-E10818. [PMID: 29162692 PMCID: PMC5740681 DOI: 10.1073/pnas.1705372114] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Posttranslational modifications can have profound effects on the biological and biophysical properties of proteins associated with misfolding and aggregation. However, their detection and quantification in clinical samples and an understanding of the mechanisms underlying the pathological properties of misfolding- and aggregation-prone proteins remain a challenge for diagnostics and therapeutics development. We have applied an ultrasensitive immunoassay platform to develop and validate a quantitative assay for detecting a posttranslational modification (phosphorylation at residue T3) of a protein associated with polyglutamine repeat expansion, namely Huntingtin, and characterized its presence in a variety of preclinical and clinical samples. We find that T3 phosphorylation is greatly reduced in samples from Huntington's disease models and in Huntington's disease patients, and we provide evidence that bona-fide T3 phosphorylation alters Huntingtin exon 1 protein conformation and aggregation properties. These findings have significant implications for both mechanisms of disease pathogenesis and the development of therapeutics and diagnostics for Huntington's disease.
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44
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Gasser T. Personalized Medicine Approaches in Parkinson's Disease: The Genetic Perspective. JOURNAL OF PARKINSONS DISEASE 2017; 6:699-701. [PMID: 27662328 DOI: 10.3233/jpd-160876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Recent discoveries with respect to the genetic and molecular basis of Parkinson's disease have led to an increasing recognition of the etiologic heterogeneity of the disorder. As in other complex diseases, it is hoped that this knowledge will allow the identification of novel therapeutic targets that will eventually lead to a more efficient treatment, based on the patient's individual genetic predispositions.
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Abstract
Human-induced pluripotent stem cells (iPSCs) offer a novel, timely approach for investigating the aetiology of neuropsychiatric disorders. Although we are starting to gain more insight into the specific mechanisms that cause Alzheimer's disease and other forms of dementia, this has not resulted in therapies to slow the pathological processes. Animal models have been paramount in studying the neurobiological processes underlying psychiatric disorders. Nonetheless, these human conditions cannot be entirely recapitulated in rodents. Human cell models derived from patients' cells now offer new hope for improving our understanding of the early molecular stages of these diseases, through to validating therapeutics. The impact of dementia is increasing, and a new model to investigate the early stages of this disease is heralded as an essential, new platform for translational research. In this paper, we review current literature using iPSCs to study Alzheimer's disease, describe drug discovery efforts using this platform, and discuss the future potential for this technology in psychiatry research.
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Affiliation(s)
- J P Robbins
- Department of Basic and Clinical Neuroscience,Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK
| | - J Price
- Department of Basic and Clinical Neuroscience,Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK
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46
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Tong G, Izquierdo P, Raashid RA. Human Induced Pluripotent Stem Cells and the Modelling of Alzheimer's Disease: The Human Brain Outside the Dish. Open Neurol J 2017; 11:27-38. [PMID: 29151989 PMCID: PMC5678240 DOI: 10.2174/1874205x01711010027] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Revised: 08/18/2017] [Accepted: 08/20/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Neurodegenerative diseases like Alzheimer's Disease (AD) are a global health issue primarily in the elderly. Although AD has been investigated using primary cultures, animal models and post-mortem human brain tissues, there are currently no effective treatments. SUMMARY With the advent of induced pluripotent stem cells (iPSCs) reprogrammed from fully differentiated adult cells such as skin fibroblasts, newer opportunities have arisen to study the pathophysiology of many diseases in more depth. It is envisioned that iPSCs could be used as a powerful tool for neurodegenerative disease modelling and eventually be an unlimited source for cell replacement therapy. This paper provides an overview of; the contribution of iPSCs towards modeling and understanding AD pathogenesis, the novel human/mouse chimeric models in elucidating current AD pathogenesis hypotheses, the possible use of iPSCs in drug screening, and perspectives on possible future directions. KEY MESSAGES Human/mouse chimeric models using iPSCs to study AD offer much promise in better replicating AD pathology and can be further exploited to elucidate disease pathogenesis with regards to the neuroinflammation hypothesis of AD.
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Affiliation(s)
- Godwin Tong
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
| | - Pablo Izquierdo
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
| | - Rana Arham Raashid
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
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47
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Stem Cell Technology for (Epi)genetic Brain Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 978:443-475. [PMID: 28523560 DOI: 10.1007/978-3-319-53889-1_23] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Despite the enormous efforts of the scientific community over the years, effective therapeutics for many (epi)genetic brain disorders remain unidentified. The common and persistent failures to translate preclinical findings into clinical success are partially attributed to the limited efficiency of current disease models. Although animal and cellular models have substantially improved our knowledge of the pathological processes involved in these disorders, human brain research has generally been hampered by a lack of satisfactory humanized model systems. This, together with our incomplete knowledge of the multifactorial causes in the majority of these disorders, as well as a thorough understanding of associated (epi)genetic alterations, has been impeding progress in gaining more mechanistic insights from translational studies. Over the last years, however, stem cell technology has been offering an alternative approach to study and treat human brain disorders. Owing to this technology, we are now able to obtain a theoretically inexhaustible source of human neural cells and precursors in vitro that offer a platform for disease modeling and the establishment of therapeutic interventions. In addition to the potential to increase our general understanding of how (epi)genetic alterations contribute to the pathology of brain disorders, stem cells and derivatives allow for high-throughput drugs and toxicity testing, and provide a cell source for transplant therapies in regenerative medicine. In the current chapter, we will demonstrate the validity of human stem cell-based models and address the utility of other stem cell-based applications for several human brain disorders with multifactorial and (epi)genetic bases, including Parkinson's disease (PD), Alzheimer's disease (AD), fragile X syndrome (FXS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Rett syndrome (RTT).
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Merienne N, Vachey G, de Longprez L, Meunier C, Zimmer V, Perriard G, Canales M, Mathias A, Herrgott L, Beltraminelli T, Maulet A, Dequesne T, Pythoud C, Rey M, Pellerin L, Brouillet E, Perrier AL, du Pasquier R, Déglon N. The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes. Cell Rep 2017; 20:2980-2991. [DOI: 10.1016/j.celrep.2017.08.075] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 07/14/2017] [Accepted: 08/23/2017] [Indexed: 10/18/2022] Open
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Desmet AS, Cirillo C, Tack J, Vandenberghe W, Vanden Berghe P. Live calcium and mitochondrial imaging in the enteric nervous system of Parkinson patients and controls. eLife 2017; 6. [PMID: 28825895 PMCID: PMC5565316 DOI: 10.7554/elife.26850] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 07/23/2017] [Indexed: 12/18/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease with motor and non-motor symptoms, including constipation. Therefore, several studies have investigated the gastrointestinal tract, and more specifically the enteric nervous system (ENS), in search of an early biomarker of PD. Besides α-synuclein aggregation, mitochondrial dysfunction and dysregulation of intracellular Ca2+ concentration probably contribute to the pathogenesis of PD. Here we assessed neuronal and mitochondrial functioning in primary enteric neurons of PD patients and their healthy partners as controls. Using a unique combination of live microscopy techniques, applied to routine duodenum biopsies, we were able to record neuronal Ca2+ responses and mitochondrial membrane potential in these nerve tissues. We found that submucous neurons were not affected in PD patients, which suggests that these neurons are not involved in the pathogenesis or the gastrointestinal symptoms of PD. Our study provides for the first time functional information on live neurons in PD patients.
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Affiliation(s)
- An-Sofie Desmet
- Laboratory for Enteric NeuroScience, University of Leuven, Leuven, Belgium.,Translational Research Center for GastroIntestinal Disorders, University of Leuven, Leuven, Belgium
| | - Carla Cirillo
- Laboratory for Enteric NeuroScience, University of Leuven, Leuven, Belgium.,Translational Research Center for GastroIntestinal Disorders, University of Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research Center for GastroIntestinal Disorders, University of Leuven, Leuven, Belgium
| | - Wim Vandenberghe
- Laboratory for Parkinson Research, Department of Neurosciences, University of Leuven, Leuven, Belgium.,Department of Neurology, University Hospitals Leuven, Leuven, Belgium
| | - Pieter Vanden Berghe
- Laboratory for Enteric NeuroScience, University of Leuven, Leuven, Belgium.,Translational Research Center for GastroIntestinal Disorders, University of Leuven, Leuven, Belgium
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Wu S, Xu R, Duan B, Jiang P. Three-Dimensional Hyaluronic Acid Hydrogel-Based Models for In Vitro Human iPSC-Derived NPC Culture and Differentiation. J Mater Chem B 2017; 5:3870-3878. [PMID: 28775848 PMCID: PMC5536346 DOI: 10.1039/c7tb00721c] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Human induced pluripotent stem cell-derived neural progenitor cells (hiPSC-NPCs) are considered as a promising cell source for transplantation and have been used for organoid fabrication to recapitulate central nervous system (CNS) diseases in vitro. The establishment of three-dimensional (3D) in vitro model with hiPSC-NPCs and control of their differentiation is significantly critical for understanding biological processes and CNS disease and regeneration. Here we implemented 3D methacrylated hyaluronic acid (Me-HA) hydrogels with encapsulation of hiPSC-NPCs as in vitro culture models and further investigated the role of the hydrogel rigidity on the cell behavior of hiPSC-NPCs. We first encapsulated single dispersive hiPSC-NPCs within both soft and stiff Me-HA hydrogel and found that hiPSC-NPCs gradually self-assembled and aggregated to form 3D spheroids. Then, the hiPSC-NPCs were laden into Me-HA hydrogels in the form of spheroids to evaluate their spontaneous differentiation in response to hydrogel rigidity. The soft Me-HA hydrogel-encapsulated hiPSC-NPCs displayed robust neurite outgrowth and showed high levels of spontaneous neural differentiation. We further encapsulated Down Syndrome (DS) patient-specific hiPSC-derived NPCs (DS-NPCs) spheroids within our hydrogels. DS-NPCs remained excellent cell viability in both soft and stiff Me-HA hydrogels. Similarly, soft hydrogels promoted neural differentiation of DS-NPCs by significantly upregulating neural maturation markers. This study demonstrates that soft matrix promotes neural differentiation of hiPSC-NPCs and HA-based hydrogels with hiPSC-NPCs or DS-NPCs are effective 3D models for CNS disease study.
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Affiliation(s)
- Shaohua Wu
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA
- Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ranjie Xu
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA
| | - Bin Duan
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA
- Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Peng Jiang
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA
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