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Lei T, Fu G, Xue X, Yang H. Tianma Gouteng Decoction improve neuronal synaptic plasticity and oligodendrocyte apoptosis in Parkinson's disease mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156553. [PMID: 40023970 DOI: 10.1016/j.phymed.2025.156553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 02/05/2025] [Accepted: 02/20/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Parkinson's disease (PD) is a complex and multifactorial disorder of the nervous system. Tianma Gouteng Decoction (TGD) is a clinical prescription of traditional Chinese medicine for PD, but its neuroprotective effects and mechanisms for PD are poorly understood. PURPOSE The aim of this study was to explore the mechanism of TGD in the treatment of PD. STUDY DESIGN Serum pharmacochemistry, single cell sequencing, network pharmacology, and validation experiment were combined to study the effect of TGD in PD model. METHODS TGD water extract and its distribution in serum of PD mice were analyzed by secondary metabolomics. The crossing blood-brain barrier components and targets were preliminarily identified. Target cells and pathways of TGD were analyzed by network pharmacology and single cell sequencing. RESULTS TGD treatment improved the movement disorders in MPTP-induced PD mice, restoring dopaminergic neurons in the substantia nigra region and suppressing the expression of α-synuclein. We identified 1272 components in TGD, among which 73 were distributed in the serum of PD mice after oral administration. Network pharmacological analysis demonstrated that these components were involved in the regulation of apoptosis, and 15 of them could across the blood-brain barrier and bind to PD pathological proteins. Single nucleus RNA sequencing analysis identified 18 cell subpopulations, and TGD treatment restored the neuron-oligodendrocyte crosstalk. Neurons were identified as the most widely responding target cells, while oligodendrocytes were the core response target cells to TGD therapy. After treatment, the apoptosis of oligodendrocytes was inhibited, and the secretion of trophic factor was enhanced, facilitating the improvement of neuronal synaptic plasticity and neuroinflammation. CONCLUSION This study systematically elucidates the molecular mechanism of TGD improving movement disorders, which is helpful to provide new ideas for drug development of PD.
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Affiliation(s)
- Tong Lei
- Department of Disease and Syndromes Research, Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Gaoshuang Fu
- Department of Disease and Syndromes Research, Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xin Xue
- Department of Disease and Syndromes Research, Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Hongjun Yang
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
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Deng S, Xie H, Xie B. Cell-based regenerative and rejuvenation strategies for treating neurodegenerative diseases. Stem Cell Res Ther 2025; 16:167. [PMID: 40189500 PMCID: PMC11974143 DOI: 10.1186/s13287-025-04285-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 03/19/2025] [Indexed: 04/09/2025] Open
Abstract
Neurodegenerative diseases including Alzheimer's and Parkinson's disease are age-related disorders which severely impact quality of life and impose significant societal burdens. Cellular senescence is a critical factor in these disorders, contributing to their onset and progression by promoting permanent cell cycle arrest and reducing cellular function, affecting various types of cells in brain. Recent advancements in regenerative medicine have highlighted "R3" strategies-rejuvenation, regeneration, and replacement-as promising therapeutic approaches for neurodegeneration. This review aims to critically analyze the role of cellular senescence in neurodegenerative diseases and organizes therapeutic approaches within the R3 regenerative medicine paradigm. Specifically, we examine stem cell therapy, direct lineage reprogramming, and partial reprogramming in the context of R3, emphasizing how these interventions mitigate cellular senescence and counteracting aging-related neurodegeneration. Ultimately, this review seeks to provide insights into the complex interplay between cellular senescence and neurodegeneration while highlighting the promise of cell-based regenerative strategies to address these debilitating conditions.
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Affiliation(s)
- Sixiu Deng
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, 646000, China
- Department of Gastroenterology, The Shapingba Hospital, Chongqing University（ People's Hospital of Shapingba District）, Chongqing, China
| | - Huangfan Xie
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China.
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, 646000, China.
| | - Bingqing Xie
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China.
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, 646000, China.
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Remboutsika E. The Art of Neuroregeneration De Novo and In Situ. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025. [PMID: 40131703 DOI: 10.1007/5584_2025_856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
Neuroregeneration refers to the ability of the nervous system to repair or regenerate neural components subsequently to spinal cord and traumatic brain injuries, peripheral nerve damage, and neurodegenerative diseases. Here, we discuss lead effectors of the healing process, neural stem cells, and non-invasive physical methods, for neuroregeneration de novo and in situ.
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Affiliation(s)
- Eumorphia Remboutsika
- University Research Institute of Maternal and Child Health & Precision Medicine, School of Health Sciences, National and Kapoditrian University of Athens, Athens, Greece
- Thrivus Institute for Biomedical Science and Technology, Accra, Ghana
- AENAON EYZHN, Glyfada, Athens, Greece
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Nam YR, Kang M, Kim M, Seok MJ, Yang Y, Han YE, Oh SJ, Kim DG, Son H, Chang MY, Lee SH. Preparation of human astrocytes with potent therapeutic functions from human pluripotent stem cells using ventral midbrain patterning. J Adv Res 2025; 69:181-196. [PMID: 38521186 PMCID: PMC11954835 DOI: 10.1016/j.jare.2024.03.012] [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: 11/17/2023] [Revised: 02/19/2024] [Accepted: 03/16/2024] [Indexed: 03/25/2024] Open
Abstract
INTRODUCTION Astrocytes are glial-type cells that protect neurons from toxic insults and support neuronal functions and metabolism in a healthy brain. Leveraging these physiological functions, transplantation of astrocytes or their derivatives has emerged as a potential therapeutic approach for neurodegenerative disorders. METHODS To substantiate the clinical application of astrocyte-based therapy, we aimed to prepare human astrocytes with potent therapeutic capacities from human pluripotent stem cells (hPSCs). To that end, we used ventral midbrain patterning during the differentiation of hPSCs into astrocytes, based on the roles of midbrain-specific factors in potentiating glial neurotrophic/anti-inflammatory activity. To assess the therapeutic effects of human midbrain-type astrocytes, we transplanted them into mouse models of Parkinson's disease (PD) and Alzheimer's disease (AD). RESULTS Through a comprehensive series of in-vitro and in-vivo experiments, we were able to establish that the midbrain-type astrocytes exhibited the abilities to effectively combat oxidative stress, counter excitotoxic glutamate, and manage pathological protein aggregates. Our strategy for preparing midbrain-type astrocytes yielded promising results, demonstrating the strong therapeutic potential of these cells in various neurotoxic contexts. Particularly noteworthy is their efficacy in PD and AD-specific proteopathic conditions, in which the midbrain-type astrocytes outperformed forebrain-type astrocytes derived by the same organoid-based method. CONCLUSION The enhanced functions of the midbrain-type astrocytes extended to their ability to release signaling molecules that inhibited neuronal deterioration and senescence while steering microglial cells away from a pro-inflammatory state. This success was evident in both in-vitro studies using human cells and in-vivo experiments conducted in mouse models of PD and AD. In the end, our human midbrain-type astrocytes demonstrated remarkable effectiveness in alleviating neurodegeneration, neuroinflammation, and the pathologies associated with the accumulation of α-synuclein and Amyloid β proteins.
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Affiliation(s)
- Ye Rim Nam
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea; Biomedical Research Institute, Hanyang University, Seoul, Korea
| | - Minji Kang
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea; Biomedical Research Institute, Hanyang University, Seoul, Korea
| | - Minji Kim
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea; Biomedical Research Institute, Hanyang University, Seoul, Korea
| | - Min Jong Seok
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea; Biomedical Research Institute, Hanyang University, Seoul, Korea
| | - Yunseon Yang
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea; Biomedical Research Institute, Hanyang University, Seoul, Korea
| | - Young Eun Han
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea
| | - Soo-Jin Oh
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea
| | - Do Gyeong Kim
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea; Biomedical Research Institute, Hanyang University, Seoul, Korea
| | - Hyeon Son
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea; Biomedical Research Institute, Hanyang University, Seoul, Korea; Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, Korea
| | - Mi-Yoon Chang
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea; Biomedical Research Institute, Hanyang University, Seoul, Korea; Department of Premedicine, College of Medicine, Hanyang University, Korea; Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Korea.
| | - Sang-Hun Lee
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea; Biomedical Research Institute, Hanyang University, Seoul, Korea; Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, Korea.
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Weiss F, Hughes L, Fu Y, Bardy C, Halliday GM, Dzamko N. Astrocytes contribute to toll-like receptor 2-mediated neurodegeneration and alpha-synuclein pathology in a human midbrain Parkinson's model. Transl Neurodegener 2024; 13:62. [PMID: 39681872 PMCID: PMC11648304 DOI: 10.1186/s40035-024-00448-3] [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: 11/13/2023] [Accepted: 10/21/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND Parkinson's disease (PD) is characterised by degeneration of ventral midbrain dopaminergic (DA) neurons and abnormal deposition of α-synuclein (α-syn) in neurons. Activation of the innate immune pathogen recognition receptor toll-like receptor 2 (TLR2) is associated with exacerbation of α-syn pathology. TLR2 is increased on neurons in the PD brain, and its activation results in the accumulation and propagation of α-syn through autophagy inhibition in neurons. In addition to the aggregation and propagation of pathological α-syn, dysfunction of astrocytes may contribute to DA neuronal death and subsequent clinical progression of PD. However, the role of astrocytes in TLR2-mediated PD pathology is less explored but important to address, given that TLR2 is a potential therapeutic target for PD. METHODS Induced pluripotent stem cells from three controls and three PD patients were differentiated into a midbrain model comprised of neurons (including DA neurons) and astrocytes. Cells were treated with or without the TLR2 agonist Pam3CSK4, and α-syn pathology was seeded using pre-formed fibrils. Confocal imaging was used to assess lysosomal function and α-syn pathology in the different cell types, as well as DA neuron health and astrocyte activation. RESULTS TLR2 activation acutely impaired the autophagy lysosomal pathway, and potentiated α-syn pathology seeded by pre-formed fibrils in PD neurons and astrocytes, leading to degeneration and loss of DA neurons. The astrocytes displayed impaired chaperone-mediated autophagy reducing their ability to clear accumulated α-syn, and increases of A1 neurotoxic phenotypic proteins SerpinG1, complement C3, PSMB8 and GBP2. Moreover, the phenotypic changes in astrocytes correlated with a specific loss of DA neurons. CONCLUSIONS Taken together, these results support a role for astrocyte dysfunction in α-syn accumulation and DA neuronal loss following TLR2 activation in PD.
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Affiliation(s)
- Fiona Weiss
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Laura Hughes
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Yuhong Fu
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Cedric Bardy
- Laboratory for Human Neurophysiology and Genetics, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia
| | - Glenda M Halliday
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Nicolas Dzamko
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia.
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Lei T, Zhang X, Fu G, Luo S, Zhao Z, Deng S, Li C, Cui Z, Cao J, Chen P, Yang H. Advances in human cellular mechanistic understanding and drug discovery of brain organoids for neurodegenerative diseases. Ageing Res Rev 2024; 102:102517. [PMID: 39321879 DOI: 10.1016/j.arr.2024.102517] [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: 03/13/2024] [Accepted: 09/19/2024] [Indexed: 09/27/2024]
Abstract
The prevalence of neurodegenerative diseases (NDs) is increasing rapidly as the aging population accelerates, and there are still no treatments to halt or reverse the progression of these diseases. While traditional 2D cultures and animal models fail to translate into effective therapies benefit patients, 3D cultured human brain organoids (hBOs) facilitate the use of non-invasive methods to capture patient data. The purpose of this study was to review the research and application of hBO in disease models and drug screening in NDs. The pluripotent stem cells are induced in multiple stages to form cerebral organoids, brain region-specific organoids and their derived brain cells, which exhibit complex brain-like structures and perform electrophysiological activities. The brain region-specific organoids and their derived neurons or glial cells contribute to the understanding of the pathogenesis of NDs and the efficient development of drugs, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Glial-rich brain organoids facilitate the study of glial function and neuroinflammation, including astrocytes, microglia, and oligodendrocytes. Further research on the maturation enhancement, vascularization and multi-organoid assembly of hBO will help to enhance the research and application of NDs cellular models.
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Affiliation(s)
- Tong Lei
- Department of Disease and Syndromes Research, Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Xiaoshuang Zhang
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China
| | - Gaoshuang Fu
- Department of Disease and Syndromes Research, Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Shaohan Luo
- Department of Disease and Syndromes Research, Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Ziwei Zhao
- Department of Disease and Syndromes Research, Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Shiwen Deng
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Caifeng Li
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Zhao Cui
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Junxian Cao
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Peng Chen
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; Hunan Provincial Key Laboratory of Complex Effects Analysis for Chinese Patent Medicine, Yongzhou, Hunan Province 425199, China.
| | - Hongjun Yang
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; Hunan Provincial Key Laboratory of Complex Effects Analysis for Chinese Patent Medicine, Yongzhou, Hunan Province 425199, China.
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7
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Barmpa K, Saraiva C, Lopez-Pigozzi D, Gomez-Giro G, Gabassi E, Spitz S, Brandauer K, Rodriguez Gatica JE, Antony P, Robertson G, Sabahi-Kaviani R, Bellapianta A, Papastefanaki F, Luttge R, Kubitscheck U, Salti A, Ertl P, Bortolozzi M, Matsas R, Edenhofer F, Schwamborn JC. Modeling early phenotypes of Parkinson's disease by age-induced midbrain-striatum assembloids. Commun Biol 2024; 7:1561. [PMID: 39580573 PMCID: PMC11585662 DOI: 10.1038/s42003-024-07273-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 11/14/2024] [Indexed: 11/25/2024] Open
Abstract
Parkinson's disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons' loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson's disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson's disease.
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Affiliation(s)
- Kyriaki Barmpa
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Claudia Saraiva
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Diego Lopez-Pigozzi
- Department of Physics and Astronomy "G. Galilei", University of Padua, Padua, Italy
- Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
| | - Gemma Gomez-Giro
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Elisa Gabassi
- Genomics, Stem Cell & Regenerative Medicine Group and CMBI, Institute of Molecular Biology, University of Innsbruck, Innsbruck, Austria
| | - Sarah Spitz
- Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria
| | - Konstanze Brandauer
- Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria
| | | | - Paul Antony
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Graham Robertson
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | | | - Alessandro Bellapianta
- Johannes Kepler University Linz, Kepler University Hospital, University Clinic for Ophthalmology and Optometry, Linz, Austria
| | - Florentia Papastefanaki
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
- Human Embryonic and Induced Pluripotent Stem Cell Unit, Hellenic Pasteur Institute, Athens, Greece
| | - Regina Luttge
- Eindhoven University of Technology, Microsystems, Eindhoven, Netherlands
| | - Ulrich Kubitscheck
- Clausius Institute of Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany
| | - Ahmad Salti
- Genomics, Stem Cell & Regenerative Medicine Group and CMBI, Institute of Molecular Biology, University of Innsbruck, Innsbruck, Austria
- Johannes Kepler University Linz, Kepler University Hospital, University Clinic for Ophthalmology and Optometry, Linz, Austria
| | - Peter Ertl
- Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria
| | - Mario Bortolozzi
- Department of Physics and Astronomy "G. Galilei", University of Padua, Padua, Italy
- Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
| | - Rebecca Matsas
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
- Human Embryonic and Induced Pluripotent Stem Cell Unit, Hellenic Pasteur Institute, Athens, Greece
| | - Frank Edenhofer
- Genomics, Stem Cell & Regenerative Medicine Group and CMBI, Institute of Molecular Biology, University of Innsbruck, Innsbruck, Austria
| | - Jens C Schwamborn
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
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Cui X, Li X, Zheng H, Su Y, Zhang S, Li M, Hao X, Zhang S, Hu Z, Xia Z, Shi C, Xu Y, Mao C. Human midbrain organoids: a powerful tool for advanced Parkinson's disease modeling and therapy exploration. NPJ Parkinsons Dis 2024; 10:189. [PMID: 39428415 PMCID: PMC11491477 DOI: 10.1038/s41531-024-00799-8] [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: 01/06/2023] [Accepted: 10/02/2024] [Indexed: 10/22/2024] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder marked by the loss of dopaminergic neurons in the substantia nigra. Despite progress, the pathogenesis remains unclear. Human midbrain organoids (hMLOs) have emerged as a promising model for studying PD, drug screening, and potential treatments. This review discusses the development of hMLOs, their application in PD research, and current challenges in organoid construction, highlighting possible optimization strategies.
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Affiliation(s)
- Xin Cui
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xinwei Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Huimin Zheng
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yun Su
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shuyu Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Neuro-Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengjie Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xiaoyan Hao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shuo Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Zhengwei Hu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Zongping Xia
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Clinical Systems Biology Laboratories, Zhengzhou University, Zhengzhou, China
| | - Changhe Shi
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
| | - Yuming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.
| | - Chengyuan Mao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
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9
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Mazzini L, De Marchi F, Buzanska L, Follenzi A, Glover JC, Gelati M, Lombardi I, Maioli M, Mesa-Herrera F, Mitrečić D, Olgasi C, Pivoriūnas A, Sanchez-Pernaute R, Sgromo C, Zychowicz M, Vescovi A, Ferrari D. Current status and new avenues of stem cell-based preclinical and therapeutic approaches in amyotrophic lateral sclerosis. Expert Opin Biol Ther 2024; 24:933-954. [PMID: 39162129 DOI: 10.1080/14712598.2024.2392307] [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: 01/24/2024] [Accepted: 08/10/2024] [Indexed: 08/21/2024]
Abstract
INTRODUCTION Cell therapy development represents a critical challenge in amyotrophic lateral sclerosis (ALS) research. Despite more than 20 years of basic and clinical research, no definitive safety and efficacy results of cell-based therapies for ALS have been published. AREAS COVERED This review summarizes advances using stem cells (SCs) in pre-clinical studies to promote clinical translation and in clinical trials to treat ALS. New technologies have been developed and new experimental in vitro and animal models are now available to facilitate pre-clinical research in this field and to determine the most promising approaches to pursue in patients. New clinical trial designs aimed at developing personalized SC-based treatment with biological endpoints are being defined. EXPERT OPINION Knowledge of the basic biology of ALS and on the use of SCs to study and potentially treat ALS continues to grow. However, a consensus has yet to emerge on how best to translate these results into therapeutic applications. The selection and follow-up of patients should be based on clinical, biological, and molecular criteria. Planning of SC-based clinical trials should be coordinated with patient profiling genetically and molecularly to achieve personalized treatment. Much work within basic and clinical research is still needed to successfully transition SC therapy in ALS.
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Affiliation(s)
- Letizia Mazzini
- ALS Center, Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Fabiola De Marchi
- ALS Center, Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Leonora Buzanska
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Antonia Follenzi
- Dipartimento di Scienze della Salute, Università del Piemonte Orientale, Novara, Italy
- Dipartimento Attività Integrate Ricerca Innovazione, Azienda Ospedaliero-Universitaria SS. Antonio e Biagio e C. Arrigo, Alessandria, Italy
| | - Joel Clinton Glover
- Norwegian Center for Stem Cell Research, Department of Immunology and Transfusion Medicine, Oslo University Hospital; Laboratory of Neural Development and Optical Recording (NDEVOR), Oslo, Norway
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Maurizio Gelati
- Unità Produttiva per Terapie Avanzate (UPTA), IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Ivan Lombardi
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
- Center for Developmental Biology and Reprogramming-CEDEBIOR, University of Sassari, Sassari, Italy
| | - Fatima Mesa-Herrera
- Reprogramming and Neural Regeneration Lab, BioBizkaia Health Research Institute, Barakaldo, Spain
| | - Dinko Mitrečić
- Laboratory for Stem Cells, Croatian Institute for Brain Research and Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Cristina Olgasi
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Augustas Pivoriūnas
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Rosario Sanchez-Pernaute
- Reprogramming and Neural Regeneration Lab, BioBizkaia Health Research Institute, Barakaldo, Spain
- Ikerbaske, Basque Foundation for Science, Bilbao, Spain
| | - Chiara Sgromo
- Dipartimento di Scienze della Salute, Università del Piemonte Orientale, Novara, Italy
| | - Marzena Zychowicz
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Angelo Vescovi
- Unità Produttiva per Terapie Avanzate (UPTA), IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy
| | - Daniela Ferrari
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy
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Hong SJ, Bock M, Zhang S, An SB, Han I. Therapeutic Transplantation of Human Central Nervous System Organoids for Neural Reconstruction. Int J Mol Sci 2024; 25:8540. [PMID: 39126108 PMCID: PMC11313261 DOI: 10.3390/ijms25158540] [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: 06/24/2024] [Revised: 08/03/2024] [Accepted: 08/03/2024] [Indexed: 08/12/2024] Open
Abstract
Damage to the central nervous system (CNS) often leads to irreversible neurological deficits, and there are currently few effective treatments available. However, recent advancements in regenerative medicine have identified CNS organoids as promising therapeutic options for addressing CNS injuries. These organoids, composed of various neurons and supporting cells, have shown potential for direct repair at injury sites. CNS organoids resemble the structure and function of actual brain tissue, which allows them to adapt and function well within the physiological environment when transplanted into injury sites. Research findings suggest that CNS organoids can replace damaged neurons, form new neural connections, and promote neural recovery. This review highlights the emerging benefits, evaluates preclinical transplantation outcomes, and explores future strategies for optimizing neuroregeneration using CNS organoids. With continued research and technological advancements, these organoids could provide new hope for patients suffering from neurological deficits.
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Affiliation(s)
- Sung Jun Hong
- Research Competency Milestones Program (RECOMP), School of Medicine, CHA University, Seongnam-si 13488, Republic of Korea;
- Department of Medicine, School of Medicine, CHA University, Seongnam-si 13496, Republic of Korea
| | - Minsung Bock
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (M.B.); (S.Z.); (S.B.A.)
| | - Songzi Zhang
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (M.B.); (S.Z.); (S.B.A.)
| | - Seong Bae An
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (M.B.); (S.Z.); (S.B.A.)
| | - Inbo Han
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (M.B.); (S.Z.); (S.B.A.)
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11
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Liang S, Zhou J, Yu X, Lu S, Liu R. Neuronal conversion from glia to replenish the lost neurons. Neural Regen Res 2024; 19:1446-1453. [PMID: 38051886 PMCID: PMC10883502 DOI: 10.4103/1673-5374.386400] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 08/16/2023] [Indexed: 12/07/2023] Open
Abstract
ABSTRACT Neuronal injury, aging, and cerebrovascular and neurodegenerative diseases such as cerebral infarction, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Huntington's disease are characterized by significant neuronal loss. Unfortunately, the neurons of most mammals including humans do not possess the ability to self-regenerate. Replenishment of lost neurons becomes an appealing therapeutic strategy to reverse the disease phenotype. Transplantation of pluripotent neural stem cells can supplement the missing neurons in the brain, but it carries the risk of causing gene mutation, tumorigenesis, severe inflammation, and obstructive hydrocephalus induced by brain edema. Conversion of neural or non-neural lineage cells into functional neurons is a promising strategy for the diseases involving neuron loss, which may overcome the above-mentioned disadvantages of neural stem cell therapy. Thus far, many strategies to transform astrocytes, fibroblasts, microglia, Müller glia, NG2 cells, and other glial cells to mature and functional neurons, or for the conversion between neuronal subtypes have been developed through the regulation of transcription factors, polypyrimidine tract binding protein 1 (PTBP1), and small chemical molecules or are based on a combination of several factors and the location in the central nervous system. However, some recent papers did not obtain expected results, and discrepancies exist. Therefore, in this review, we discuss the history of neuronal transdifferentiation, summarize the strategies for neuronal replenishment and conversion from glia, especially astrocytes, and point out that biosafety, new strategies, and the accurate origin of the truly converted neurons in vivo should be focused upon in future studies. It also arises the attention of replenishing the lost neurons from glia by gene therapies such as up-regulation of some transcription factors or down-regulation of PTBP1 or drug interference therapies.
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Affiliation(s)
- Shiyu Liang
- National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Jing Zhou
- Department of Geriatric Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China
| | - Xiaolin Yu
- National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Shuai Lu
- National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Ruitian Liu
- National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
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12
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Carraro C, Montgomery JV, Klimmt J, Paquet D, Schultze JL, Beyer MD. Tackling neurodegeneration in vitro with omics: a path towards new targets and drugs. Front Mol Neurosci 2024; 17:1414886. [PMID: 38952421 PMCID: PMC11215216 DOI: 10.3389/fnmol.2024.1414886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 06/04/2024] [Indexed: 07/03/2024] Open
Abstract
Drug discovery is a generally inefficient and capital-intensive process. For neurodegenerative diseases (NDDs), the development of novel therapeutics is particularly urgent considering the long list of late-stage drug candidate failures. Although our knowledge on the pathogenic mechanisms driving neurodegeneration is growing, additional efforts are required to achieve a better and ultimately complete understanding of the pathophysiological underpinnings of NDDs. Beyond the etiology of NDDs being heterogeneous and multifactorial, this process is further complicated by the fact that current experimental models only partially recapitulate the major phenotypes observed in humans. In such a scenario, multi-omic approaches have the potential to accelerate the identification of new or repurposed drugs against a multitude of the underlying mechanisms driving NDDs. One major advantage for the implementation of multi-omic approaches in the drug discovery process is that these overarching tools are able to disentangle disease states and model perturbations through the comprehensive characterization of distinct molecular layers (i.e., genome, transcriptome, proteome) up to a single-cell resolution. Because of recent advances increasing their affordability and scalability, the use of omics technologies to drive drug discovery is nascent, but rapidly expanding in the neuroscience field. Combined with increasingly advanced in vitro models, which particularly benefited from the introduction of human iPSCs, multi-omics are shaping a new paradigm in drug discovery for NDDs, from disease characterization to therapeutics prediction and experimental screening. In this review, we discuss examples, main advantages and open challenges in the use of multi-omic approaches for the in vitro discovery of targets and therapies against NDDs.
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Affiliation(s)
- Caterina Carraro
- Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany
- Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Jessica V. Montgomery
- Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany
| | - Julien Klimmt
- Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
| | - Dominik Paquet
- Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Joachim L. Schultze
- Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany
- Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
- PRECISE, Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn and West German Genome Center, Bonn, Germany
| | - Marc D. Beyer
- Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany
- PRECISE, Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn and West German Genome Center, Bonn, Germany
- Immunogenomics & Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany
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13
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Yang L, Liu SC, Liu YY, Zhu FQ, Xiong MJ, Hu DX, Zhang WJ. Therapeutic role of neural stem cells in neurological diseases. Front Bioeng Biotechnol 2024; 12:1329712. [PMID: 38515621 PMCID: PMC10955145 DOI: 10.3389/fbioe.2024.1329712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 02/12/2024] [Indexed: 03/23/2024] Open
Abstract
The failure of endogenous repair is the main feature of neurological diseases that cannot recover the damaged tissue and the resulting dysfunction. Currently, the range of treatment options for neurological diseases is limited, and the approved drugs are used to treat neurological diseases, but the therapeutic effect is still not ideal. In recent years, different studies have revealed that neural stem cells (NSCs) have made exciting achievements in the treatment of neurological diseases. NSCs have the potential of self-renewal and differentiation, which shows great foreground as the replacement therapy of endogenous cells in neurological diseases, which broadens a new way of cell therapy. The biological functions of NSCs in the repair of nerve injury include neuroprotection, promoting axonal regeneration and remyelination, secretion of neurotrophic factors, immune regulation, and improve the inflammatory microenvironment of nerve injury. All these reveal that NSCs play an important role in improving the progression of neurological diseases. Therefore, it is of great significance to better understand the functional role of NSCs in the treatment of neurological diseases. In view of this, we comprehensively discussed the application and value of NSCs in neurological diseases as well as the existing problems and challenges.
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Affiliation(s)
- Ling Yang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
- Department of Physical Examination, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Si-Cheng Liu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Yi-Yi Liu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Fu-Qi Zhu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Mei-Juan Xiong
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Dong-Xia Hu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Wen-Jun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
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14
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Wang F, Cheng XY, Zhang YT, Bai QR, Zhang XQ, Sun XC, Ma QH, Zhao XF, Liu CF. Transplantation of human neural stem cell prevents symptomatic motor behavior disability in a rat model of Parkinson's disease. Open Life Sci 2024; 19:20220834. [PMID: 38465343 PMCID: PMC10921471 DOI: 10.1515/biol-2022-0834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 03/12/2024] Open
Abstract
Parkinson's disease (PD) is a ubiquitous brain cell degeneration disease and presents a significant therapeutic challenge. By injecting 6-hydroxydopamine (6-OHDA) into the left medial forebrain bundle, rats were made to exhibit PD-like symptoms and treated by intranasal administration of a low-dose (2 × 105) or high-dose (1 × 106) human neural stem cells (hNSCs). Apomorphine-induced rotation test, stepping test, and open field test were implemented to evaluate the motor behavior and high-performance liquid chromatography was carried out to detect dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin, and 5-hydroxyindole-3-acetic acid in the striatum of rats. Animals injected with 6-OHDA showed significant motor function deficits and damaged dopaminergic system compared to the control group, which can be restored by hNSCs treatment. Treatment with hNSCs significantly increased the tyrosine hydroxylase-immunoreactive cell count in the substantia nigra of PD animals. Moreover, the levels of neurotransmitters exhibited a significant decline in the striatum tissue of animals injected with 6-OHDA when compared to that of the control group. However, transplantation of hNSCs significantly elevated the concentration of DA and DOPAC in the injured side of the striatum. Our study offered experimental evidence to support prospects of hNSCs for clinical application as a cell-based therapy for PD.
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Affiliation(s)
- Fen Wang
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou215004, China
- Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Xiao-Yu Cheng
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou215004, China
| | - Yu-Ting Zhang
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou215004, China
- Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Qing-Ran Bai
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200333, China
| | - Xiao-Qi Zhang
- Shanghai Angecon Biotechnology Co., Ltd, Shanghai, 201318, China
| | - Xi-Cai Sun
- Shanghai Angecon Biotechnology Co., Ltd, Shanghai, 201318, China
| | - Quan-Hong Ma
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou215004, China
- Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Xiong-Fei Zhao
- Shanghai Angecon Biotechnology Co., Ltd, Shanghai, 201318, China
| | - Chun-Feng Liu
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou215004, China
- Institute of Neuroscience, Soochow University, Suzhou, 215123, China
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15
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Zhang L, Yang H. Research progress of neural stem cells as a source of dopaminergic neurons for cell therapy in Parkinson's disease. Mol Biol Rep 2024; 51:347. [PMID: 38400887 DOI: 10.1007/s11033-024-09294-y] [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: 12/12/2023] [Accepted: 01/29/2024] [Indexed: 02/26/2024]
Abstract
Parkinson's disease (PD) is a neurodegenerative disease, the most characteristic pathological feature is the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compactus (SNpc) of the mesencephalon, along with reduced dopamine content in the striatum. Researchers have been searching for drugs and therapies to treat PD in decades. However, no approach could stop the progression of the disease, and even some of them caused adverse clinical side effects. PD has a well-defined lesion. Therefore, it is considered to be one of the most curable central nervous system diseases by cell replacement treatment. Fetal ventral mesencephalic tissue transplantation has been used to treat patients with PD and obtained positive treatment results. However, ethical issues, such as limited donor tissue, and side effects including graft-induced dyskinesias, limit its clinical applications. Neural stem cell (NSC) transplantation is a viable therapy choice because it possesses multipotency, self-renewal ability, and differentiation into DA neurons, which may substitute for lost DA neurons and slow down the neurodegenerative process in PD. Studies that investigated the delivery of NSCs by using animal models of PD revealed survival, migration, and even amelioration of behavioral deficits. Here, the research progress of NSCs or NSC-derived DA neurons in treating PD was reviewed, and the practicability of present manufacturing processes for clinical testing was considered. This review is expected to offer ideas for practical strategies to solve the present technical and biological problems related to the clinical application of NSCs in PD.
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Affiliation(s)
- Lingling Zhang
- Translational Medicine Center, Honghui Hospital, Xi'an Jiaotong University, 555 East Youyi Road, Beilin District, Xi'an, 710054, China.
| | - Hao Yang
- Translational Medicine Center, Honghui Hospital, Xi'an Jiaotong University, 555 East Youyi Road, Beilin District, Xi'an, 710054, China
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16
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Li M, Sun H, Hou Z, Hao S, Jin L, Wang B. Engineering the Physical Microenvironment into Neural Organoids for Neurogenesis and Neurodevelopment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2306451. [PMID: 37771182 DOI: 10.1002/smll.202306451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/04/2023] [Indexed: 09/30/2023]
Abstract
Understanding the signals from the physical microenvironment is critical for deciphering the processes of neurogenesis and neurodevelopment. The discovery of how surrounding physical signals shape human developing neurons is hindered by the bottleneck of conventional cell culture and animal models. Notwithstanding neural organoids provide a promising platform for recapitulating human neurogenesis and neurodevelopment, building neuronal physical microenvironment that accurately mimics the native neurophysical features is largely ignored in current organoid technologies. Here, it is discussed how the physical microenvironment modulates critical events during the periods of neurogenesis and neurodevelopment, such as neural stem cell fates, neural tube closure, neuronal migration, axonal guidance, optic cup formation, and cortical folding. Although animal models are widely used to investigate the impacts of physical factors on neurodevelopment and neuropathy, the important roles of human stem cell-derived neural organoids in this field are particularly highlighted. Considering the great promise of human organoids, building neural organoid microenvironments with mechanical forces, electrophysiological microsystems, and light manipulation will help to fully understand the physical cues in neurodevelopmental processes. Neural organoids combined with cutting-edge techniques, such as advanced atomic force microscopes, microrobots, and structural color biomaterials might promote the development of neural organoid-based research and neuroscience.
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Affiliation(s)
- Minghui Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Heng Sun
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
| | - Zongkun Hou
- Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550025, China
| | - Shilei Hao
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
| | - Liang Jin
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
| | - Bochu Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
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17
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Beltran AS. Novel Approaches to Studying SLC13A5 Disease. Metabolites 2024; 14:84. [PMID: 38392976 PMCID: PMC10890222 DOI: 10.3390/metabo14020084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 01/17/2024] [Accepted: 01/18/2024] [Indexed: 02/25/2024] Open
Abstract
The role of the sodium citrate transporter (NaCT) SLC13A5 is multifaceted and context-dependent. While aberrant dysfunction leads to neonatal epilepsy, its therapeutic inhibition protects against metabolic disease. Notably, insights regarding the cellular and molecular mechanisms underlying these phenomena are limited due to the intricacy and complexity of the latent human physiology, which is poorly captured by existing animal models. This review explores innovative technologies aimed at bridging such a knowledge gap. First, I provide an overview of SLC13A5 variants in the context of human disease and the specific cell types where the expression of the transporter has been observed. Next, I discuss current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids. Finally, I explore the relevance of these cellular models as platforms for delving into the intricate molecular and cellular mechanisms underlying SLC13A5-related disorders.
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Affiliation(s)
- Adriana S Beltran
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
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18
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Wang Z, Zhang Y, Li Z, Wang H, Li N, Deng Y. Microfluidic Brain-on-a-Chip: From Key Technology to System Integration and Application. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2304427. [PMID: 37653590 DOI: 10.1002/smll.202304427] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/02/2023] [Indexed: 09/02/2023]
Abstract
As an ideal in vitro model, brain-on-chip (BoC) is an important tool to comprehensively elucidate brain characteristics. However, the in vitro model for the definition scope of BoC has not been universally recognized. In this review, BoC is divided into brain cells-on-a- chip, brain slices-on-a-chip, and brain organoids-on-a-chip according to the type of culture on the chip. Although these three microfluidic BoCs are constructed in different ways, they all use microfluidic chips as carrier tools. This method can better meet the needs of maintaining high culture activity on a chip for a long time. Moreover, BoC has successfully integrated cell biology, the biological material platform technology of microenvironment on a chip, manufacturing technology, online detection technology on a chip, and so on, enabling the chip to present structural diversity and high compatibility to meet different experimental needs and expand the scope of applications. Here, the relevant core technologies, challenges, and future development trends of BoC are summarized.
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Affiliation(s)
- Zhaohe Wang
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Yongqian Zhang
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Zhe Li
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Hao Wang
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Nuomin Li
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Yulin Deng
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
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19
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Moon H, Kim B, Kwon I, Oh Y. Challenges involved in cell therapy for Parkinson's disease using human pluripotent stem cells. Front Cell Dev Biol 2023; 11:1288168. [PMID: 37886394 PMCID: PMC10598731 DOI: 10.3389/fcell.2023.1288168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 09/25/2023] [Indexed: 10/28/2023] Open
Abstract
Neurons derived from human pluripotent stem cells (hPSCs) provide a valuable tool for studying human neural development and neurodegenerative diseases. The investigation of hPSC-based cell therapy, involving the differentiation of hPSCs into target cells and their transplantation into affected regions, is of particular interest. One neurodegenerative disease that is being extensively studied for hPSC-based cell therapy is Parkinson's disease (PD), the second most common among humans. Various research groups are focused on differentiating hPSCs into ventral midbrain dopaminergic (vmDA) progenitors, which have the potential to further differentiate into neurons closely resembling DA neurons found in the substantia nigra pars compacta (SNpc) after transplantation, providing a promising treatment option for PD. In vivo experiments, where hPSC-derived vmDA progenitor cells were transplanted into the striatum or SNpc of animal PD models, the transplanted cells demonstrated stable engraftment and resulted in behavioral recovery in the transplanted animals. Several differentiation protocols have been developed for this specific cell therapy. However, the lack of a reliable live-cell lineage identification method presents a significant obstacle in confirming the precise lineage of the differentiated cells intended for transplantation, as well as identifying potential contamination by non-vmDA progenitors. This deficiency increases the risk of adverse effects such as dyskinesias and tumorigenicity, highlighting the importance of addressing this issue before proceeding with transplantation. Ensuring the differentiation of hPSCs into the target cell lineage is a crucial step to guarantee precise therapeutic effects in cell therapy. To underscore the significance of lineage identification, this review focuses on the differentiation protocols of hPSC-derived vmDA progenitors developed by various research groups for PD treatment. Moreover, in vivo experimental results following transplantation were carefully analyzed. The encouraging outcomes from these experiments demonstrate the potential efficacy and safety of hPSC-derived vmDA progenitors for PD cell therapy. Additionally, the results of clinical trials involving the use of hPSC-derived vmDA progenitors for PD treatment were briefly reviewed, shedding light on the progress and challenges faced in translating this promising therapy into clinical practice.
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Affiliation(s)
- Heechang Moon
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea
| | - Bokwang Kim
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea
| | - Inbeom Kwon
- Department of Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Yohan Oh
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Advanced BioConvergence, Hanyang University, Seoul, Republic of Korea
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Chen J, Ma H, Deng Z, Luo Q, Gong H, Long B, Li X. Cerebral Organoid Arrays for Batch Phenotypic Analysis in Sections and Three Dimensions. Int J Mol Sci 2023; 24:13903. [PMID: 37762204 PMCID: PMC10530571 DOI: 10.3390/ijms241813903] [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: 08/09/2023] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Organoids can recapitulate human-specific phenotypes and functions in vivo and have great potential for research in development, disease modeling, and drug screening. Due to the inherent variability among organoids, experiments often require a large sample size. Embedding, staining, and imaging each organoid individually require a lot of reagents and time. Hence, there is an urgent need for fast and efficient methods for analyzing the phenotypic changes in organoids in batches. Here, we provide a comprehensive strategy for array embedding, staining, and imaging of cerebral organoids in both agarose sections and in 3D to analyze the spatial distribution of biomarkers in organoids in situ. We constructed several disease models, particularly an aging model, as examples to demonstrate our strategy for the investigation of the phenotypic analysis of organoids. We fabricated an array mold to produce agarose support with microwells, which hold organoids in place for live/dead imaging. We performed staining and imaging of sectioned organoids embedded in agarose and 3D imaging to examine phenotypic changes in organoids using fluorescence micro-optical sectioning tomography (fMOST) and whole-mount immunostaining. Parallel studies of organoids in arrays using the same staining and imaging parameters enabled easy and reliable comparison among different groups. We were able to track all the data points obtained from every organoid in an embedded array. This strategy could help us study the phenotypic changes in organoids in disease models and drug screening.
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Affiliation(s)
- Juan Chen
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Haihua Ma
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Zhiyu Deng
- Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou 570228, China
| | - Qingming Luo
- Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou 570228, China
| | - Hui Gong
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China
- HUST-Suzhou Institute for Brainsmatics, Jiangsu Industrial Technology Research Institute, Suzhou 215125, China
| | - Ben Long
- Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou 570228, China
- HUST-Suzhou Institute for Brainsmatics, Jiangsu Industrial Technology Research Institute, Suzhou 215125, China
| | - Xiangning Li
- Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou 570228, China
- HUST-Suzhou Institute for Brainsmatics, Jiangsu Industrial Technology Research Institute, Suzhou 215125, China
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21
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Lutfi Ismaeel G, Makki AlHassani OJ, S Alazragi R, Hussein Ahmed A, H Mohamed A, Yasir Jasim N, Hassan Shari F, Almashhadani HA. Genetically engineered neural stem cells (NSCs) therapy for neurological diseases; state-of-the-art. Biotechnol Prog 2023; 39:e3363. [PMID: 37221947 DOI: 10.1002/btpr.3363] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/28/2023] [Accepted: 05/01/2023] [Indexed: 05/25/2023]
Abstract
Neural stem cells (NSCs) are multipotent stem cells with remarkable self-renewal potential and also unique competencies to differentiate into neurons, astrocytes, and oligodendrocytes (ODCs) and improve the cellular microenvironment. In addition, NSCs secret diversity of mediators, including neurotrophic factors (e.g., BDNF, NGF, GDNF, CNTF, and NT-3), pro-angiogenic mediators (e.g., FGF-2 and VEGF), and anti-inflammatory biomolecules. Thereby, NSCs transplantation has become a reasonable and effective treatment for various neurodegenerative disorders by their capacity to induce neurogenesis and vasculogenesis and dampen neuroinflammation and oxidative stress. Nonetheless, various drawbacks such as lower migration and survival and less differential capacity to a particular cell lineage concerning the disease pathogenesis hinder their application. Thus, genetic engineering of NSCs before transplantation is recently regarded as an innovative strategy to bypass these hurdles. Indeed, genetically modified NSCs could bring about more favored therapeutic influences post-transplantation in vivo, making them an excellent option for neurological disease therapy. This review for the first time offers a comprehensive review of the therapeutic capability of genetically modified NSCs rather than naïve NSCs in neurological disease beyond brain tumors and sheds light on the recent progress and prospect in this context.
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Affiliation(s)
- Ghufran Lutfi Ismaeel
- Department of Pharmacology, College of Pharmacy, University of Al-Ameed, Karbala, Iraq
| | | | - Reem S Alazragi
- Department of Biochemistry, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Ammar Hussein Ahmed
- Department of Radiology and Sonar, College of Medical Techniques, Al-Farahidi University, Baghdad, Iraq
| | - Asma'a H Mohamed
- Intelligent Medical Systems Department, Al-Mustaqbal University College, Babylon, Iraq
| | - Nisreen Yasir Jasim
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Falah Hassan Shari
- Department of Clinical Laboratory Sciences, College of Pharmacy, University of Basrah, Basrah, Iraq
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22
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Kim SH, Chang MY. Application of Human Brain Organoids-Opportunities and Challenges in Modeling Human Brain Development and Neurodevelopmental Diseases. Int J Mol Sci 2023; 24:12528. [PMID: 37569905 PMCID: PMC10420018 DOI: 10.3390/ijms241512528] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/03/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
Brain organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that reflect early brain organization. These organoids contain different cell types, including neurons and glia, similar to those found in the human brain. Human brain organoids provide unique opportunities to model features of human brain development that are not well-reflected in animal models. Compared with traditional cell cultures and animal models, brain organoids offer a more accurate representation of human brain development and function, rendering them suitable models for neurodevelopmental diseases. In particular, brain organoids derived from patients' cells have enabled researchers to study diseases at different stages and gain a better understanding of disease mechanisms. Multi-brain regional assembloids allow for the investigation of interactions between distinct brain regions while achieving a higher level of consistency in molecular and functional characterization. Although organoids possess promising features, their usefulness is limited by several unresolved constraints, including cellular stress, hypoxia, necrosis, a lack of high-fidelity cell types, limited maturation, and circuit formation. In this review, we discuss studies to overcome the natural limitations of brain organoids, emphasizing the importance of combinations of all neural cell types, such as glia (astrocyte, oligodendrocytes, and microglia) and vascular cells. Additionally, considering the similarity of organoids to the developing brain, regionally patterned brain organoid-derived neural stem cells (NSCs) could serve as a scalable source for cell replacement therapy. We highlight the potential application of brain organoid-derived cells in disease cell therapy within this field.
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Affiliation(s)
- Soo-hyun Kim
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Seoul 04763, Republic of Korea;
- Biomedical Research Institute, Hanyang University, Seoul 04763, Republic of Korea
| | - Mi-Yoon Chang
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Seoul 04763, Republic of Korea;
- Biomedical Research Institute, Hanyang University, Seoul 04763, Republic of Korea
- Department of Premedicine, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Republic of Korea
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23
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Saeb S, Wallet C, Rohr O, Schwartz C, Loustau T. Targeting and eradicating latent CNS reservoirs of HIV-1: original strategies and new models. Biochem Pharmacol 2023:115679. [PMID: 37399950 DOI: 10.1016/j.bcp.2023.115679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/28/2023] [Accepted: 06/29/2023] [Indexed: 07/05/2023]
Abstract
Nowadays, combination antiretroviral therapy (cART) is the standard treatment for all people with human immunodeficiency virus (HIV-1). Although cART is effective in treating productive infection, it does not eliminate latent reservoirs of the virus. This leads to lifelong treatment associated with the occurrence of side effects and the development of drug-resistant HIV-1. Suppression of viral latency is therefore the major hurdle to HIV-1 eradication. Multiple mechanisms exist to regulate viral gene expression and drive the transcriptional and post-transcriptional establishment of latency. Epigenetic processes are amongst the most studied mechanisms influencing both productive and latent infection states. The central nervous system (CNS) represents a key anatomical sanctuary for HIV and is the focal point of considerable research efforts. However, limited and difficult access to CNS compartments makes understanding the HIV-1 infection state in latent brain cells such as microglial cells, astrocytes, and perivascular macrophages challenging. This review examines the latest advances on epigenetic transformations involved in CNS viral latency and targeting of brain reservoirs. Evidence from clinical studies as well as in vivo and in vitro models of HIV-1 persistence in the CNS will be discussed, with a special focus on recent 3D in vitro models such as human brain organoids. Finally, the review will address therapeutic considerations for targeting latent CNS reservoirs.
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Affiliation(s)
- Sepideh Saeb
- Department of Allied Medicine, Qaen Faculty of Medical Sciences, Birjand University of Medical Sciences, Birjand, Iran; Strasbourg University, Research Unit 7292, DHPI, IUT Louis Pasteur, Schiltigheim, France
| | - Clémentine Wallet
- Strasbourg University, Research Unit 7292, DHPI, IUT Louis Pasteur, Schiltigheim, France
| | - Olivier Rohr
- Strasbourg University, Research Unit 7292, DHPI, IUT Louis Pasteur, Schiltigheim, France
| | - Christian Schwartz
- Strasbourg University, Research Unit 7292, DHPI, IUT Louis Pasteur, Schiltigheim, France
| | - Thomas Loustau
- Strasbourg University, Research Unit 7292, DHPI, IUT Louis Pasteur, Schiltigheim, France.
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24
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Sugeno N, Hasegawa T. Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification. Int J Mol Sci 2023; 24:ijms24076645. [PMID: 37047616 PMCID: PMC10094812 DOI: 10.3390/ijms24076645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 03/21/2023] [Accepted: 03/31/2023] [Indexed: 04/05/2023] Open
Abstract
Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the SNCA gene. Point mutations and gene multiplication of SNCA cause rare familial forms of Parkinson’s disease (PD). Misfolded αS is cytotoxic and is a component of Lewy bodies, which are a pathological hallmark of PD. Because SNCA multiplication is sufficient to cause full-blown PD, gene dosage likely has a strong impact on pathogenesis. In sporadic PD, increased SNCA expression resulting from a minor genetic background and various environmental factors may contribute to pathogenesis in a complementary manner. With respect to genetic background, several risk loci neighboring the SNCA gene have been identified, and epigenetic alterations, such as CpG methylation and regulatory histone marks, are considered important factors. These alterations synergistically upregulate αS expression and some post-translational modifications of αS facilitate its translocation to the nucleus. Nuclear αS interacts with DNA, histones, and their modifiers to alter epigenetic status; thereby, influencing the stability of neuronal function. Epigenetic changes do not affect the gene itself but can provide an appropriate transcriptional response for neuronal survival through DNA methylation or histone modifications. As a new approach, publicly available RNA sequencing datasets from human midbrain-like organoids may be used to compare transcriptional responses through epigenetic alterations. This informatic approach combined with the vast amount of transcriptomics data will lead to the discovery of novel pathways for the development of disease-modifying therapies for PD.
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Affiliation(s)
- Naoto Sugeno
- Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Takafumi Hasegawa
- Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
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25
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Astragaloside IV: A promising natural neuroprotective agent for neurological disorders. Biomed Pharmacother 2023; 159:114229. [PMID: 36652731 DOI: 10.1016/j.biopha.2023.114229] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/05/2023] [Accepted: 01/05/2023] [Indexed: 01/18/2023] Open
Abstract
Neurological disorders are characterized by high morbidity, disability, and mortality rates, which seriously threaten human health. However, clinically satisfactory agents for treatment are still currently lacking. Therefore, finding neuroprotective agents with minimum side effects and better efficacy is a challenge. Chinese herbal medicine, particularly natural preparations extracted from herbs or plants, has become an unparalleled resource for discovering new agent candidates. Astragali Radix is an important Qi tonic drug in traditional Chinese medicine and has a long medicinal history. As a natural medicine, it has a good prevention and treatment effect on neurological disorders. Here, the role and mechanism of astragaloside IV in the treatment of neurological disorders were evaluated and discussed through previous research results. Related information from major scientific databases, such as PubMed, MEDLINE, Web of Science, ScienceDirect, Embase, BIOSIS Previews, and the Cochrane Central Register of Controlled Trials and Cochrane Library, covering between 2001 and 2021 was compiled, using "Astragaloside IV" and "Neurological disorders," "Astragaloside IV," and "Neurodegenerative diseases" as reference terms. By summarizing previous research results, we found that astragaloside IV may play a neuroprotective role through various mechanisms: anti-inflammatory, anti-oxidative, anti-apoptotic protection of nerve cells and regulation of nerve growth factor, as well as by inhibiting neurodegeneration and promoting nerve regeneration. Astragaloside IV is a promising natural neuroprotective agent. By determining its pharmacological mechanism, astragaloside IV may be a new candidate drug for the treatment of neurological disorders.
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26
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Yeap YJ, Teddy TJW, Lee MJ, Goh M, Lim KL. From 2D to 3D: Development of Monolayer Dopaminergic Neuronal and Midbrain Organoid Cultures for Parkinson's Disease Modeling and Regenerative Therapy. Int J Mol Sci 2023; 24:ijms24032523. [PMID: 36768843 PMCID: PMC9917335 DOI: 10.3390/ijms24032523] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023] Open
Abstract
Parkinson's Disease (PD) is a prevalent neurodegenerative disorder that is characterized pathologically by the loss of A9-specific dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Despite intensive research, the etiology of PD is currently unresolved, and the disease remains incurable. This, in part, is due to the lack of an experimental disease model that could faithfully recapitulate the features of human PD. However, the recent advent of induced pluripotent stem cell (iPSC) technology has allowed PD models to be created from patient-derived cells. Indeed, DA neurons from PD patients are now routinely established in many laboratories as monolayers as well as 3D organoid cultures that serve as useful toolboxes for understanding the mechanism underlying PD and also for drug discovery. At the same time, the iPSC technology also provides unprecedented opportunity for autologous cell-based therapy for the PD patient to be performed using the patient's own cells as starting materials. In this review, we provide an update on the molecular processes underpinning the development and differentiation of human pluripotent stem cells (PSCs) into midbrain DA neurons in both 2D and 3D cultures, as well as the latest advancements in using these cells for drug discovery and regenerative medicine. For the novice entering the field, the cornucopia of differentiation protocols reported for the generation of midbrain DA neurons may seem daunting. Here, we have distilled the essence of the different approaches and summarized the main factors driving DA neuronal differentiation, with the view to provide a useful guide to newcomers who are interested in developing iPSC-based models of PD.
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Affiliation(s)
- Yee Jie Yeap
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
| | - Tng J. W. Teddy
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
- Interdisciplinary Graduate Programme (IGP-Neuroscience), Nanyang Technological University, Singapore 639798, Singapore
| | - Mok Jung Lee
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
| | - Micaela Goh
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
| | - Kah Leong Lim
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
- National Neuroscience Institute, Singapore 308433, Singapore
- Department of Brain Sciences, Imperial College London, London SW7 2AZ, UK
- Department of Anatomy, Shanxi Medical University, Taiyuan 030001, China
- Correspondence:
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27
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Lachman HM. Use of cerebral organoids to model environmental and gene x environment interactions in the developing fetus and neurodegenerative disorders. PHENOTYPING OF HUMAN IPSC-DERIVED NEURONS 2023:173-200. [DOI: 10.1016/b978-0-12-822277-5.00006-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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28
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Cuevas-Diaz Duran R, González-Orozco JC, Velasco I, Wu JQ. Single-cell and single-nuclei RNA sequencing as powerful tools to decipher cellular heterogeneity and dysregulation in neurodegenerative diseases. Front Cell Dev Biol 2022; 10:884748. [PMID: 36353512 PMCID: PMC9637968 DOI: 10.3389/fcell.2022.884748] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 10/06/2022] [Indexed: 08/10/2023] Open
Abstract
Neurodegenerative diseases affect millions of people worldwide and there are currently no cures. Two types of common neurodegenerative diseases are Alzheimer's (AD) and Parkinson's disease (PD). Single-cell and single-nuclei RNA sequencing (scRNA-seq and snRNA-seq) have become powerful tools to elucidate the inherent complexity and dynamics of the central nervous system at cellular resolution. This technology has allowed the identification of cell types and states, providing new insights into cellular susceptibilities and molecular mechanisms underlying neurodegenerative conditions. Exciting research using high throughput scRNA-seq and snRNA-seq technologies to study AD and PD is emerging. Herein we review the recent progress in understanding these neurodegenerative diseases using these state-of-the-art technologies. We discuss the fundamental principles and implications of single-cell sequencing of the human brain. Moreover, we review some examples of the computational and analytical tools required to interpret the extensive amount of data generated from these assays. We conclude by highlighting challenges and limitations in the application of these technologies in the study of AD and PD.
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Affiliation(s)
| | | | - Iván Velasco
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Mexico City, Mexico
| | - Jia Qian Wu
- The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
- Center for Stem Cell and Regenerative Medicine, UT Brown Foundation Institute of Molecular Medicine, Houston, TX, United States
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States
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29
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Drozd AM, Mariani L, Guo X, Goitea V, Menezes NA, Ferretti E. Progesterone Receptor Modulates Extraembryonic Mesoderm and Cardiac Progenitor Specification during Mouse Gastrulation. Int J Mol Sci 2022; 23:ijms231810307. [PMID: 36142249 PMCID: PMC9499561 DOI: 10.3390/ijms231810307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/30/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
Progesterone treatment is commonly employed to promote and support pregnancy. While maternal tissues are the main progesterone targets in humans and mice, its receptor (PGR) is expressed in the murine embryo, questioning its function during embryonic development. Progesterone has been previously associated with murine blastocyst development. Whether it contributes to lineage specification is largely unknown. Gastrulation initiates lineage specification and generation of the progenitors contributing to all organs. Cells passing through the primitive streak (PS) will give rise to the mesoderm and endoderm. Cells emerging posteriorly will form the extraembryonic mesodermal tissues supporting embryonic growth. Cells arising anteriorly will contribute to the embryonic heart in two sets of distinct progenitors, first (FHF) and second heart field (SHF). We found that PGR is expressed in a posterior–anterior gradient in the PS of gastrulating embryos. We established in vitro differentiation systems inducing posterior (extraembryonic) and anterior (cardiac) mesoderm to unravel PGR function. We discovered that PGR specifically modulates extraembryonic and cardiac mesoderm. Overexpression experiments revealed that PGR safeguards cardiac differentiation, blocking premature SHF progenitor specification and sustaining the FHF progenitor pool. This role of PGR in heart development indicates that progesterone administration should be closely monitored in potential early-pregnancy patients undergoing infertility treatment.
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Affiliation(s)
- Anna Maria Drozd
- Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark
| | - Luca Mariani
- Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark
| | - Xiaogang Guo
- Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark
| | - Victor Goitea
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark
| | - Niels Alvaro Menezes
- Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark
| | - Elisabetta Ferretti
- Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark
- Correspondence:
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30
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Lou S, Huang T, Qi J, Zhang T, Gao J, Cui S. Discovery of (2-phenylthiazol-4-yl)urea derivatives that induce neuronal differentiation from mesenchymal stem cells. Bioorg Med Chem Lett 2022; 69:128798. [PMID: 35580725 DOI: 10.1016/j.bmcl.2022.128798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 05/05/2022] [Accepted: 05/11/2022] [Indexed: 11/28/2022]
Abstract
The success of stem cells therapy to treat neurodegenerative diseases is currently restricted by the lack of suitable stem cells. Mesenchymal stem cells (MSCs) have demonstrated several advantages as seed-cells for the stem cells therapy. In particular, the low immunogenicity and multiple lineages differentiation capability enables the possibility of using MSCs to treat neurodegenerative diseases. However, a more potent neuronal differentiation capacity of MSCs is required during a success treatment against neurodegenerative diseases. Bioengineering using small molecules to boost the neuronal differentiation of MSCs has been proposed as a promising strategy. Herein, we developed a new series of (2-phenylthiazol-4-yl)urea derivatives and one of them, 18g were observed to successfully promote neuronal differentiation of MSCs after culturing MSCs with 18g for 4 days. In addition, neither significant cytotoxicity nor cell cycle altering were found after the incubation. Interestingly, the osteogenic differentiation potential of MSCs was not affected after 18g treatment. The present study provides a promising small molecule to boost the innate neuronal differentiation capacity of MSCs with no serious detrimental effects.
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Affiliation(s)
- Shengying Lou
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, PR China
| | - Ting Huang
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, PR China
| | - Jifeng Qi
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, PR China
| | - Tianyuan Zhang
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, PR China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, PR China.
| | - Jianqing Gao
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, PR China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, PR China
| | - Sunliang Cui
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, PR China.
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31
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Zhang SY, Zhao J, Ni JJ, Li H, Quan ZZ, Qing H. Application and prospects of high-throughput screening for in vitro neurogenesis. World J Stem Cells 2022; 14:393-419. [PMID: 35949394 PMCID: PMC9244953 DOI: 10.4252/wjsc.v14.i6.393] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 04/07/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Over the past few decades, high-throughput screening (HTS) has made great contributions to new drug discovery. HTS technology is equipped with higher throughput, minimized platforms, more automated and computerized operating systems, more efficient and sensitive detection devices, and rapid data processing systems. At the same time, in vitro neurogenesis is gradually becoming important in establishing models to investigate the mechanisms of neural disease or developmental processes. However, challenges remain in generating more mature and functional neurons with specific subtypes and in establishing robust and standardized three-dimensional (3D) in vitro models with neural cells cultured in 3D matrices or organoids representing specific brain regions. Here, we review the applications of HTS technologies on in vitro neurogenesis, especially aiming at identifying the essential genes, chemical small molecules and adaptive microenvironments that hold great prospects for generating functional neurons or more reproductive and homogeneous 3D organoids. We also discuss the developmental tendency of HTS technology, e.g., so-called next-generation screening, which utilizes 3D organoid-based screening combined with microfluidic devices to narrow the gap between in vitro models and in vivo situations both physiologically and pathologically.
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Affiliation(s)
- Shu-Yuan Zhang
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Juan Zhao
- Aerospace Medical Center, Aerospace Center Hospital, Beijing 100049, China
| | - Jun-Jun Ni
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Hui Li
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Zhen-Zhen Quan
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Hong Qing
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
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32
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Abstract
ABSTRACT As human life expectancy continues to increase and the birth rate continues to decline, the phenomenon of aging is becoming more prominent worldwide. Therefore, addressing the problems associated with global aging has become a current research focus. The main manifestations of human aging are structural degeneration and functional decline of aging tissues and organs, quality of life decline, decreased ability to resist diseases, and high incidence rates of a variety of senile degenerative diseases. Thus far, no ideal treatments have been found. Stem cell (SC) therapies have broad application prospects in the field of regenerative medicine due to the inherent biological characteristics of SCs, such as their plasticity, self-renewal, and multidirectional differentiation potential. Thus, SCs could delay or even reverse aging. This manuscript reviews the causes of human aging, the biological characteristics of SCs, and research progress on age reversal.
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Affiliation(s)
- Le Chang
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
- Kunming Medical University, Kunming, Yunnan 650500, China
| | - Weiwen Fan
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
- Kunming Medical University, Kunming, Yunnan 650500, China
| | - Xinghua Pan
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
| | - Xiangqing Zhu
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
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