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1
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Huang LX, Sun T, Sun J, Wu ZM, Ling C, Zhang BY, Chen C, Wang H. Non-Coding RNA in Schwann Cell and Peripheral Nerve Injury: A Review. Adv Biol (Weinh) 2025; 9:e2400357. [PMID: 39185790 DOI: 10.1002/adbi.202400357] [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: 06/21/2024] [Revised: 07/28/2024] [Indexed: 08/27/2024]
Abstract
Peripheral nerve injury (PNI) can result in severe disabilities, profoundly impacting patients' quality of life and potentially endangering their lives. Therefore, understanding the potential molecular mechanisms that facilitate the regeneration of damaged nerves is crucial. Evidence indicates that Schwann cells (SCs) play a pivotal role in repairing peripheral nerve injuries. Previous studies have shown that RNA, particularly non-coding RNA (ncRNA), plays a crucial role in nerve regeneration, including the proliferation and dedifferentiation of SCs. In this review, the individual roles of ncRNA in SCs and PNI are analyzed. This review not only enhances the understanding of ncRNA's role in nerve injury repair but also provides a significant theoretical foundation and inspiration for the development of new therapeutic strategies.
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Affiliation(s)
- Li-Xin Huang
- Department of Neurosurgery, The Third Affiliated Hospital, 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Tao Sun
- Department of Neurosurgery, The Third Affiliated Hospital, 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Jun Sun
- Department of Neurosurgery, The Third Affiliated Hospital, 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Zhi-Min Wu
- Department of Neurosurgery, The Third Affiliated Hospital, 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Cong Ling
- Department of Neurosurgery, The Third Affiliated Hospital, 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Bao-Yu Zhang
- Department of Neurosurgery, The Third Affiliated Hospital, 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Chuan Chen
- Department of Neurosurgery, The Third Affiliated Hospital, 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Hui Wang
- Department of Neurosurgery, The Third Affiliated Hospital, 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
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2
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Tang X, Deng P, Li L, He Y, Wang J, Hao D, Yang H. Advances in genetically modified neural stem cell therapy for central nervous system injury and neurological diseases. Stem Cell Res Ther 2024; 15:482. [PMID: 39696712 DOI: 10.1186/s13287-024-04089-1] [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: 04/22/2024] [Accepted: 12/03/2024] [Indexed: 12/20/2024] Open
Abstract
Neural stem cells (NSCs) have increasingly been recognized as the most promising candidates for cell-based therapies for the central nervous system (CNS) injuries, primarily due to their pluripotent differentiation capabilities, as well as their remarkable secretory and homing properties. In recent years, extensive research efforts have been initiated to explore the therapeutic potential of NSC transplantation for CNS injuries, yielding significant advancements. Nevertheless, owing to the formation of adverse microenvironment at post-injury leading to suboptimal survival, differentiation, and integration within the host neural network of transplanted NSCs, NSC-based transplantation therapies often fall short of achieving optimal therapeutic outcomes. To address this challenge, genetic modification has been developed an attractive strategy to improve the outcomes of NSC therapies. This is mainly attributed to its potential to not only enhance the differentiation capacity of NSCs but also to boost a range of biological activities, such as the secretion of bioactive factors, anti-inflammatory effects, anti-apoptotic properties, immunomodulation, antioxidative functions, and angiogenesis. Furthermore, genetic modification empowers NSCs to play a more robust neuroprotective role in the context of nerve injury. In this review, we will provide an overview of recent advances in the roles and mechanisms of NSCs genetically modified with various therapeutic genes in the treatment of neural injuries and neural disorders. Also, an update on current technical parameters suitable for NSC transplantation and functional recovery in clinical studies are summarized.
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Affiliation(s)
- Xiangwen Tang
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Peng Deng
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
- Basic Medical School Academy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Lin Li
- Basic Medical School Academy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Yuqing He
- Basic Medical School Academy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Jinchao Wang
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Dingjun Hao
- Department of Spine Surgery, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Hao Yang
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China.
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3
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Baroudi M, Rezk A, Daher M, Balmaceno-Criss M, Gregoryczyk JG, Sharma Y, McDonald CL, Diebo BG, Daniels AH. Management of traumatic spinal cord injury: A current concepts review of contemporary and future treatment. Injury 2024; 55:111472. [PMID: 38460480 DOI: 10.1016/j.injury.2024.111472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 02/03/2024] [Accepted: 02/25/2024] [Indexed: 03/11/2024]
Abstract
Spinal Cord Injury (SCI) is a condition leading to inflammation, edema, and dysfunction of the spinal cord, most commonly due to trauma, tumor, infection, or vascular disturbance. Symptoms include sensory and motor loss starting at the level of injury; the extent of damage depends on injury severity as detailed in the ASIA score. In the acute setting, maintaining mean arterial pressure (MAP) higher than 85 mmHg for up to 7 days following injury is preferred; although caution must be exercised when using vasopressors such as phenylephrine due to serious side effects such as pulmonary edema and death. Decompression surgery (DS) may theoretically relieve edema and reduce intraspinal pressure, although timing of surgery remains a matter of debate. Methylprednisolone (MP) is currently used due to its ability to reduce inflammation but more recent studies question its clinical benefits, especially with inconsistency in recommending it nationally and internationally. The choice of MP is further complicated by conflicting evidence for optimal timing to initiate treatment, and by the reported observation that higher doses are correlated with increased risk of complications. Thyrotropin-releasing hormone may be beneficial in less severe injuries. Finally, this review discusses many options currently being researched and have shown promising pre-clinical results.
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Affiliation(s)
- Makeen Baroudi
- Department of Orthopedic Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Anna Rezk
- Department of Orthopedic Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Mohammad Daher
- Department of Orthopedic Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Mariah Balmaceno-Criss
- Department of Orthopedic Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Jerzy George Gregoryczyk
- Department of Orthopedic Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Yatharth Sharma
- Department of Orthopedic Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Christopher L McDonald
- Department of Orthopedic Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Bassel G Diebo
- Department of Orthopedic Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Alan H Daniels
- Department of Orthopedic Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA.
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4
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Hosseini SM, Borys B, Karimi-Abdolrezaee S. Neural stem cell therapies for spinal cord injury repair: an update on recent preclinical and clinical advances. Brain 2024; 147:766-793. [PMID: 37975820 DOI: 10.1093/brain/awad392] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/22/2023] [Accepted: 11/02/2023] [Indexed: 11/19/2023] Open
Abstract
Traumatic spinal cord injury (SCI) is a leading cause of lifelong disabilities. Permanent sensory, motor and autonomic impairments after SCI are substantially attributed to degeneration of spinal cord neurons and axons, and disintegration of neural network. To date, minimal regenerative treatments are available for SCI with an unmet need for new therapies to reconstruct the damaged spinal cord neuron-glia network and restore connectivity with the supraspinal pathways. Multipotent neural precursor cells (NPCs) have a unique capacity to generate neurons, oligodendrocytes and astrocytes. Due to this capacity, NPCs have been an attractive cell source for cellular therapies for SCI. Transplantation of NPCs has been extensively tested in preclinical models of SCI in the past two decades. These studies have identified opportunities and challenges associated with NPC therapies. While NPCs have the potential to promote neuroregeneration through various mechanisms, their low long-term survival and integration within the host injured spinal cord limit the functional benefits of NPC-based therapies for SCI. To address this challenge, combinatorial strategies have been developed to optimize the outcomes of NPC therapies by enriching SCI microenvironment through biomaterials, genetic and pharmacological therapies. In this review, we will provide an in-depth discussion on recent advances in preclinical NPC-based therapies for SCI. We will discuss modes of actions and mechanism by which engrafted NPCs contribute to the repair process and functional recovery. We will also provide an update on current clinical trials and new technologies that have facilitated preparation of medical-grade human NPCs suitable for transplantation in clinical studies.
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Affiliation(s)
- Seyed Mojtaba Hosseini
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba Winnipeg, Manitoba R3E 0J9, Canada
- Manitoba Multiple Sclerosis Research Center, Winnipeg, Manitoba R3E 0J9, Canada
| | - Ben Borys
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba Winnipeg, Manitoba R3E 0J9, Canada
| | - Soheila Karimi-Abdolrezaee
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba Winnipeg, Manitoba R3E 0J9, Canada
- Manitoba Multiple Sclerosis Research Center, Winnipeg, Manitoba R3E 0J9, Canada
- Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada
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5
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Zhang C, Talifu Z, Xu X, Liu W, Ke H, Pan Y, Li Y, Bai F, Jing Y, Li Z, Li Z, Yang D, Gao F, Du L, Li J, Yu Y. MicroRNAs in spinal cord injury: A narrative review. Front Mol Neurosci 2023; 16:1099256. [PMID: 36818651 PMCID: PMC9931912 DOI: 10.3389/fnmol.2023.1099256] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/12/2023] [Indexed: 02/05/2023] Open
Abstract
Spinal cord injury (SCI) is a global medical problem with high disability and mortality rates. At present, the diagnosis and treatment of SCI are still lacking. Spinal cord injury has a complex etiology, lack of diagnostic methods, poor treatment effect and other problems, which lead to the difficulty of spinal cord regeneration and repair, and poor functional recovery. Recent studies have shown that gene expression plays an important role in the regulation of SCI repair. MicroRNAs (miRNAs) are non-coding RNA molecules that target mRNA expression in order to silence, translate, or interfere with protein synthesis. Secondary damage, such as oxidative stress, apoptosis, autophagy, and inflammation, occurs after SCI, and differentially expressed miRNAs contribute to these events. This article reviews the pathophysiological mechanism of miRNAs in secondary injury after SCI, focusing on the mechanism of miRNAs in secondary neuroinflammation after SCI, so as to provide new ideas and basis for the clinical diagnosis and treatment of miRNAs in SCI. The mechanisms of miRNAs in neurological diseases may also make them potential biomarkers and therapeutic targets for spinal cord injuries.
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Affiliation(s)
- Chunjia Zhang
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Zuliyaer Talifu
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, Shandong Province, China
| | - Xin Xu
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Wubo Liu
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China,Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Han Ke
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China,Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Yunzhu Pan
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, Shandong Province, China
| | - Yan Li
- China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Fan Bai
- China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Yingli Jing
- China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Zihan Li
- China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Zehui Li
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Degang Yang
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Feng Gao
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Liangjie Du
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China
| | - Jianjun Li
- School of Rehabilitation, Capital Medical University, Beijing, China,,Department of Spinal and Neural Functional Reconstruction, China Rehabilitation Research Center, Beijing, China,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, Shandong Province, China,Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China,*Correspondence: Jianjun Li,
| | - Yan Yu
- School of Rehabilitation, Capital Medical University, Beijing, China,,China Rehabilitation Science Institute, Beijing, China,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China,Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, China,Yan Yu,
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Xu J, Zheng Y, Wang L, Liu Y, Wang X, Li Y, Chi G. miR-124: A Promising Therapeutic Target for Central Nervous System Injuries and Diseases. Cell Mol Neurobiol 2022; 42:2031-2053. [PMID: 33886036 PMCID: PMC11421642 DOI: 10.1007/s10571-021-01091-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 04/12/2021] [Indexed: 02/07/2023]
Abstract
Central nervous system injuries and diseases, such as ischemic stroke, spinal cord injury, neurodegenerative diseases, glioblastoma, multiple sclerosis, and the resulting neuroinflammation often lead to death or long-term disability. MicroRNAs are small, non-coding, single-stranded RNAs that regulate posttranscriptional gene expression in both physiological and pathological cellular processes, including central nervous system injuries and disorders. Studies on miR-124, one of the most abundant microRNAs in the central nervous system, have shown that its dysregulation is related to the occurrence and development of pathology within the central nervous system. Herein, we review the molecular regulatory functions, underlying mechanisms, and effective delivery methods of miR-124 in the central nervous system, where it is involved in pathological conditions. The review also provides novel insights into the therapeutic target potential of miR-124 in the treatment of human central nervous system injuries or diseases.
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Affiliation(s)
- Jinying Xu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130000, People's Republic of China
| | - Yangyang Zheng
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130000, People's Republic of China
| | - Liangjia Wang
- Clinical Medical College, Jilin University, Changchun, 130000, People's Republic of China
| | - Yining Liu
- Clinical Medical College, Jilin University, Changchun, 130000, People's Republic of China
| | - Xishu Wang
- Clinical Medical College, Jilin University, Changchun, 130000, People's Republic of China
| | - Yulin Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130000, People's Republic of China.
| | - Guangfan Chi
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130000, People's Republic of China.
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Guo W, Zhang X, Zhai J, Xue J. The roles and applications of neural stem cells in spinal cord injury repair. Front Bioeng Biotechnol 2022; 10:966866. [PMID: 36105599 PMCID: PMC9465243 DOI: 10.3389/fbioe.2022.966866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 07/28/2022] [Indexed: 12/05/2022] Open
Abstract
Spinal cord injury (SCI), which has no current cure, places a severe burden on patients. Stem cell-based therapies are considered promising in attempts to repair injured spinal cords; such options include neural stem cells (NSCs). NSCs are multipotent stem cells that differentiate into neuronal and neuroglial lineages. This feature makes NSCs suitable candidates for regenerating injured spinal cords. Many studies have revealed the therapeutic potential of NSCs. In this review, we discuss from an integrated view how NSCs can help SCI repair. We will discuss the sources and therapeutic potential of NSCs, as well as representative pre-clinical studies and clinical trials of NSC-based therapies for SCI repair.
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Affiliation(s)
- Wen Guo
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xindan Zhang
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, China
| | - Jiliang Zhai
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Beijing, China
- *Correspondence: Jiliang Zhai, ; Jiajia Xue,
| | - Jiajia Xue
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, China
- *Correspondence: Jiliang Zhai, ; Jiajia Xue,
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8
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Correlation between miRNA-124, miRNA-544a, and TNF-α levels in acute spinal cord injury. Spinal Cord 2022; 60:779-783. [PMID: 35292776 PMCID: PMC9436774 DOI: 10.1038/s41393-022-00763-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 01/22/2023]
Abstract
STUDY DESIGN Retrospective. OBJECTIVES Acute spinal cord injury (ASCI) is caused by direct or indirect strikes from external forces on the spinal cord. Here, we investigated the correlation between the miR-124, miR-544a, and TNF-α levels in patients with ASCI, aiming to evaluate the potential usage of miR-124 and miR-544a in ASCI diagnosis. SETTING University/hospital. METHODS A total of 90 (58 male/32 female) ASIA patients and 15 (9 male/6 female) control patients (with acute limb trauma) were involved in the presented study. The ASIA patients were further subclustered based on the International Standards for the Neurological Classification of SCI (ISNCSCI) exam. 30 (18 male/12 female)cases were determined to have complete spinal cord injury (CSCI) and classified as ASIA grade A (Complete); 30 (20 male/10 female) cases were determined to have incomplete spinal cord injury (ISCI) and classified as ASIA grade B (sensory incomplete), C (motor incomplete), or D (motor incomplete); 30 (20 male/10 female) cases were determined to have normal neurological function (NNF) and classified as ASIA grade E (Normal). Plasma miR-124, miRNA-544a, and tumor necrosis factor-alpha (TNF-α) levels were measured from the blood samples collected 24 h, 48 h, and 72 h after trauma. RESULTS The levels of miR-124 and miR-544a in the CSCI and ISCI groups were significantly higher than those of the NNF and the control group 24 h after injury (P < 0.05). The increased levels gradually declined from 24 h to 72 h after injury. The area under the receiver operating characteristic curve (ROC) of miR-124, miR-544a and TNF-α 24 h after trauma in patients with acute spinal cord injury were 0.948 [95% CI (0.890, 1.000)], 0.815 [95% CI (0.638, 0.994)] and 0.770 [95% CI (0.641, 0.879)], respectively. CONCLUSION The miRNA-124 and miRNA-544a levels increased significantly in ASCI patients compared with control patients 24 h after injury. These increased levels gradually reduced from 24 h to 72 h after injury. There is a strong positive correlation between miRNA-124, miRNA-544a, and acute spinal cord injury. SPONSORSHIP The present study was supported by a University-level project of Ningxia Medical University (Project Number: XY2017147).
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9
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Huang W, Lin M, Yang C, Wang F, Zhang M, Gao J, Yu X. Rat Bone Mesenchymal Stem Cell-Derived Exosomes Loaded with miR-494 Promoting Neurofilament Regeneration and Behavioral Function Recovery after Spinal Cord Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:1634917. [PMID: 34635862 PMCID: PMC8501401 DOI: 10.1155/2021/1634917] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 09/05/2021] [Accepted: 09/09/2021] [Indexed: 01/08/2023]
Abstract
Exosomes (Exo) exhibit numerous advantages (e.g., good encapsulation, high targeting efficiency, and easy to penetrate the blood-brain barrier to the central nervous system). Exosomes are recognized as prominent carriers of mRNAs, siRNAs, miRNAs, proteins, and other bioactive molecules. As confirmed by existing studies, miR-494 is important to regulate the occurrence, progression, and repair of spinal cord injury (SCI). We constructed miR-494-modified exosomes (Exo-miR-494). As indicated from related research in vitro and vivo, Exo-miR-494 is capable of effectively inhibiting the inflammatory response and neuronal apoptosis in the injured area, as well as upregulating various anti-inflammatory factors and miR-494 to protect neurons. Moreover, it can promote the regeneration of the neurofilament and improve the recovery of behavioral function of SCI rats.
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Affiliation(s)
- Wei Huang
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
- Department of Orthopaedics, Dongguan Tungwah Hospital, Dongguan 523000, China
| | - Miaoman Lin
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Cunheng Yang
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Fumin Wang
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Meng Zhang
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Junxiao Gao
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Xiaobing Yu
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
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10
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Nasirishargh A, Kumar P, Ramasubramanian L, Clark K, Hao D, Lazar SV, Wang A. Exosomal microRNAs from mesenchymal stem/stromal cells: Biology and applications in neuroprotection. World J Stem Cells 2021; 13:776-794. [PMID: 34367477 PMCID: PMC8316862 DOI: 10.4252/wjsc.v13.i7.776] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/29/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are extensively studied as cell-therapy agents for neurological diseases. Recent studies consider exosomes secreted by MSCs as important mediators for MSCs' neuroprotective functions. Exosomes transfer functional molecules including proteins, lipids, metabolites, DNAs, and coding and non-coding RNAs from MSCs to their target cells. Emerging evidence shows that exosomal microRNAs (miRNAs) play a key role in the neuroprotective properties of these exosomes by targeting several genes and regulating various biological processes. Multiple exosomal miRNAs have been identified to have neuroprotective effects by promoting neurogenesis, neurite remodeling and survival, and neuroplasticity. Thus, exosomal miRNAs have significant therapeutic potential for neurological disorders such as stroke, traumatic brain injury, and neuroinflammatory or neurodegenerative diseases and disorders. This review discusses the neuroprotective effects of selected miRNAs (miR-21, miR-17-92, miR-133, miR-138, miR-124, miR-30, miR146a, and miR-29b) and explores their mechanisms of action and applications for the treatment of various neurological disease and disorders. It also provides an overview of state-of-the-art bioengineering approaches for isolating exosomes, optimizing their yield and manipulating the miRNA content of their cargo to improve their therapeutic potential.
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Affiliation(s)
- Aida Nasirishargh
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
| | - Priyadarsini Kumar
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Lalithasri Ramasubramanian
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States
| | - Kaitlin Clark
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Dake Hao
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Sabrina V Lazar
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
| | - Aijun Wang
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States.
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11
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MicroRNA124 and microRNA21-5p regulate migration, proliferation and differentiation of rat bone marrow mesenchymal stem cells. Biosci Rep 2021; 40:226597. [PMID: 33026076 PMCID: PMC7584812 DOI: 10.1042/bsr20193531] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 08/29/2020] [Accepted: 10/02/2020] [Indexed: 12/28/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells that can be a useful source of cells for the treatment of many diseases, including neurologic diseases. The curative effect of MSCs relies mostly on cell’s capacity of migration, proliferation and differentiation. MicroRNAs (miRNAs) are small non-coding RNAs that play important roles on regulating various cell behaviors. Here, we report that miRNA-124 (miR124) and miRNA-21-5p (miR21-5p) display different regulatory roles on migration, proliferation and neuron differentiation of MSCs. MiR124 was shown greatly promoting MSCs migration and neuronal differentiation. MiR21-5p could significantly enhance the proliferation and neuronal differentiation ability of MSCs. MiR124 and miR21-5p synergistically promote differentiation of MSCs into neurons. Collectively, miR124 and miR21-5p can functionally regulate cell migration, proliferation and neuronal differentiation of MSCs. Therefore, miR124 and miR21-5p may be promising tools to improve transplantation efficiency for neural injury.
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12
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Abstract
Traumatic spinal cord injury (SCI) results in direct and indirect damage to neural tissues, which results in motor and sensory dysfunction, dystonia, and pathological reflex that ultimately lead to paraplegia or tetraplegia. A loss of cells, axon regeneration failure, and time-sensitive pathophysiology make tissue repair difficult. Despite various medical developments, there are currently no effective regenerative treatments. Stem cell therapy is a promising treatment for SCI due to its multiple targets and reactivity benefits. The present review focuses on SCI stem cell therapy, including bone marrow mesenchymal stem cells, umbilical mesenchymal stem cells, adipose-derived mesenchymal stem cells, neural stem cells, neural progenitor cells, embryonic stem cells, induced pluripotent stem cells, and extracellular vesicles. Each cell type targets certain features of SCI pathology and shows therapeutic effects via cell replacement, nutritional support, scaffolds, and immunomodulation mechanisms. However, many preclinical studies and a growing number of clinical trials found that single-cell treatments had only limited benefits for SCI. SCI damage is multifaceted, and there is a growing consensus that a combined treatment is needed.
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Affiliation(s)
- Liyi Huang
- Department of Rehabilitation Medicine Center, 34753West China Hospital/West China School of Medicine, Sichuan University, Chengdu, Sichuan, PR China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Sichuan University, Chengdu, Sichuan Province, PR China
| | - Chenying Fu
- State Key Laboratory of Biotherapy, 34753West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Feng Xiong
- Department of Rehabilitation Medicine Center, 34753West China Hospital/West China School of Medicine, Sichuan University, Chengdu, Sichuan, PR China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Sichuan University, Chengdu, Sichuan Province, PR China
| | - Chengqi He
- Department of Rehabilitation Medicine Center, 34753West China Hospital/West China School of Medicine, Sichuan University, Chengdu, Sichuan, PR China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Sichuan University, Chengdu, Sichuan Province, PR China
| | - Quan Wei
- Department of Rehabilitation Medicine Center, 34753West China Hospital/West China School of Medicine, Sichuan University, Chengdu, Sichuan, PR China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Sichuan University, Chengdu, Sichuan Province, PR China
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13
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Emerging role of microRNAs in ischemic stroke with comorbidities. Exp Neurol 2020; 331:113382. [DOI: 10.1016/j.expneurol.2020.113382] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/07/2020] [Accepted: 06/14/2020] [Indexed: 02/06/2023]
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14
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mRNA Profiling for miR-124-mediated Repair in Spinal Cord Injury. Neuroscience 2020; 438:158-168. [DOI: 10.1016/j.neuroscience.2020.05.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 01/01/2023]
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15
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Qian K, Xu TY, Wang X, Ma T, Zhang KX, Yang K, Qian TD, Shi J, Li LX, Wang Z. Effects of neural stem cell transplantation on the motor function of rats with contusion spinal cord injuries: a meta-analysis. Neural Regen Res 2020; 15:748-758. [PMID: 31638100 PMCID: PMC6975148 DOI: 10.4103/1673-5374.266915] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Objective To judge the efficacies of neural stem cell (NSC) transplantation on functional recovery following contusion spinal cord injuries (SCIs). Data sources Studies in which NSCs were transplanted into a clinically relevant, standardized rat model of contusion SCI were identified by searching the PubMed, Embase and Cochrane databases, and the extracted data were analyzed by Stata 14.0. Data selection Inclusion criteria were that NSCs were used in in vivo animal studies to treat contusion SCIs and that behavioral assessment of locomotor functional recovery was performed using the Basso, Beattie, and Bresnahan lo-comotor rating scale. Exclusion criteria included a follow-up of less than 4 weeks and the lack of control groups. Outcome measures The restoration of motor function was assessed by the Basso, Beattie, and Bresnahan locomotor rating scale. Results We identified 1756 non-duplicated papers by searching the aforementioned electronic databases, and 30 full-text articles met the inclusion criteria. A total of 37 studies reported in the 30 articles were included in the meta-analysis. The meta-analysis results showed that transplanted NSCs could improve the motor function recovery of rats following contusion SCIs, to a moderate extent (pooled standardized mean difference (SMD) = 0.73; 95% confidence interval (CI): 0.47-1.00; P < 0.001). NSCs obtained from different donor species (rat: SMD = 0.74; 95% CI: 0.36-1.13; human: SMD = 0.78; 95% CI: 0.31-1.25), at different donor ages (fetal: SMD = 0.67; 95% CI: 0.43-0.92; adult: SMD = 0.86; 95% CI: 0.50-1.22) and from different origins (brain-derived: SMD = 0.59; 95% CI: 0.27-0.91; spinal cord-derived: SMD = 0.51; 95% CI: 0.22-0.79) had similar efficacies on improved functional recovery; however, adult induced pluripotent stem cell-derived NSCs showed no significant efficacies. Furthermore, the use of higher doses of transplanted NSCs or the administration of immunosuppressive agents did not promote better locomotor function recovery (SMD = 0.45; 95% CI: 0.21-0.70). However, shorter periods between the contusion induction and the NSC transplantation showed slightly higher efficacies (acute: SMD = 1.22; 95% CI: 0.81-1.63; subacute: SMD = 0.75; 95% CI: 0.42-1.09). For chronic injuries, NSC implantation did not significantly improve functional recovery (SMD = 0.25; 95% CI: -0.16 to 0.65). Conclusion NSC transplantation alone appears to be a positive yet limited method for the treatment of contusion SCIs.
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Affiliation(s)
- Kai Qian
- Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Tuo-Ye Xu
- Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xi Wang
- Department of Intensive Care Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Tao Ma
- Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing; Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Kai-Xin Zhang
- Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province; Department of Neurosurgery, Huangshan City People's Hospital, Huangshan, Anhui Province, China
| | - Kun Yang
- Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University; Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Teng-Da Qian
- Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing; Department of Neurosurgery, Jintan Hospital Affiliated to Jiangsu University, Jintan, Jiangsu Province, China
| | - Jing Shi
- Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Li-Xin Li
- Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zheng Wang
- Department of Gerontology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
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16
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Cui Y, Yin Y, Xiao Z, Zhao Y, Chen B, Yang B, Xu B, Song H, Zou Y, Ma X, Dai J. LncRNA Neat1 mediates miR-124-induced activation of Wnt/β-catenin signaling in spinal cord neural progenitor cells. Stem Cell Res Ther 2019; 10:400. [PMID: 31852544 PMCID: PMC6921476 DOI: 10.1186/s13287-019-1487-3] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 10/04/2019] [Accepted: 11/05/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Emerging evidence suggests that miR-124 performs important biological functions in neural stem cells (NSCs); it regulates NSC behavior and promotes the differentiation of NSCs into neurons, but the exact molecular mechanism remains unknown. And also, the role of miR-124 during spinal cord injury regeneration is unclear. MATERIALS AND METHODS In order to explore the function of miR-124 in neural differentiation, the molecular markers (Tuj1, Map2, and GFAP) correlated with the differentiation of NSCs were detected by immunofluorescence staining both in cultured mouse spinal cord progenitor cells (SC-NPCs) and in spinal cord injury (SCI) animal models. The migration ability and apoptosis of cultured SC-NPCs were also evaluated by Transwell migration assay and TUNEL assay. In addition, the relative expression of lnRNA Neat1- and Wnt/β-catenin signaling-related genes were detected by quantitative real-time PCR. RESULTS In this study, we revealed that lncRNA Neat1 is involved in regulating Wnt/β-catenin signaling that is activated by miR-124 in SC-NPCs. LncRNA Neat1 was also found to play an important role in regulating neuronal differentiation, apoptosis, and migration of SC-NPCs. Furthermore, we demonstrated that overexpression of miR-124 resulted in elevated Neat1 expression, accompanied with the functional recovery of locomotion in a mouse model of spinal cord injury. CONCLUSIONS Our results confirm the therapeutic effectiveness of miR-124 on the functional recovery of injured spinal cord, supporting the rationale and feasibility of miR-124 for spinal cord injury treatment in future clinical therapy. Furthermore, we concluded that the miR-124-Neat1-Wnt/β-catenin signaling axis is involved in regulating the cell function of SC-NPCs, and this may offer novel therapeutic avenues for future treatment of SCI.
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Affiliation(s)
- Yi Cui
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, 100081, China
| | - Yanyun Yin
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing, 100080, China
| | - Zhifeng Xiao
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing, 100080, China
| | - Yannan Zhao
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing, 100080, China
| | - Bing Chen
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing, 100080, China
| | - Bin Yang
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing, 100080, China
| | - Bai Xu
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing, 100080, China
| | - Hongwei Song
- Orthopaedics Surgery Department, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun, 130033, Jilin Province, China
| | - Yunlong Zou
- EHBIO Gene Technology, No. 46, Jiugulou Street, Beijing, 100100, China
| | - Xu Ma
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, 100081, China.
| | - Jianwu Dai
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing, 100080, China.
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17
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Xu Z, Zhang K, Wang Q, Zheng Y. MicroRNA‑124 improves functional recovery and suppresses Bax‑dependent apoptosis in rats following spinal cord injury. Mol Med Rep 2019; 19:2551-2560. [PMID: 30720072 PMCID: PMC6423616 DOI: 10.3892/mmr.2019.9904] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 01/14/2019] [Indexed: 12/15/2022] Open
Abstract
Spinal cord injury (SCI) induces aberrant expression of microRNAs (miRNAs), causing various secondary injury responses, including inflammation, apoptosis and oxidative stress. However, the mechanisms underlying miRNA-mediated apoptosis have not been fully elucidated. In the present study, a rat SCI model was established and a miRNA microarray was analyzed to detect miRNA expression profiles at different times post-SCI. The Basso, Beattie and Bresnahan score, cresyl violet staining and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling staining were used to evaluate locomotor activity, lesion volume and neuronal cell apoptosis, respectively, at different time points post-SCI. It was observed that numerous miRNAs were altered at 14 days post-SCI and miR-124 was one of the most notably downregulated miRNAs. The present results demonstrated that overexpression of miR-124 by agomir-124 improves functional recovery, decreases lesion size and suppresses neuronal cell apoptosis in a rat SCI model. Luciferase reporter assay demonstrated that miR-124 inhibited apoptosis regulator BAX (Bax) expression, a key molecule in the activation of the mitochondrial apoptotic pathway, by targeting its 3′-untranslated region in BV-2 cells. Furthermore, restoration of Bax by pc-DNA-Bax inhibits the protective effect of miR-124 in H2O2-treated BV-2 cells. Notably, the present results demonstrated that miR-124 may block the mitochondrial apoptotic pathway by inhibiting Bax, cleaved-caspase-9 and cleaved-caspase-3 expression in rats following SCI. Collectively, the present results suggested that miR-124 may improve functional recovery and supress neuronal cell apoptosis by blocking the mitochondrial apoptotic pathway in SCI rats, suggesting that miR-124 may serve as a potential therapeutic target in SCI treatment.
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Affiliation(s)
- Zhongyang Xu
- Department of Orthopedics, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Kefeng Zhang
- Department of Orthopedics, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Qian Wang
- Department of Orthopedics, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Yanping Zheng
- Department of Orthopedics, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
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18
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Gong G, Gu Y, Zhang Y, Liu W, Li L, Li J. RETRACTED: Tanshinone IIA alleviates oxidative damage after spinal cord injury in vitro and in vivo through up-regulating miR-124. Life Sci 2018; 216:147-155. [PMID: 30468834 DOI: 10.1016/j.lfs.2018.11.046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 11/19/2018] [Accepted: 11/20/2018] [Indexed: 12/21/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).
This article has been retracted at the request of the Corresponding Author with the agreement of the editor.
The authors used DMSO (dimethyl sulfoxide) to dissolve tanshinone IIA in this experiment, but even after dilution, DMSO also can induce toxicity of PC12 cells, which also can affect the result of the experiment. After discussion, the authors found that sulfotanshinone sodium injection can be used to replace tanshinone II A, which is both an aqueous solution and has been clinically proved to be an ideal substitute.
Further, in error, the authors used 0μM /12.5μM /50μM /100μM /200μM H2O2 to stimulate oxidative injury as in figure 1A, but missed 25μM H2O2, which may also affect the experimental results.
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Affiliation(s)
- Gu Gong
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun130033, Jilin, China
| | - Yiqi Gu
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun130033, Jilin, China
| | - Yunfeng Zhang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun130033, Jilin, China
| | - Wanguo Liu
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun130033, Jilin, China
| | - Li Li
- Department of Physiology, School of Basic Medical Sciences, Shenzhen University Health Sciences Center, Shenzhen518060, China
| | - Juan Li
- School of Public Health Jilin University, Changchun130021, Jilin, China.
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19
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Abstract
Central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), are important causes of death and long-term disability worldwide. MicroRNA (miRNA), small non-coding RNA molecules that negatively regulate gene expression, can serve as diagnostic biomarkers and are emerging as novel therapeutic targets for CNS injuries. MiRNA-based therapeutics include miRNA mimics and inhibitors (antagomiRs) to respectively decrease and increase the expression of target genes. In this review, we summarize current miRNA-based therapeutic applications in stroke, TBI and SCI. Administration methods, time windows and dosage for effective delivery of miRNA-based drugs into CNS are discussed. The underlying mechanisms of miRNA-based therapeutics are reviewed including oxidative stress, inflammation, apoptosis, blood-brain barrier protection, angiogenesis and neurogenesis. Pharmacological agents that protect against CNS injuries by targeting specific miRNAs are presented along with the challenges and therapeutic potential of miRNA-based therapies.
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Affiliation(s)
- Ping Sun
- Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Da Zhi Liu
- Department of Neurology and the M.I.N.D. Institute, University of California at Davis, Sacramento, CA, USA
| | - Glen C Jickling
- Department of Neurology, University of Alberta, Edmonton, Alberta, Canada
| | - Frank R Sharp
- Department of Neurology and the M.I.N.D. Institute, University of California at Davis, Sacramento, CA, USA
| | - Ke-Jie Yin
- Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Ke-Jie Yin, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, 200 Lothrop Street, BST S514, Pittsburgh, PA 15213, USA. Da Zhi Liu, Department of Neurology, University of California at Davis, Sacramento, CA 95817, USA.
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20
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Cui Y, Han J, Xiao Z, Qi Y, Zhao Y, Chen B, Fang Y, Liu S, Wu X, Dai J. Systematic Analysis of mRNA and miRNA Expression of 3D-Cultured Neural Stem Cells (NSCs) in Spaceflight. Front Cell Neurosci 2018; 11:434. [PMID: 29375320 PMCID: PMC5768636 DOI: 10.3389/fncel.2017.00434] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 12/26/2017] [Indexed: 12/16/2022] Open
Abstract
Recently, with the development of the space program there are growing concerns about the influence of spaceflight on tissue engineering. The purpose of this study was thus to determine the variations of neural stem cells (NSCs) during spaceflight. RNA-Sequencing (RNA-Seq) based transcriptomic profiling of NSCs identified many differentially expressed mRNAs and miRNAs between space and earth groups. Subsequently, those genes with differential expression were subjected to bioinformatic evaluation using gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) and miRNA-mRNA network analyses. The results showed that NSCs maintain greater stemness ability during spaceflight although the growth rate of NSCs was slowed down. Furthermore, the results indicated that NSCs tended to differentiate into neuron in outer space conditions. Detailed genomic analyses of NSCs during spaceflight will help us to elucidate the molecular mechanisms behind their differentiation and proliferation when they are in outer space.
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Affiliation(s)
- Yi Cui
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China
| | - Jin Han
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Zhifeng Xiao
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Yiduo Qi
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Yannan Zhao
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Bing Chen
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Yongxiang Fang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Sumei Liu
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Xianming Wu
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Jianwu Dai
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
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21
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Huang L, Wang G. The Effects of Different Factors on the Behavior of Neural Stem Cells. Stem Cells Int 2017; 2017:9497325. [PMID: 29358957 PMCID: PMC5735681 DOI: 10.1155/2017/9497325] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 10/18/2017] [Indexed: 02/07/2023] Open
Abstract
The repair of central nervous system (CNS) injury has been a worldwide problem in the biomedical field. How to reduce the damage to the CNS and promote the reconstruction of the damaged nervous system structure and function recovery has always been the concern of nerve tissue engineering. Multiple differentiation potentials of neural stem cell (NSC) determine the application value for the repair of the CNS injury. Thus, how to regulate the behavior of NSCs becomes the key to treating the CNS injury. So far, a large number of researchers have devoted themselves to searching for a better way to regulate the behavior of NSCs. This paper summarizes the effects of different factors on the behavior of NSCs in the past 10 years, especially on the proliferation and differentiation of NSCs. The final purpose of this review is to provide a more detailed theoretical basis for the clinical repair of the CNS injury by nerve tissue engineering.
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Affiliation(s)
- Lixiang Huang
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan 410073, China
| | - Gan Wang
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan 410073, China
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22
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Epigenetic regulation of neural stem cell differentiation towards spinal cord regeneration. Cell Tissue Res 2017; 371:189-199. [PMID: 28695279 DOI: 10.1007/s00441-017-2656-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 05/31/2017] [Indexed: 12/20/2022]
Abstract
Severe spinal cord injury (SCI) leads to almost complete neural cell loss at the injured site, causing the irreversible disruption of neuronal circuits. The transplantation of neural stem or precursor cells (NS/PCs) has been regarded as potentially effective for SCI treatment because NS/PCs can compensate for the injured sites by differentiating into neurons and glial cells (astrocytes and oligodendrocytes). An understanding of the molecular mechanisms that regulate the proliferation, fate specification and maturation of NS/PCs and their progeny would facilitate the establishment of better therapeutic strategies for regeneration after SCI. In recent years, several studies of SCI animal models have demonstrated that the modulation of specific epigenetic marks by histone modifiers and non-coding RNAs directs the setting of favorable cellular environments that promote the neuronal differentiation of NS/PCs and/or the elongation of the axons of the surviving neurons at the injured sites. In this review, we provide an overview of recent progress in the epigenetic regulation/manipulation of neural cells for the treatment of SCI.
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Abstract
Spinal cord injury (SCI) represents one of the most complicated and heterogeneous pathological processes of central nervous system (CNS) impairments, which is still beyond functional regeneration. Transplantation of mesenchymal stem cells (MSCs) has been shown to promote the repair of the injured spinal cord tissues in animal models, and therefore, there is much interest in the clinical use of these cells. However, many questions which are essential to improve the therapy effects remain unanswered. For instance, the functional roles and related molecular regulatory mechanisms of MSCs in vivo are not yet completely determined. It is important for transplanted cells to migrate into the injured tissue, to survive and undergo neural differentiation, or to play neural protection roles by various mechanisms after SCI. In this review, we will focus on some of the recent knowledge about the biological behavior and function of MSCs in SCI. Meanwhile, we highlight the function of biomaterials to direct the behavior of MSCs based on our series of work on silk fibroin biomaterials and attempt to emphasize combinational strategies such as tissue engineering for functional improvement of SCI.
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A causal relationship between the neurotherapeutic effects of miR182/7a and decreased expression of PRDM5. Biochem Biophys Res Commun 2017; 490:1-7. [PMID: 28552531 DOI: 10.1016/j.bbrc.2017.05.141] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 05/10/2017] [Accepted: 05/24/2017] [Indexed: 11/23/2022]
Abstract
BACKGROUND Spinal cord injury (SCI) is terrible damage resulting in the deficiencies and necrosis of neurology and causes infinite inconvenience to sufferers. The therapy of SCI still meets a larger number of problems. Therefore, the underlying mechanism and novel therapy of acute SCI (ASCI) are urgent to explore. MATERIALS AND METHODS The SCI model was established in rats. The expression of miR-182/miR-7a and PRDM5 at mRNA level was detected by quantitative real-time PCR and the protein expression of PRDM5 and c-caspase 3 was assessed by western blotting assays. The apoptosis of spinal cord neurons (SCN) was assessed on flow cytometry. The transfection of cells was performed by Lipofectamine 2000 kit. The relationship between PRDM5 and miR-182/miR-7a was examined by Luciferase assay. RESULTS The expression of PRDM5 was up-regulated at either mRNA (2.212 folds) or protein level after SCI in rats, and knockdown of PRDM5 in SCN declined the c-caspase3 expression. In addition, the expression of miR-182 and miR-7a was decreased by 44.6% and 39.3% after SCI in rats. Moreover, the expression of miR-182 and miR-7a were negatively correlated with the level of PRDM5 expression, and the expression of PRDM5 was inhibited due to the increase of miR-182 and/or miR-7a expression. Moreover, both miR-182 and miR-7a could regulate PRDM5 to control SCN apoptosis. According to the BBB score increased 2 folds, the intrathecal injection of miR-182 and miR-7a improved the neurological function of rats. CONCLUSION Inhibition of PRDM5 which was apparently negative correlation with miR-182 and miR-7a could suppress the neurons apoptosis to attenuate acute spinal cord injury in rats.
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Song JL, Zheng W, Chen W, Qian Y, Ouyang YM, Fan CY. Lentivirus-mediated microRNA-124 gene-modified bone marrow mesenchymal stem cell transplantation promotes the repair of spinal cord injury in rats. Exp Mol Med 2017; 49:e332. [PMID: 28524176 PMCID: PMC5454445 DOI: 10.1038/emm.2017.48] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 12/02/2016] [Accepted: 12/09/2016] [Indexed: 12/16/2022] Open
Abstract
Our study aims to explore the effects of lentivirus-mediated microRNA-124 (miR-124) gene-modified bone marrow mesenchymal stem cell (BMSC) transplantation on the repair of spinal cord injury (SCI) in rats. BMSCs were isolated from the bone marrow of rats. The target gene miR-124 was identified using a luciferase-reporter gene assay. Seventy-two rats were selected for construction of the SCI model, and the rats were randomly divided into the blank group, sham group, SCI group, negative control (NC) group, overexpressed miR-124 group and si-PDXK group. The mRNA expression of miR-124 and the mRNA and protein expression of pyridoxal kinase (PDXK) were detected by quantitative real-time polymerase chain reaction and western blotting. The locomotor capacity of the rats was evaluated using the Basso, Beattie and Bresnahan (BBB) scale. Brdu, neuron-specific enolase (NSE), neurofilament (NF) and microtubule-associated protein 2 (MAP2) were detected using immunohistochemistry. The expression levels of thyrotropin-releasing hormone (TRH), prostacyclin (PGI2) and gangliosides (GM) were measured using an enzyme-linked immunosorbent assay. PDXK was identified as the target gene of miR-124. The overexpressed miR-124 group exhibited higher miR-124 expression than the SCI, NC and si-PDXK groups. Compared with the SCI and NC groups, the PDXK expression was downregulated in the overexpressed miR-124 and si-PDXK groups, and the BBB scores were significantly increased 7, 21 and 35 days after transplantation. The double-labeled positive cell densities (Brdu+NSE/NF/MAP2) and the expression levels of TRH, PGI2 and GM in the overexpressed miR-124 group were significantly higher than those in the NC and SCI groups. These results indicated that miR-124 targeted PDXK to accelerate the differentiation of BMSCs into neurocytes and promote SCI repair.
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Affiliation(s)
- Jia-Lin Song
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wei Zheng
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wei Chen
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yun Qian
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yuan-Ming Ouyang
- Department of Orthopedics, The East Campus of Shanghai Sixth People's Hospital, Shanghai University of Medical and Health, Shanghai, China
| | - Cun-Yi Fan
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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26
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Martirosyan NL, Carotenuto A, Patel AA, Kalani MYS, Yagmurlu K, Lemole GM, Preul MC, Theodore N. The Role of microRNA Markers in the Diagnosis, Treatment, and Outcome Prediction of Spinal Cord Injury. Front Surg 2016; 3:56. [PMID: 27878119 PMCID: PMC5099153 DOI: 10.3389/fsurg.2016.00056] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 09/29/2016] [Indexed: 12/14/2022] Open
Abstract
Spinal cord injury (SCI) is a devastating condition that affects many people worldwide. Treatment focuses on controlling secondary injury cascade and improving regeneration. It has recently been suggested that both the secondary injury cascade and the regenerative process are heavily regulated by microRNAs (miRNAs). The measurement of specific biomarkers could improve our understanding of the disease processes, and thereby provide clinicians with the opportunity to guide treatment and predict clinical outcomes after SCI. A variety of miRNAs exhibit important roles in processes of inflammation, cell death, and regeneration. These miRNAs can be used as diagnostic tools for predicting outcome after SCI. In addition, miRNAs can be used in the treatment of SCI and its symptoms. Significant laboratory and clinical evidence exist to show that miRNAs could be used as robust diagnostic and therapeutic tools for the treatment of patients with SCI. Further clinical studies are warranted to clarify the importance of each subtype of miRNA in SCI management.
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Affiliation(s)
- Nikolay L Martirosyan
- Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA; Division of Neurosurgery, University of Arizona, Tucson, AZ, USA
| | | | - Arpan A Patel
- College of Medicine - Phoenix, University of Arizona , Phoenix, AZ , USA
| | - M Yashar S Kalani
- Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center , Phoenix, AZ , USA
| | - Kaan Yagmurlu
- Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center , Phoenix, AZ , USA
| | - G Michael Lemole
- Division of Neurosurgery, University of Arizona , Tucson, AZ , USA
| | - Mark C Preul
- Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center , Phoenix, AZ , USA
| | - Nicholas Theodore
- Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center , Phoenix, AZ , USA
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Zhou S, Ding F, Gu X. Non-coding RNAs as Emerging Regulators of Neural Injury Responses and Regeneration. Neurosci Bull 2016; 32:253-64. [PMID: 27037691 DOI: 10.1007/s12264-016-0028-7] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 03/14/2016] [Indexed: 02/06/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are a large cluster of RNAs that do not encode proteins, but have multiple functions in diverse cellular processes. Mounting evidence indicates the involvement of ncRNAs in the physiology and pathophysiology of the central and peripheral nervous systems. It has been shown that numerous ncRNAs, especially microRNAs and long non-coding RNAs, are differentially expressed after insults such as acquired brain injury, spinal cord injury, and peripheral nerve injury. These ncRNAs affect neuronal survival, neurite regrowth, and glial phenotype primarily by targeting specific mRNAs, resulting in translation repression or degradation of the mRNAs. An increasing number of studies have investigated the regulatory roles of microRNAs and long non-coding RNAs in neural injury and regeneration, and thus a new research field is emerging. In this review, we highlight current progress in the field in an attempt to provide further insight into post-transcriptional changes occurring after neural injury, and to facilitate the potential use of ncRNAs for improving neural regeneration. We also suggest potential directions for future studies.
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Affiliation(s)
- Songlin Zhou
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China
| | - Fei Ding
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China
| | - Xiaosong Gu
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
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28
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Tenga A, Beard JA, Takwi A, Wang YM, Chen T. Regulation of Nuclear Receptor Nur77 by miR-124. PLoS One 2016; 11:e0148433. [PMID: 26840408 PMCID: PMC4739595 DOI: 10.1371/journal.pone.0148433] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 01/18/2016] [Indexed: 01/26/2023] Open
Abstract
The nuclear receptor Nur77 is commonly upregulated in adult cancers and has oncogenic functions. Nur77 is an immediate-early response gene that acts as a transcription factor to promote proliferation and protect cells from apoptosis. Conversely, Nur77 can translocate to the mitochondria and induce apoptosis upon treatment with various cytotoxic agents. Because Nur77 is upregulated in cancer and may have a role in cancer progression, it is of interest to understand the mechanism controlling its expression. MicroRNAs (miRNAs) are responsible for inhibiting translation of their target genes by binding to the 3'UTR and either degrading the mRNA or preventing it from being translated into protein, thereby making these non-coding endogenous RNAs vital regulators of every cellular process. Several miRNAs have been predicted to target Nur77; however, strong evidence showing the regulation of Nur77 by any miRNA is lacking. In this study, we used a luciferase reporter assay containing the 3'UTR of Nur77 to screen 296 miRNAs and found that miR-124, which is the most abundant miRNA in the brain and has a role in promoting neuronal differentiation, caused the greatest reduction in luciferase activity. Interestingly, we discovered an inverse relationship in Daoy medulloblastoma cells and undifferentiated granule neuron precursors in which Nur77 is upregulated and miR-124 is downregulated. Exogenous expression to further elevate Nur77 levels in Daoy cells increased proliferation and viability, but knocking down Nur77 via siRNA resulted in the opposite phenotype. Importantly, exogenous expression of miR-124 reduced Nur77 expression, cell viability, proliferation, and tumor spheroid size in 3D culture. In all, we have discovered miR-124 to be downregulated in instances of medulloblastoma in which Nur77 is upregulated, resulting in a proliferative state that abets cancer progression. This study provides evidence for increasing miR-124 expression as a potential therapy for cancers with elevated levels of Nur77.
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MESH Headings
- 3' Untranslated Regions
- Cell Line, Tumor
- Cell Proliferation
- Cell Survival/genetics
- Gene Expression Regulation, Neoplastic
- Humans
- Medulloblastoma/genetics
- Medulloblastoma/metabolism
- Medulloblastoma/pathology
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Mitochondria/genetics
- Mitochondria/metabolism
- Mitochondria/pathology
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
- Protein Transport
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Spheroids, Cellular/metabolism
- Spheroids, Cellular/pathology
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Affiliation(s)
- Alexa Tenga
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, United States of America
- Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, United States of America
| | - Jordan A. Beard
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, United States of America
- Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, United States of America
| | - Apana Takwi
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, United States of America
| | - Yue-Ming Wang
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, United States of America
| | - Taosheng Chen
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, United States of America
- Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, United States of America
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29
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Yu B, Zhou S, Yi S, Gu X. The regulatory roles of non-coding RNAs in nerve injury and regeneration. Prog Neurobiol 2015; 134:122-39. [PMID: 26432164 DOI: 10.1016/j.pneurobio.2015.09.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 08/20/2015] [Accepted: 09/05/2015] [Indexed: 12/16/2022]
Abstract
Non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have attracted much attention since their regulatory roles in diverse cell processes were recognized. Emerging studies demonstrate that many ncRNAs are differentially expressed after injury to the nervous system, significantly affecting nerve regeneration. In this review, we compile the miRNAs and lncRNAs that have been reported to be dysregulated following a variety of central and peripheral nerve injuries, including acquired brain injury, spinal cord injury, and peripheral nerve injury. We also list investigations on how these miRNAs and lncRNAs exert the regulatory actions in neurodegenerative and neuroregenerative processes through different mechanisms involving their interaction with target coding genes. We believe that comprehension of the expression profiles and the possible functions of ncRNAs during the processes of nerve injury and regeneration will help understand the molecular mechanisms responsible for post-nerve-injury changes, and may contribute to the potential use of ncRNAs as a diagnostic marker and therapeutic target for nerve injury.
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Affiliation(s)
- Bin Yu
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Songlin Zhou
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Sheng Yi
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Xiaosong Gu
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China.
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30
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Zhao Y, Zhang H, Zhang D, Yu CY, Zhao XH, Liu FF, Bian GL, Ju G, Wang J. Loss of microRNA-124 expression in neurons in the peri-lesion area in mice with spinal cord injury. Neural Regen Res 2015; 10:1147-52. [PMID: 26330841 PMCID: PMC4541249 DOI: 10.4103/1673-5374.156983] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2015] [Indexed: 12/21/2022] Open
Abstract
MicroRNA-124 (miR-124) is abundantly expressed in neurons in the mammalian central nervous system, and plays critical roles in the regulation of gene expression during embryonic neurogenesis and postnatal neural differentiation. However, the expression profile of miR-124 after spinal cord injury and the underlying regulatory mechanisms are not well understood. In the present study, we examined the expression of miR-124 in mouse brain and spinal cord after spinal cord injury using in situ hybridization. Furthermore, the expression of miR-124 was examined with quantitative RT-PCR at 1, 3 and 7 days after spinal cord injury. The miR-124 expression in neurons at the site of injury was evaluated by in situ hybridization combined with NeuN immunohistochemical staining. The miR-124 was mainly expressed in neurons throughout the brain and spinal cord. The expression of miR-124 in neurons significantly decreased within 7 days after spinal cord injury. Some of the neurons in the peri-lesion area were NeuN(+)/miR-124(-). Moreover, the neurons distal to the peri-lesion site were NeuN(+)/miR-124(+). These findings indicate that miR-124 expression in neurons is reduced after spinal cord injury, and may reflect the severity of spinal cord injury.
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Affiliation(s)
- Yu Zhao
- Department of Anatomy, Hebei North University, Zhangjiakou, Hebei Province, China
| | - Hui Zhang
- Department of Anatomy, Hebei North University, Zhangjiakou, Hebei Province, China
| | - Dan Zhang
- Department of Stomatology, the First Hospital of Zhangjiakou, Zhangjiakou, Hebei Province, China
| | - Cai-yong Yu
- Institute of Neurosciences, the Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Xiang-hui Zhao
- Institute of Neurosciences, the Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Fang-fang Liu
- Institute of Neurosciences, the Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Gan-lan Bian
- Institute of Neurosciences, the Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Gong Ju
- Institute of Neurosciences, the Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Jian Wang
- Institute of Neurosciences, the Fourth Military Medical University, Xi’an, Shaanxi Province, China
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31
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Schomberg D, Miranpuri G, Duellman T, Crowell A, Vemuganti R, Resnick D. Spinal cord injury induced neuropathic pain: Molecular targets and therapeutic approaches. Metab Brain Dis 2015; 30:645-58. [PMID: 25588751 DOI: 10.1007/s11011-014-9642-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 12/05/2014] [Indexed: 10/24/2022]
Abstract
Neuropathic pain, especially that resulting from spinal cord injury, is a tremendous clinical challenge. A myriad of biological changes have been implicated in producing these pain states including cellular interactions, extracellular proteins, ion channel expression, and epigenetic influences. Physiological consequences of these changes are varied and include functional deficits and pain responses. Developing therapies that effectively address the cause of these symptoms require a deeper knowledge of alterations in the molecular pathways. Matrix metalloproteinases and tissue inhibitors of metalloproteinases are two promising therapeutic targets. Matrix metalloproteinases interact with and influence many of the studied pain pathways. Gene expression of ion channels and inflammatory mediators clearly contributes to neuropathic pain. Localized and time dependent targeting of these proteins could alleviate and even prevent neuropathic pain from developing. Current therapeutic options for neuropathic pain are limited primarily to analgesics targeting the opioid pathway. Therapies directed at molecular targets are highly desirable and in early stages of development. These include transplantation of exogenously engineered cell populations and targeted gene manipulation. This review describes specific molecular targets amenable to therapeutic intervention using currently available delivery systems.
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Affiliation(s)
- Dominic Schomberg
- Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, Madison, WI, 53792, USA
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32
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Lepp AC, Carlone RL. RARβ2 expression is induced by the down-regulation of microRNA 133a during caudal spinal cord regeneration in the adult newt. Dev Dyn 2014; 243:1581-90. [DOI: 10.1002/dvdy.24210] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Revised: 09/15/2014] [Accepted: 09/20/2014] [Indexed: 11/09/2022] Open
Affiliation(s)
- A. C. Lepp
- Department of Biological Sciences; Brock University; St. Catharines Ontario Canada
| | - R. L. Carlone
- Department of Biological Sciences; Brock University; St. Catharines Ontario Canada
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33
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Zou D, Chen Y, Han Y, Lv C, Tu G. Overexpression of microRNA-124 promotes the neuronal differentiation of bone marrow-derived mesenchymal stem cells. Neural Regen Res 2014; 9:1241-8. [PMID: 25206789 PMCID: PMC4146284 DOI: 10.4103/1673-5374.135333] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2014] [Indexed: 12/21/2022] Open
Abstract
microRNAs (miRNAs) play an important regulatory role in the self-renewal and differentiation of stem cells. In this study, we examined the effects of miRNA-124 (miR-124) overexpression in bone marrow-derived mesenchymal stem cells. In particular, we focused on the effect of overexpression on the differentiation of bone marrow-derived mesenchymal stem cells into neurons. First, we used GeneChip technology to analyze the expression of miRNAs in bone marrow-derived mesenchymal stem cells, neural stem cells and neurons. miR-124 expression was substantially reduced in bone marrow-derived mesenchymal stem cells compared with the other cell types. We constructed a lentiviral vector overexpressing miR-124 and transfected it into bone marrow-derived mesenchymal stem cells. Intracellular expression levels of the neuronal early markers β-III tubulin and microtubule-associated protein-2 were significantly increased, and apoptosis induced by oxygen and glucose deprivation was reduced in transfected cells. After miR-124-transfected bone marrow-derived mesenchymal stem cells were transplanted into the injured rat spinal cord, a large number of cells positive for the neuronal marker neurofilament-200 were observed in the transplanted region. The Basso-Beattie-Bresnahan locomotion scores showed that the motor function of the hind limb of rats with spinal cord injury was substantially improved. These results suggest that miR-124 plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells into neurons. Our findings should facilitate the development of novel strategies for enhancing the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation for spinal cord injury.
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Affiliation(s)
- Defeng Zou
- Department of Orthopedics, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yi Chen
- Department of Orthopedics, Jinhua Central Hospital of Zhejiang University, Jinhua, Zhejiang Province, China
| | - Yaxin Han
- Department of Orthopedics, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Chen Lv
- Department of Orthopedics, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Guanjun Tu
- Department of Orthopedics, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
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34
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Zhang R, Zhang K, Li J, Liu Q, Xie J. In vivo tracking of neuronal-like cells by magnetic resonance in rabbit models of spinal cord injury. Neural Regen Res 2014; 8:3373-81. [PMID: 25206659 PMCID: PMC4146005 DOI: 10.3969/j.issn.1673-5374.2013.36.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Accepted: 11/17/2013] [Indexed: 01/25/2023] Open
Abstract
In vitro experiments have demonstrated that neuronal-like cells derived from bone marrow mesenchymal stem cells can survive, migrate, integrate and help to restore the function and behaviors of spinal cord injury models, and that they may serve as a suitable approach to treating spinal cord injury. However, it is very difficult to track transplanted cells in vivo. In this study, we injected superparamagnetic iron oxide-labeled neuronal-like cells into the subarachnoid space in a rabbit model of spinal cord injury. At 7 days after cell transplantation, a small number of dot-shaped low signal intensity shadows were observed in the spinal cord injury region, and at 14 days, the number of these shadows increased on T2-weighted imaging. Perl's Prussian blue staining detected dot-shaped low signal intensity shadows in the spinal cord injury region, indicative of superparamagnetic iron oxide nanoparticle-labeled cells. These findings suggest that transplanted neuronal-like cells derived from bone marrow mesenchymal stem cells can migrate to the spinal cord injury region and can be tracked by magnetic resonance in vivo. Magnetic resonance imaging represents an efficient noninvasive technique for visually tracking transplanted cells in vivo.
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Affiliation(s)
- Ruiping Zhang
- Department of Radiology, First Hospital, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Kun Zhang
- Department of Radiology, Medical Imaging Centre, Navy General Hospital, Beijing 100048, China
| | - Jianding Li
- Department of Radiology, First Hospital, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Qiang Liu
- Department of Orthopedics, Shanxi Dayi Hospital, Taiyuan 030032, Shanxi Province, China
| | - Jun Xie
- Department of Molecular Biology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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35
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Gao WL, Tian F, Zhang SQ, Zhang H, Yin ZS. Epidermal growth factor increases the expression of Nestin in rat reactive astrocytes through the Ras–Raf–ERK pathway. Neurosci Lett 2014; 562:54-9. [DOI: 10.1016/j.neulet.2014.01.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Revised: 12/19/2013] [Accepted: 01/13/2014] [Indexed: 12/18/2022]
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Vemuganti R. All's well that transcribes well: non-coding RNAs and post-stroke brain damage. Neurochem Int 2013; 63:438-49. [PMID: 23954844 PMCID: PMC3805745 DOI: 10.1016/j.neuint.2013.07.014] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Revised: 07/26/2013] [Accepted: 07/28/2013] [Indexed: 12/13/2022]
Abstract
The mammalian genome is replete with various classes of non-coding (nc) RNA genes. Many of them actively transcribe, and their relevance to CNS diseases is just beginning to be understood. CNS is one of the organs in the body that shows very high ncRNAs activity. Recent studies demonstrated that cerebral ischemia rapidly changes the expression profiles of different classes of ncRNAs: including microRNA, long noncoding RNA and piwi-interacting RNA. Several studies further showed that post-ischemic neuronal death and/or plasticity/regeneration can be altered by modulating specific microRNAs. These studies are of interest for therapeutic development as they may contribute to identifying new ncRNA targets that can be modulated to prevent secondary brain damage after stroke.
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Affiliation(s)
- Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA.
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