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Lian Z, Luo Y, Li Y, Gao Y, Xiong X, Gu L. CD4 + T cells in ischemic stroke: effects and therapeutic targets. Front Immunol 2025; 16:1512634. [PMID: 40352928 PMCID: PMC12061934 DOI: 10.3389/fimmu.2025.1512634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 03/27/2025] [Indexed: 05/14/2025] Open
Abstract
Ischemic stroke (IS) is a significant contributor to disability and death worldwide, with limited treatments beyond early intervention. The importance of CD4+ T cells in the advancement of IS has been highlighted by recent studies, providing new insights into immunomodulatory strategies. This review describes the spatiotemporal dynamics of CD4+ T cells and their subsets at different stages of IS. The signaling pathways activated by IS regulate the distribution of CD4+ T cells and their subsets, which further influences the inflammatory response and disease progression. In the acute and subacute stages, CD4+ T cells exacerbate neuronal damage. In contrast, CD4+ T cells, which are predominantly composed of Treg cells (Tregs), promote tissue repair and neurological recovery in the chronic stage. In light of recent findings that challenge traditional views, we analyze the underlying mechanisms and potential explanations for these discrepancies. In addition, we summarize the potential of targeting CD4+ T cells as a therapeutic strategy for IS. Although no drugs specifically targeting CD4+ T cells have been developed, certain drugs that modulate CD4+ T cells show potential for IS treatment. Moreover, multitarget drugs integrated with nanomaterials are currently undergoing preclinical investigation. We further explore the challenges in the clinical translation of CD4+ T-cell-targeted therapies and discuss potential strategies to address these challenges. In conclusion, a deeper comprehension of the complex effects of CD4+ T cells and their subsets on IS will contribute to disease management and drug development, thereby improving the quality of life for IS patients.
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Affiliation(s)
- Zhengqi Lian
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ying Luo
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yina Li
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yikun Gao
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
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Liu L, Liu W, Han Z, Shan Y, Xie Y, Wang J, Qi H, Xu Q. Extracellular Vesicles-in-Hydrogel (EViH) targeting pathophysiology for tissue repair. Bioact Mater 2025; 44:283-318. [PMID: 39507371 PMCID: PMC11539077 DOI: 10.1016/j.bioactmat.2024.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 10/08/2024] [Accepted: 10/17/2024] [Indexed: 11/08/2024] Open
Abstract
Regenerative medicine endeavors to restore damaged tissues and organs utilizing biological approaches. Utilizing biomaterials to target and regulate the pathophysiological processes of injured tissues stands as a crucial method in propelling this field forward. The Extracellular Vesicles-in-Hydrogel (EViH) system amalgamates the advantages of extracellular vesicles (EVs) and hydrogels, rendering it a prominent biomaterial in regenerative medicine with substantial potential for clinical translation. This review elucidates the development and benefits of the EViH system in tissue regeneration, emphasizing the interaction and impact of EVs and hydrogels. Furthermore, it succinctly outlines the pathophysiological characteristics of various types of tissue injuries such as wounds, bone and cartilage injuries, cardiovascular diseases, nerve injuries, as well as liver and kidney injuries, underscoring how EViH systems target these processes to address related tissue damage. Lastly, it explores the challenges and prospects in further advancing EViH-based tissue regeneration, aiming to impart a comprehensive understanding of EViH. The objective is to furnish a thorough overview of EViH in enhancing regenerative medicine applications and to inspire researchers to devise innovative tissue engineering materials for regenerative medicine.
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Affiliation(s)
- Lubin Liu
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Wei Liu
- Department of Emergency Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266003, China
| | - Zeyu Han
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Yansheng Shan
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Yutong Xie
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Jialu Wang
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Hongzhao Qi
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Quanchen Xu
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
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Wu Z, Qian Y, Shang Y, Zhang Y, Wang M, Jiao M. Exploring common biomarkers of ischemic stroke and obstructive sleep apnea through bioinformatics analysis. PLoS One 2024; 19:e0312013. [PMID: 39475897 PMCID: PMC11524449 DOI: 10.1371/journal.pone.0312013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 09/29/2024] [Indexed: 11/02/2024] Open
Abstract
BACKGROUND Clinical observations have shown that many patients with ischemic stroke (IS) have a history of obstructive sleep apnea (OSA) both before and after the stroke's onset, suggesting potential underlying connections and shared comorbid mechanisms between the two conditions. The aim of this study is to identify the genetic characteristics of OSA patients who develop IS and to establish a reliable disease diagnostic model to assess the risk of IS in OSA patients. METHODS We selected IS and OSA datasets from the Gene Expression Omnibus (GEO) database as training sets. Core genes were identified using the Limma package, Weighted Gene Co-expression Network Analysis (WGCNA), and machine learning algorithms. Gene Set Variation Analysis (GSVA) was conducted for pathway enrichment analysis, while single-sample gene set enrichment analysis (ssGSEA) was employed for immune infiltration analysis. Finally, a diagnostic model was developed using Least Absolute Shrinkage and Selection Operator (LASSO) regression, with its diagnostic efficacy validated using receiver operating characteristic (ROC) curves across two independent validation sets. RESULTS The results revealed that differential analysis and machine learning identified two common genes, TM9SF2 and CCL8, shared between IS and OSA. Additionally, seven signaling pathways were found to be commonly upregulated in both conditions. Immune infiltration analysis demonstrated a significant decrease in monocyte levels, with TM9SF2 showing a negative correlation and CCL8 showing a positive correlation with monocytes. The diagnostic model we developed exhibited excellent predictive value in the validation set. CONCLUSIONS In summary, two immune-related core genes, TM9SF2 and CCL8, were identified as common to both IS and OSA. The diagnostic model developed based on these genes may be used to predict the risk of IS in OSA patients.
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Affiliation(s)
- Zhe Wu
- Rehabilitation Department, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Yutong Qian
- School of Acupuncture-Moxibustion and Tuina, Shanghai University of Chinese Medicine, Shanghai, P.R. China
| | - Yaxin Shang
- First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, P.R. China
| | - Yu Zhang
- Department of Integrated Traditional Chinese and Western Medicine in Gynecology, Shanghai Jiading Maternal Child Health Hospital, Shanghai, P.R. China
| | - Meilin Wang
- Department of Orthopedic and Spinal Rehabilitation, Ningbo Rehabilitation Hospital, Ningbo, P.R. China
| | - Mingyuan Jiao
- Research and Teaching Department, Jinhua Maternal Child Health Hospital, Jinhua, P.R. China
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Kremer LPM, Cerrizuela S, El-Sammak H, Al Shukairi ME, Ellinger T, Straub J, Korkmaz A, Volk K, Brunken J, Kleber S, Anders S, Martin-Villalba A. DNA methylation controls stemness of astrocytes in health and ischaemia. Nature 2024; 634:415-423. [PMID: 39232166 PMCID: PMC11464379 DOI: 10.1038/s41586-024-07898-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 08/01/2024] [Indexed: 09/06/2024]
Abstract
Astrocytes are the most abundant cell type in the mammalian brain and provide structural and metabolic support to neurons, regulate synapses and become reactive after injury and disease. However, a small subset of astrocytes settles in specialized areas of the adult brain where these astrocytes instead actively generate differentiated neuronal and glial progeny and are therefore referred to as neural stem cells1-3. Common parenchymal astrocytes and quiescent neural stem cells share similar transcriptomes despite their very distinct functions4-6. Thus, how stem cell activity is molecularly encoded remains unknown. Here we examine the transcriptome, chromatin accessibility and methylome of neural stem cells and their progeny, and of astrocytes from the striatum and cortex in the healthy and ischaemic adult mouse brain. We identify distinct methylation profiles associated with either astrocyte or stem cell function. Stem cell function is mediated by methylation of astrocyte genes and demethylation of stem cell genes that are expressed later. Ischaemic injury to the brain induces gain of stemness in striatal astrocytes7. We show that this response involves reprogramming the astrocyte methylome to a stem cell methylome and is absent if the de novo methyltransferase DNMT3A is missing. Overall, we unveil DNA methylation as a promising target for regenerative medicine.
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Affiliation(s)
- Lukas P M Kremer
- Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- BioQuant Centre, University of Heidelberg, Heidelberg, Germany
| | - Santiago Cerrizuela
- Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hadil El-Sammak
- Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Tobias Ellinger
- Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jannes Straub
- Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Aylin Korkmaz
- Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Katrin Volk
- Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jan Brunken
- Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Susanne Kleber
- Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Simon Anders
- BioQuant Centre, University of Heidelberg, Heidelberg, Germany.
| | - Ana Martin-Villalba
- Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Chen C, Chang ZH, Yao B, Liu XY, Zhang XW, Liang J, Wang JJ, Bao SQ, Chen MM, Zhu P, Li XH. 3D printing of interferon γ-preconditioned NSC-derived exosomes/collagen/chitosan biological scaffolds for neurological recovery after TBI. Bioact Mater 2024; 39:375-391. [PMID: 38846528 PMCID: PMC11153920 DOI: 10.1016/j.bioactmat.2024.05.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/13/2024] [Accepted: 05/13/2024] [Indexed: 06/09/2024] Open
Abstract
The reconstruction of neural function and recovery of chronic damage following traumatic brain injury (TBI) remain significant clinical challenges. Exosomes derived from neural stem cells (NSCs) offer various benefits in TBI treatment. Numerous studies confirmed that appropriate preconditioning methods enhanced the targeted efficacy of exosome therapy. Interferon-gamma (IFN-γ) possesses immunomodulatory capabilities and is widely involved in neurological disorders. In this study, IFN-γ was employed for preconditioning NSCs to enhance the efficacy of exosome (IFN-Exo, IE) for TBI. miRNA sequencing revealed the potential of IFN-Exo in promoting neural differentiation and modulating inflammatory responses. Through low-temperature 3D printing, IFN-Exo was combined with collagen/chitosan (3D-CC-IE) to preserve the biological activity of the exosome. The delivery of exosomes via biomaterial scaffolds benefited the retention and therapeutic potential of exosomes, ensuring that they could exert long-term effects at the injury site. The 3D-CC-IE scaffold exhibited excellent biocompatibility and mechanical properties. Subsequently, 3D-CC-IE scaffold significantly improved impaired motor and cognitive functions after TBI in rat. Histological results showed that 3D-CC-IE scaffold markedly facilitated the reconstruction of damaged neural tissue and promoted endogenous neurogenesis. Further mechanistic validation suggested that IFN-Exo alleviated neuroinflammation by modulating the MAPK/mTOR signaling pathway. In summary, the results of this study indicated that 3D-CC-IE scaffold engaged in long-term pathophysiological processes, fostering neural function recovery after TBI, offering a promising regenerative therapy avenue.
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Affiliation(s)
- Chong Chen
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China
- Tianjin Key Laboratory of Neurotrauma Repair, Characteristic Medical Center of People's Armed Police Forces, Tianjin, 300162, China
| | - Zhe-Han Chang
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China
| | - Bin Yao
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510100, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, 510100, China
| | - Xiao-Yin Liu
- Tianjin Key Laboratory of Neurotrauma Repair, Characteristic Medical Center of People's Armed Police Forces, Tianjin, 300162, China
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xiao-Wang Zhang
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China
| | - Jun Liang
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China
| | - Jing-Jing Wang
- Tianjin Key Laboratory of Neurotrauma Repair, Characteristic Medical Center of People's Armed Police Forces, Tianjin, 300162, China
| | - Shuang-Qing Bao
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China
| | - Meng-Meng Chen
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510100, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, 510100, China
| | - Xiao-Hong Li
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China
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Song J, Zhou D, Cui L, Wu C, Jia L, Wang M, Li J, Ya J, Ji X, Meng R. Advancing stroke therapy: innovative approaches with stem cell-derived extracellular vesicles. Cell Commun Signal 2024; 22:369. [PMID: 39039539 PMCID: PMC11265156 DOI: 10.1186/s12964-024-01752-1] [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: 05/17/2024] [Accepted: 07/16/2024] [Indexed: 07/24/2024] Open
Abstract
Stroke is a leading cause of mortality and long-term disability globally, with acute ischemic stroke (AIS) being the most common subtype. Despite significant advances in reperfusion therapies, their limited time window and associated risks underscore the necessity for novel treatment strategies. Stem cell-derived extracellular vesicles (EVs) have emerged as a promising therapeutic approach due to their ability to modulate the post-stroke microenvironment and facilitate neuroprotection and neurorestoration. This review synthesizes current research on the therapeutic potential of stem cell-derived EVs in AIS, focusing on their origin, biogenesis, mechanisms of action, and strategies for enhancing their targeting capacity and therapeutic efficacy. Additionally, we explore innovative combination therapies and discuss both the challenges and prospects of EV-based treatments. Our findings reveal that stem cell-derived EVs exhibit diverse therapeutic effects in AIS, such as promoting neuronal survival, diminishing neuroinflammation, protecting the blood-brain barrier, and enhancing angiogenesis and neurogenesis. Various strategies, including targeting modifications and cargo modifications, have been developed to improve the efficacy of EVs. Combining EVs with other treatments, such as reperfusion therapy, stem cell transplantation, nanomedicine, and gut microbiome modulation, holds great promise for improving stroke outcomes. However, challenges such as the heterogeneity of EVs and the need for standardized protocols for EV production and quality control remain to be addressed. Stem cell-derived EVs represent a novel therapeutic avenue for AIS, offering the potential to address the limitations of current treatments. Further research is needed to optimize EV-based therapies and translate their benefits to clinical practice, with an emphasis on ensuring safety, overcoming regulatory hurdles, and enhancing the specificity and efficacy of EV delivery to target tissues.
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Affiliation(s)
- Jiahao Song
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Da Zhou
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China.
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
| | - Lili Cui
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Chuanjie Wu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Lina Jia
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Mengqi Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Jingrun Li
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Jingyuan Ya
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, England
| | - Xunming Ji
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Ran Meng
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China.
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
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Gu C, Li Y, Liu J, Liu S, Long J, Zhang Q, Duan W, Feng T, Huang J, Qiu Y, Ahmed W, Cai H, Hu Y, Wu Y, Chen L. Neural stem cell-derived exosomes-loaded adhesive hydrogel controlled-release promotes cerebral angiogenesis and neurological function in ischemic stroke. Exp Neurol 2023; 370:114547. [PMID: 37743000 DOI: 10.1016/j.expneurol.2023.114547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 08/31/2023] [Accepted: 09/21/2023] [Indexed: 09/26/2023]
Abstract
OBJECTIVE Ischemic stroke has become one of the leading diseases for international death, which brings burden to the economy and society. Exosomes (Exos) derived following neural stem cells (NSCs) stimulation promote neurogenesis and migration of NSCs. However, Exos themselves are easily to be removed in vivo. Our study is to investigate whether adhesive hyaluronic acid (HAD) hydrogel loading NSCs-derived-Exo (HAD-Exo) would promote the recovery of ischemic stroke. METHODS A mouse model of middle cerebral artery occlusion (MCAO) was established. PBS, Exo, HAD, and HAD-Exo groups were independently stereotactically injected in mice, respectively. The modified neurological severity score scale and behaviour tests were used to evaluate neurological improvement. Neuroimagings were used to observe the improvement of cerebral infarct volume and vessels. Immunofluorescence staining was used to verify the expression of vascular and cell proliferation-related proteins. RESULTS The structural and mechanical property of HAD and HAD-Exo were detected. Behavioral results showed that HAD-Exo significantly improved neurological functions, especially motor function. Neuroimagings showed that HAD-Exo significantly promoted infarct volume and angiogenesis. Immunofluorescence staining showed that HAD-Exo significantly promoted the cerebral angiogenesis and anti-inflammation. CONCLUSION NSCs derived exosomes-loaded adhesive HAD hydrogel controlled-release could promote cerebral angiogenesis and neurological function for ischemic stroke.
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Affiliation(s)
- Chenyang Gu
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China; Department of Neurology, Affiliated Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, PR China
| | - Yajing Li
- The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan 523059, PR China
| | - Jiale Liu
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Sitian Liu
- Guangdong Engineering Research Centre for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Medical Biomechanics, Department of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, PR China
| | - Jun Long
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Qiankun Zhang
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Wenjie Duan
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Tingle Feng
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Jiajun Huang
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Yunhui Qiu
- Department of Pathology, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Waqas Ahmed
- Department of Neurology, Affiliated Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, PR China
| | - Hengsen Cai
- Department of Neurosurgery, The Second People's Hospital of Pingnan, Pingnan 537300, PR China
| | - Yong Hu
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hongkong 999077, PR China
| | - Yaobin Wu
- Guangdong Engineering Research Centre for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Medical Biomechanics, Department of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, PR China.
| | - Lukui Chen
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China.
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Tang X, Wu L, Zhu J, Xu M, Li S, Zeng G, Zhu S, Jiang Y. GABAergic neurons differentiated from BDNF- and Dlx2-modified neural stem cells restore disrupted neural circuits in brainstem stroke. Stem Cell Res Ther 2023; 14:170. [PMID: 37365654 DOI: 10.1186/s13287-023-03378-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 05/12/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Brainstem stroke causes severe and persistent neurological impairment. Due to the limited spontaneous recovery and regeneration of the disrupted neural circuits, transplantation of exogenous neural stem cells (NSCs) was an alternative, while there were limitations for primitive NSCs. METHODS We established a mouse model of brainstem stroke by injecting endothelin in the right pons. Brain-derived neurotrophic factor (BDNF)- and distal-less homeobox 2 (Dlx2)-modified NSCs were transplanted to treat brainstem stroke. Transsynaptic viral tracking, immunostaining, magnetic resonance imaging, behavioral testing, and whole-cell patch clamp recordings were applied to probe the pathophysiology and therapeutic prospects of BDNF- and Dlx2-modified NSCs. RESULTS GABAergic neurons were predominantly lost after the brainstem stroke. No endogenous NSCs were generated in situ or migrated from the neurogenesis niches within the brainstem infarct region. Co-overexpressions of BDNF and Dlx2 not only promoted the survival of NSCs, but also boosted the differentiation of NSCs into GABAergic neurons. Results from transsynaptic virus tracking, immunostaining, and evidence from whole-cell patch clamping revealed the morphological and functional integration of the grafted BDNF- and Dlx2-modified NSCs-derived neurons with the host neural circuits. Neurological function was improved by transplantation of BDNF- and Dlx2-modified NSCs in brainstem stroke. CONCLUSIONS These findings demonstrated that BDNF- and Dlx2-modified NSCs differentiated into GABAergic neurons, integrated into and reconstituted the host neural networks, and alleviated the ischemic injury. It thus provided a potential therapeutic strategy for brainstem stroke.
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Affiliation(s)
- Xiangyue Tang
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, 510260, China
| | - Li Wu
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, 510260, China
| | - Juehua Zhu
- Department of Neurology, The First Affiliated Hospital of SooChow University, 899 Pinghai Road, Suzhou, 215006, Jiangsu, China
| | - Mindong Xu
- School of Basic Medical Sciences, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, 510260, China
| | - Shaojun Li
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, 510260, China
| | - Guanfeng Zeng
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, 510260, China
| | - Shuanggen Zhu
- Shenzhen Longhua District Central Hospital, The Affiliated Hospital of Guangdong Medical University, 187 Guanlan West Road, Shenzhen, 518110, China.
- Department of Neurology, People's Hospital of Longhua, Shenzhen, 518109, China.
| | - Yongjun Jiang
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, 510260, China.
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Lei X, Hu Q, Ge H, Zhang X, Ru X, Chen Y, Hu R, Feng H, Deng J, Huang Y, Li W. A redox-reactive delivery system via neural stem cell nanoencapsulation enhances white matter regeneration in intracerebral hemorrhage mice. Bioeng Transl Med 2023; 8:e10451. [PMID: 36925711 PMCID: PMC10013746 DOI: 10.1002/btm2.10451] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/25/2022] [Accepted: 11/09/2022] [Indexed: 11/18/2022] Open
Abstract
Intracerebral hemorrhage (ICH) poses a great threat to human health because of its high mortality and morbidity. Neural stem cell (NSC) transplantation is promising for treating white matter injury following ICH to promote functional recovery. However, reactive oxygen species (ROS)-induced NSC apoptosis and uncontrolled differentiation hindered the effectiveness of the therapy. Herein, we developed a single-cell nanogel system by layer-by-layer (LbL) hydrogen bonding of gelatin and tannic acid (TA), which was modified with a boronic ester-based compound linking triiodothyronine (T3). In vitro, NSCs in nanogel were protected from ROS-induced apoptosis, with apoptotic signaling pathways downregulated. This process of ROS elimination by material shell synergistically triggered T3 release to induce NSC differentiation into oligodendrocytes. Furthermore, in animal studies, ICH mice receiving nanogels performed better in behavioral evaluation, neurological scaling, and open field tests. These animals exhibited enhanced differentiation of NSCs into oligodendrocytes and promoted white matter tract regeneration on Day 21 through activation of the αvβ3/PI3K/THRA pathway. Consequently, transplantation of LbL(T3) nanogels largely resolved two obstacles in NSC therapy synergistically: low survival and uncontrolled differentiation, enhancing white matter regeneration and behavioral performance of ICH mice. As expected, nanoencapsulation with synergistic effects would efficiently provide hosts with various biological benefits and minimize the difficulty in material fabrication, inspiring next-generation material design for tackling complicated pathological conditions.
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Affiliation(s)
- Xuejiao Lei
- Department of NeurosurgerySouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Quan Hu
- Department of EmergencyAffiliated Hospital, Zunyi Medical UniversityZunyiGuizhouChina
| | - Hongfei Ge
- Department of NeurosurgerySouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Xuyang Zhang
- Department of NeurosurgerySouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Xufang Ru
- Department of NeurosurgerySouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Yujie Chen
- Department of NeurosurgerySouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Rong Hu
- Department of NeurosurgerySouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Hua Feng
- Department of NeurosurgerySouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Jun Deng
- Institute of Burn Research, State Key Lab of Trauma, Burn, and Combined Injury, Chongqing Key Laboratory for Disease ProteomicsSouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Yan Huang
- Institute of Materia Medica and Department of PharmaceuticsCollege of Pharmacy, Third Military Medical University (Army Medical University)ChongqingChina
| | - Wenyan Li
- Department of NeurosurgerySouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
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10
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Nistor-Cseppentö DC, Jurcău MC, Jurcău A, Andronie-Cioară FL, Marcu F. Stem Cell- and Cell-Based Therapies for Ischemic Stroke. Bioengineering (Basel) 2022; 9:717. [PMID: 36421118 PMCID: PMC9687728 DOI: 10.3390/bioengineering9110717] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 09/12/2023] Open
Abstract
Stroke is the second cause of disability worldwide as it is expected to increase its incidence and prevalence. Despite efforts to increase the number of patients eligible for recanalization therapies, a significant proportion of stroke survivors remain permanently disabled. This outcome boosted the search for efficient neurorestorative methods. Stem cells act through multiple pathways: cell replacement, the secretion of growth factors, promoting endogenous reparative pathways, angiogenesis, and the modulation of neuroinflammation. Although neural stem cells are difficult to obtain, pose a series of ethical issues, and require intracerebral delivery, mesenchymal stem cells are less immunogenic, are easy to obtain, and can be transplanted via intravenous, intra-arterial, or intranasal routes. Extracellular vesicles and exosomes have similar actions and are easier to obtain, also allowing for engineering to deliver specific molecules or RNAs and to promote the desired effects. Appropriate timing, dosing, and delivery protocols must be established, and the possibility of tumorigenesis must be settled. Nonetheless, stem cell- and cell-based therapies for stroke have already entered clinical trials. Although safe, the evidence for efficacy is less impressive so far. Hopefully, the STEP guidelines and the SPAN program will improve the success rate. As such, stem cell- and cell-based therapy for ischemic stroke holds great promise.
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Affiliation(s)
- Delia Carmen Nistor-Cseppentö
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | | | - Anamaria Jurcău
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Felicia Liana Andronie-Cioară
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Florin Marcu
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
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11
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Zhai QY, Ren YQ, Ni QS, Song ZH, Ge KL, Guo YL. Transplantation of Human Umbilical Cord Mesenchymal Stem Cells-Derived Neural Stem Cells Pretreated with Neuregulin1β Ameliorate Cerebral Ischemic Reperfusion Injury in Rats. Biomolecules 2022; 12:428. [PMID: 35327620 PMCID: PMC8945978 DOI: 10.3390/biom12030428] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/28/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Ischemic stroke is a common cerebrovascular disease and recovering blood flow as early as possible is essential to reduce ischemic damage and maintain neuronal viability, but the reperfusion process usually causes additional damage to the brain tissue in the ischemic area, namely ischemia reperfusion injury. The accumulated studies have revealed that transplantation of exogenous neural stem cells (NSCs) is an ideal choice for the treatment of ischemia reperfusion injury. At present, the source and efficacy of exogenous NSCs after transplantation is still one of the key issues that need to be resolved. In this study, human umbilical cord mesenchymal stem cells (hUC-MSCs) were obtained and induced into NSCs byadding growth factor and neuregulin1β (NRG1β) was introduced during the differentiation process of NSCs. Then, the rat middle cerebral artery occlusion/reperfusion (MCAO/R) models were established, and the therapeutic effects were evaluated among groups treated by NRG1β, NSCs and NSCs pretreated with 10 nM NRG1β (NSCs-10 nM NRG1β) achieved through intra-arterial injection. Our data show that the NSCs-10 nM NRG1β group significantly improves neurobehavioral function and infarct volume after MCAO/R, as well as cerebral cortical neuron injury, ferroptosis-related indexes and mitochondrial injury. Additionally, NSCs-10 nM NRG1β intervention may function through regulating the p53/GPX4/SLC7A11 pathway, and reducing the level of ferroptosis in cells, further enhance the neuroprotective effect on injured cells.
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Affiliation(s)
- Qiu-Yue Zhai
- Institute of Cerebrovascular Diseases, Medical Research Center, The Affiliated Hospital of Qingdao University, Taishan Scholars Construction Project Excellent Innovative Team of Shandong Province, Qingdao 266003, China; (Q.-Y.Z.); (Y.-Q.R.); (Q.-S.N.)
| | - Yu-Qian Ren
- Institute of Cerebrovascular Diseases, Medical Research Center, The Affiliated Hospital of Qingdao University, Taishan Scholars Construction Project Excellent Innovative Team of Shandong Province, Qingdao 266003, China; (Q.-Y.Z.); (Y.-Q.R.); (Q.-S.N.)
| | - Qin-Shuai Ni
- Institute of Cerebrovascular Diseases, Medical Research Center, The Affiliated Hospital of Qingdao University, Taishan Scholars Construction Project Excellent Innovative Team of Shandong Province, Qingdao 266003, China; (Q.-Y.Z.); (Y.-Q.R.); (Q.-S.N.)
| | - Zhen-Hua Song
- Institute of Pharmacology, Qingdao Medical College, Qingdao University, Qingdao 266021, China;
| | - Ke-Li Ge
- Institute of Integrative Medicine, Qingdao Medical College, Qingdao University, Qingdao 266021, China;
| | - Yun-Liang Guo
- Institute of Cerebrovascular Diseases, Medical Research Center, The Affiliated Hospital of Qingdao University, Taishan Scholars Construction Project Excellent Innovative Team of Shandong Province, Qingdao 266003, China; (Q.-Y.Z.); (Y.-Q.R.); (Q.-S.N.)
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12
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Prowse N, Hayley S. Microglia and BDNF at the crossroads of stressor related disorders: Towards a unique trophic phenotype. Neurosci Biobehav Rev 2021; 131:135-163. [PMID: 34537262 DOI: 10.1016/j.neubiorev.2021.09.018] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 12/16/2022]
Abstract
Stressors ranging from psychogenic/social to neurogenic/injury to systemic/microbial can impact microglial inflammatory processes, but less is known regarding their effects on trophic properties of microglia. Recent studies do suggest that microglia can modulate neuronal plasticity, possibly through brain derived neurotrophic factor (BDNF). This is particularly important given the link between BDNF and neuropsychiatric and neurodegenerative pathology. We posit that certain activated states of microglia play a role in maintaining the delicate balance of BDNF release onto neuronal synapses. This focused review will address how different "activators" influence the expression and release of microglial BDNF and address the question of tropomyosin receptor kinase B (TrkB) expression on microglia. We will then assess sex-based differences in microglial function and BDNF expression, and how microglia are involved in the stress response and related disorders such as depression. Drawing on research from a variety of other disorders, we will highlight challenges and opportunities for modulators that can shift microglia to a "trophic" phenotype with a view to potential therapeutics relevant for stressor-related disorders.
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Affiliation(s)
- Natalie Prowse
- Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
| | - Shawn Hayley
- Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
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13
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Berlet R, Anthony S, Brooks B, Wang ZJ, Sadanandan N, Shear A, Cozene B, Gonzales-Portillo B, Parsons B, Salazar FE, Lezama Toledo AR, Monroy GR, Gonzales-Portillo JV, Borlongan CV. Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke. Biomolecules 2021; 11:1316. [PMID: 34572529 PMCID: PMC8468342 DOI: 10.3390/biom11091316] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/31/2021] [Accepted: 09/01/2021] [Indexed: 12/14/2022] Open
Abstract
Stem cell transplantation with rehabilitation therapy presents an effective stroke treatment. Here, we discuss current breakthroughs in stem cell research along with rehabilitation strategies that may have a synergistic outcome when combined together after stroke. Indeed, stem cell transplantation offers a promising new approach and may add to current rehabilitation therapies. By reviewing the pathophysiology of stroke and the mechanisms by which stem cells and rehabilitation attenuate this inflammatory process, we hypothesize that a combined therapy will provide better functional outcomes for patients. Using current preclinical data, we explore the prominent types of stem cells, the existing theories for stem cell repair, rehabilitation treatments inside the brain, rehabilitation modalities outside the brain, and evidence pertaining to the benefits of combined therapy. In this review article, we assess the advantages and disadvantages of using stem cell transplantation with rehabilitation to mitigate the devastating effects of stroke.
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Affiliation(s)
- Reed Berlet
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL 60064, USA;
| | - Stefan Anthony
- Lake Erie College of Osteopathic Medicine, 5000 Lakewood Ranch Boulevard, Bradenton, FL 34211, USA;
| | - Beverly Brooks
- Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA; (B.B.); (Z.-J.W.)
| | - Zhen-Jie Wang
- Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA; (B.B.); (Z.-J.W.)
| | | | - Alex Shear
- University of Florida, 205 Fletcher Drive, Gainesville, FL 32611, USA;
| | - Blaise Cozene
- Tulane University, 6823 St. Charles Ave, New Orleans, LA 70118, USA;
| | | | - Blake Parsons
- Washington and Lee University, 204 W Washington St, Lexington, VA 24450, USA;
| | - Felipe Esparza Salazar
- Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, Huixquilucan 52786, Mexico; (F.E.S.); (A.R.L.T.); (G.R.M.)
| | - Alma R. Lezama Toledo
- Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, Huixquilucan 52786, Mexico; (F.E.S.); (A.R.L.T.); (G.R.M.)
| | - Germán Rivera Monroy
- Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, Huixquilucan 52786, Mexico; (F.E.S.); (A.R.L.T.); (G.R.M.)
| | | | - Cesario V. Borlongan
- Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA; (B.B.); (Z.-J.W.)
- Center of Excellence for Aging and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
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14
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Ejma M, Madetko N, Brzecka A, Alster P, Budrewicz S, Koszewicz M, Misiuk-Hojło M, Tomilova IK, Somasundaram SG, Kirkland CE, Aliev G. The Role of Stem Cells in the Therapy of Stroke. Curr Neuropharmacol 2021; 20:630-647. [PMID: 34365923 PMCID: PMC9608230 DOI: 10.2174/1570159x19666210806163352] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/19/2021] [Accepted: 06/03/2021] [Indexed: 11/22/2022] Open
Abstract
Background: Stroke is a major challenge in neurology due to its multifactorial genesis and irreversible consequences. Processes of endogenous post-stroke neurogenesis, although insufficient, may indicate possible direction of future therapy. Multiple research considers stem-cell-based approaches in order to maximize neuroregeneration and minimize post-stroke deficits. Objective: Aim of this study is to review current literature considering post-stroke stem-cell-based therapy and possibilities of inducing neuroregeneration after brain vascular damage. Methods: Papers included in this article were obtained from PubMed and MEDLINE databases. The following medical subject headings (MeSH) were used: “stem cell therapy”, “post-stroke neurogenesis”, “stem-cells stroke”, “stroke neurogenesis”, “stroke stem cells”, “stroke”, “cell therapy”, “neuroregeneration”, “neurogenesis”, “stem-cell human”, “cell therapy in human”. Ultimate inclusion was made after manual review of the obtained reference list. Results: Attempts of stimulating neuroregeneration after stroke found in current literature include supporting endogenous neurogenesis, different routes of exogenous stem cells supplying and extracellular vesicles used as a method of particle transport. Conclusion: Although further research in this field is required, post stroke brain recovery supported by exogenous stem cells seems to be promising future therapy revolutionizing modern neurology.
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Affiliation(s)
- Maria Ejma
- Department of Neurology, Wroclaw Medical University, 50-556 Wrocław, Borowska 213. Poland
| | - Natalia Madetko
- Department of Neurology, Medical University of Warsaw, Kondratowicza 8, 03-242 Warszawa. Poland
| | - Anna Brzecka
- Department of Pulmonology and Lung Oncology, Wroclaw Medical University, Grabiszynska 105, 53-439 Wroclaw. Poland
| | - Piotr Alster
- Department of Neurology, Medical University of Warsaw, Kondratowicza 8, 03-242 Warszawa. Poland
| | - Sławomir Budrewicz
- Department of Neurology, Wroclaw Medical University, 50-556 Wrocław, Borowska 213. Poland
| | - Magdalena Koszewicz
- Department of Neurology, Wroclaw Medical University, 50-556 Wrocław, Borowska 213. Poland
| | - Marta Misiuk-Hojło
- Department of Ophthalmology, Wroclaw Medical University, 50-556 Wroclaw, Borowska 213. Poland
| | - Irina K Tomilova
- Department of Biochemistry, Ivanovo State Medical Academy, Avenue Sheremetyevsky 8, Ivanovo, 153012. Russian Federation
| | - Siva G Somasundaram
- Department of Biological Sciences, Salem University, Salem, WV, 26426. United States
| | - Cecil E Kirkland
- Department of Biological Sciences, Salem University, Salem, WV, 26426. United States
| | - Gjumrakch Aliev
- Wroclaw Medical University, Department of Pulmonology and Lung Oncology, Wroclaw. Poland
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15
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Jiao Y, Liu YW, Chen WG, Liu J. Neuroregeneration and functional recovery after stroke: advancing neural stem cell therapy toward clinical application. Neural Regen Res 2021; 16:80-92. [PMID: 32788451 PMCID: PMC7818886 DOI: 10.4103/1673-5374.286955] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Stroke is a main cause of death and disability worldwide. The ability of the brain to self-repair in the acute and chronic phases after stroke is minimal; however, promising stem cell-based interventions are emerging that may give substantial and possibly complete recovery of brain function after stroke. Many animal models and clinical trials have demonstrated that neural stem cells (NSCs) in the central nervous system can orchestrate neurological repair through nerve regeneration, neuron polarization, axon pruning, neurite outgrowth, repair of myelin, and remodeling of the microenvironment and brain networks. Compared with other types of stem cells, NSCs have unique advantages in cell replacement, paracrine action, inflammatory regulation and neuroprotection. Our review summarizes NSC origins, characteristics, therapeutic mechanisms and repair processes, then highlights current research findings and clinical evidence for NSC therapy. These results may be helpful to inform the direction of future stroke research and to guide clinical decision-making.
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Affiliation(s)
- Yang Jiao
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University; Dalian Innovation Institute of Stem Cells and Precision Medicine, Dalian, Liaoning Province, China
| | - Yu-Wan Liu
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Wei-Gong Chen
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University; Dalian Innovation Institute of Stem Cells and Precision Medicine, Dalian, Liaoning Province, China
| | - Jing Liu
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University; Dalian Innovation Institute of Stem Cells and Precision Medicine, Dalian, Liaoning Province, China
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16
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Zhang G, Zhu Z, Wang H, Yu Y, Chen W, Waqas A, Wang Y, Chen L. Exosomes derived from human neural stem cells stimulated by interferon gamma improve therapeutic ability in ischemic stroke model. J Adv Res 2020; 24:435-445. [PMID: 32551140 PMCID: PMC7289755 DOI: 10.1016/j.jare.2020.05.017] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 05/13/2020] [Accepted: 05/14/2020] [Indexed: 12/16/2022] Open
Abstract
hNSC-Exo presented therapeutic roles in brain ischemic stroke model of rats. IFN-γ preconditioning significantly altered the abilities and contents of hNSC-Exo. IFN-γ-hNSC-Exo shown more therapeutic benefits than hNSC-Exo in vitro and in vivo. Exosomal miRNAs in IFN-γ-hNSC-Exo mediated the potential effects on cell survival. Transplanted neural stem cells promote neural tissue regeneration and functional recovery primarily by releasing paracrine factors. Exosomes act as important secreted paracrine molecules to deliver therapeutic agents involved in cellular functions. Here, we focused on the role of exosomes (hNSC-Exo) derived from human neural stem cells (hNSCs). We utilized the pro-inflammatory factor interferon gamma (IFN-γ) to induce the generation of altered exosomes (IFN-γ-hNSC-Exo), and compared their roles with those of hNSC-Exo and explored the potential mechanism. Importantly, IFN-γ preconditioning did not affect the secretion, but significantly altered the ability of exosomes derived from hNSCs. Moreover, IFN-γ-hNSC-Exo was functionally superior to hNSC-Exo; showed increased cell proliferation and cell survival and decreased cell apoptosis in vitro. Furthermore, IFN-γ-hNSC-Exo further exerted therapeutic effects (showed better behavioral and structural outcomes) compared to those of hNSCs-Exo in an ischemic stroke rat model. Next-generation sequencing (NGS) revealed specific exosomal miRNAs (hsa-miR-206, hsa-miR-133a-3p and hsa-miR-3656) in IFN-γ-hNSC-Exo with important roles in cell survival. Thus, our findings demonstrate that the inflammatory factor IFN-γ can regulate the functions of exosomes and highlight its role in regulating the application of neural stem cell-derived exosomes.
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Affiliation(s)
- Guilong Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Zhihan Zhu
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Hong Wang
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Yongbo Yu
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Wanghao Chen
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Ahmed Waqas
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Yezhong Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Lukui Chen
- Department of Neurosurgery, Neuroscience Center, Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, China
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17
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Corey S, Bonsack B, Heyck M, Shear A, Sadanandan N, Zhang H, Borlongan CV. Harnessing the anti-inflammatory properties of stem cells for transplant therapy in hemorrhagic stroke. BRAIN HEMORRHAGES 2020; 1:24-33. [PMID: 34056567 PMCID: PMC8158660 DOI: 10.1016/j.hest.2019.12.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hemorrhagic stroke is a global health crisis plagued by neuroinflammation in the acute and chronic phases. Neuroinflammation approximates secondary cell death, which in turn robustly contributes to stroke pathology. Both the physiological and behavioral symptoms of stroke correlate with various inflammatory responses in animal and human studies. That slowing the secondary cell death mediated by this inflammation may attenuate stroke pathology presents a novel treatment strategy. To this end, experimental therapies employing stem cell transplants support their potential for neuroprotection and neuroregeneration after hemorrhagic stroke. In this review, we evaluate experiments using different types of stem cell transplants as treatments for stroke-induced neuroinflammation. We also update this emerging area by examining recent preclinical and clinical trials that have deployed these therapies. While further investigations are warranted to solidify their therapeutic profile, the reviewed studies largely posit stem cells as safe and potent biologics for stroke, specifically owing to their mode of action for sequestering neuroinflammation and promoting neuroregenerative processes.
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Affiliation(s)
- Sydney Corey
- Center of Excellence for Aging and Brain Repair, University of South Florida, College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Brooke Bonsack
- Center of Excellence for Aging and Brain Repair, University of South Florida, College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Matt Heyck
- Center of Excellence for Aging and Brain Repair, University of South Florida, College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Alex Shear
- Center of Excellence for Aging and Brain Repair, University of South Florida, College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Nadia Sadanandan
- Center of Excellence for Aging and Brain Repair, University of South Florida, College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Henry Zhang
- Center of Excellence for Aging and Brain Repair, University of South Florida, College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Cesar V Borlongan
- Center of Excellence for Aging and Brain Repair, University of South Florida, College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
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18
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Zhu Z, Kalyan BS, Chen L. Therapeutic potential role of exosomes for ischemic stroke. BRAIN SCIENCE ADVANCES 2020. [DOI: 10.1177/2096595820902588] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Exosomes are extracellular vesicles with a diameter of 30–100 nm, which are released into the extracellular space by fusion of multivesicular and plasma membranes. These vesicles actually play a distinct role in cell communication, although they were considered as membrane debris in the past. The endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent mechanisms are currently considered to be involved in the sorting of exosomes, and the release of exosomes is related to the members of Rab protein family and SNARE family. In recent years, the therapeutic potential of exosomes has become apparent. For example, via the direct transplantation of exosomes, the ischemic area after stroke is reduced, and the neurological function is improved significantly. Furthermore, they can be used as effective drug delivery vehicles due to their unique characteristics such as low immunogenicity and nanometer size. In conclusion, exosomes provide a cell-free treatment for ischemic stroke.
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Affiliation(s)
- Zhihan Zhu
- Department of Neurosurgery, School of Medicine, Southeast University, Nanjing 210009, Jiangsu, China
| | - Bikram Shah Kalyan
- Department of Neurosurgery, School of Medicine, Southeast University, Nanjing 210009, Jiangsu, China
| | - Lukui Chen
- Department of Neurosurgery, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, Guangdong, China
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19
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Zhang GL, Zhu ZH, Wang YZ. Neural stem cell transplantation therapy for brain ischemic stroke: Review and perspectives. World J Stem Cells 2019; 11:817-830. [PMID: 31692854 PMCID: PMC6828598 DOI: 10.4252/wjsc.v11.i10.817] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 08/11/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023] Open
Abstract
Brain ischemic stroke is one of the most common causes of death and disability, currently has no efficient therapeutic strategy in clinic. Due to irreversible functional neurons loss and neural tissue injury, stem cell transplantation may be the most promising treatment approach. Neural stem cells (NSCs) as the special type of stem cells only exist in the nervous system, can differentiate into neurons, astrocytes, and oligodendrocytes, and have the abilities to compensate insufficient endogenous nerve cells and improve the inflammatory microenvironment of cell survival. In this review, we focused on the important role of NSCs therapy for brain ischemic stroke, mainly introduced the methods of optimizing the therapeutic efficacy of NSC transplantation, such as transfection and overexpression of specific genes, pretreatment of NSCs with inflammatory factors, and co-transplantation with cytokines. Next, we discussed the potential problems of NSC transplantation which seriously limited their rapid clinical transformation and application. Finally, we expected a new research topic in the field of stem cell research. Based on the bystander effect, exosomes derived from NSCs can overcome many of the risks and difficulties associated with cell therapy. Thus, as natural seed resource of nervous system, NSCs-based cell-free treatment is a newly therapy strategy, will play more important role in treating ischemic stroke in the future.
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Affiliation(s)
- Gui-Long Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Zhi-Han Zhu
- Department of Neurosurgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ye-Zhong Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
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Zhu Z, Kalyan BS, Chen L. Therapeutic potential role of exosomes for ischemic stroke. BRAIN SCIENCE ADVANCES 2019. [DOI: 10.26599/bsa.2019.9050013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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He HW, Zhang YL, Yu BQ, Ye G, You W, So KF, Li X. Soluble Nogo receptor 1 fusion protein protects neural progenitor cells in rats with ischemic stroke. Neural Regen Res 2019; 14:1755-1764. [PMID: 31169193 PMCID: PMC6585563 DOI: 10.4103/1673-5374.257531] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Soluble Nogo66 receptor-Fc protein (sNgR-Fc) enhances axonal regeneration following central nervous system injury. However, the underlying mechanisms remain unclear. In this study, we investigated the effects of sNgR-Fc on the proliferation and differentiation of neural progenitor cells. The photothrombotic cortical injury model of ischemic stroke was produced in the parietal cortex of Sprague-Dawley rats. The rats with photothrombotic cortical injury were randomized to receive infusion of 400 μg/kg sNgR-Fc (sNgR-Fc group) or an equal volume of phosphate-buffered saline (photothrombotic cortical injury group) into the lateral ventricle for 3 days. The effects of sNgR-Fc on the proliferation and differentiation of endogenous neural progenitor cells were examined using BrdU staining. Neurological function was evaluated with the Morris water maze test. To further examine the effects of sNgR-Fc treatment on neural progenitor cells, photothrombotic cortical injury was produced in another group of rats that received transplantation of neural progenitor cells from the hippocampus of embryonic Sprague-Dawley rats. The animals were then given an infusion of phosphate-buffered saline (neural progenitor cells group) or sNgR-Fc (sNgR-Fc + neural progenitor cells group) into the lateral ventricle for 3 days. sNgR-Fc enhanced the proliferation of cultured neural progenitor cells in vitro as well as that of endogenous neural progenitor cells in vivo, compared with phosphate-buffered saline, and it also induced the differentiation of neural progenitor cells into neurons. Compared with the photothrombotic cortical injury group, escape latency in the Morris water maze and neurological severity score were greatly reduced, and distance traveled in the target quadrant was considerably increased in the sNgR-Fc group, indicating a substantial improvement in neurological function. Furthermore, compared with phosphate-buffered saline infusion, sNgR-Fc infusion strikingly improved the survival and differentiation of grafted neural progenitor cells. Our findings show that sNgR-Fc regulates neural progenitor cell proliferation, migration and differentiation. Therefore, sNgR-Fc is a potential novel therapy for stroke and neurodegenerative diseases, The protocols were approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong (approval No. 4560-17) in November, 2015.
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Affiliation(s)
- Hai-Wei He
- School of Medicine, South China University of Technology; Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China
| | - Yue-Lin Zhang
- Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China
| | - Bao-Qi Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Key Laboratory of Remodelling- related Cardiovascular Diseases, Ministry of Education, Beijing, China
| | - Gen Ye
- Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China
| | - Wei You
- Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China
| | - Kwok-Fai So
- School of Biomedical Sciences, The State Key Laboratory of Brain and Cognitive sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Xin Li
- School of Medicine, South China University of Technology; Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China
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