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Gotoh S, Kawabori M, Yamaguchi S, Nakahara Y, Yoshie E, Konno K, Mizuno Y, Fujioka Y, Ohba Y, Kuge Y, Watanabe M, Fujimura M. Intranasal administration of stem cell-derived exosome alleviates cognitive impairment against subarachnoid hemorrhage. Exp Neurol 2025; 386:115143. [PMID: 39800250 DOI: 10.1016/j.expneurol.2025.115143] [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: 08/21/2024] [Revised: 01/05/2025] [Accepted: 01/06/2025] [Indexed: 01/15/2025]
Abstract
INTRODUCTION Brain damage caused by subarachnoid hemorrhage (SAH) currently lacks effective treatment, leading to stagnation in the improvement of functional outcomes for decades. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells (MSC), which effectively attenuate neuronal apoptosis and inflammation in neurological diseases. Due to the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a novel approach for targeting the brain. In this study, we investigate the effects of intranasally administered MSC-derived exosomes in a SAH animal model and elucidate their mode of action. METHODS Exosomes were isolated from the cell supernatants of amnion-derived MSC. SAH was induced in 8-week-old Sprague-Dawley rats using an autologous blood prechiasmatic cistern injection model. A total of 1.2 × 1010 particles of exosomes in 200 μL of PBS or PBS alone were intranasally administered immediately and 24 h post-injury. Neurological function was assessed up to 7 days after injury, and histological analysis was performed to evaluate their anti-apoptotic and anti-inflammatory effects. The biodistribution of exosomes was assessed using PET/CT imaging of 64Cu labeled exosome. In vitro analyses were performed using primary glial cells and cell lines to evaluate the anti-inflammatory effects of the exosomes. RESULTS Animals treated with exosomes exhibited significant improvement in cognitive function compared with PBS treated animal. Apoptotic cells and inflammation were reduced for the exosome group in the hippocampal CA1 area and in cortex, resulting in better neuronal cell survival. Blood brain barrier permeability was also preserved in the exosome group. Nuclear imaging revealed that exosomes were primarily transferred to the olfactory nerve and cerebrum; furthermore, exosomes were also observed in the trigeminal nerve and brainstem, where exosomes were co-localized with microglia and with endothelial cells. In vitro assessment showed that exosome administration ameliorated inflammation and prevented the death of glial cells. CONCLUSIONS MSC-derived exosomes were successfully transferred into the brain through intranasal administration and alleviated brain damage following SAH.
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Affiliation(s)
- Shuho Gotoh
- Department of Neurosurgery, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Masahito Kawabori
- Department of Neurosurgery, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
| | - Sho Yamaguchi
- Regenerative Medicine and Cell Therapy Laboratories, Kaneka Corporation, Kobe, Hyogo, Japan
| | - Yo Nakahara
- Department of Neurosurgery, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Erika Yoshie
- Department of Neurosurgery, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Kohtarou Konno
- Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Yuki Mizuno
- Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan
| | - Yoichiro Fujioka
- Department of Cell Physiology, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Yusuke Ohba
- Department of Cell Physiology, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Yuji Kuge
- Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan
| | - Masahiko Watanabe
- Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Miki Fujimura
- Department of Neurosurgery, Faculty of Medicine, Hokkaido University, Sapporo, Japan
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Kanamaru H, Suzuki H. Therapeutic potential of stem cells in subarachnoid hemorrhage. Neural Regen Res 2025; 20:936-945. [PMID: 38989928 PMCID: PMC11438332 DOI: 10.4103/nrr.nrr-d-24-00124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 04/27/2024] [Indexed: 07/12/2024] Open
Abstract
Aneurysm rupture can result in subarachnoid hemorrhage, a condition with potentially severe consequences, such as disability and death. In the acute stage, early brain injury manifests as intracranial pressure elevation, global cerebral ischemia, acute hydrocephalus, and direct blood-brain contact due to aneurysm rupture. This may subsequently cause delayed cerebral infarction, often with cerebral vasospasm, significantly affecting patient outcomes. Chronic complications such as brain volume loss and chronic hydrocephalus can further impact outcomes. Investigating the mechanisms of subarachnoid hemorrhage-induced brain injury is paramount for identifying effective treatments. Stem cell therapy, with its multipotent differentiation capacity and anti-inflammatory effects, has emerged as a promising approach for treating previously deemed incurable conditions. This review focuses on the potential application of stem cells in subarachnoid hemorrhage pathology and explores their role in neurogenesis and as a therapeutic intervention in preclinical and clinical subarachnoid hemorrhage studies.
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Affiliation(s)
- Hideki Kanamaru
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
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Zhang X, Zhang Y, Peng X, Yang L, Miao J, Yue Y, Wang Y, Wang X, Zhu C, Song J. Targeting Neuroinflammation in Preterm White Matter Injury: Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes. Cell Mol Neurobiol 2025; 45:23. [PMID: 40072734 PMCID: PMC11903990 DOI: 10.1007/s10571-025-01540-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 03/02/2025] [Indexed: 03/14/2025]
Abstract
Neuroinflammation is a key factor in the development of preterm white matter injury (PWMI), leading to glial cell dysfunction, arrest of oligodendrocyte maturation, and long-term neurological damage. As a potential therapeutic strategy, mesenchymal stem cells (MSCs) exhibit significant immunomodulatory and regenerative potential. Recent studies suggest that the primary mechanism of MSC action is their paracrine effects, particularly mediated by extracellular vesicles, with MSC-derived exosomes (MSC-Exos) being the key mediators. MSC-Exos, enriched with lipids, proteins, and nucleic acids, regulate neuroinflammation by modulating glial cell activity and influencing signaling pathways associated with inflammation and repair. Preclinical evidence has indicated that MSC-Exos can suppress the activation of microglia and astrocytes, promote oligodendrocyte maturation, and enhance myelination, highlighting their potential as a cell-free treatment for PWMI. However, there are a paucity of comprehensive reviews on how MSC-Exos regulate neuroinflammation in PWMI through specific signaling pathways. This review aims to summarize the key signaling pathways through which MSC-Exos modulate neuroinflammation in PWMI and discuss the challenges associated with the clinical application of MSC-Exos-based therapies.
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Affiliation(s)
- Xinling Zhang
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Kangfu Qian Street 7, Zhengzhou, 450052, China
| | - Yuhang Zhang
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Kangfu Qian Street 7, Zhengzhou, 450052, China
| | - Xirui Peng
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Kangfu Qian Street 7, Zhengzhou, 450052, China
| | - Luxiang Yang
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Kangfu Qian Street 7, Zhengzhou, 450052, China
| | - Jingwen Miao
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Kangfu Qian Street 7, Zhengzhou, 450052, China
| | - Yuyang Yue
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Kangfu Qian Street 7, Zhengzhou, 450052, China
| | - Yong Wang
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Kangfu Qian Street 7, Zhengzhou, 450052, China
| | - Xiaoyang Wang
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Kangfu Qian Street 7, Zhengzhou, 450052, China
- Center for Perinatal Medicine and Health, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 40530, Gothenburg, Sweden
| | - Changlian Zhu
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Kangfu Qian Street 7, Zhengzhou, 450052, China.
- Department of Women's and Children's Health, Karolinska Institutet, 17176, Stockholm, Sweden.
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 11, Box 436, 405 30, Gothenburg, Sweden.
| | - Juan Song
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Kangfu Qian Street 7, Zhengzhou, 450052, China.
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Wang W, Wang Y, Gao L. Stem Cells Treatment for Subarachnoid Hemorrhage. Neurologist 2025; 30:80-86. [PMID: 39450602 DOI: 10.1097/nrl.0000000000000589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024]
Abstract
BACKGROUND Subarachnoid hemorrhage (SAH) refers to bleeding in the subarachnoid space, which is a serious neurologic emergency. However, the treatment effects of SAH are limited. In recent years, stem cell (SC) therapy has gradually become a very promising therapeutic method and advanced scientific research area for SAH. REVIEW SUMMARY The SCs used for SAH treatment are mainly bone marrow mesenchymal stem cells (BMSCs), umbilical cord mesenchymal stem cells (hUC-MSCs), dental pulp stem cells (DPSCs), neural stem cells (NSCs)/neural progenitor cell (NPC), and endothelial progenitor cell (EPC). The mechanisms mainly included differentiation and migration of SCs for tissue repair; alleviating neuronal apoptosis; anti-inflammatory effects; and blood-brain barrier (BBB) protection. The dosage of SCs was generally 10 6 orders of magnitude. The administration methods included intravenous injection, nasal, occipital foramen magnum, and intraventricular administration. The administration time is generally 1 hour after SAH modeling, but it may be as late as 24 hours or 6 days. Existing studies have confirmed the neuroprotective effect of SCs in the treatment of SAH. CONCLUSIONS SC has great potential application value in SAH treatment, a few case reports have provided support for this. However, the relevant research is still insufficient and there is still a lack of clinical research on the SC treatment for SAH to further evaluate the effectiveness and safety before it can go from experiment to clinical application.
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Affiliation(s)
| | | | - Liansheng Gao
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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He P, Zhang H, Wang J, Guo Y, Tian Q, Liu C, Gong P, Ye Q, Peng Y, Li M. Dental Pulp Stem Cells Attenuate Early Brain Injury After Subarachnoid Hemorrhage via miR-26a-5p/PTEN/AKT Pathway. Neurochem Res 2025; 50:91. [PMID: 39883266 DOI: 10.1007/s11064-025-04340-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/06/2025] [Accepted: 01/13/2025] [Indexed: 01/31/2025]
Abstract
Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke with high morbidity, mortality and disability, and early brain injury (EBI) after SAH is crucial for prognosis. Recently, stem cell therapy has garnered significant attention in the treatment of neurological diseases. Compared to other stem cells, dental pulp stem cells (DPSCs) possess several advantages, including abundant sources, absence of ethical concerns, non-invasive procurement, non-tumorigenic history and neuroprotective potential. Therefore, we aim to investigate whether DPSCs can improve EBI after SAH, and explore the mechanisms. In our study, we utilized the endovascular perforation method to establish a SAH mouse model and investigated whether DPSCs administered via tail vein injection could improve EBI after SAH. Furthermore, we used hemin-stimulated HT22 cells to simulate neuronal cell injury induced by SAH and employed a co-culture approach to examine the effects of DPSCs on these cells. To gain insights into the potential mechanisms underlying the improvement of SAH-induced EBI by DPSCs, we conducted bioinformatics analysis. Finally, we further validated our findings through experiments. In vivo experiments, we found that DPSCs administration improved neurological dysfunction, reduced brain edema, and prevented neuronal apoptosis in SAH mice. Additionally, we observed a decrease in the expression level of miR-26a-5p in the cortical tissues of SAH mice, which was significantly increased following intravenous injection of DPSCs. Through bioinformatic analysis and luciferase reporter assay, we confirmed the target relationship between miR-26a-5p and PTEN. Moreover, we demonstrated that DPSCs exerted neuroprotective effects by modulating the miR-26a-5p/PTEN/AKT pathway. Our study demonstrates that DPSCs can improve EBI after SAH through the miR-26a-5p/PTEN/AKT pathway, laying a foundation for the application of DPSCs in SAH treatment. These findings provide a theoretical basis for further investigating the therapeutic mechanisms of DPSCs and developing novel treatment strategies in SAH.
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Affiliation(s)
- Peibang He
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Hui Zhang
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Jianfeng Wang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Yujia Guo
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Qi Tian
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Chengli Liu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Pian Gong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Qingsong Ye
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Youjian Peng
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
| | - Mingchang Li
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
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Sankarappan K, Shetty AK. Promise of mesenchymal stem cell-derived extracellular vesicles for alleviating subarachnoid hemorrhage-induced brain dysfunction by neuroprotective and antiinflammatory effects. Brain Behav Immun Health 2024; 40:100835. [PMID: 39165307 PMCID: PMC11334735 DOI: 10.1016/j.bbih.2024.100835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 07/22/2024] [Accepted: 08/01/2024] [Indexed: 08/22/2024] Open
Abstract
Subarachnoid hemorrhage (SAH), accounting for ∼5% of all strokes, represents a catastrophic subtype of cerebrovascular accident. SAH predominantly results from intracranial aneurysm ruptures and affects ∼30,000 individuals annually in the United States and ∼6 individuals per 100,000 people worldwide. Recent studies have implicated that administering mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) may be beneficial in inducing neuroprotective and antiinflammatory effects following SAH. EVs are nanosized particles bound by a lipid bilayer. MSC-EVs comprise a therapeutic cargo of nucleic acids, lipids, and proteins, having the promise to ease SAH-induced long-term brain impairments. This review evaluated the findings of published studies on the therapeutic efficacy of MSC-EVs in the context of SAH. A growing body of evidence points out the therapeutic potential of MSC-EVs for improving brain function in animal models of SAH. Specifically, studies demonstrated their ability to reduce neuronal apoptosis and neuroinflammation and enhance neurological recovery through neuroprotective and antiinflammatory mechanisms. Such outcomes reported in various studies suggest that MSC-EVs hold great potential as a novel and minimally invasive approach to ameliorate SAH-induced neurological damage and improve patient outcomes. The review also discusses the limitations of EV therapy and the required future research efforts toward harnessing the full potential of MSC-EVs in treating SAH.
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Affiliation(s)
- Kiran Sankarappan
- Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University Health Science Center School of Medicine, College Station, TX, USA
| | - Ashok K. Shetty
- Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University Health Science Center School of Medicine, College Station, TX, USA
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Wang YY, Li K, Wang JJ, Hua W, Liu Q, Sun YL, Qi JP, Song YJ. Bone marrow-derived mesenchymal stem cell-derived exosome-loaded miR-129-5p targets high-mobility group box 1 attenuates neurological-impairment after diabetic cerebral hemorrhage. World J Diabetes 2024; 15:1979-2001. [PMID: 39280179 PMCID: PMC11372641 DOI: 10.4239/wjd.v15.i9.1979] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Diabetic intracerebral hemorrhage (ICH) is a serious complication of diabetes. The role and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived exosomes (BMSC-exo) in neuroinflammation post-ICH in patients with diabetes are unknown. In this study, we investigated the regulation of BMSC-exo on hyperglycemia-induced neuroinflammation. AIM To study the mechanism of BMSC-exo on nerve function damage after diabetes complicated with cerebral hemorrhage. METHODS BMSC-exo were isolated from mouse BMSC media. This was followed by transfection with microRNA-129-5p (miR-129-5p). BMSC-exo or miR-129-5p-overexpressing BMSC-exo were intravitreally injected into a diabetes mouse model with ICH for in vivo analyses and were cocultured with high glucose-affected BV2 cells for in vitro analyses. The dual luciferase test and RNA immunoprecipitation test verified the targeted binding relationship between miR-129-5p and high-mobility group box 1 (HMGB1). Quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were conducted to assess the levels of some inflammation factors, such as HMGB1, interleukin 6, interleukin 1β, toll-like receptor 4, and tumor necrosis factor α. Brain water content, neural function deficit score, and Evans blue were used to measure the neural function of mice. RESULTS Our findings indicated that BMSC-exo can promote neuroinflammation and functional recovery. MicroRNA chip analysis of BMSC-exo identified miR-129-5p as the specific microRNA with a protective role in neuroinflammation. Overexpression of miR-129-5p in BMSC-exo reduced the inflammatory response and neurological impairment in comorbid diabetes and ICH cases. Furthermore, we found that miR-129-5p had a targeted binding relationship with HMGB1 mRNA. CONCLUSION We demonstrated that BMSC-exo can reduce the inflammatory response after ICH with diabetes, thereby improving the neurological function of the brain.
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Affiliation(s)
- Yue-Ying Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ke Li
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Jia-Jun Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Wei Hua
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Qi Liu
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Lan Sun
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ji-Ping Qi
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yue-Jia Song
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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Wang YY, Li K, Wang JJ, Hua W, Liu Q, Sun YL, Qi JP, Song YJ. Bone marrow-derived mesenchymal stem cell-derived exosome-loaded miR-129-5p targets high-mobility group box 1 attenuates neurological-impairment after diabetic cerebral hemorrhage. World J Diabetes 2024; 15:1978-2000. [DOI: 10.4239/wjd.v15.i9.1978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Diabetic intracerebral hemorrhage (ICH) is a serious complication of diabetes. The role and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived exosomes (BMSC-exo) in neuroinflammation post-ICH in patients with diabetes are unknown. In this study, we investigated the regulation of BMSC-exo on hyperglycemia-induced neuroinflammation.
AIM To study the mechanism of BMSC-exo on nerve function damage after diabetes complicated with cerebral hemorrhage.
METHODS BMSC-exo were isolated from mouse BMSC media. This was followed by transfection with microRNA-129-5p (miR-129-5p). BMSC-exo or miR-129-5p-overexpressing BMSC-exo were intravitreally injected into a diabetes mouse model with ICH for in vivo analyses and were cocultured with high glucose-affected BV2 cells for in vitro analyses. The dual luciferase test and RNA immunoprecipitation test verified the targeted binding relationship between miR-129-5p and high-mobility group box 1 (HMGB1). Quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were conducted to assess the levels of some inflammation factors, such as HMGB1, interleukin 6, interleukin 1β, toll-like receptor 4, and tumor necrosis factor α. Brain water content, neural function deficit score, and Evans blue were used to measure the neural function of mice.
RESULTS Our findings indicated that BMSC-exo can promote neuroinflammation and functional recovery. MicroRNA chip analysis of BMSC-exo identified miR-129-5p as the specific microRNA with a protective role in neuroinflammation. Overexpression of miR-129-5p in BMSC-exo reduced the inflammatory response and neurological impairment in comorbid diabetes and ICH cases. Furthermore, we found that miR-129-5p had a targeted binding relationship with HMGB1 mRNA.
CONCLUSION We demonstrated that BMSC-exo can reduce the inflammatory response after ICH with diabetes, thereby improving the neurological function of the brain.
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Affiliation(s)
- Yue-Ying Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ke Li
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Jia-Jun Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Wei Hua
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Qi Liu
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Lan Sun
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ji-Ping Qi
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yue-Jia Song
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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Jiang S, Hu L, Zhou H, Wu J, Zhou J, Yu X, Chen G. Novel Therapeutic Mechanisms and Strategies for Intracerebral Hemorrhage: Focusing on Exosomes. Int J Nanomedicine 2024; 19:8987-9007. [PMID: 39246427 PMCID: PMC11378801 DOI: 10.2147/ijn.s473611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 08/20/2024] [Indexed: 09/10/2024] Open
Abstract
Intracerebral hemorrhage (ICH) is a primary, non-traumatic cerebral event associated with substantial mortality and disability. Despite advancements in understanding its etiology and refining diagnostic techniques, a validated treatment to significantly improve ICH prognosis remains elusive. Exosomes, a subtype of extracellular vesicles, encapsulate bioactive components, predominantly microRNAs (miRNAs), facilitating and regulating intercellular communication. Currently, exosomes have garnered considerable interests in clinical transformation for their nanostructure, minimal immunogenicity, low toxicity, inherent stability, and the ability to traverse the blood-brain barrier. A wealth of studies has demonstrated that exosomes can improve the prognosis of ICH through anti-apoptosis, neurogenesis, angiogenesis, anti-inflammation, immunomodulation, and autophagy, primarily via the transportation or overexpression of selected miRNAs. More importantly, exosomes can be easily customized with specific miRNAs or bioactive compounds to establish delivery systems, broadening their potential applications. This review focuses on the therapeutic potential of exosomes in ICH, reviewing the mechanisms of molecular biology mediated by certain miRNAs, discussing the benefits, challenges, and future prospects in ICH treatment. We hope comprehensive understanding of exosomes based on miRNAs will provide new insights into the treatment of ICH and guide the translation of exosome's research from laboratory to clinical practice.
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Affiliation(s)
- Shandong Jiang
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Libin Hu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Hang Zhou
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Jianan Wu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Jiayin Zhou
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Xian Yu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Gao Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
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Fang X, Zhou D, Wang X, Ma Y, Zhong G, Jing S, Huang S, Wang Q. Exosomes: A Cellular Communication Medium That Has Multiple Effects On Brain Diseases. Mol Neurobiol 2024; 61:6864-6892. [PMID: 38356095 DOI: 10.1007/s12035-024-03957-4] [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: 09/18/2023] [Accepted: 01/12/2024] [Indexed: 02/16/2024]
Abstract
Exosomes, as membranous vesicles generated by multiple cell types and secreted to extracellular space, play a crucial role in a range of brain injury-related brain disorders by transporting diverse proteins, RNA, DNA fragments, and other functional substances. The nervous system's pathogenic mechanisms are complicated, involving pathological processes like as inflammation, apoptosis, oxidative stress, and autophagy, all of which result in blood-brain barrier damage, cognitive impairment, and even loss of normal motor function. Exosomes have been linked to the incidence and progression of brain disorders in recent research. As a result, a thorough knowledge of the interaction between exosomes and brain diseases may lead to the development of more effective therapeutic techniques that may be implemented in the clinic. The potential role of exosomes in brain diseases and the crosstalk between exosomes and other pathogenic processes were discussed in this paper. Simultaneously, we noted the delicate events in which exosomes as a media allow the brain to communicate with other tissues and organs in physiology and disease, and compiled a list of natural compounds that modulate exosomes, in order to further improve our understanding of exosomes and propose new ideas for treating brain disorders.
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Affiliation(s)
- Xiaoling Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Dishu Zhou
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Xinyue Wang
- Department of Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510405, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 510405, Guangzhou, China
| | - Yujie Ma
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Guangcheng Zhong
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Shangwen Jing
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Shuiqing Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China.
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China.
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11
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Ge Y, Wu J, Zhang L, Huang N, Luo Y. A New Strategy for the Regulation of Neuroinflammation: Exosomes Derived from Mesenchymal Stem Cells. Cell Mol Neurobiol 2024; 44:24. [PMID: 38372822 PMCID: PMC10876823 DOI: 10.1007/s10571-024-01460-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/28/2024] [Indexed: 02/20/2024]
Abstract
Neuroinflammation is an important pathogenesis of neurological diseases and causes a series of physiopathological changes, such as abnormal activation of glial cells, neuronal degeneration and death, and disruption of the blood‒brain barrier. Therefore, modulating inflammation may be an important therapeutic tool for treating neurological diseases. Mesenchymal stem cells (MSCs), as pluripotent stem cells, have great therapeutic potential for neurological diseases due to their regenerative ability, immunity, and ability to regulate inflammation. However, recent studies have shown that MSC-derived exosomes (MSC-Exos) play a major role in this process and play a key role in neuroprotection by regulating neuroglia. This review summarizes the recent progress made in regulating neuroinflammation by focusing on the mechanisms by which MSC-Exos are involved in the regulation of glial cells through signaling pathways such as the TLR, NF-κB, MAPK, STAT, and NLRP3 pathways to provide some references for subsequent research and therapy.
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Affiliation(s)
- Ying Ge
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Jingjing Wu
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
- Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Li Zhang
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Nanqu Huang
- National Drug Clinical Trial Institution, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China.
| | - Yong Luo
- Department of Neurology, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China.
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12
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Tang S, Lai N, Xu L. Neuronal pyroptosis mediated by STAT3 in early brain injury after subarachnoid hemorrhage. Brain Res 2024; 1822:148666. [PMID: 37949309 DOI: 10.1016/j.brainres.2023.148666] [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: 08/16/2023] [Revised: 10/20/2023] [Accepted: 10/31/2023] [Indexed: 11/12/2023]
Abstract
Neuroinflammation induced by early brain injury (EBI) seriously affects the prognosis of patients after subarachnoid hemorrhage (SAH). Pyroptosis can aggravate inflammatory injury by promoting the secretion of inflammatory cytokines. Meanwhile, STAT3 plays a critical role in the inflammatory response of EBI after SAH. However, whether it plays a pyroptotic role in SAH is mainly unknown. This study aimed to explore the mechanism of STAT3 in pyroptosis in EBI after SAH. C57BL/6J mice were used to establish the SAH model. Brain tissues were collected at different time points for q-RT-PCR and western blot to detect the expression level of STAT3. After intracerebroventricular injection of STAT3 inhibitor S3I-201, they were divided into sham, SAH, SAH + Vehicle, and SAH + S3I-201. Then, the SAH grade, cerebral edema content, blood-brain barrier (BBB) damage, and neurological scores of mice in each group were detected. qRT-PCR and western blot were used to detect related genes and proteins, and enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of IL-18 and IL-1β. Immunofluorescence staining was used to observe the expression level of proteins. At the same time, S3I-201 was added to the primary neuron cells of the culture medium containing OxyHb to simulate the in vitro experiment, and the relevant indicators consistent with the in vivo experiment were detected. The expression of STAT3 was upregulated after SAH. Inhibition of STAT3 with S3I-201 attenuated neurological deficits, cerebral edema, and BBB damage after SAH. In addition, S3I-201 can also reduce the expression of pyroptosis-related inflammasomes such as GSDMD, NLRP3, Caspase 1, and AIM2 after SAH and the neurological damage caused by IL-18 and IL-1β. Further studies have shown that STAT3 regulates pyroptosis by promoting the nuclear translocation of NF-κB p65. Our finding demonstrated that STAT3 regulates neuronal pyroptosis in EBI after SAH. Inhibition of STAT3 may be a potential target to attenuate the damage that triggers neuroinflammation after SAH.
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Affiliation(s)
- Shengjie Tang
- The First School of Clinical Medicine, Xuzhou Medical University, Xuzhou, China
| | - Niansheng Lai
- The Translational Research Institute for Neurological Disorders of Wannan Medical College, Department of Neurosurgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China
| | - Liang Xu
- Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou), Chuzhou, China.
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Liao L, Wang H, Wei D, Yi M, Gu Y, Zhang M, Wang L. Exosomal microRNAs: implications in the pathogenesis and clinical applications of subarachnoid hemorrhage. Front Mol Neurosci 2023; 16:1300864. [PMID: 38143562 PMCID: PMC10748509 DOI: 10.3389/fnmol.2023.1300864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 11/22/2023] [Indexed: 12/26/2023] Open
Abstract
Subarachnoid hemorrhage (SAH) is a severe acute neurological disorder with a high fatality rate. Early brain injury (EBI) and cerebral vasospasm are two critical complications of SAH that significantly contribute to poor prognosis. Currently, surgical intervention and interventional therapy are the main treatment options for SAH, but their effectiveness is limited. Exosomes, which are a type of extracellular vesicles, play a crucial role in intercellular communication and have been extensively studied in the past decade due to their potential influence on disease progression, diagnosis, and treatment. As one of the most important components of exosomes, miRNA plays both direct and indirect roles in affecting disease progression. Previous research has found that exosomal miRNA is involved in the development of various diseases, such as tumors, chronic hepatitis, atherosclerosis, diabetes, and SAH. This review focuses on exploring the impact of exosomal miRNA on SAH, including its influence on neuronal apoptosis, inflammatory response, and immune activation following SAH. Furthermore, this review highlights the potential clinical applications of exosomal miRNA in the treatment of SAH. Although current research on this topic is limited and the clinical application of exosomal miRNA has inherent limitations, we aim to provide a concise summary of existing research progress and offer new insights for future research directions and trends in this field.
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Affiliation(s)
- Lishang Liao
- Department of Neurosurgery, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Haoran Wang
- Department of Neurosurgery, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Deli Wei
- Department of Neurosurgery, The People’s Hospital of Fushun County, Zigong, China
| | - Mingliang Yi
- Department of Neurosurgery, The People’s Hospital of Fushun County, Zigong, China
| | - Yingjiang Gu
- Department of Neurosurgery, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Department of Neurosurgery, The People’s Hospital of Fushun County, Zigong, China
| | - Mingwei Zhang
- Department of Neurosurgery, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Li Wang
- Department of Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
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Han W, Zhang H, Feng L, Dang R, Wang J, Cui C, Jiang P. The emerging role of exosomes in communication between the periphery and the central nervous system. MedComm (Beijing) 2023; 4:e410. [PMID: 37916034 PMCID: PMC10616655 DOI: 10.1002/mco2.410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 11/03/2023] Open
Abstract
Exosomes, membrane-enclosed vesicles, are secreted by all types of cells. Exosomes can transport various molecules, including proteins, lipids, functional mRNAs, and microRNAs, and can be circulated to various recipient cells, leading to the production of local paracrine or distal systemic effects. Numerous studies have proved that exosomes can pass through the blood-brain barrier, thus, enabling the transfer of peripheral substances into the central nervous system (CNS). Consequently, exosomes may be a vital factor in the exchange of information between the periphery and CNS. This review will discuss the structure, biogenesis, and functional characterization of exosomes and summarize the role of peripheral exosomes deriving from tissues like the lung, gut, skeletal muscle, and various stem cell types in communicating with the CNS and influencing the brain's function. Then, we further discuss the potential therapeutic effects of exosomes in brain diseases and the clinical opportunities and challenges. Gaining a clearer insight into the communication between the CNS and the external areas of the body will help us to ascertain the role of the peripheral elements in the maintenance of brain health and illness and will facilitate the design of minimally invasive techniques for diagnosing and treating brain diseases.
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Affiliation(s)
- Wenxiu Han
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Hailiang Zhang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Lei Feng
- Department of NeurosurgeryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
| | - Ruili Dang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Jing Wang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Changmeng Cui
- Department of NeurosurgeryAffiliated Hospital of Jining Medical UniversityJiningP. R. China
| | - Pei Jiang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
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15
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Elizaldi SR, Hawes CE, Verma A, Dinasarapu AR, Lakshmanappa YS, Schlegel BT, Rajasundaram D, Li J, Durbin-Johnson BP, Ma ZM, Beckman D, Ott S, Lifson J, Morrison JH, Iyer SS. CCR7+ CD4 T Cell Immunosurveillance Disrupted in Chronic SIV-Induced Neuroinflammation in Rhesus Brain. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.28.555037. [PMID: 37693567 PMCID: PMC10491118 DOI: 10.1101/2023.08.28.555037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
CD4 T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4 T cells resembling lymph node central memory (T CM ) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of T CM . Brain CCR7+ CD4 T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside other CNS border tissues. Sequestering T CM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4 T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL57 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4 T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4 T cells in CNS immune surveillance and their decline during chronic SIV-induced neuroinflammation highlights their responsiveness to neuroinflammatory processes. GRAPHICAL ABSTRACT In Brief Utilizing single-cell and spatial transcriptomics on adult rhesus brain, we uncover a unique CCR7+ CD4 T cell subset resembling central memory T cells (T CM ) within brain and border tissues, including skull bone marrow. Our findings show decreased frequencies of this subset during SIV- induced chronic neuroinflammation, emphasizing responsiveness of CCR7+ CD4 T cells to CNS disruptions. Highlights CCR7+ CD4 T cells survey border and parenchymal CNS compartments during homeostasis; reduced presence of CCR7+ CD4 T cells in cerebrospinal fluid leads to immune activation, implying a role in neuroimmune homeostasis. CNS CCR7+ CD4 T cells exhibit phenotypic and functional features of central memory T cells (T CM ) including production of interleukin 2 and the capacity for rapid recall proliferation. Furthermore, CCR7+ CD4 T cells reside in the skull bone marrow. CCR7+ CD4 T cells are markedly decreased within the brain parenchyma during chronic viral neuroinflammation.
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Aravindraja C, Jeepipalli S, Vekariya KM, Botello-Escalante R, Chan EKL, Kesavalu L. Oral Spirochete Treponema denticola Intraoral Infection Reveals Unique miR-133a, miR-486, miR-126-3p, miR-126-5p miRNA Expression Kinetics during Periodontitis. Int J Mol Sci 2023; 24:12105. [PMID: 37569480 PMCID: PMC10418472 DOI: 10.3390/ijms241512105] [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: 07/10/2023] [Revised: 07/25/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
miRNAs are major regulators of eukaryotic gene expression and host immunity, and play an important role in the inflammation-mediated pathways in periodontal disease (PD) pathogenesis. Expanding our previous observation with the global miRNA profiling using partial human mouth microbes, and lack of in vivo studies involving oral spirochete Treponema denticola-induced miRNAs, this study was designed to delineate the global miRNA expression kinetics during progression of periodontitis in mice infected with T. denticola by using NanoString nCounter® miRNA panels. All of the T. denticola-infected male and female mice at 8 and 16 weeks demonstrated bacterial colonization (100%) on the gingival surface, and an increase in alveolar bone resorption (p < 0.0001). A total of 70 miRNAs with at least 1.0-fold differential expression/regulation (DE) (26 upregulated and 44 downregulated) were identified. nCounter miRNA expression profiling identified 13 upregulated miRNAs (e.g., miR-133a, miR-378) and 25 downregulated miRNAs (e.g., miR-375, miR-34b-5p) in T. denticola-infected mouse mandibles during 8 weeks of infection, whereas 13 upregulated miRNAs (e.g., miR-486, miR-126-5p) and 19 downregulated miRNAs (miR-2135, miR-142-3p) were observed during 16 weeks of infection. One miRNA (miR-126-5p) showed significant difference between 8 and 16 weeks of infection. Interestingly, miR-126-5p has been presented as a potential biomarker in patients with periodontitis and coronary artery disease. Among the upregulated miRNAs, miR-486, miR-126-3p, miR-126-5p, miR-378a-3p, miR-22-3p, miR-151a-3p, miR-423-5p, and miR-221 were reported in human gingival plaques and saliva samples from periodontitis and with diabetes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed various functional pathways of DE miRNAs, such as bacterial invasion of epithelial cells, Ras signaling, Fc gamma R-mediated phagocytosis, osteoclast differentiation, adherens signaling, and ubiquitin mediated proteolysis. This is the first study of DE miRNAs in mouse mandibles at different time-points of T. denticola infection; the combination of three specific miRNAs, miR-486, miR-126-3p, and miR-126-5p, may serve as an invasive biomarker of T. denticola in PD. These miRNAs may have a significant role in PD pathogenesis, and this research establishes a link between miRNA, periodontitis, and systemic diseases.
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Affiliation(s)
- Chairmandurai Aravindraja
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.)
| | - Syam Jeepipalli
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.)
| | - Krishna Mukesh Vekariya
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.)
| | - Ruben Botello-Escalante
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.)
| | - Edward K. L. Chan
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
| | - Lakshmyya Kesavalu
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.)
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
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17
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Aguilar MA, Ebanks S, Markus H, Lewis MM, Midya V, Vrana K, Huang X, Hall MA, Kawasawa YI. Neuronally enriched microvesicle RNAs are differentially expressed in the serums of Parkinson's patients. Front Neurosci 2023; 17:1145923. [PMID: 37483339 PMCID: PMC10357515 DOI: 10.3389/fnins.2023.1145923] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 06/19/2023] [Indexed: 07/25/2023] Open
Abstract
Background Circulating small RNAs (smRNAs) originate from diverse tissues and organs. Previous studies investigating smRNAs as potential biomarkers for Parkinson's disease (PD) have yielded inconsistent results. We investigated whether smRNA profiles from neuronally-enriched serum exosomes and microvesicles are altered in PD patients and discriminate PD subjects from controls. Methods Demographic, clinical, and serum samples were obtained from 60 PD subjects and 40 age- and sex-matched controls. Exosomes and microvesicles were extracted and isolated using a validated neuronal membrane marker (CD171). Sequencing and bioinformatics analyses were used to identify differentially expressed smRNAs in PD and control samples. SmRNAs also were tested for association with clinical metrics. Logistic regression and random forest classification models evaluated the discriminative value of the smRNAs. Results In serum CD171 enriched exosomes and microvesicles, a panel of 29 smRNAs was expressed differentially between PD and controls (false discovery rate (FDR) < 0.05). Among the smRNAs, 23 were upregulated and 6 were downregulated in PD patients. Pathway analysis revealed links to cellular proliferation regulation and signaling. Least absolute shrinkage and selection operator adjusted for the multicollinearity of these smRNAs and association tests to clinical parameters via linear regression did not yield significant results. Univariate logistic regression models showed that four smRNAs achieved an AUC ≥ 0.74 to discriminate PD subjects from controls. The random forest model had an AUC of 0.942 for the 29 smRNA panel. Conclusion CD171-enriched exosomes and microvesicles contain the differential expression of smRNAs between PD and controls. Future studies are warranted to follow up on the findings and understand the scientific and clinical relevance.
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Affiliation(s)
- Morris A. Aguilar
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States
- Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, United States
| | - Shauna Ebanks
- Department of Neurology, College of Medicine, The Pennsylvania State University, Hershey, PA, United States
| | - Havell Markus
- Department of Neurology, College of Medicine, The Pennsylvania State University, Hershey, PA, United States
| | - Mechelle M. Lewis
- Department of Neurology, College of Medicine, The Pennsylvania State University, Hershey, PA, United States
- Department of Pharmacology, College of Medicine, The Pennsylvania State University, Hershey, PA, United States
| | - Vishal Midya
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Kent Vrana
- Department of Pharmacology, College of Medicine, The Pennsylvania State University, Hershey, PA, United States
| | - Xuemei Huang
- Department of Neurology, College of Medicine, The Pennsylvania State University, Hershey, PA, United States
- Department of Pharmacology, College of Medicine, The Pennsylvania State University, Hershey, PA, United States
| | - Molly A. Hall
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States
- Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, United States
| | - Yuka Imamura Kawasawa
- Department of Pharmacology, College of Medicine, The Pennsylvania State University, Hershey, PA, United States
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, United States
- Institute for Personalized Medicine, College of Medicine, The Pennsylvania State University, Hershey, PA, United States
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18
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Thomaidou AC, Goulielmaki M, Tsintarakis A, Zoumpourlis P, Toya M, Christodoulou I, Zoumpourlis V. miRNA-Guided Regulation of Mesenchymal Stem Cells Derived from the Umbilical Cord: Paving the Way for Stem-Cell Based Regeneration and Therapy. Int J Mol Sci 2023; 24:ijms24119189. [PMID: 37298143 DOI: 10.3390/ijms24119189] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 05/19/2023] [Accepted: 05/21/2023] [Indexed: 06/12/2023] Open
Abstract
The human body is an abundant source of multipotent cells primed with unique properties that can be exploited in a multitude of applications and interventions. Mesenchymal stem cells (MSCs) represent a heterogenous population of undifferentiated cells programmed to self-renew and, depending on their origin, differentiate into distinct lineages. Alongside their proven ability to transmigrate toward inflammation sites, the secretion of various factors that participate in tissue regeneration and their immunoregulatory function render MSCs attractive candidates for use in the cytotherapy of a wide spectrum of diseases and conditions, as well as in different aspects of regenerative medicine. In particular, MSCs that can be found in fetal, perinatal, or neonatal tissues possess additional capabilities, including predominant proliferation potential, increased responsiveness to environmental stimuli, and hypoimmunogenicity. Since microRNA (miRNA)-guided gene regulation governs multiple cellular functions, miRNAs are increasingly being studied in the context of driving the differentiation process of MSCs. In the present review, we explore the mechanisms of miRNA-directed differentiation of MSCs, with a special focus on umbilical cord-derived mesenchymal stem cells (UCMSCs), and we identify the most relevant miRNAs and miRNA sets and signatures. Overall, we discuss the potent exploitations of miRNA-driven multi-lineage differentiation and regulation of UCMSCs in regenerative and therapeutic protocols against a range of diseases and/or injuries that will achieve a meaningful clinical impact through maximizing treatment success rates, while lacking severe adverse events.
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Affiliation(s)
- Arsinoe C Thomaidou
- Laboratory of Clinical Virology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Maria Goulielmaki
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522 Athens, Greece
| | - Antonis Tsintarakis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece
| | - Panagiotis Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece
| | - Marialena Toya
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece
| | - Ioannis Christodoulou
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece
| | - Vassilis Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece
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Segherlou ZH, Saldarriaga L, Azizi E, Vo KA, Reddy R, Siyanaki MRH, Lucke-Wold B. MicroRNAs' Role in Diagnosis and Treatment of Subarachnoid Hemorrhage. Diseases 2023; 11:77. [PMID: 37366865 DOI: 10.3390/diseases11020077] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/11/2023] [Accepted: 05/17/2023] [Indexed: 06/28/2023] Open
Abstract
Subarachnoid hemorrhage (SAH) is most commonly seen in patients over 55 years of age and often results in a loss of many productive years. SAH has a high mortality rate, and survivors often suffer from early and secondary brain injuries. Understanding the pathophysiology of the SAH is crucial in identifying potential therapeutic agents. One promising target for the diagnosis and prognosis of SAH is circulating microRNAs, which regulate gene expression and are involved in various physiological and pathological processes. In this review, we discuss the potential of microRNAs as a target for diagnosis, treatment, and prognosis in SAH.
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Affiliation(s)
| | | | - Esaan Azizi
- College of Medicine, University of Florida, Gainesville, FL 32661, USA
| | - Kim-Anh Vo
- College of Medicine, University of Florida, Gainesville, FL 32661, USA
| | - Ramya Reddy
- College of Medicine, University of Florida, Gainesville, FL 32661, USA
| | | | - Brandon Lucke-Wold
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, FL 32661, USA
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Zou Y, Liao L, Dai J, Mazhar M, Yang G, Wang H, Dechsupa N, Wang L. Mesenchymal stem cell-derived extracellular vesicles/exosome: A promising therapeutic strategy for intracerebral hemorrhage. Regen Ther 2023; 22:181-190. [PMID: 36860266 PMCID: PMC9969203 DOI: 10.1016/j.reth.2023.01.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/15/2023] [Accepted: 01/26/2023] [Indexed: 02/22/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is the second largest type of stroke with high mortality and morbidity. The vast majority of survivors suffer from serious neurological defects. Despite the well-established etiology and diagnose, there is still some controversy over the ideal treatment strategy. MSC-based therapy has become an attractive and promising strategy for the treatment of ICH through immune regulation and tissue regeneration. However, accumulating studies have revealed that MSC-based therapeutic effects are mainly attributed to the paracrine properties of MSC, especially small extracellular vesicles/exosome (EVs/exo) which are considered to be the key mediators of the protective efficacy from MSCs. Moreover, some papers reported that MSC-EVs/exo have better therapeutic effects than MSCs. Therefore, EVs/exo has become a new choice for the treatment of ICH stroke in recent years. In this review, we mainly concentrate on the current research progress on the use of MSC-EVs/exo in the treatment of ICH and the existing challenges in their transplation from lab to clinical practice.
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Affiliation(s)
- Yuanxia Zou
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China,Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand,Department of Newborn Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Lishang Liao
- Department of Neurosurgery,The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Jian Dai
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, China
| | - Maryam Mazhar
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China,Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, China
| | - Guoqiang Yang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China,Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Honglian Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand,Corresponding author.
| | - Li Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China,Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, China,Corresponding author.
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21
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Lu Z, Tang H, Li S, Zhu S, Li S, Huang Q. Role of Circulating Exosomes in Cerebrovascular Diseases: A Comprehensive Review. Curr Neuropharmacol 2023; 21:1575-1593. [PMID: 36847232 PMCID: PMC10472809 DOI: 10.2174/1570159x21666230214112408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 10/04/2022] [Accepted: 11/03/2022] [Indexed: 03/01/2023] Open
Abstract
Exosomes are lipid bilayer vesicles that contain multiple macromolecules secreted by the parent cells and play a vital role in intercellular communication. In recent years, the function of exosomes in cerebrovascular diseases (CVDs) has been intensively studied. Herein, we briefly review the current understanding of exosomes in CVDs. We discuss their role in the pathophysiology of the diseases and the value of the exosomes for clinical applications as biomarkers and potential therapies.
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Affiliation(s)
- Zhiwen Lu
- Department of Neurovascular Centre, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Haishuang Tang
- Department of Nerurosurgery, Naval Medical Center of PLA, Navy Medical University, Shanghai, 200050, China
| | - Sisi Li
- Department of Cerebrovascular Intervention, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Shijie Zhu
- Department of Neurovascular Centre, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Siqi Li
- Department of Neurovascular Centre, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Qinghai Huang
- Department of Neurovascular Centre, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
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22
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He J, Liu J, Huang Y, Lan Z, Tang X, Hu Z. Mesenchymal stem cells-derived therapies for subarachnoid hemorrhage in preclinical rodent models: a meta-analysis. Stem Cell Res Ther 2022; 13:42. [PMID: 35093176 PMCID: PMC8800223 DOI: 10.1186/s13287-022-02725-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 12/18/2021] [Indexed: 12/11/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) and MSCs-derived extracellular vesicles (EVs) have emerged as potential novel therapies for subarachnoid hemorrhage (SAH). However, their effects remain incompletely understood. We aim to comprehensively evaluate the effect of MSCs-derived therapies in rodent models of SAH. Methods We searched PubMed, EMBASE, and Web of Science up to September 2021 to identify studies that reported the effects of MSCs or MSCs-derived EVs in a rodent SAH model. Neurobehavioral score was extracted as the functional outcome, and brain water content was measured as the histopathological outcome. A random-effects model was used to calculate the standardized mean difference (SMD) and confidence interval (CI). Results Nine studies published from 2018 to 2021 met the inclusion criteria. Studies quality scores ranged from 5 to 10, with a mean value of 7.22. Our results revealed an overall positive effect of MSCs and MSCs-derived EVs on the neurobehavioral score with a SMD of − 2.21 (95% CI − 3.14, − 1.08; p < 0.0001). Meanwhile, we also found that MSCs and MSCs-derived EVs reduced brain water content by a SMD of − 2.09 (95% CI − 2.99, − 1.19; p < 0.00001). Significant heterogeneity among studies was observed, further stratified and sensitivity analyses did not identify the source of heterogeneity. Conclusions Our results suggested that MSCs-derived therapies prominently improved functional recovery and reduced brain edema in the rodent models of SAH. Notably, the limitations of small sample size should be considered when interpreting the results, and large animal studies and human trials are needed for further investigation. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02725-2.
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