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Zhang J, Han J, Li N, Zhou W. Deciphering the Protective Role of HIF-1α Downregulation on HIBD through the MALAT1/miR-140-5p/TGFBR1/NF-κB Signaling Pathway. Mol Neurobiol 2025; 62:3343-3360. [PMID: 39278884 DOI: 10.1007/s12035-024-04451-7] [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: 11/08/2023] [Accepted: 08/21/2024] [Indexed: 09/18/2024]
Abstract
Hypoxic-ischemic brain damage (HIBD) in neonates is a substantial cause of mortality and neurodevelopmental impairment, with the exact molecular mechanisms still being elucidated. The involvement of HIF-1α, MALAT1, miR-140-5p, TGFBR1, and the NF-κB signaling pathway in such injury cascades is of increasing research interest due to their pivotal roles in cellular and pathological processes. This study aimed to explore how HIF-1α regulates the MALAT1/miR-140-5p/TGFBR1/NF-κB signaling axis to participate in the molecular mechanisms of HIBD in neonatal rats. Utilizing bioinformatic analyses and a suite of experimental approaches, the study delineated interactions and regulatory relationships among the molecules. Knockdown of HIF-1α was shown to mitigate brain tissue damage in a neonatal HIBD rat model through the MALAT1/miR-140-5p/TGFBR1/NF-κB signaling axis, revealing a protective effect achieved by inhibiting hippocampal neuron apoptosis and potentially guiding the way toward therapeutic interventions in HIBD. This study implicates the HIF-1α mediated regulation of the MALAT1/miR-140-5p/TGFBR1/NF-κB signaling axis in the pathological development of HIBD, offering insights into novel potential interventional strategies.
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MESH Headings
- Animals
- MicroRNAs/metabolism
- MicroRNAs/genetics
- RNA, Long Noncoding/metabolism
- RNA, Long Noncoding/genetics
- Signal Transduction/physiology
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- NF-kappa B/metabolism
- Down-Regulation
- Hypoxia-Ischemia, Brain/metabolism
- Hypoxia-Ischemia, Brain/pathology
- Hypoxia-Ischemia, Brain/genetics
- Receptor, Transforming Growth Factor-beta Type I/metabolism
- Animals, Newborn
- Rats, Sprague-Dawley
- Rats
- Apoptosis
- Neurons/metabolism
- Neurons/pathology
- Hippocampus/pathology
- Hippocampus/metabolism
- Male
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Affiliation(s)
- Jiantao Zhang
- Colorectal & Anal Surgery Department, General Surgery Center, First Hospital of Jilin University, Changchun, 130000, People's Republic of China
| | - Jun Han
- Department of Neonatology, the First Hospital of Jilin University, No. 71, Xinmin Street, Changchun, 130000, Jilin Province, People's Republic of China
| | - Nan Li
- Department of Neonatology, the First Hospital of Jilin University, No. 71, Xinmin Street, Changchun, 130000, Jilin Province, People's Republic of China
| | - Wenli Zhou
- Department of Neonatology, the First Hospital of Jilin University, No. 71, Xinmin Street, Changchun, 130000, Jilin Province, People's Republic of China.
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Maltais-Bilodeau C, Henckel E, Deguise MO, Lesage F, Cobey KD, Ahmadzai N, Skidmore B, Ferretti E, Thébaud B. Cell-based therapies in preclinical models of necrotizing enterocolitis: a systematic review and meta-analysis. Stem Cells Transl Med 2025; 14:szae102. [PMID: 40036304 PMCID: PMC11878585 DOI: 10.1093/stcltm/szae102] [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: 08/29/2024] [Accepted: 12/18/2024] [Indexed: 03/06/2025] Open
Abstract
Necrotizing enterocolitis (NEC) remains an incurable gut complication of prematurity with significant morbidity and mortality. Cell therapies, including mesenchymal stromal cells (MSCs), may be a promising treatment given their anti-inflammatory and regenerative potential. We assessed the effect of MSCs and other cell therapies (not classified as MSCs) on incidence, severity, and mortality in preclinical models of NEC. Bibliographic and gray literature searches yielded 17 371 records with 107 full-text articles assessed and ultimately 16 studies were included. These studies featured only rodents NEC models via combination of hyperosmolar feeds, hypoxia, hypothermia, or lipopolysaccharides. Ten studies used interventions with MSCs. Only 2 met the minimal criteria to define MSCs proposed by the International Society for Cell & Gene Therapy (ISCT). The overall risk of bias was assessed as high partly due to paucity of data with important gaps in reporting, reinforcing the importance of rigorous research framework, appropriate cell-therapy and outcome reporting in preclinical research. A reduction in the incidence of NEC (odds ratio [OR] 0.32, 95% CI [0.17, 0.62]), severe NEC (OR 0.30, 95% CI [0.18, 0.50]), and mortality (OR 0.30, 95% CI [0.16, 0.55]) was noted with MSCs treatment, seemingly more pronounced for ISCT-defined (ISCT+) MSCs. Amniotic fluid stem cells, neural stem cells, and placenta stem cells also showed a reduction in these measures. Given their accessibility (ie, umbilical cord) and proven safety profile in extremely preterm infants, our analysis provides a foundation for considering MSCs as promising candidate that requires further evaluation for the treatment of NEC.
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Affiliation(s)
- Camille Maltais-Bilodeau
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
- Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital, General Campus, Ottawa, ON K1H 8L6, Canada
| | - Ewa Henckel
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm 171 77, Sweden
- Department of Neonatology, Karolinska University Hospital, Stockholm 171 77, Sweden
- Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Marc-Olivier Deguise
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
- Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital, General Campus, Ottawa, ON K1H 8L6, Canada
- Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Flore Lesage
- Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Kelly D Cobey
- Meta Research and Open Science Program, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada
- School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Nadera Ahmadzai
- Independent Information Specialist, Ottawa, ON K1T 3Z2, Canada
| | - Becky Skidmore
- Independent Information Specialist, Ottawa, ON K1T 3Z2, Canada
| | - Emanuela Ferretti
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
- Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital, General Campus, Ottawa, ON K1H 8L6, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Bernard Thébaud
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
- Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital, General Campus, Ottawa, ON K1H 8L6, Canada
- Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
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Kim S, Sharma C, Hong J, Kim JH, Nam Y, Kim MS, Lee TY, Kim KS, Suk K, Lee HW, Kim SR. Post-symptomatic administration of hMSCs exerts therapeutic effects in SCA2 mice. Stem Cell Res Ther 2024; 15:411. [PMID: 39521966 PMCID: PMC11550562 DOI: 10.1186/s13287-024-04020-8] [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: 03/04/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Defects in the ataxin-2 (ATXN-2) protein and CAG trinucleotide repeat expansion in its coding gene, Atxn-2, cause the neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2). While clinical studies suggest potential benefits of human-derived mesenchymal stem cells (hMSCs) for treating various ataxias, the exact mechanisms underlying their therapeutic effects and interaction with host tissue to stimulate neurotrophin expression remain unclear specifically in the context of SCA2. METHODS Human bone marrow-derived MSCs (hMSCs) were injected into the cisterna magna of 26-week-old wild-type and SCA2 mice. Mice were assessed for impaired motor coordination using the accelerating rotarod, open field test, and composite phenotype scoring. At 50 weeks, the cerebellum vermis was harvested for protein assessment and immunohistochemical analysis. RESULTS Significant loss of NeuN and calbindin was observed in 25-week-old SCA2 mice. However, after receiving multiple injections of hMSCs starting at 26 weeks of age, these mice exhibited a significant improvement in abnormal motor performance and a protective effect on Purkinje cells. This beneficial effect persisted until the mice reached 50 weeks of age, at which point they were sacrificed to study further mechanistic events triggered by the administration of hMSCs. Calbindin-positive cells in the Purkinje cell layer expressed bone-derived neurotrophic factor after hMSC administration, contributing to the protection of cerebellar neurons from cell death. CONCLUSION In conclusion, repeated administration of hMSCs shows promise in alleviating SCA2 symptoms by preserving Purkinje cells, improving neurotrophic support, and reducing inflammation, ultimately leading to the preservation of locomotor function in SCA2 mice.
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Affiliation(s)
- Sehwan Kim
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, Korea
- Brain Science and Engineering Institute, Kyungpook National University, Daegu, 41944, Korea
| | - Chanchal Sharma
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, Korea
- Byrd Alzheimer's Centre and Research Institute, University of South Florida, Tampa, FL, 33620, USA
| | - Jungwan Hong
- Brain Science and Engineering Institute, Kyungpook National University, Daegu, 41944, Korea
| | - Jong-Heon Kim
- Brain Science and Engineering Institute, Kyungpook National University, Daegu, 41944, Korea
| | - Youngpyo Nam
- Brain Science and Engineering Institute, Kyungpook National University, Daegu, 41944, Korea
| | - Min Sung Kim
- Bioengineering Institute, Corestemchemon Inc, Seoul, 13486, Korea
| | - Tae Yong Lee
- Bioengineering Institute, Corestemchemon Inc, Seoul, 13486, Korea
| | - Kyung-Suk Kim
- Bioengineering Institute, Corestemchemon Inc, Seoul, 13486, Korea
| | - Kyoungho Suk
- Brain Science and Engineering Institute, Kyungpook National University, Daegu, 41944, Korea
- Department of Pharmacology and Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, Korea
| | - Ho-Won Lee
- Brain Science and Engineering Institute, Kyungpook National University, Daegu, 41944, Korea
- Department of Neurology, Kyungpook National University Chilgok Hospital, Daegu, 41404, Korea
| | - Sang Ryong Kim
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, Korea.
- Brain Science and Engineering Institute, Kyungpook National University, Daegu, 41944, Korea.
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Zhang C, Ye W, Zhao M, Long L, Xia D, Fan Z. MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. Int J Oral Sci 2023; 15:48. [PMID: 37852994 PMCID: PMC10584904 DOI: 10.1038/s41368-023-00253-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 10/20/2023] Open
Abstract
Mesenchymal stem cell (MSC)-based therapy has emerged as a promising treatment for spinal cord injury (SCI), but improving the neurogenic potential of MSCs remains a challenge. Mixed lineage leukemia 1 (MLL1), an H3K4me3 methyltransferases, plays a critical role in regulating lineage-specific gene expression and influences neurogenesis. In this study, we investigated the role and mechanism of MLL1 in the neurogenesis of stem cells from apical papilla (SCAPs). We examined the expression of neural markers, and the nerve repair and regeneration ability of SCAPs using dynamic changes in neuron-like cells, immunofluorescence staining, and a SCI model. We employed a coimmunoprecipitation (Co-IP) assay, real-time RT-PCR, microarray analysis, and chromatin immunoprecipitation (ChIP) assay to investigate the molecular mechanism. The results showed that MLL1 knock-down increased the expression of neural markers, including neurogenic differentiation factor (NeuroD), neural cell adhesion molecule (NCAM), tyrosine hydroxylase (TH), βIII-tubulin and Nestin, and promoted neuron-like cell formation in SCAPs. In vivo, a transplantation experiment showed that depletion of MLL 1 in SCAPs can restore motor function in a rat SCI model. MLL1 can combine with WD repeat domain 5 (WDR5) and WDR5 inhibit the expression of neural markers in SCAPs. MLL1 regulates Hairy and enhancer of split 1 (HES1) expression by directly binds to HES1 promoters via regulating H3K4me3 methylation by interacting with WDR5. Additionally, HES1 enhances the expression of neural markers in SCAPs. Our findings demonstrate that MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. These results provide a potential therapeutic target for promoting the recovery of motor function in SCI patients.
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Affiliation(s)
- Chen Zhang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
- Department of Dental Emergency, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Weilong Ye
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Mengyao Zhao
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Lujue Long
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Dengsheng Xia
- Department of Dental Emergency, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Zhipeng Fan
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China.
- Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China.
- Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China.
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5
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Chen N, Wang YL, Sun HF, Wang ZY, Zhang Q, Fan FY, Ma YC, Liu FX, Zhang YK. Potential regulatory effects of stem cell exosomes on inflammatory response in ischemic stroke treatment. World J Stem Cells 2023; 15:561-575. [PMID: 37424949 PMCID: PMC10324506 DOI: 10.4252/wjsc.v15.i6.561] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 04/22/2023] [Accepted: 05/16/2023] [Indexed: 06/26/2023] Open
Abstract
The high incidence and disability rates of stroke pose a heavy burden on society. Inflammation is a significant pathological reaction that occurs after an ischemic stroke. Currently, therapeutic methods, except for intravenous thrombolysis and vascular thrombectomy, have limited time windows. Mesenchymal stem cells (MSCs) can migrate, differentiate, and inhibit inflammatory immune responses. Exosomes (Exos), which are secretory vesicles, have the characteristics of the cells from which they are derived, making them attractive targets for research in recent years. MSC-derived exosomes can attenuate the inflammatory response caused by cerebral stroke by modulating damage-associated molecular patterns. In this review, research on the inflammatory response mechanisms associated with Exos therapy after an ischemic injury is discussed to provide a new approach to clinical treatment.
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Affiliation(s)
- Na Chen
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Yan-Lin Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Hui-Fang Sun
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhuo-Ya Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Qi Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Fei-Yan Fan
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Yu-Cheng Ma
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Fei-Xiang Liu
- Department of Neurology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Yun-Ke Zhang
- Department of Neurology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
- School of Rehabilitation Medicine, Henan University of Chinese Medicine, Zhengzhou 450008, Henan Province, China
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6
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Gao J, Liang Y, Chen J, Shen H, Liu H. CXCR4 enhances the inhibitory effects of bone mesenchymal stem cells on lung cell apoptosis in a rat model of smoking-induced COPD. Apoptosis 2023; 28:639-652. [PMID: 36719470 PMCID: PMC9888343 DOI: 10.1007/s10495-022-01800-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2022] [Indexed: 02/01/2023]
Abstract
Chronic obstructive pulmonary disease is the 3rd leading cause of death worldwide, and the available treatments are unsatisfactory, resulting in a major economic burden. As cellular therapy is commonly used for lung disease, we investigated a treatment with CXCR4-overexpressing BMSCs in a COPD model. We extracted and purified Bone marrow mesenchymal stem cells (BMSCs) from SD rats. COPD apoptosis model was established by cigarette smoke exposure. BMSCs (1 × 106 cells per injection)were transplanted in vivo twice a month during model establishment, and alveolar rupture in the lung was assessed. Lung cell apoptosis was assessed by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) analysis, and the concentrations of apoptotic proteins in the lungs were detected by Western blotting. We successfully isolated BMSCs and established CXCR4-overexpressing BMSCs. qRT‒PCR and Western blotting detection both reveal that CXCR4 mRNA level and protein both significantly higher expression in CXCR4-BMSCs than the pBABE-BMSCs. Continuous cigarette smoke exposure caused alveolar septal rupture: In the model group, the alveolar mean linear intercept in the first month was significantly lower than that in the third month (p < 0.05). In the third month, the alveolar mean linear intercept values of the control and CXCR4-BMSC groups were lower than those of the model group (control group p < 0.01, CXCR4-BMSC group p < 0.05), and TUNEL staining revealed that the apoptosis rates of the control and CXCR4-BMSC groups were significantly lower than those of the model group (p < 0.01). Furthermore, the levels of the apoptotic proteins cleaved caspase-8, cleaved caspase-3 and cleaved PARP-1 were higher in the model group than in the control group (p < 0.05) and significantly lower in the CXCR4-BMSC group than in the model group (p < 0.05). The transplantation of CXCR4-overexpressing BMSCs during COPD model generation significantly inhibited apoptosis via the extrinsic apoptosis pathway. CXCR4 enhances the inhibitory effects of bone mesenchymal stem cells on lung cell apoptosis in a rat model of smoking-induced COPD.
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Affiliation(s)
- Jiansheng Gao
- First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yuli Liang
- First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiabao Chen
- First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Huihui Shen
- First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Hua Liu
- First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.
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7
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Isaković J, Šerer K, Barišić B, Mitrečić D. Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force? Front Bioeng Biotechnol 2023; 11:1139359. [PMID: 36926687 PMCID: PMC10011535 DOI: 10.3389/fbioe.2023.1139359] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Neurological disorders are recognized as major causes of death and disability worldwide. Because of this, they represent one of the largest public health challenges. With awareness of the massive burden associated with these disorders, came the recognition that treatment options were disproportionately scarce and, oftentimes, ineffective. To address these problems, modern research is increasingly looking into novel, more effective methods to treat neurological patients; one of which is cell-based therapies. In this review, we present a critical analysis of the features, challenges, and prospects of one of the stem cell types that can be employed to treat numerous neurological disorders-mesenchymal stem cells (MSCs). Despite the fact that several studies have already established the safety of MSC-based treatment approaches, there are still some reservations within the field regarding their immunocompatibility, heterogeneity, stemness stability, and a range of adverse effects-one of which is their tumor-promoting ability. We additionally examine MSCs' mechanisms of action with respect to in vitro and in vivo research as well as detail the findings of past and ongoing clinical trials for Parkinson's and Alzheimer's disease, ischemic stroke, glioblastoma multiforme, and multiple sclerosis. Finally, this review discusses prospects for MSC-based therapeutics in the form of biomaterials, as well as the use of electromagnetic fields to enhance MSCs' proliferation and differentiation into neuronal cells.
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Affiliation(s)
- Jasmina Isaković
- Omnion Research International, Zagreb, Croatia.,Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Klara Šerer
- University of Zagreb School of Medicine, Zagreb, Croatia
| | - Barbara Barišić
- University of Zagreb School of Dental Medicine, Zagreb, Croatia
| | - Dinko Mitrečić
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia.,Laboratory for Stem Cells, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
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8
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Asgari Taei A, Khodabakhsh P, Nasoohi S, Farahmandfar M, Dargahi L. Paracrine Effects of Mesenchymal Stem Cells in Ischemic Stroke: Opportunities and Challenges. Mol Neurobiol 2022; 59:6281-6306. [PMID: 35922728 DOI: 10.1007/s12035-022-02967-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 07/17/2022] [Indexed: 10/16/2022]
Abstract
It is well acknowledged that neuroprotective effects of transplanted mesenchymal stem cells (MSCs) in ischemic stroke are attributed to their paracrine-mediated actions or bystander effects rather than to cell replacement in infarcted areas. This therapeutic plasticity is due to MSCs' ability to secrete a broad range of bioactive molecules including growth factors, trophic factors, cytokines, chemokines, and extracellular vesicles, overall known as the secretome. The secretome derivatives, such as conditioned medium (CM) or purified extracellular vesicles (EVs), exert remarkable advantages over MSC transplantation in stroke treating. Here, in this review, we used published information to provide an overview on the secretome composition of MSCs, underlying mechanisms of therapeutic effects of MSCs, and preclinical studies on MSC-derived products application in stroke. Furthermore, we discussed current advantages and challenges for successful bench-to-bedside translation.
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Affiliation(s)
- Afsaneh Asgari Taei
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pariya Khodabakhsh
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sanaz Nasoohi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Farahmandfar
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Dargahi
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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9
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Neuroprotection of Bone Marrow-Derived Mesenchymal Stem Cell-Derived Extracellular Vesicle-Enclosed miR-410 Correlates with HDAC4 Knockdown in Hypoxic-Ischemic Brain Damage. Neurochem Res 2022; 47:3150-3166. [PMID: 36028735 DOI: 10.1007/s11064-022-03670-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 06/07/2022] [Accepted: 06/23/2022] [Indexed: 10/15/2022]
Abstract
Evidence exists reporting that miR-410 may rescue neurological deficits, neuronal injury, and neuronal apoptosis after experimental hypoxic ischemia. This study aimed to explore the mechanism by which miR-410 transferred by bone marrow-derived mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) may alleviate hypoxic-ischemic brain damage (HIBD) in newborn mice. BMSCs were isolated from total bone marrow cells of femur and tibia of newborn mice, and primary neurons were extracted from the cerebral cortex of newborn mice within 24 h of birth. EVs were extracted from BMSCs transfected with the mimic or inhibitor of miR-410. Primary neurons were subjected to hypoxia and treated with overexpression (oe)-HDAC4, small interfering RNA (siRNA)-β-catenin, or Wnt pathway inhibitor and/or EV (miR-410 mimic) or EV (miR-410 inhibitor). A neonatal mouse HIBD model was established and treated with EVs. When BMSC-EVs were endocytosed by primary neurons, miR-410 was upregulated, neuronal viability was elevated, and apoptosis was inhibited. miR-410 in BMSC-EVs targeted HDAC4, thus increasing neuronal viability and reducing apoptosis. Conversely, overexpression of HDAC4 activated the Wnt pathway and enhanced the nuclear translocation of β-catenin. Treatment with miR-410-containing BMSC-EVs improved learning and memory abilities of HIBD mice while attenuating apoptosis by inactivating the Wnt pathway via targeting HDAC4. Taken together, the findings suggest that miR-410 delivered by BMSC-EVs alleviates HIBD by inhibiting HDAC4-dependent Wnt pathway activation.
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10
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Shibl NG, Fikry EM, Mansour HA, Alsemeh AE, Abdel-Ghany RH, El-Sayed SS. Ameliorative effect of bone marrow-derived mesenchymal stem cells on burn-induced hepatic and metabolic derangements in rats. Life Sci 2022; 307:120891. [PMID: 36007609 DOI: 10.1016/j.lfs.2022.120891] [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: 04/16/2022] [Revised: 08/08/2022] [Accepted: 08/16/2022] [Indexed: 11/18/2022]
Abstract
AIMS The current study aims to investigate the therapeutic potential of bone marrow-derived mesenchymal stem cells (MSCs) as a solo therapy in ameliorating both skin lesions and liver injury induced by cutaneous severe burn injury (SBI) in rats. MAIN METHODS In anesthetized male adult Wistar albino rats, 30 % total burn surface area and established hepatic injury was achieved via direct contact of each experimental animal's dorsum with heated metal rod (100 °C) for 10 s. On the next day following burn, human MSCs or mouse MSCs was administered locally around the burn site and intraperitonially (0.5 × 106 cells/rat for each route) and outcomes were investigated at 4 and 14 days following burn induction. KEY FINDINGS Both types of MSCs significantly improved skin and liver histology, decreased liver enzymes, and ameliorated oxidative stress in hepatocytes of SBI-rats. Further, SBI-induced rises in hepatic apoptotic marker (caspase-3, Bax) and serum inflammatory markers (TNF-α, IL-1β, and IL-6) were reduced following either human or mouse MSC administration. In addition, MSCs augmented insulin receptor substrate-1, phosphorylated protein kinase-B (phospho-Akt), while alleviating serum glucose levels in SBI-rats. These previous effects persisted even at the 14-day time point. SIGNIFICANCE Following single administration, bone marrow-derived MSCs is capable of counteracting SBI-induced skin lesions as well as related hepatic complications, specifically via mitigating postburn hyperglycemia and hyperinflammation.
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Affiliation(s)
- Nourhan G Shibl
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
| | - Ebtehal Mohammad Fikry
- Department of Pharmacology, Egyptian Drug Authority (EDA), formerly National Organization for Drug Control and Research (NODCAR), Giza, Egypt
| | - Hanaa A Mansour
- Department of Pharmacology, Egyptian Drug Authority (EDA), formerly National Organization for Drug Control and Research (NODCAR), Giza, Egypt
| | - Amira Ebrahim Alsemeh
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Rasha H Abdel-Ghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
| | - Shaimaa S El-Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
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11
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Ahmed L, Al-Massri K. New Approaches for Enhancement of the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cardiovascular Diseases. Tissue Eng Regen Med 2022; 19:1129-1146. [PMID: 35867309 DOI: 10.1007/s13770-022-00469-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 06/03/2022] [Accepted: 06/08/2022] [Indexed: 11/28/2022] Open
Abstract
Cardiovascular diseases (CVDs) remain a major health concern worldwide, where mesenchymal stem cells (MSCs) therapy gives great promise in their management through their regenerative and paracrine actions. In recent years, many studies have shifted from the use of transplanted stem cells to their secreted exosomes for the management of various CVDs and cardiovascular-related diseases including atherosclerosis, stroke, myocardial infarction, heart failure, peripheral arterial diseases, and pulmonary hypertension. In different models, MSC-derived exosomes have shown beneficial outcomes similar to cell therapy concerning regenerative and neovascular actions in addition to their anti-apoptotic, anti-remodeling, and anti-inflammatory actions. Compared with their parent cells, exosomes have also demonstrated several advantages, including lower immunogenicity and no risk of tumor formation. However, the maintenance of stability and efficacy of exosomes after in vivo transplantation is still a major concern in their clinical application. Recently, new approaches have been developed to enhance their efficacy and stability including their preconditioning before transplantation, use of genetically modified MSC-derived exosomes, or their utilization as a targeted drug delivery system. Herein, we summarized the use of MSC-derived exosomes as therapies in different CVDs in addition to recent advances for the enhancement of their efficacy in these conditions.
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Affiliation(s)
- Lamiaa Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini St., Cairo, 11562, Egypt.
| | - Khaled Al-Massri
- Department of Pharmacy and Biotechnology, Faculty of Medicine and Health Sciences, University of Palestine, Gaza, Palestine
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12
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Pang R, Mujuni BM, Martinello KA, Webb EL, Nalwoga A, Ssekyewa J, Musoke M, Kurinczuk JJ, Sewegaba M, Cowan FM, Cose S, Nakakeeto M, Elliott AM, Sebire NJ, Klein N, Robertson NJ, Tann CJ. Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes. Pediatr Res 2022; 92:180-189. [PMID: 33674741 PMCID: PMC9411052 DOI: 10.1038/s41390-021-01438-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/27/2021] [Accepted: 02/01/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Neonatal encephalopathy (NE) contributes substantially to child mortality and disability globally. We compared cytokine profiles in term Ugandan neonates with and without NE, with and without perinatal infection or inflammation and identified biomarkers predicting neonatal and early childhood outcomes. METHODS In this exploratory biomarker study, serum IL-1α, IL-6, IL-8, IL-10, TNFα, and VEGF (<12 h) were compared between NE and non-NE infants with and without perinatal infection/inflammation. Neonatal (severity of NE, mortality) and early childhood (death or neurodevelopmental impairment to 2.5 years) outcomes were assessed. Predictors of outcomes were explored with multivariable linear and logistic regression and receiver-operating characteristic analyses. RESULTS Cytokine assays on 159 NE and 157 non-NE infants were performed; data on early childhood outcomes were available for 150 and 129, respectively. NE infants had higher IL-10 (p < 0.001), higher IL-6 (p < 0.017), and lower VEGF (p < 0.001) levels. Moderate and severe NE was associated with higher IL-10 levels compared to non-NE infants (p < 0.001). Elevated IL-1α was associated with perinatal infection/inflammation (p = 0.013). Among NE infants, IL-10 predicted neonatal mortality (p = 0.01) and adverse early childhood outcome (adjusted OR 2.28, 95% CI 1.35-3.86, p = 0.002). CONCLUSIONS Our findings support a potential role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy. IMPACT Neonatal encephalopathy is a common cause of child death and disability globally. Inflammatory cytokines are potential biomarkers of encephalopathy severity and outcome. In this Ugandan health facility-based cohort, neonatal encephalopathy was associated with elevated serum IL-10 and IL-6, and reduced VEGF at birth. Elevated serum IL-10 within 12 h after birth predicted severity of neonatal encephalopathy, neonatal mortality, and adverse early childhood developmental outcomes, independent of perinatal infection or inflammation, and provides evidence to the contribution of the inflammatory processes. Our findings support a role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy in a sub-Saharan African cohort.
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Affiliation(s)
- Raymand Pang
- Institute for Women's Health, University College London, London, UK
| | - Brian M Mujuni
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | | | - Emily L Webb
- MRC International Statistics and Epidemiology Group, London School of Hygiene and Tropical Medicine, London, UK
| | - Angela Nalwoga
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Julius Ssekyewa
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Margaret Musoke
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | | | - Margaret Sewegaba
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Frances M Cowan
- Department of Pediatrics, Imperial College London, London, UK
| | - Stephen Cose
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
- Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK
| | - Margaret Nakakeeto
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Alison M Elliott
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
- Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK
| | - Neil J Sebire
- UCL Institute of Child Health and GOSH BRC, UCL, London, UK
| | - Nigel Klein
- UCL Institute of Child Health and GOSH BRC, UCL, London, UK
| | - Nicola J Robertson
- Institute for Women's Health, University College London, London, UK
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Cally J Tann
- Institute for Women's Health, University College London, London, UK.
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda.
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
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13
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Asgari Taei A, Dargahi L, Khodabakhsh P, Kadivar M, Farahmandfar M. Hippocampal neuroprotection mediated by secretome of human mesenchymal stem cells against experimental stroke. CNS Neurosci Ther 2022; 28:1425-1438. [PMID: 35715988 PMCID: PMC9344087 DOI: 10.1111/cns.13886] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 12/26/2022] Open
Abstract
Aims Regenerative medicine literature has demonstrated that the therapeutic potentials of mesenchymal stem cells (MSCs) in experimental stroke are attributed to secreted bioactive factors rather than to cell replacement. Here, we explored the effects of secretome or conditioned medium (CM) derived from human embryonic stem cell‐derived MSCs (hESC‐MSCs) on hippocampal neurogenesis, inflammation, and apoptosis in experimental stroke. Methods Ischemic stroke was induced by right middle cerebral artery occlusion (MCAO) in male Wistar rats, and CM was infused either one time (1‐h post‐stroke; CM1) or three times (1‐, 24‐, and 48‐h post‐stroke; CM3) into left lateral ventricle. Neurogenesis markers (Nestin, Ki67, Doublecortin, and Reelin) were assessed at transcript and protein levels in the dentate gyrus of the hippocampus on day seven following MCAO. In parallel, changes in the gene expression of markers of apoptosis (Bax and Bim, as well as an anti‐apoptotic marker of Bcl2), inflammation (IL‐1β and IL‐6, as well as IL‐10 as an anti‐inflammatory cytokine), trophic factors (BDNF, GDNF, NGF, and NT‐3), and angiogenesis (CD31 and VEGF) in the hippocampus were assessed. Results Our results demonstrate that CM3 treatment could stimulate neurogenesis and angiogenesis concomitant with inhibition of inflammation, apoptosis, and neuronal loss in ischemic brains. Furthermore, rats treated with CM3 exhibited upregulation in neurotrophic factors. Conclusion Our results suggest that hESC‐MSC‐CM could promote neurogenesis and protect brain tissue from ischemic injury, partly mediated by induction of angiogenesis and neurotrophic factors and inhibition of inflammatory and apoptotic factors expression.
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Affiliation(s)
- Afsaneh Asgari Taei
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Dargahi
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pariya Khodabakhsh
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Kadivar
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| | - Maryam Farahmandfar
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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14
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Chaubey S, Bhandari V. Stem cells in neonatal diseases: An overview. Semin Fetal Neonatal Med 2022; 27:101325. [PMID: 35367186 DOI: 10.1016/j.siny.2022.101325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Preterm birth and its common complications are major causes of infant mortality and long-term morbidity. Despite great advances in understanding the pathogenesis of neonatal diseases and improvements in neonatal intensive care, effective therapies for the prevention or treatment for these conditions are still lacking. Stem cell (SC) therapy is rapidly emerging as a novel therapeutic tool for several diseases of the newborn with encouraging pre-clinical results that hold promise for translation to the bedside. The utility of different types of SCs in neonatal diseases is being explored. SC therapeutic efficacy is closely associated with its secretome-conditioned media and SC-derived extracellular vesicles, and a subsequent paracrine action in response to tissue injuries. In the current review, we summarize the pre-clinical and clinical studies of SCs and its secretome in diverse preterm and term birth-related diseases, thereby providing new insights for future therapies in neonatal medicine.
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Affiliation(s)
- Sushma Chaubey
- Department of Biomedical Engineering, Widener University, Chester, PA, 19013, USA.
| | - Vineet Bhandari
- Neonatology Research Laboratory, Department of Pediatrics, The Children's Regional Hospital at Cooper, Cooper Medical School of Rowan University, Suite Dorrance 755, One Cooper Plaza, Camden, NJ, 08103, USA.
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15
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Dong X, Luo S, Hu D, Cao R, Wang Q, Meng Z, Feng Z, Zhou W, Song W. Gallic acid inhibits neuroinflammation and reduces neonatal hypoxic-ischemic brain damages. Front Pediatr 2022; 10:973256. [PMID: 36619526 PMCID: PMC9813953 DOI: 10.3389/fped.2022.973256] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022] Open
Abstract
Neuroinflammation is a leading cause of secondary neuronal injury in neonatal hypoxic-ischemic encephalopathy (HIE). Regulation of neuroinflammation may be beneficial for treatment of HIE and its secondary complications. Gallic acid (GA) has been shown to have anti-inflammatory and antioxidant effects. In this report we found that oxygen-glucose deprivation and/reoxygenation (OGD/R)-induced cell death, and the generation of excessive reactive oxygen species (ROS) and inflammatory cytokines by microglia were inhibited by GA treatment. Furthermore, GA treatment reduced neuroinflammation and neuronal loss, and alleviated motor and cognitive impairments in rats with hypoxic-ischemic brain damage (HIBD). Together, our results reveal that GA is an effective regulator of neuroinflammation and has potential as a pharmaceutical intervention for HIE therapy.
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Affiliation(s)
- Xiangjun Dong
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Shuyue Luo
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Dongjie Hu
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ruixue Cao
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and Kangning Hospital, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China
| | - Qunxian Wang
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Zijun Meng
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Zijuan Feng
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Weihui Zhou
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Weihong Song
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and Kangning Hospital, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.,Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, China
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16
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Comprehensive Analysis of RNA Expression Profile Identifies Hub miRNA-circRNA Interaction Networks in the Hypoxic Ischemic Encephalopathy. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2021; 2021:6015473. [PMID: 34603484 PMCID: PMC8481051 DOI: 10.1155/2021/6015473] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/21/2021] [Accepted: 08/24/2021] [Indexed: 11/18/2022]
Abstract
Hypoxic ischemic encephalopathy (HIE) is classified as a sort of serious nervous system syndrome that occurs in the early life period. Noncoding RNAs had been confirmed to have crucial roles in human diseases. So far, there were few systematical and comprehensive studies towards the expression profile of RNAs in the brain after hypoxia ischemia. In this study, 31 differentially expressed microRNAs (miRNAs) with upregulation were identified. In addition, 5512 differentially expressed mRNAs, long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) were identified in HIE groups. Bioinformatics analysis showed these circRNAs and mRNAs were significantly enriched in regulation of leukocyte activation, response to virus, and neutrophil degranulation. Pathway and its related gene network analysis indicated that HLA - DPA1, HLA - DQA2, HLA - DQB1, and HLA - DRB4 have a more crucial role in HIE. Finally, miRNA-circRNA-mRNA interaction network analysis was also performed to identify hub miRNAs and circRNAs. We found that miR-592 potentially targeting 5 circRNAs, thus affecting 15 mRNA expressions in HIR. hsa_circ_0068397 and hsa_circ_0045698 were identified as hub circRNAs in HIE. Collectively, using RNA-seq, bioinformatics analysis, and circRNA/miRNA interaction prediction, we systematically investigated the differentially expressed RNAs in HIE, which could give a new hint of understanding the pathogenesis of HIE.
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17
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Bai X, Xiong LL, Fang CL, Zhou HL, Xue LL, Hu Y, Xia QJ, Liu J, Zhang JY, Wang TH, Yang SJ. Interleukin 10 Plays an Important Role in Neonatal Rats with Hypoxic-Ischemia Associated with B-Cell Lymphoma 2 and Endoplasmic Reticulum Protein 29. Anal Cell Pathol (Amst) 2021; 2021:6622713. [PMID: 34123712 PMCID: PMC8189815 DOI: 10.1155/2021/6622713] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 05/10/2021] [Indexed: 02/05/2023] Open
Abstract
Interleukin 10 (IL-10) is a synthetic inhibitor of human cytokines with immunomodulatory and anti-inflammatory effects. This study was designed to investigate the expression variation of IL-10 in the multiple sites including cortex, hippocampus, and lung tissues of neonatal hypoxic-ischemic (HI) rats and explore the crucial role of IL-10 in alleviating HI brain damage. In this study, neonatal Sprague-Dawley rats were subjected to the right common carotid artery ligation, followed by 2 h of hypoxia. The expression of IL-10 in the cortex, hippocampus, and lung tissues was measured with immunohistochemistry, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot (WB). Immunofluorescence double staining was performed to observe the localization of IL-10 in neurons and astrocytes. Moreover, not-targeting and targeting IL-10 siRNA lentivirus vectors were injected into the rats of the negative control (NC) and IL-10 group, respectively, and the mRNA levels of B-cell lymphoma 2 (Bcl-2) and endoplasmic reticulum protein 29 (ERp29) were detected by RT-qPCR following IL-10 silence. The results demonstrated that the IL-10 expression was markedly increased after HI and IL-10 were colocalized with neurons and astrocytes which were badly injured by HI insult. In addition, Bcl-2 and ERp29 were remarkably decreased following IL-10 mRNA interference compared with the NC group. Our findings revealed that IL-10 exerted its antiapoptotic and neuroprotective effects by regulating the expression of Bcl-2 and ERp29, indicating that IL-10 may be a promising molecule target for HIE treatment.
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Affiliation(s)
- Xue Bai
- Department of Cardiac and Cerebral Diseases, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
| | - Liu-Lin Xiong
- School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide 5000, Australia
| | - Chang-Le Fang
- Department of Cardiac and Cerebral Diseases, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
| | - Hao-Li Zhou
- Institute of Neurological Disease, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lu-Lu Xue
- Institute of Neuroscience, Animal Zoology Department, Kunming Medical University, Kunming 650031, China
| | - Yue Hu
- Institute of Neurological Disease, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qing-Jie Xia
- Institute of Neurological Disease, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jia Liu
- Institute of Neuroscience, Animal Zoology Department, Kunming Medical University, Kunming 650031, China
| | - Jun-Yan Zhang
- Department of Cardiac and Cerebral Diseases, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
| | - Ting-Hua Wang
- Institute of Neurological Disease, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Neuroscience, Animal Zoology Department, Kunming Medical University, Kunming 650031, China
| | - Si-Jin Yang
- Department of Cardiac and Cerebral Diseases, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
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18
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Tian H, Li G, Xu G, Liu J, Wan X, Zhang J, Xie S, Cheng J, Gao S. Inflammatory cytokines derived from peripheral blood contribute to the modified electroconvulsive therapy-induced cognitive deficits in major depressive disorder. Eur Arch Psychiatry Clin Neurosci 2021; 271:475-485. [PMID: 32361811 DOI: 10.1007/s00406-020-01128-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 04/14/2020] [Indexed: 12/20/2022]
Abstract
Little is known about the pathophysiology of memory deficits in patients with major depressive disorder (MDD) treated with modified electroconvulsive therapy (MECT). This study examined the profiles of cytokines, the memory function, and their association in MECT-treated MDD patients. Forty first-episode, drug-free MDD patients and 40 healthy controls were recruited. MECT was started with antidepressant treatment at a stable initial dose. The Wechsler Memory Scale (WMS) and Hamilton Rating Scale for Depression 17 (HRSD-17) were used to assess the cognitive function. MDD patients were divided into the memory impairment group (WMS < 50) and the non-memory impairment group (WMS ≥ 50) based on the total WMS scores after MECT. The levels of NOD-like receptor 3 (NLRP3) inflammasome, interleukin-18 (IL-18) and nuclear factor kappa-B (NF-κB) in the serum were measured. MDD patients showed significantly higher levels of NLRP3 inflammasome, IL-18 and NF-κB than that in the controls prior to MECT, and the levels also significantly increased after MECT. In MDD patients, the serum levels of these inflammatory cytokines were negatively associated with the total WMS scores and likely contributed to the scores independently. The receiver operating characteristic curve showed that the serum levels of these inflammatory cytokines may predict the cognitive impairment risk in MDD patients receiving MECT. Abnormal levels of NLRP3 inflammasome, IL-18 and NF-κB reflecting the disturbed balance of pro-inflammatory and anti-inflammatory mechanisms likely contribute to the MECT-induced cognitive deficits in MDD patients.
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Affiliation(s)
- Haihua Tian
- Department of Affective Disorder, Ningbo Kangning Hospital, Ningbo, 315201, Zhejiang, China
| | - Guangxue Li
- Department of Affective Disorder, Ningbo Kangning Hospital, Ningbo, 315201, Zhejiang, China
| | - Guoan Xu
- Department of Affective Disorder, Ningbo Kangning Hospital, Ningbo, 315201, Zhejiang, China
| | - Jimeng Liu
- Department of Affective Disorder, Ningbo Kangning Hospital, Ningbo, 315201, Zhejiang, China
| | - Xiaohan Wan
- Department of Affective Disorder, Ningbo Kangning Hospital, Ningbo, 315201, Zhejiang, China
- School of Medicine, Ningbo University, Ningbo, 315211, Zhejiang, China
| | - Jiao Zhang
- Department of Affective Disorder, Ningbo Kangning Hospital, Ningbo, 315201, Zhejiang, China
- School of Medicine, Ningbo University, Ningbo, 315211, Zhejiang, China
| | - Shuguang Xie
- Department of Affective Disorder, Ningbo Kangning Hospital, Ningbo, 315201, Zhejiang, China
| | - Jia Cheng
- Department of Affective Disorder, Ningbo Kangning Hospital, Ningbo, 315201, Zhejiang, China.
- Zhongshan Hospital, Xiamen University, Xiamen, 361004, China.
| | - Shugui Gao
- Department of Affective Disorder, Ningbo Kangning Hospital, Ningbo, 315201, Zhejiang, China.
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19
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Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review of Preclinical Studies. Int J Mol Sci 2021; 22:ijms22063142. [PMID: 33808671 PMCID: PMC8003344 DOI: 10.3390/ijms22063142] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/12/2021] [Accepted: 03/17/2021] [Indexed: 12/15/2022] Open
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of mortality and morbidity in the perinatal period. This condition results from a period of ischemia and hypoxia to the brain of neonates, leading to several disorders that profoundly affect the daily life of patients and their families. Currently, therapeutic hypothermia (TH) is the standard of care in developing countries; however, TH is not always effective, especially in severe cases of HIE. Addressing this concern, several preclinical studies assessed the potential of stem cell therapy (SCT) for HIE. With this systematic review, we gathered information included in 58 preclinical studies from the last decade, focusing on the ones using stem cells isolated from the umbilical cord blood, umbilical cord tissue, placenta, and bone marrow. Outstandingly, about 80% of these studies reported a significant improvement of cognitive and/or sensorimotor function, as well as decreased brain damage. These results show the potential of SCT for HIE and the possibility of this therapy, in combination with TH, becoming the next therapeutic approach for HIE. Nonetheless, few preclinical studies assessed the combination of TH and SCT for HIE, and the existent studies show some contradictory results, revealing the need to further explore this line of research.
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Stem Cell-Engineered Nanovesicles Exert Proangiogenic and Neuroprotective Effects. MATERIALS 2021; 14:ma14051078. [PMID: 33669122 PMCID: PMC7956182 DOI: 10.3390/ma14051078] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/20/2021] [Accepted: 02/22/2021] [Indexed: 02/06/2023]
Abstract
As a tissue regeneration strategy, the utilization of mesenchymal stem cells (MSCs) has drawn considerable attention. Comprehensive research using MSCs has led to significant preclinical or clinical outcomes; however, improving the survival rate, engraftment efficacy, and immunogenicity of implanted MSCs remains challenging. Although MSC-derived exosomes were recently introduced and reported to have great potential to replace conventional MSC-based therapeutics, the poor production yield and heterogeneity of exosomes are critical hurdles for their further applications. Herein, we report the fabrication of exosome-mimetic MSC-engineered nanovesicles (MSC-NVs) by subjecting cells to serial extrusion through filters. The fabricated MSC-NVs exhibit a hydrodynamic size of ~120 nm, which is considerably smaller than the size of MSCs (~30 μm). MSC-NVs contain both MSC markers and exosome markers. Importantly, various therapeutic growth factors originating from parent MSCs are encapsulated in the MSC-NVs. The MSC-NVs exerted various therapeutic effects comparable to those of MSCs. They also significantly induced the angiogenesis of endothelial cells and showed neuroprotective effects in damaged neuronal cells. The results collectively demonstrate that the fabricated MSC-NVs can serve as a nanosized therapeutic agent for tissue regeneration.
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21
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Therapeutic potential of stem cells for preterm infant brain damage: Can we move from the heterogeneity of preclinical and clinical studies to established therapeutics? Biochem Pharmacol 2021; 186:114461. [PMID: 33571501 DOI: 10.1016/j.bcp.2021.114461] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/27/2021] [Accepted: 02/02/2021] [Indexed: 12/17/2022]
Abstract
Acquired perinatal brain injuries are a set of conditions that remains a key challenge for neonatologists and that have significant social, emotional and financial implications for our communities. In our perspective article, we will introduce perinatal brain injury focusing specifically on the events leading to brain damage in preterm born infants and outcomes for these infants. Then we will summarize and discuss the preclinical and clinical studies testing the efficacy of stem cells as neuroprotectants in the last ten years in perinatal brain injury. There are no therapies to treat brain damage in preterm born infants and a primary finding from this review is that there is a scarcity of stem cell trials focused on overcoming brain injuries in these infants. Overall, across all forms of perinatal brain injury there is a remarkable heterogeneity in previous and on-going preclinical and clinical studies in terms of the stem cell type, animal models/patient selection, route and time of administration. Despite the quality of many of the studies this variation makes it difficult to reach a valid consensus for future developments. However, it is clear that stem cells (and stem cell derived exosomes) can reduce perinatal brain injury and our field needs to work collectively to refine an effective protocol for each type of injury. The use of standardized stem cell products and testing these products across multiple models of injury will provide a stronger framework for clinical trials development.
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Abstract
Hypoxic-ischemic brain damage (HIBD) represents one of the leading causes of neonatal mortality and permanent neurological disability worldwide. Compelling studies have identified implication of microRNAs (miRNAs) in HIBD. However, the molecular mechanism of miR-21 underlying the disease pathogenesis is unknown. The present study aims to explore the role of miR-21 in neonatal rats with HIBD. HIBD rat models were developed by carotid artery ligation and hypoxia treatment, and in vitro cell models were induced by oxygen-glucose deprivation. Through RT-qPCR and western blot analysis, high expression of CCL3 and poor expression of miR-21 were detected in brain tissues of rats with HIBD. Results of dual-luciferase reporter gene assay demonstrated that miR-21 could target and downregulate CCL3. The effect of miR-21 on the neurobehavioral ability of rats, the pathological characteristics of brain tissues, neuron apoptosis and as well as its impact on the NF-κB signaling pathway-related factors was examined by gain- and loss-of-function experiments. The obtained data suggested that upregulation of miR-21 resulted in significantly reduced cerebral infarct volume and degree of brain tissue damage, and improved neurobehavioral ability and memory ability in rats with HIBD through downregulation of CCL3. Besides, overexpression of miR-21 downregulated CCL3 to repress IKKα/β and p65 phosphorylation both in vivo and in vitro, hence disrupting the NF-κB signaling pathway. Taken together, the key findings of the current study underlie the cerebral protective effect of miR-21 against HIBD in neonatal rats through the inhibition of CCL3.
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23
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Therapeutic Effects of Human Mesenchymal Stem Cells in a Mouse Model of Cerebellar Ataxia with Neuroinflammation. J Clin Med 2020; 9:jcm9113654. [PMID: 33202913 PMCID: PMC7698164 DOI: 10.3390/jcm9113654] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/12/2020] [Accepted: 11/12/2020] [Indexed: 12/12/2022] Open
Abstract
Cerebellar ataxias (CAs) are neurological diseases characterized by loss of muscle coordination that is a result of damage and inflammation to the cerebellum. Despite considerable efforts in basic and clinical research, most CAs are currently incurable. In this study, we evaluated the therapeutic potential of human mesenchymal stem cells (hMSCs) against CAs associated with neuroinflammation. We observed that hMSC treatment significantly inhibited the symptoms of ataxia in lipopolysaccharide (LPS)-induced inflammatory CA (ICA) mice, which were recently reported as a potential animal model of ICA, through the anti-inflammatory effect of hMSC-derived TNFα-stimulated gene-6 (TSG-6), the protection of Purkinje cells by inhibition of apoptosis, and the modulatory effect for microglial M2 polarization. Thus, our results suggest that hMSC treatment may be an effective therapeutic approach for preventing or improving ataxia symptoms.
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24
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Cell Death Pathways in Ischemic Stroke and Targeted Pharmacotherapy. Transl Stroke Res 2020; 11:1185-1202. [PMID: 32219729 DOI: 10.1007/s12975-020-00806-z] [Citation(s) in RCA: 211] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 03/04/2020] [Accepted: 03/10/2020] [Indexed: 02/07/2023]
Abstract
Ischemic stroke is one of the significant causes of morbidity and mortality, affecting millions of people across the globe. Cell injury in the infarct region is an inevitable consequence of focal cerebral ischemia. Subsequent reperfusion exacerbates the harmful effect and increases the infarct volume. These cellular injuries follow either a regulated pathway involving tightly structured signaling cascades and molecularly defined effector mechanisms or a non-regulated pathway, also known as accidental cell death, where the process is biologically uncontrolled. Classical cell death pathways are long established and well reported in several articles that majorly define apoptotic cell death. A recent focus on cell death study also considers investigation on non-classical pathways that are tightly regulated, may or may not involve caspases, but non-apoptotic. Pathological cell death is a cardinal feature of different neurodegenerative diseases. Although ischemia cannot be classified as a neurodegenerative disease, it is a cerebrovascular event where the infarct region exhibits aberrant cell death. Over the past few decades, several therapeutic options have been implicated for ischemic stroke. However, their use has been hampered owing to the number of limitations that they possess. Ischemic penumbral neurons undergo apoptosis and become dysfunctional; however, they are salvageable. Thus, understanding the role of different cell death pathways is crucial to aid in the modern treatment of protecting apoptotic neurons.
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25
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Deng Y, Liu K, Pan Y, Ren J, Shang J, Chen L, Liu H. TLR2 antagonism attenuates the hippocampal neuronal damage in a murine model of sleep apnea via inhibiting neuroinflammation and oxidative stress. Sleep Breath 2020; 24:1613-1621. [PMID: 32170671 DOI: 10.1007/s11325-020-02030-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 01/28/2020] [Accepted: 02/05/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND Obstructive sleep apnea (OSA) in humans chronically promotes the neuronal damage in the hippocampus. Toll-like receptor 2 (TLR2) is pivotal for the development of numerous hippocampal diseases. Chronic intermittent hypoxia (CIH) is a prominent feature of OSA. Here in our study, the effects of TLR2 antagonism on the neural damage elicited by CIH were examined. METHODS Ortho-vanillin (O-vanillin) is an inhibitor of TLR2. Adult male mice were subjected to 8 h of intermittent hypoxia per day with or without O-vanillin for 28 days. Neuronal damage, the number of microglia, the interaction of TLR2 with its adapter protein myeloid differentiation factor 88 (MYD88), the expressions of inflammatory cytokines, and the oxidative stress were observed. RESULTS O-vanillin inhibited the increased interaction of TLR2 and MyD88, the activation of NFκB, the aggregation of microglia, the overexpression of proinflammatory agents, the elevation of oxidative stress, and hippocampal neuron cell apoptosis induced by CIH. CONCLUSIONS Our experiments indicate that TLR2 antagonism may alleviate the hippocampal neuronal damage caused by CIH via inhibiting neuroinflammation and oxidative stress.
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Affiliation(s)
- Yan Deng
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China
| | - Kui Liu
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China
| | - Yueying Pan
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China
| | - Jie Ren
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China
| | - Jin Shang
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China
| | - Lei Chen
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China
| | - Huiguo Liu
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China.
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26
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Kim HY, Kim TJ, Kang L, Kim YJ, Kang MK, Kim J, Ryu JH, Hyeon T, Yoon BW, Ko SB, Kim BS. Mesenchymal stem cell-derived magnetic extracellular nanovesicles for targeting and treatment of ischemic stroke. Biomaterials 2020; 243:119942. [PMID: 32179302 DOI: 10.1016/j.biomaterials.2020.119942] [Citation(s) in RCA: 201] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 02/28/2020] [Accepted: 03/04/2020] [Indexed: 02/07/2023]
Abstract
Exosomes and extracellular nanovesicles (NV) derived from mesenchymal stem cells (MSC) may be used for the treatment of ischemic stroke owing to their multifaceted therapeutic benefits that include the induction of angiogenesis, anti-apoptosis, and anti-inflammation. However, the most serious drawback of using exosomes and NV for ischemic stroke is the poor targeting on the ischemic lesion of brain after systemic administration, thereby yielding a poor therapeutic outcome. In this study, we show that magnetic NV (MNV) derived from iron oxide nanoparticles (IONP)-harboring MSC can drastically improve the ischemic-lesion targeting and the therapeutic outcome. Because IONP stimulated expressions of therapeutic growth factors in the MSC, MNV contained greater amounts of those therapeutic molecules compared to NV derived from naive MSC. Following the systemic injection of MNV into transient middle-cerebral-artery-occlusion (MCAO)-induced rats, the magnetic navigation increased the MNV localization to the ischemic lesion by 5.1 times. The MNV injection and subsequent magnetic navigation promoted the anti-inflammatory response, angiogenesis, and anti-apoptosis in the ischemic brain lesion, thereby yielding a considerably decreased infarction volume and improved motor function. Overall, the proposed MNV approach may overcome the major drawback of the conventional MSC-exosome therapy or NV therapy for the treatment of ischemic stroke.
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Affiliation(s)
- Han Young Kim
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Tae Jung Kim
- Department of Neurology, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Lami Kang
- Department of Neurology, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Young-Ju Kim
- Department of Neurology, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Min Kyoung Kang
- Department of Neurology, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Jonghoon Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea; Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
| | - Ju Hee Ryu
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| | - Taeghwan Hyeon
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea; Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
| | - Byung-Woo Yoon
- Department of Neurology, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Sang-Bae Ko
- Department of Neurology, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
| | - Byung-Soo Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea; Interdisciplinary Program of Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea; Institute of Chemical Processes, Seoul National University, Seoul, 08826, Republic of Korea.
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27
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Nitkin CR, Rajasingh J, Pisano C, Besner GE, Thébaud B, Sampath V. Stem cell therapy for preventing neonatal diseases in the 21st century: Current understanding and challenges. Pediatr Res 2020; 87:265-276. [PMID: 31086355 PMCID: PMC6854309 DOI: 10.1038/s41390-019-0425-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 04/24/2019] [Indexed: 02/06/2023]
Abstract
Diseases of the preterm newborn such as bronchopulmonary dysplasia, necrotizing enterocolitis, cerebral palsy, and hypoxic-ischemic encephalopathy continue to be major causes of infant mortality and long-term morbidity. Effective therapies for the prevention or treatment for these conditions are still lacking as recent clinical trials have shown modest or no benefit. Stem cell therapy is rapidly emerging as a novel therapeutic tool for several neonatal diseases with encouraging pre-clinical results that hold promise for clinical translation. However, there are a number of unanswered questions and facets to the development of stem cell therapy as a clinical intervention. There is much work to be done to fully elucidate the mechanisms by which stem cell therapy is effective (e.g., anti-inflammatory versus pro-angiogenic), identifying important paracrine mediators, and determining the timing and type of therapy (e.g., cellular versus secretomes), as well as patient characteristics that are ideal. Importantly, the interaction between stem cell therapy and current, standard-of-care interventions is nearly completely unknown. In this review, we will focus predominantly on the use of mesenchymal stromal cells for neonatal diseases, highlighting the promises and challenges in clinical translation towards preventing neonatal diseases in the 21st century.
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Affiliation(s)
- Christopher R Nitkin
- Division of Neonatology, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Johnson Rajasingh
- Department of Cardiovascular Medicine, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, MO, USA
| | - Courtney Pisano
- Department of Pediatric Surgery, Center for Perinatal Research, Nationwide Children's Hospital, Columbus, OH, USA
| | - Gail E Besner
- Department of Pediatric Surgery, Center for Perinatal Research, Nationwide Children's Hospital, Columbus, OH, USA
| | - Bernard Thébaud
- Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Ottawa, ON, Canada
- Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada
| | - Venkatesh Sampath
- Division of Neonatology, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA.
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28
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Heidarzadeh M, Roodbari F, Hassanpour M, Ahmadi M, Saberianpour S, Rahbarghazi R. Toll-like receptor bioactivity in endothelial progenitor cells. Cell Tissue Res 2019; 379:223-230. [PMID: 31754781 DOI: 10.1007/s00441-019-03119-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 10/06/2019] [Indexed: 12/12/2022]
Abstract
Cardiovascular disease is the main cause of death globally that can be mitigated by the modulation of angiogenesis. To achieve this goal, the application of endothelial progenitor cells and other stem cell types is useful. Following the onset of cardiovascular disease and pro-inflammatory conditions as seen during bacterial sepsis, endothelial progenitor cells enter systemic circulation in response to multiple cytokines and activation of various intracellular mechanisms. The critical role of Toll-like receptors has been previously identified in the dynamics of various cell types, in particular, immune cells. To our knowledge, there are a few experiments related to the role of Toll-like receptors in endothelial progenitor cell activity. Emerging data point of endothelial progenitor cells and other stem cells having the potential to express Toll-like receptors to control different activities such as multipotentiality and dynamics of growth. In this review article, we aim to collect data related to the role of Toll-like receptors in endothelial progenitor cells bioactivity and angiogenic potential.
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Affiliation(s)
- Morteza Heidarzadeh
- Department of Microbiology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Roodbari
- Department of Microbiology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Iran.
| | - Mehdi Hassanpour
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Ahmadi
- Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shirin Saberianpour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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29
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Hu W, Yang S, Shimada Y, Münch M, Marín-Juez R, Meijer AH, Spaink HP. Infection and RNA-seq analysis of a zebrafish tlr2 mutant shows a broad function of this toll-like receptor in transcriptional and metabolic control and defense to Mycobacterium marinum infection. BMC Genomics 2019; 20:878. [PMID: 31747871 PMCID: PMC6869251 DOI: 10.1186/s12864-019-6265-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 11/05/2019] [Indexed: 02/07/2023] Open
Abstract
Background The function of Toll-like receptor 2 (TLR2) in host defense against pathogens, especially Mycobacterium tuberculosis (Mtb) is poorly understood. To investigate the role of TLR2 during mycobacterial infection, we analyzed the response of tlr2 zebrafish mutant larvae to infection with Mycobacterium marinum (Mm), a close relative to Mtb, as a model for tuberculosis. We measured infection phenotypes and transcriptome responses using RNA deep sequencing in mutant and control larvae. Results tlr2 mutant embryos at 2 dpf do not show differences in numbers of macrophages and neutrophils compared to control embryos. However, we found substantial changes in gene expression in these mutants, particularly in metabolic pathways, when compared with the heterozygote tlr2+/− control. At 4 days after Mm infection, the total bacterial burden and the presence of extracellular bacteria were higher in tlr2−/− larvae than in tlr2+/−, or tlr2+/+ larvae, whereas granuloma numbers were reduced, showing a function of Tlr2 in zebrafish host defense. RNAseq analysis of infected tlr2−/− versus tlr2+/− shows that the number of up-regulated and down-regulated genes in response to infection was greatly diminished in tlr2 mutants by at least 2 fold and 10 fold, respectively. Analysis of the transcriptome data and qPCR validation shows that Mm infection of tlr2 mutants leads to decreased mRNA levels of genes involved in inflammation and immune responses, including il1b, tnfb, cxcl11aa/ac, fosl1a, and cebpb. Furthermore, RNAseq analyses revealed that the expression of genes for Maf family transcription factors, vitamin D receptors, and Dicps proteins is altered in tlr2 mutants with or without infection. In addition, the data indicate a function of Tlr2 in the control of induction of cytokines and chemokines, such as the CXCR3-CXCL11 signaling axis. Conclusion The transcriptome and infection burden analyses show a function of Tlr2 as a protective factor against mycobacteria. Transcriptome analysis revealed tlr2-specific pathways involved in Mm infection, which are related to responses to Mtb infection in human macrophages. Considering its dominant function in control of transcriptional processes that govern defense responses and metabolism, the TLR2 protein can be expected to be also of importance for other infectious diseases and interactions with the microbiome.
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Affiliation(s)
- Wanbin Hu
- Institute of Biology, Leiden University, P.O. Box 9505, 2300 RA, Leiden, the Netherlands
| | - Shuxin Yang
- Institute of Biology, Leiden University, P.O. Box 9505, 2300 RA, Leiden, the Netherlands.,Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Yasuhito Shimada
- Institute of Biology, Leiden University, P.O. Box 9505, 2300 RA, Leiden, the Netherlands.,Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Magnus Münch
- Mathematical Institute, Leiden University, Leiden, the Netherlands.,Department of Epidemiology & Biostatistics, Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Rubén Marín-Juez
- Institute of Biology, Leiden University, P.O. Box 9505, 2300 RA, Leiden, the Netherlands.,Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany
| | - Annemarie H Meijer
- Institute of Biology, Leiden University, P.O. Box 9505, 2300 RA, Leiden, the Netherlands
| | - Herman P Spaink
- Institute of Biology, Leiden University, P.O. Box 9505, 2300 RA, Leiden, the Netherlands.
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30
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Zhao C, Zhou X, Qiu J, Xin D, Li T, Chu X, Yuan H, Wang H, Wang Z, Wang D. Exosomes Derived From Bone Marrow Mesenchymal Stem Cells Inhibit Complement Activation In Rats With Spinal Cord Injury. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:3693-3704. [PMID: 31695336 PMCID: PMC6817353 DOI: 10.2147/dddt.s209636] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022]
Abstract
Purpose Spinal cord injury (SCI) is a relatively common, devastating traumatic condition resulting in permanent disability. In this study, the use of exosomes derived from bone mesenchymal stem cells (BMSCs-Exo) as a cell-free therapy for the treatment of SCI in rats was investigated to gain insights into their mechanisms of action. Methods Rats were randomly divided into three groups, Sham (treated with PBS), SCI (SCI injury + PBS) and SCI + Exo (SCI injury + BMSCs-Exo). Changes in the complement system between the three groups were assessed with the use of proteomics. The proteomic data were verified using reverse transcription-polymerase chain reaction (RT-PCR). In addition, the distributions of BMSCs-Exo in rats with SCI were detected by immunofluorescence. Moreover, SCI-activated NF-κB levels were determined using Western blot. Results SCI insult increased complement levels, including C4, C5, C6, C4 binding protein alpha and complement factor H. In contrast, the SCI + BMSCs-Exo group exhibited attenuated SCI-induced complement levels. Immunofluorescence assay results revealed that BMSCs-Exo mainly accumulated at the spinal cord injury site and were bound to microglia cells. Western blot analysis of tissue lysates showed that BMSCs-Exo treatment also inhibited SCI-activated nuclear factor kappa-B (NF-κB). Conclusion BMSCs-Exo play a protective role in spinal cord injury by inhibiting complement mRNA synthesis and release and by inhibiting SCI-activated NF-κB by binding to microglia.
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Affiliation(s)
- Chuanliang Zhao
- Department of Spinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.,Department of Physiology, Shandong University School of Basic Medical Sciences, Jinan, Shandong, People's Republic of China.,Department of Orthopedic, Feicheng Hospital of Traditional Chinese Medicine, Feicheng, Shandong, People's Republic of China
| | - Xin Zhou
- Department of Spinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.,Department of Physiology, Shandong University School of Basic Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Jie Qiu
- Department of Spinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.,Department of Physiology, Shandong University School of Basic Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Danqing Xin
- Department of Physiology, Shandong University School of Basic Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Tingting Li
- Department of Physiology, Shandong University School of Basic Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Xili Chu
- Department of Physiology, Shandong University School of Basic Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Hongtao Yuan
- Department of Physiology, Shandong University School of Basic Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Haifeng Wang
- Department of Spinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
| | - Zhen Wang
- Department of Physiology, Shandong University School of Basic Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Dachuan Wang
- Department of Spinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
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31
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Park JW, Ko JH, Kim BH, Ryu JS, Kim HJ, Kim MK, Oh JY. Inhibition of mTOR by Rapamycin Aggravates Corneal Epithelial Stem Cell Deficiency by Upregulating Inflammatory Response. Stem Cells 2019; 37:1212-1222. [DOI: 10.1002/stem.3036] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 04/29/2019] [Indexed: 01/21/2023]
Affiliation(s)
- Jong Woo Park
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute; Seoul National University Hospital; Seoul South Korea
| | - Jung Hwa Ko
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute; Seoul National University Hospital; Seoul South Korea
| | - Bo Hee Kim
- Department of Ophthalmology; Seoul National University Hospital; Seoul South Korea
| | - Jin Suk Ryu
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute; Seoul National University Hospital; Seoul South Korea
| | - Hyun Ji Kim
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute; Seoul National University Hospital; Seoul South Korea
| | - Mee Kum Kim
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute; Seoul National University Hospital; Seoul South Korea
- Department of Ophthalmology; Seoul National University Hospital; Seoul South Korea
| | - Joo Youn Oh
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute; Seoul National University Hospital; Seoul South Korea
- Department of Ophthalmology; Seoul National University Hospital; Seoul South Korea
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32
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Vaes JEG, Vink MA, de Theije CGM, Hoebeek FE, Benders MJNL, Nijboer CHA. The Potential of Stem Cell Therapy to Repair White Matter Injury in Preterm Infants: Lessons Learned From Experimental Models. Front Physiol 2019; 10:540. [PMID: 31143126 PMCID: PMC6521595 DOI: 10.3389/fphys.2019.00540] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/17/2019] [Indexed: 12/12/2022] Open
Abstract
Diffuse white matter injury (dWMI) is a major cause of morbidity in the extremely preterm born infant leading to life-long neurological impairments, including deficits in cognitive, motor, sensory, psychological, and behavioral functioning. At present, no treatment options are clinically available to combat dWMI and therefore exploration of novel strategies is urgently needed. In recent years, the pathophysiology underlying dWMI has slowly started to be unraveled, pointing towards the disturbed maturation of oligodendrocytes (OLs) as a key mechanism. Immature OL precursor cells in the developing brain are believed to be highly sensitive to perinatal inflammation and cerebral oxygen fluctuations, leading to impaired OL differentiation and eventually myelination failure. OL lineage development under normal and pathological circumstances and the process of (re)myelination have been studied extensively over the years, often in the context of other adult and pediatric white matter pathologies such as stroke and multiple sclerosis (MS). Various studies have proposed stem cell-based therapeutic strategies to boost white matter regeneration as a potential strategy against a wide range of neurological diseases. In this review we will discuss experimental studies focusing on mesenchymal stem cell (MSC) therapy to reduce white matter injury (WMI) in multiple adult and neonatal neurological diseases. What lessons have been learned from these previous studies and how can we translate this knowledge to application of MSCs for the injured white matter in the preterm infant? A perspective on the current state of stem cell therapy will be given and we will discuss different important considerations of MSCs including cellular sources, timing of treatment and administration routes. Furthermore, we reflect on optimization strategies that could potentially reinforce stem cell therapy, including preconditioning and genetic engineering of stem cells or using cell-free stem cell products, to optimize cell-based strategy for vulnerable preterm infants in the near future.
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Affiliation(s)
- Josine E G Vaes
- NIDOD Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Neonatology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Marit A Vink
- NIDOD Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Caroline G M de Theije
- NIDOD Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Freek E Hoebeek
- NIDOD Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Manon J N L Benders
- Department of Neonatology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Cora H A Nijboer
- NIDOD Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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Fang H, Li HF, Yang M, Liao R, Wang RR, Wang QY, Zheng PC, Zhang FX, Zhang JP. NF-κB signaling pathway inhibition suppresses hippocampal neuronal apoptosis and cognitive impairment via RCAN1 in neonatal rats with hypoxic-ischemic brain damage. Cell Cycle 2019; 18:1001-1018. [PMID: 30990350 PMCID: PMC6527272 DOI: 10.1080/15384101.2019.1608128] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
NF-κB is a core transcription factor, the activation of which can lead to hypoxic-ischemic brain damage (HIBD), while RCAN1 plays a protective role in HIBD. However, the relationship between NF-κB and RCAN1 in HIBD remains unclear. This study aimed to explore the mechanism of NF-κB signaling pathway in hippocampal neuron apoptosis and cognitive impairment of neonatal rats with HIBD in relation to RCAN1. Initially, microarray analysis was used to determine the differentially expressed genes related to HIBD. After the establishment of HIBD rat models, gain- or loss-of-function assay was performed to explore the functional role of NF-κB signaling pathway in HIBD. Then, the learning and memory ability of rats was evaluated. Expression of RCAN1, NF-κB signaling pathway-related genes and glial fibrillary acidic protein (GFAP), S-100β and acetylcholine (Ach) level, and acetylcholinesterase (AchE) activity were determined with neuron apoptosis detected to further explore the function of NF-κB signaling pathway. RCAN1 could influence the development of HIBD. In the HIBD model, the expression of RCAN1 and NF-κB-related genes increased, and NF-κB p65 showed a significant nuclear shift. By activation of NF-κB or overexpression of RCAN1, the number of neuronal apoptosis, S-100β protein level, and AchE level increased significantly, Ach activity decreased significantly, and GFAP positive cells increased. In addition, after the activation of NF-κB or overexpression of RCAN1, the learning and memory ability of HIBD rats was inhibited. All the results show that activation of NF-κB signaling pathway promotes RCAN1 expression, thus increasing neuronal apoptosis and aggravating cognitive impairment in HIBD rats.
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Affiliation(s)
- Hua Fang
- a Department of Anesthesiology , Guizhou Provincial People's Hospital , Guiyang , P. R. China.,b Department of Anesthesiology , Guizhou University People's Hospital, , Guiyang, P. R. China
| | - Hua-Feng Li
- c Department of Anesthesiology, West China Second University Hospital , Sichuan University , Chengdu , P. R. China
| | - Miao Yang
- a Department of Anesthesiology , Guizhou Provincial People's Hospital , Guiyang , P. R. China.,b Department of Anesthesiology , Guizhou University People's Hospital, , Guiyang, P. R. China
| | - Ren Liao
- d Department of Anesthesiology, West China Hospital , Sichuan University , Chengdu , P. R. China
| | - Ru-Rong Wang
- d Department of Anesthesiology, West China Hospital , Sichuan University , Chengdu , P. R. China
| | - Quan-Yun Wang
- d Department of Anesthesiology, West China Hospital , Sichuan University , Chengdu , P. R. China
| | - Peng-Cheng Zheng
- e Guizhou University Research Center for Analysis of Drugs and Metabolites , Guizhou University , Chengdu , P. R. China
| | - Fang-Xiang Zhang
- a Department of Anesthesiology , Guizhou Provincial People's Hospital , Guiyang , P. R. China.,b Department of Anesthesiology , Guizhou University People's Hospital, , Guiyang, P. R. China
| | - Jian-Ping Zhang
- a Department of Anesthesiology , Guizhou Provincial People's Hospital , Guiyang , P. R. China.,b Department of Anesthesiology , Guizhou University People's Hospital, , Guiyang, P. R. China
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Li M, Liu J, Bi Y, Chen J, Zhao L. Potential Medications or Compounds Acting on Toll-like Receptors in Cerebral Ischemia. Curr Neuropharmacol 2018; 16:160-175. [PMID: 28571545 PMCID: PMC5883378 DOI: 10.2174/1570159x15666170601125139] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 05/24/2017] [Accepted: 05/31/2017] [Indexed: 01/22/2023] Open
Abstract
Background: Toll-like receptors play an integral role in the process of inflammatory response after ischemic in-jury. The therapeutic potential acting on TLRs is worth of evaluations. The aim of this review was to introduce readers some potential medications or compounds which could alleviate the ischemic damage via TLRs. Methods: Research articles online on TLRs were reviewed. Categorizations were listed according to the follows, methods acting on TLRs directly, modulations of MyD88 or TRIF signaling pathway, and the ischemic tolerance induced by the pre-conditioning or postconditioning with TLR ligands or minor cerebral ischemia via acting on TLRs. Results: There are only a few studies concerning on direct effects. Anti-TLR4 or anti-TLR2 therapies may serve as promis-ing strategies in acute events. Approaches targeting on inhibiting NF-κB signaling pathway and enhancing interferon regu-latory factor dependent signaling have attracted great interests. Not only drugs but compounds extracted from traditional Chinese medicine have been used to identify their neuroprotective effects against cerebral ischemia. In addition, many re-searchers have reported the positive therapeutic effects of preconditioning with agonists of TLR2, 3, 4, 7 and 9. Several trails have also explored the potential of postconditioning, which provide a new idea in ischemic treatments. Considering all the evidence above, many drugs and new compounds may have great potential to reduce ischemic insults. Conclusion: This review will focus on promising therapies which exerting neuroprotective effects against ischemic injury by acting on TLRs.
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Affiliation(s)
- Man Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jing Liu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Department of Neurology, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, China
| | - Ying Bi
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jixiang Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lei Zhao
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Sugiyama Y, Sato Y, Kitase Y, Suzuki T, Kondo T, Mikrogeorgiou A, Horinouchi A, Maruyama S, Shimoyama Y, Tsuji M, Suzuki S, Yamamoto T, Hayakawa M. Intravenous Administration of Bone Marrow-Derived Mesenchymal Stem Cell, but not Adipose Tissue-Derived Stem Cell, Ameliorated the Neonatal Hypoxic-Ischemic Brain Injury by Changing Cerebral Inflammatory State in Rat. Front Neurol 2018; 9:757. [PMID: 30254603 PMCID: PMC6141968 DOI: 10.3389/fneur.2018.00757] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 08/20/2018] [Indexed: 01/17/2023] Open
Abstract
Perinatal hypoxic-ischemic (HI) brain injury occurs in 1 in 1,000 live births and remains the main cause of neurological disability and death in term infants. Cytotherapy has recently emerged as a novel treatment for tissue injury. In particular, mesenchymal stem cells (MSCs) are thought to have therapeutic potential, but little is known about the differences according to their origin. In the current study, we investigated the therapeutic effects and safety of intravenous injection of allogeneic bone marrow-derived MSCs (BM-MSCs) and adipose-derived stem cells (ADSCs) in a rat model of HI brain injury. HI models were generated by ligating the left carotid artery of postnatal day 7 Wistar/ST rats and exposing them to 8% hypoxia for 60 min. Bone marrow and adipose tissue were harvested from adult green fluorescent protein transgenic Wistar rats, and cells were isolated and cultured to develop BM-MSCs and ADSCs. At passaging stages 2–3, 1 × 105 cells were intravenously injected into the external right jugular vein of the HI rats at 4 or 24 h after hypoxia. Brain damage was evaluated by counting the number of cells positive for active caspase-3 in the entire dentate gyrus. Microglial isotypes and serum cytokines/chemokines were also evaluated. Distribution of each cell type after intravenous injection was investigated pathologically and bio-optically by ex vivo imaging (IVIS®) with a fluorescent lipophilic tracer DiR. The mortality rate was higher in the ADSC group compared to the BM-MSC group, in pups injected with cells 4 h after hypoxia. The number of active caspase-3-positive cells significantly decreased in the BM-MSC group, and the percentage of M1 microglia (a proinflammatory isotype) was also lower in the BM-MSC vs control group in the penumbra of the cortex. Moreover, BM-MSC administration increased anti-inflammatory cytokine and growth factor levels, while ADSCs did not. Each injected cell type was mainly distributed in the lungs and liver, but ADSCs remained in the lungs longer. Pathologically, pulmonary embolisms and diffuse alveolar hemorrhages were seen in the ADSC group. These results indicated that injection of allogeneic BM-MSCs ameliorated neonatal HI brain injury, whereas ADSCs induced severe lung hemorrhage and higher mortality.
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Affiliation(s)
- Yuichiro Sugiyama
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan
| | - Yoshiaki Sato
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan
| | - Yuma Kitase
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan
| | - Toshihiko Suzuki
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan
| | - Taiki Kondo
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan
| | - Alkisti Mikrogeorgiou
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan
| | - Asuka Horinouchi
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshie Shimoyama
- Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan
| | - Masahiro Tsuji
- Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Satoshi Suzuki
- Center for Advanced Medicine and Clinical Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tokunori Yamamoto
- Center for Advanced Medicine and Clinical Research, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Laboratory for Clinical Application of Adipose-Derived Regenerative Cells, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiro Hayakawa
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan
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Wang H, Chen Z, Li Y, Ji Q. NG25, an inhibitor of transforming growth factor‑β‑activated kinase 1, ameliorates neuronal apoptosis in neonatal hypoxic‑ischemic rats. Mol Med Rep 2018; 17:1710-1716. [PMID: 29138854 PMCID: PMC5780114 DOI: 10.3892/mmr.2017.8024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 08/29/2017] [Indexed: 01/27/2023] Open
Abstract
Transforming growth factor (TGF)‑β‑activated kinase 1 (TAK1) was found to be activated by TGF‑β and acts as a central regulator of cell death in various types of disease. However, the expression and function of TAK1 in the neonatal brain following hypoxia‑ischemia (HI) remains unclear. In the present study, western blotting and immunofluorescence were employed to determine the expression and distribution of TAK1 in the brain cortex of a perinatal HI rat model. In addition, the specific inhibitor of TAK1, NG25 was administered via intracerebroventricular injection, prior to insult of the neonatal rat brains, for neuroprotection. Western blotting and double immunofluorescence indicated that an increased expression level of phosphorylated‑TAK1 was observed, and was localized with neurons and astrocytes, compared with the sham group. Further study demonstrated that injection of NG25 prior to insult significantly inhibited TAK1/c‑Jun N‑terminal kinases activity and dramatically ameliorated acute hypoxic‑ischemic cerebral injury by inhibiting cell apoptosis in perinatal rats. Thus, NG25 ameliorates neuronal apoptosis in neonatal HI rats by inhibiting TAK1 expression and cell apoptosis. In addition, NG25 may serve as a promising novel neuroprotective inhibitor for perinatal cerebral injury.
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Affiliation(s)
- Hua Wang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Zhong Chen
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yu Li
- Department of Ophthalmology, Fourth Affiliated Hospital of Sichuan University, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qiaoyun Ji
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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37
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Han HW, Hsu SH. Chitosan derived co-spheroids of neural stem cells and mesenchymal stem cells for neural regeneration. Colloids Surf B Biointerfaces 2017; 158:527-538. [DOI: 10.1016/j.colsurfb.2017.07.036] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 07/10/2017] [Accepted: 07/15/2017] [Indexed: 12/15/2022]
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He ML, Lv ZY, Shi X, Yang T, Zhang Y, Li TY, Chen J. Interleukin-10 release from astrocytes suppresses neuronal apoptosis via the TLR2/NFκB pathway in a neonatal rat model of hypoxic-ischemic brain damage. J Neurochem 2017; 142:920-933. [PMID: 28700093 DOI: 10.1111/jnc.14126] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 06/27/2017] [Accepted: 06/28/2017] [Indexed: 12/16/2022]
Abstract
The biological function of interleukin-10 (IL-10) and the relationship between IL-10 secretion and the Toll-like receptor 2 (TLR2) expression levels in the central nervous system following hypoxic-ischemic brain damage (HIBD) are poorly understood. Here, we intend to elucidate the biological function and mechanism of IL-10 secretion following HIBD. In this study, we used a neonatal rat model of HIBD and found that rats injected with adeno-associated virus-IL-10-shRNA (short hairpin RNA) exhibited partially impaired learning and memory function compared to rats administered adeno-associated virus-control-shRNA. In vitro oxygen-glucose deprivation (OGD) induced IL-10 release from astrocytes but not from neurons. Pretreatment with exogenous recombinant IL-10 alleviated OGD-mediated apoptosis of neurons but not astrocytes. In addition, we also observed that hypoxic injury induced a marked increase in IL-10 expression in astrocytes as a result of activation of the TLR2/phosphorylated nuclear factor kappa B (p-NFκB) p65 signaling cascade; furthermore, this effect disappeared upon small interfering RNA targeting rat TLR2 gene (siTLR2) treatment. Pyrrolidinedithiocarbamate, an inhibitor of NFκB activation, reduced the IL-10 expression levels in both OGD-injured astrocytes in vitro and the hippocampi of HIBD rats in vivo but did not significantly affect TLR2 expression. Furthermore, a luciferase assay revealed that p-NFκB p65 could bind the -1700/-1000 bp proximal region of the IL-10 gene promoter to regulate IL-10 secretion from astrocytes and that this interaction could be controlled by OGD treatment. These data suggest that HIBD induces IL-10 secretion from astrocytes to exert a paracrine-induced anti-apoptotic effect on injured neurons via the TLR2/NFκB signaling pathway, which may improve learning and memory dysfunction after ischemic injury.
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Affiliation(s)
- Mu Lan He
- Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Stem Cell Therapy Engineering Technical Center, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ze Yu Lv
- Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Stem Cell Therapy Engineering Technical Center, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xia Shi
- Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Stem Cell Therapy Engineering Technical Center, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ting Yang
- Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Stem Cell Therapy Engineering Technical Center, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yun Zhang
- Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Stem Cell Therapy Engineering Technical Center, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ting-Yu Li
- Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, China
| | - Jie Chen
- Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Stem Cell Therapy Engineering Technical Center, Children's Hospital of Chongqing Medical University, Chongqing, China
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Kakizaki M, Watanabe R. IL-10 expression in pyramidal neurons after neuropathogenic coronaviral infection. Neuropathology 2017; 37:398-406. [PMID: 28493345 PMCID: PMC7167951 DOI: 10.1111/neup.12386] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 03/24/2017] [Accepted: 03/25/2017] [Indexed: 02/04/2023]
Abstract
The apoptosis of pyramidal neurons in CA2 and CA3 subregions of the hippocampus is induced after infection with Mu-3 virus (Mu-3), a neuropathogenic strain of the JHM virus (JHMV), at 4-5 days post-inoculation (dpi). The viral antigens in the hippocampus are mainly found in the CD11b-positive cells distributed in the stratum oriens located outside the pyramidal layer, and only a few pyramidal neurons are infected. Furthermore, the apoptotic cells, indicated as showing caspase 3 (Cas3) activation, consist of a high number of uninfected cells. Therefore, it is considered that the apoptotic lesions occur through the indirect effects of infection, and not as a result of direct infection with Mu-3, similar to the reported neuronal apoptosis in the hippocampus after other types of infection. The apoptosis in the pyramidal neurons is accompanied by various types of proinflammatory cytokines depending on the causative agents. Thus, the local expression of proinflammatory cytokines was studied, revealing no correlation in the distribution of cytokine expression with the subregions showing apoptosis. However, the anti-inflammatory cytokine IL-10 was produced by pyramidal neurons of CA2 and CA3 at 3 dpi when there is no destructive change or viral invasion in the hippocampus.
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Affiliation(s)
- Masatoshi Kakizaki
- Department of Bioinformatics, Graduate School of Engineering, Soka University, Hachioji, Tokyo, Japan
| | - Rihito Watanabe
- Department of Bioinformatics, Graduate School of Engineering, Soka University, Hachioji, Tokyo, Japan
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40
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Bai X, Xi J, Bi Y, Zhao X, Bing W, Meng X, Liu Y, Zhu Z, Song G. TNF-α promotes survival and migration of MSCs under oxidative stress via NF-κB pathway to attenuate intimal hyperplasia in vein grafts. J Cell Mol Med 2017; 21:2077-2091. [PMID: 28266177 PMCID: PMC5571532 DOI: 10.1111/jcmm.13131] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 01/16/2017] [Indexed: 12/18/2022] Open
Abstract
The oxidative stress caused by endothelial injury is involved in intimal hyperplasia (IH) in vein grafts. Mesenchymal stem cells (MSCs) can home to injured intima and promote endothelial repair. However, MSC apoptosis is increased accompanied by decreased functional activity under oxidative stress. Thus, we investigate whether tumour necrosis factor‐α (TNF‐α) can promote the survival and activity of MSCs under oxidative stress to reduce IH more effectively, and establish what role the NF‐κB pathway plays in this. In this study, we preconditioned MSCs with TNF‐α (TNF‐α‐PCMSCs) for 24 hrs and measured the activation of the IKK/NF‐κB pathway. EdU and transwell assays were performed to assess proliferation and migration of TNF‐α‐PCMSCs. Apoptosis and migration of TNF‐α‐PCMSCs were evaluated in conditions of oxidative stress by analysis of the expression of Bcl‐2 and CXCR4 proteins. TNF‐α‐PCMSCs were transplanted into a vein graft model, so that cell homing could be tracked, and endothelial apoptosis and IH of vein grafts were measured. The results demonstrated that TNF‐α promotes proliferation and migration of MSCs. Furthermore, survival and migration of TNF‐α‐PCMSCs under oxidative stress were both enhanced. A greater number of MSCs migrated to the intima of vein grafts after preconditioning with TNF‐α, and the formation of neointima was significantly reduced. These effects could be partially abolished by IKK XII (NF‐κB inhibitor). All these results indicate that preconditioning with TNF‐α can promote survival and migration of MSCs under oxidative stress via the NF‐κB pathway and thus attenuate IH of vein grafts.
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Affiliation(s)
- Xiao Bai
- Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Jie Xi
- Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yanwen Bi
- Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xin Zhao
- Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Weidong Bing
- Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xiangbin Meng
- Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yimin Liu
- Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Zhonglai Zhu
- Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Guangmin Song
- Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
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Involvement of Toll Like Receptor 2 Signaling in Secondary Injury during Experimental Diffuse Axonal Injury in Rats. Mediators Inflamm 2017; 2017:1570917. [PMID: 28293064 PMCID: PMC5331293 DOI: 10.1155/2017/1570917] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 12/17/2016] [Accepted: 01/04/2017] [Indexed: 12/16/2022] Open
Abstract
Treatment of diffuse axonal injury (DAI) remains challenging in clinical practice due to the unclear pathophysiological mechanism. Uncontrolled, excessive inflammation is one of the most recognized mechanisms that contribute to the secondary injury after DAI. Toll like receptor 2 (TLR2) is highlighted for the initiation of a vicious self-propagating inflammatory circle. However, the role and detailed mechanism of TLR2 in secondary injury is yet mostly unknown. In this study, we demonstrated the expression of TLR2 levels in cortex, corpus callosum, and internal capsule and the localization of TLR2 in neurons and glial cells in rat DAI models. Intracerebral knockdown of TLR2 significantly downregulated TLR2 expression, attenuated cortical apoptosis, lessened glial response, and reduced the secondary axonal and neuronal injury in the cortex by inhibiting phosphorylation of mitogen-activated protein kinases (MAPK) including Erk, JNK, and p38, translocation of NF-κB p65 from the cytoplasm to the nucleus, and decreasing levels of proinflammatory cytokines including interleukin-6, interleukin-1β, and tumor necrosis factor-α. On the contrary, administration of TLR2 agonist to DAI rats achieved an opposite effect. Collectively, we demonstrated that TLR2 was involved in mediating secondary injury after DAI by inducing inflammation via the MAPK and NF-κB pathways.
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Synergistic effect of tanshinone IIA and mesenchymal stem cells on preventing learning and memory deficits via anti-apoptosis, attenuating tau phosphorylation and enhancing the activity of central cholinergic system in vascular dementia. Neurosci Lett 2017; 637:175-181. [DOI: 10.1016/j.neulet.2016.11.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 11/07/2016] [Accepted: 11/09/2016] [Indexed: 11/20/2022]
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Awan SJ, Baig MT, Yaqub F, Tayyeb A, Ali G. In vitro differentiated hepatic oval-like cells enhance hepatic regeneration in CCl 4 -induced hepatic injury. Cell Biol Int 2016; 41:51-61. [PMID: 27805290 DOI: 10.1002/cbin.10699] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 10/29/2016] [Indexed: 02/06/2023]
Abstract
Hepatic oval cells are likely to be activated during advanced stage of liver fibrosis to reconstruct damaged hepatic tissue. However, their scarcity, difficulties in isolation, and in vitro expansion hampered their transplantation in fibrotic liver. This study was aimed to investigate the repair potential of in vitro differentiated hepatic oval-like cells in CCl4 -induced liver fibrosis. BMSCs and oval cells were isolated and characterized from C57BL/6 GFP+ mice. BMSCs were differentiated into oval cells by preconditioning with HGF, EGF, SCF, and LIF and analyzed for the oval cells-specific genes. Efficiency of oval cells to reduce hepatocyte injury was studied by determining cell viability, release of LDH, and biochemical tests in a co-culture system. Further, in vivo repair potential of differentiated oval cells was determined in CCl4 -induced fibrotic model by gene expression analysis, biochemical tests, mason trichrome, and Sirius red staining. Differentiated oval cells expressed hepatic oval cells-specific markers AFP, ALB, CK8, CK18, CK19. These differentiated cells when co-cultured with injured hepatocytes showed significant hepato-protection as measured by reduction in apoptosis, LDH release, and improvement in liver functions. Transplantation of differentiated oval cells like cells in fibrotic livers exhibited enhanced homing, reduced liver fibrosis, and improved liver functions by augmenting hepatic microenvironment by improved liver functions. This preconditioning strategy to differentiate BMSCs into oval cell leads to improved survival and homing of transplanted cells. In addition, reduction in fibrosis and functional improvement in mice with CCl4 -induced liver fibrosis was achieved.
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Affiliation(s)
- Sana Javaid Awan
- National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.,Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore, Pakistan
| | - Maria Tayyab Baig
- National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Faiza Yaqub
- National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Asima Tayyeb
- School of Biological Sciences, University of the Punjab, Lahore, Pakistan
| | - Gibran Ali
- National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
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Could stem cells be the future therapy for sepsis? Blood Rev 2016; 30:439-452. [PMID: 27297212 DOI: 10.1016/j.blre.2016.05.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 05/27/2016] [Accepted: 05/31/2016] [Indexed: 12/15/2022]
Abstract
The severity and threat of sepsis is well known, and despite several decades of research, the mortality continues to be high. Stem cells have great potential to be used in various clinical disorders. The innate ability of stem cells such as pluripotency, self-renewal makes them potential agents for therapeutic intervention. The pathophysiology of sepsis is a plethora of complex mechanisms which include the initial microbial infection, followed by "cytokine storm," endothelial dysfunction, coagulation cascade, and the late phase of apoptosis and immune paralysis which ultimately results in multiple organ dysfunction. Stem cells could potentially alter each step of this complex pathophysiology of sepsis. Multiple organ dysfunction associated with sepsis most often leads to death and stem cells have shown their ability to prevent the organ damage and improve the organ function. The possible mechanisms of therapeutic potential of stem cells in sepsis have been discussed in detail. The route of administration, dose level, and timing also play vital role in the overall effect of stem cells in sepsis.
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