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1
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Sakuma R, Minato Y, Maeda S, Yagi H. Nrf2 phosphorylation contributes to acquisition of pericyte reprogramming via the PKCδ pathway. Neurobiol Dis 2025; 206:106824. [PMID: 39900301 DOI: 10.1016/j.nbd.2025.106824] [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: 10/09/2024] [Revised: 01/15/2025] [Accepted: 01/29/2025] [Indexed: 02/05/2025] Open
Abstract
Pericytes (PCs) are vascular mural cells embedded in the basement membrane of micro blood vessels. It has been proposed using a C.B-17 mouse model of stroke that normal brain PCs are converted to ischemic PCs (iPCs), some of which express various stem cell markers. We previously reported that nuclear factor erythroid-2-related factor 2 (Nrf2) protected against oxidative stress following ischemia and promoted the PC reprogramming process. The present study examined the molecular mechanisms underlying the induction of Nrf2. We revealed that oxidative stress and pNrf2 induced by stroke proceeded the expression of nestin in meningeal cells and reactive PCs within the post-stroke area. PKCδ inhibitor treatment suppressed pNrf2 activation and restored the down-regulated expression of stem cell markers in iPCs in vitro. The PKCδ inhibitor treatment also suppressed the production of iPCs. These results suggest the potential of Nrf2 phosphorylation via PKCδ as a novel strategy for the treatment of ischemic injury.
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Affiliation(s)
- Rika Sakuma
- Department of Anatomy and Cell Biology, Faculty of Medicine, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya-shi, Hyogo 663-8501, Japan.
| | - Yusuke Minato
- Department of Anatomy and Cell Biology, Faculty of Medicine, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya-shi, Hyogo 663-8501, Japan
| | - Seishi Maeda
- Department of Anatomy and Cell Biology, Faculty of Medicine, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya-shi, Hyogo 663-8501, Japan
| | - Hideshi Yagi
- Department of Anatomy and Cell Biology, Faculty of Medicine, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya-shi, Hyogo 663-8501, Japan
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2
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Tang H, Li Y, Tang W, Zhu J, Parker GC, Zhang JH. Endogenous Neural Stem Cell-induced Neurogenesis after Ischemic Stroke: Processes for Brain Repair and Perspectives. Transl Stroke Res 2023; 14:297-303. [PMID: 36057034 DOI: 10.1007/s12975-022-01078-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/22/2022] [Accepted: 08/25/2022] [Indexed: 10/14/2022]
Abstract
Ischemic stroke is a very common cerebrovascular accident that occurred in adults and causes higher risk of neural deficits. After ischemic stroke, patients are often left with severe neurological deficits. Therapeutic strategies for ischemic stroke might mitigate neuronal loss due to delayed neural cell death in the penumbra or seek to replace dead neural cells in the ischemic core. Currently, stem cell therapy is the most promising approach for inducing neurogenesis for neural repair after ischemic stroke. Stem cell treatments include transplantation of exogenous stem cells but also stimulating endogenous neural stem cells (NSCs) proliferation and differentiation into neural cells. In this review, we will discuss endogenous NSCs-induced neurogenesis after ischemic stroke and provide perspectives for the therapeutic effects of endogenous NSCs in ischemic stroke. Our review would inform future therapeutic development not only for patients with ischemic stroke but also with other neurological deficits.
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Affiliation(s)
- Hailiang Tang
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, National Center for Neurological Disorders, National Key Laboratory for Medical Neurobiology, Institutes of Brain Science, Shanghai Key Laboratory of Brain Function and Regeneration, Institute of Neurosurgery, MOE Frontiers Center for Brain Science, Shanghai, China
| | - Yao Li
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Weijun Tang
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jianhong Zhu
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, National Center for Neurological Disorders, National Key Laboratory for Medical Neurobiology, Institutes of Brain Science, Shanghai Key Laboratory of Brain Function and Regeneration, Institute of Neurosurgery, MOE Frontiers Center for Brain Science, Shanghai, China.
| | - Graham C Parker
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
| | - John H Zhang
- Department of Neurosurgery, Loma Linda University, 11234 Anderson Street, Loma Linda, CA, 92354, USA.
- Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus Street, Loma Linda, CA, 92354, USA.
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3
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Kim H, Jang EJ, Sankpal NV, Patel M, Patel R. Recent Development of Brain Organoids for Biomedical Application. Macromol Biosci 2023; 23:e2200346. [PMID: 36469016 DOI: 10.1002/mabi.202200346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 11/11/2022] [Indexed: 12/12/2022]
Abstract
Over the years, scientists have studied the behavior and anatomy of many animals to understand the own species. However, despite the continuous efforts, it is often difficult to know for certain how the brain works due to the differences between the brains of animals and the human brain. While the use of animal models for research continues, the origin of human cognition and neurological disorders needs further elucidation. To that end, in vitro organoids that exhibit in vivo characteristics of the human brain have been recently developed. These brain-like organoids enable researchers to dive deeper into understanding the human brain, its neurological structures, and the causes of neurological pathologies. This paper reviews the recent developments in the regeneration of brain-like organoids using Matrigel and other alternatives. Further, gel-free methods that may enhance the regeneration process of organoids are discussed. Finally, the vascularized brain organoid growth and development in both in vitro and in vivo conditions are detailed.
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Affiliation(s)
- HanSol Kim
- Bio-Convergence (BC), Integrated Science and Engineering Division (ISED), Underwood International College, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, South Korea
| | - Eun Jo Jang
- Nano Science and Engineering, Integrated Science and Engineering Division (ISED), Underwood International College, Yonsei University, Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, South Korea
| | - Narendra V Sankpal
- Norton Thoracic Institute St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA
| | - Madhumita Patel
- Department of Chemistry and Nanoscience, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, South Korea
| | - Rajkumar Patel
- Energy & Environmental Science and Engineering (EESE), Integrated Science and Engineering Division (ISED), Underwood International College, Yonsei University, 85 Songdogwahak-ro, Yeonsugu, Incheon, 21938, South Korea
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4
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Liu H, Wei T, Huang Q, Liu W, Yang Y, Jin Y, Wu D, Yuan K, Zhang P. The roles, mechanism, and mobilization strategy of endogenous neural stem cells in brain injury. Front Aging Neurosci 2022; 14:924262. [PMID: 36062152 PMCID: PMC9428262 DOI: 10.3389/fnagi.2022.924262] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Brain injury poses a heavy disease burden in the world, resulting in chronic deficits. Therapies for brain injuries have been focused on pharmacologic, small molecule, endocrine and cell-based therapies. Endogenous neural stem cells (eNSCs) are a group of stem cells which can be activated in vivo by damage, neurotrophic factors, physical factor stimulation, and physical exercise. The activated eNSCs can proliferate, migrate and differentiate into neuron, oligodendrocyte and astrocyte, and play an important role in brain injury repair and neural plasticity. The roles of eNSCs in the repair of brain injury include but are not limited to ameliorating cognitive function, improving learning and memory function, and promoting functional gait behaviors. The activation and mobilization of eNSCs is important to the repair of injured brain. In this review we describe the current knowledge of the common character of brain injury, the roles and mechanism of eNSCs in brain injury. And then we discuss the current mobilization strategy of eNSCs following brain injury. We hope that a comprehensive awareness of the roles and mobilization strategy of eNSCs in the repair of cerebral ischemia may help to find some new therapeutic targets and strategy for treatment of stroke.
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Affiliation(s)
- Haijing Liu
- Key Laboratory of Acupuncture and Massage for Treatment of Encephalopathy, College of Acupuncture, Tuina and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Tao Wei
- Library, Kunming Medical University, Kunming, China
- School of Continuing Education, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Qin Huang
- Department of Teaching Affairs and Administration, Kunming Medical University, Kunming, China
| | - Wei Liu
- School of Public Health, Kunming Medical University, Kunming, China
| | - Yaopeng Yang
- Department of Pulmonary and Critical Care Medicine, The Sixth Affiliated Hospital of Kunming Medical University, Yuxi, China
| | - Yaju Jin
- Key Laboratory of Acupuncture and Massage for Treatment of Encephalopathy, College of Acupuncture, Tuina and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Danli Wu
- Key Laboratory of Acupuncture and Massage for Treatment of Encephalopathy, College of Acupuncture, Tuina and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Kai Yuan
- Key Laboratory of Acupuncture and Massage for Treatment of Encephalopathy, College of Acupuncture, Tuina and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Pengyue Zhang
- Key Laboratory of Acupuncture and Massage for Treatment of Encephalopathy, College of Acupuncture, Tuina and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China
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5
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Zhang K, Yang Y, Ge H, Wang J, Lei X, Chen X, Wan F, Feng H, Tan L. Neurogenesis and Proliferation of Neural Stem/Progenitor Cells Conferred by Artesunate via FOXO3a/p27Kip1 Axis in Mouse Stroke Model. Mol Neurobiol 2022; 59:4718-4729. [PMID: 35596896 DOI: 10.1007/s12035-021-02710-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/21/2021] [Indexed: 11/24/2022]
Abstract
Promoting neurogenesis and proliferation of endogenous neural stem/progenitor cells (NSPCs) is considered a promising strategy for neurorehabilitation after stroke. Our previous study revealed that a moderate dose of artesunate (ART, 150 mg/kg) could enhance functional recovery in middle cerebral artery occlusion (MCAO) mice. This study aimed to investigate the effects of ART treatment on neurogenesis and proliferation of NSPCs using a rodent MCAO model. MRI results indicated that the ischemic brain volume of MCAO mice was reduced by ART treatment. The results of diffusion tensor imaging, electron microscopic, and immunofluorescence of Tuj-1 also revealed that ischemia-induced white matter lesion was alleviated by ART treatment. After ischemia/reperfusion, the proportion of Brdu + endogenous NSPCs in the ipsilateral subventricular zone and peri-infarct cortex was increased by ART treatment. Furthermore, the neuro-restorative effects of ART were abolished by the overexpression of FOXO3a. These findings suggested that ART could rescue ischemia/reperfusion damage and alleviate white matter injury, subsequently contributing to post-stroke functional recovery by promoting neurogenesis and proliferation of endogenous NSPCs via the FOXO3a/p27Kip1 pathway.
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Affiliation(s)
- Kaiyuan Zhang
- Department of Neurosurgery, Southwest Hospital, the Third Military Medical University (Army Military Medical University), Chongqing, China
- Department of Neurosurgery, General Hospital of Xinjiang Military Command, Urumqi, Xinjiang, China
| | - Yang Yang
- Department of Neurosurgery, Southwest Hospital, the Third Military Medical University (Army Military Medical University), Chongqing, China
- Department of Neurosurgery, 904Th Hospital of the PLA, Medical School of Anhui Medical University, Wuxi, Jiangsu, China
| | - Hongfei Ge
- Department of Neurosurgery, Southwest Hospital, the Third Military Medical University (Army Military Medical University), Chongqing, China
| | - Ju Wang
- Department of Neurosurgery, Southwest Hospital, the Third Military Medical University (Army Military Medical University), Chongqing, China
| | - Xuejiao Lei
- Department of Neurosurgery, Southwest Hospital, the Third Military Medical University (Army Military Medical University), Chongqing, China
| | - Xuezhu Chen
- Department of Neurosurgery, Southwest Hospital, the Third Military Medical University (Army Military Medical University), Chongqing, China
| | - Feng Wan
- Department of Electrical and Computer Engineering, Faculty of Science and Technology, University of Macau, Macau, China
| | - Hua Feng
- Department of Neurosurgery, Southwest Hospital, the Third Military Medical University (Army Military Medical University), Chongqing, China
| | - Liang Tan
- Department of Neurosurgery, Southwest Hospital, the Third Military Medical University (Army Military Medical University), Chongqing, China.
- Department of Electrical and Computer Engineering, Faculty of Science and Technology, University of Macau, Macau, China.
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6
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Picoli CC, Gonçalves BÔP, Santos GSP, Rocha BGS, Costa AC, Resende RR, Birbrair A. Pericytes cross-talks within the tumor microenvironment. Biochim Biophys Acta Rev Cancer 2021; 1876:188608. [PMID: 34384850 DOI: 10.1016/j.bbcan.2021.188608] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 07/14/2021] [Accepted: 08/05/2021] [Indexed: 02/07/2023]
Abstract
Cancer cells are embedded within the tumor microenvironment and interact dynamically with its components during tumor progression. Understanding the molecular mechanisms by which the tumor microenvironment components communicate is crucial for the success of therapeutic applications. Recent studies show, by using state-of-the-art technologies, including sophisticated in vivo inducible Cre/loxP mediated systems and CRISPR-Cas9 gene editing, that pericytes communicate with cancer cells. The arising knowledge on cross-talks within the tumor microenvironment will be essential for the development of new therapies against cancer. Here, we review recent progress in our understanding of pericytes roles within tumors.
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Affiliation(s)
- Caroline C Picoli
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Bryan Ô P Gonçalves
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Gabryella S P Santos
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Beatriz G S Rocha
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Alinne C Costa
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Rodrigo R Resende
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Department of Radiology, Columbia University Medical Center, New York, NY, USA.
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7
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Haque ME, Hasan KM, George S, Sitton C, Boren S, Arevalo OD, Vahidy F, Zhang X, Cox CS, Alderman S, Aronowski J, Grotta JC, Savitz SI. Longitudinal neuroimaging evaluation of the corticospinal tract in patients with stroke treated with autologous bone marrow cells. Stem Cells Transl Med 2021; 10:943-955. [PMID: 33689219 PMCID: PMC8235123 DOI: 10.1002/sctm.20-0369] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 12/30/2020] [Accepted: 01/18/2021] [Indexed: 12/15/2022] Open
Abstract
Bone marrow mononuclear cells (MNCs) attenuate secondary degeneration and enhance recovery in stroke animal models. In a nonrandomized clinical trial, we imaged 37 patients with stroke: 17 patients treated with MNCs (treated) and 20 patients who received standard of care (nontreated) at 1, 3, and 12 months onset of stroke on 3.0T MRI system. Three-dimensional anatomical and diffusion tensor images were obtained. The integrity of the corticospinal tract was assessed by measuring absolute and relative fractional anisotropy (FA) and mean diffusivity (MD) in the rostral pons (RP), posterior limb of the internal capsule, and corona radiata by drawing regions of interest. Infarct volume and stroke severity, which was assessed via the NIH Stroke Scale (NIHSS), were higher in the MNC group compared with the nontreated patients, which is a major limitation. Overall, the relative FA (rFA) of the nontreated patients exhibited continued reduction and an increase in relative MD (rMD) from 1 to 12 months, whereas despite larger infarcts and higher severity, treated patients displayed an increase in rFA from 3 to 12 months and no change in rMD. Contrary to the nontreated group, the treated patients' rFA was also significantly correlated (P < .05) with NIHSS score in the RP at all time points, whereas rMD at the last two.
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Affiliation(s)
- Muhammad E. Haque
- Institute for Stroke and Cerebrovascular DiseasesMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
| | - Khader M. Hasan
- Department of Diagnostic and Interventional ImagingMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
| | - Sarah George
- Institute for Stroke and Cerebrovascular DiseasesMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
| | - Clark Sitton
- Department of Diagnostic and Interventional ImagingMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
| | - Seth Boren
- Institute for Stroke and Cerebrovascular DiseasesMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
| | - Octavio D. Arevalo
- Department of Diagnostic and Interventional ImagingMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
| | - Farhaan Vahidy
- Institute for Stroke and Cerebrovascular DiseasesMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
| | - Xu Zhang
- Department of Biostatistics, Epidemiology, and Research Design Component of the Center for Clinical and Translational SciencesMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
| | - Charles S. Cox
- Department of Pediatric SurgeryMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
| | - Susan Alderman
- Institute for Stroke and Cerebrovascular DiseasesMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
| | - Jaroslaw Aronowski
- Institute for Stroke and Cerebrovascular DiseasesMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
| | | | - Sean I. Savitz
- Institute for Stroke and Cerebrovascular DiseasesMcGovern Medical School and University of Texas Health Science CenterHoustonTexasUSA
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Song G, Zhao M, Chen H, Zhou X, Lenahan C, Ou Y, He Y. The Application of Brain Organoid Technology in Stroke Research: Challenges and Prospects. Front Cell Neurosci 2021; 15:646921. [PMID: 34234646 PMCID: PMC8257041 DOI: 10.3389/fncel.2021.646921] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
Stroke is a neurological disease responsible for significant morbidity and disability worldwide. However, there remains a dearth of effective therapies. The failure of many therapies for stroke in clinical trials has promoted the development of human cell-based models, such as brain organoids. Brain organoids differ from pluripotent stem cells in that they recapitulate various key features of the human central nervous system (CNS) in three-dimensional (3D) space. Recent studies have demonstrated that brain organoids could serve as a new platform to study various neurological diseases. However, there are several limitations, such as the scarcity of glia and vasculature in organoids, which are important for studying stroke. Herein, we have summarized the application of brain organoid technology in stroke research, such as for modeling and transplantation purposes. We also discuss methods to overcome the limitations of brain organoid technology, as well as future prospects for its application in stroke research. Although there are many difficulties and challenges associated with brain organoid technology, it is clear that this approach will play a critical role in the future exploration of stroke treatment.
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Affiliation(s)
- Guini Song
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Zhao
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hanmin Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangyue Zhou
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cameron Lenahan
- Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, NM, United States
| | - Yibo Ou
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yue He
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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9
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Nakagomi T, Tanaka Y, Nakagomi N, Matsuyama T, Yoshimura S. How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke. Int J Mol Sci 2020; 21:ijms21176360. [PMID: 32887241 PMCID: PMC7504064 DOI: 10.3390/ijms21176360] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 12/19/2022] Open
Abstract
Ischemic stroke caused by cerebral artery occlusion induces neurological deficits because of cell damage or death in the central nervous system. Given the recent therapeutic advances in reperfusion therapies, some patients can now recover from an ischemic stroke with no sequelae. Currently, reperfusion therapies focus on rescuing neural lineage cells that survive in spite of decreases in cerebral blood flow. However, vascular lineage cells are known to be more resistant to ischemia/hypoxia than neural lineage cells. This indicates that ischemic areas of the brain experience neural cell death but without vascular cell death. Emerging evidence suggests that if a vascular cell-mediated healing system is present within ischemic areas following reperfusion, the therapeutic time window can be extended for patients with stroke. In this review, we present our comments on this subject based upon recent findings from lethal ischemia following reperfusion in a mouse model of stroke.
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Affiliation(s)
- Takayuki Nakagomi
- Institute for Advanced Medical Sciences, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya 663-8501, Japan;
- Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya 663-8501, Japan;
- Correspondence: ; Tel.: +81-798-45-6821; Fax: +81-798-45-6823
| | - Yasue Tanaka
- Department of Neurosurgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya 663-8501, Japan;
| | - Nami Nakagomi
- Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya 663-8501, Japan;
| | - Tomohiro Matsuyama
- Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya 663-8501, Japan;
| | - Shinichi Yoshimura
- Institute for Advanced Medical Sciences, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya 663-8501, Japan;
- Department of Neurosurgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya 663-8501, Japan;
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10
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Tu T, Peng J, Jiang Y. FNDC5/Irisin: A New Protagonist in Acute Brain Injury. Stem Cells Dev 2020; 29:533-543. [PMID: 31914844 DOI: 10.1089/scd.2019.0232] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Tianqi Tu
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jianhua Peng
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Neurosurgical Clinical Research Center of Sichuan Province, Luzhou, China
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yong Jiang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Neurosurgical Clinical Research Center of Sichuan Province, Luzhou, China
- Laboratory of Neurological Diseases and Brain Functions, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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11
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Liu H, Xu X, Tu Y, Chen K, Song L, Zhai J, Chen S, Rong L, Zhou L, Wu W, So KF, Ramakrishna S, He L. Engineering Microenvironment for Endogenous Neural Regeneration after Spinal Cord Injury by Reassembling Extracellular Matrix. ACS APPLIED MATERIALS & INTERFACES 2020; 12:17207-17219. [PMID: 32207300 DOI: 10.1021/acsami.9b19638] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The formation of a fluid-filled cystic cavity after spinal cord injury (SCI) is a major obstacle for neural regeneration. In this study, the post-SCI cavity was bridged by a functional self-assembling peptide (F-SAP) nanofiber hydrogel coupled with growth factor "cocktail". A sustained release of growth factors was achieved by carefully tailoring the physical hindrances and charge-induced interactions between the growth factors and the peptide nanofibers. Such an engineering microenvironment elicited axon regeneration, as determined by tracing of the descending pathway in the dorsal columns and immunochemical detection of regenerating axons beyond the lesion. Furthermore, the dynamic spatiotemporal activation line of endogenous NSCs (eNSCs) after severe SCI was thoroughly investigated. The results indicated that the growth factor-coupled F-SAP greatly facilitated eNSC proliferation, neuronal differentiation, maturation, myelination, and more importantly, the formation of interconnection with severed descending corticospinal tracts. The robust endogenous neurogenesis essentially led to the recovery of locomotion and electrophysiological properties. In conclusion, the growth factor-coupled F-SAP nanofiber hydrogel elucidated the therapeutic effect of eliciting endogenous neurogenesis by locally reassembling an extracellular matrix.
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Affiliation(s)
- Haiqian Liu
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
| | - Xiaoting Xu
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
| | - Yujie Tu
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
| | - Kaixin Chen
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
| | - Li Song
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
| | - Jingyan Zhai
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
| | - Shengfeng Chen
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
| | - Limin Rong
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
| | - Libing Zhou
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
| | - Wutian Wu
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
| | - Kwok-Fai So
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
| | - Seeram Ramakrishna
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
- Department of Mechanical Engineering, Faculty of Engineering, National University of Singapore, Singapore 117576, Singapore
| | - Liumin He
- MOE Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632, China
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
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12
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Sawada R, Nakano-Doi A, Matsuyama T, Nakagomi N, Nakagomi T. CD44 expression in stem cells and niche microglia/macrophages following ischemic stroke. Stem Cell Investig 2020; 7:4. [PMID: 32309418 DOI: 10.21037/sci.2020.02.02] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 02/18/2020] [Indexed: 12/30/2022]
Abstract
Background CD44, an adhesion molecule in the hyaluronate receptor family, plays diverse and important roles in multiple cell types and organs. Increasing evidence is mounting for CD44 expression in various types of stem cells and niche cells surrounding stem cells. However, the precise phenotypes of CD44+ cells in the brain under pathologic conditions, such as after ischemic stroke, remain unclear. Methods In the present study, using a mouse model for cerebral infarction by middle cerebral artery (MCA) occlusion, we examined the localization and traits of CD44+ cells. Results In sham-mice operations, CD44 was rarely observed in the cortex of MCA regions. Following ischemic stroke, CD44+ cells emerged in ischemic areas of the MCA cortex during the acute phase. Although CD44 at ischemic areas was, in part, expressed in stem cells, it was also expressed in hematopoietic lineages, including activated microglia/macrophages, surrounding the stem cells. CD44 expression in microglia/macrophages persisted through the chronic phase following ischemic stroke. Conclusions These data demonstrate that CD44 is expressed in stem cells and cells in the niches surrounding them, including inflammatory cells, suggesting that CD44 may play an important role in reparative processes within ischemic areas under neuroinflammatory conditions; in particular, strokes.
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Affiliation(s)
- Rikako Sawada
- Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.,Graduate School of Science and Technology, Kwansei Gakuin University, Sanda, Hyogo, Japan
| | - Akiko Nakano-Doi
- Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.,Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Tomohiro Matsuyama
- Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Nami Nakagomi
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Takayuki Nakagomi
- Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.,Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
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13
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Cerebral Organoids Repair Ischemic Stroke Brain Injury. Transl Stroke Res 2019; 11:983-1000. [PMID: 31889243 PMCID: PMC7496035 DOI: 10.1007/s12975-019-00773-0] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 10/27/2019] [Accepted: 12/11/2019] [Indexed: 12/31/2022]
Abstract
Stroke is the second leading cause of death and main cause of disability worldwide, but with few effective therapies. Although stem cell-based therapy has been proposed as an exciting regenerative medicine strategy for brain injury, there are limitations. The developed cerebral organoids (COs) represent a promising transplantation source for stroke that remains to be answered. Here, we transplanted COs at 55 days and explored the feasibility in the rat middle cerebral artery occlusion (MCAO) model of stroke. COs transplantation at 6 h or even 24 h after MCAO significantly reduces brain infarct volume and improves neurological motor function. Transplanted COs show the potential of multilineage differentiation to mimic in vivo cortical development, support motor cortex region-specific reconstruction, form neurotransmitter-related neurons, and achieve synaptic connection with host brain via in situ differentiation and cell replacement in stroke. Cells from transplanted COs show extensive migration into different brain regions along corpus callosum. The mechanisms underlying COs transplantation therapy are also associated with enhanced neurogenesis, synaptic reconstruction, axonal regeneration and angiogenesis, and decreased neural apoptosis with more survival neurons after stroke. Moreover, COs transplantation promotes predominantly exogenous neurogenesis in the transplantation periphery of ipsilateral cortex and predominantly endogenous neurogenesis in the hippocampus and subventricular zone. Together, we demonstrate the efficacy and underlying mechanisms of COs transplantation in stroke. This preliminary but promising study provides first-hand preclinical evidence for COs transplantation as a potential and effective intervention for stroke treatment.
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14
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Andreotti JP, Silva WN, Costa AC, Picoli CC, Bitencourt FCO, Coimbra-Campos LMC, Resende RR, Magno LAV, Romano-Silva MA, Mintz A, Birbrair A. Neural stem cell niche heterogeneity. Semin Cell Dev Biol 2019; 95:42-53. [PMID: 30639325 PMCID: PMC6710163 DOI: 10.1016/j.semcdb.2019.01.005] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/02/2018] [Accepted: 01/08/2019] [Indexed: 12/15/2022]
Abstract
In mammals, new neurons can be generated from neural stem cells in specific regions of the adult brain. Neural stem cells are characterized by their abilities to differentiate into all neural lineages and to self-renew. The specific microenvironments regulating neural stem cells, commonly referred to as neurogenic niches, comprise multiple cell populations whose precise contributions are under active current exploration. Understanding the cross-talk between neural stem cells and their niche components is essential for the development of therapies against neurological disorders in which neural stem cells function is altered. In this review, we describe and discuss recent studies that identified novel components in the neural stem cell niche. These discoveries bring new concepts to the field. Here, we evaluate these recent advances that change our understanding of the neural stem cell niche heterogeneity and its influence on neural stem cell function.
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Affiliation(s)
- Julia P Andreotti
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Walison N Silva
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Alinne C Costa
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Caroline C Picoli
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Flávia C O Bitencourt
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Rodrigo R Resende
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Luiz A V Magno
- Department of Mental Health, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Marco A Romano-Silva
- Department of Mental Health, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Akiva Mintz
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
| | - Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Department of Radiology, Columbia University Medical Center, New York, NY, USA.
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15
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Treadmill Exercise Suppresses Cognitive Decline and Increases White Matter Oligodendrocyte Precursor Cells in a Mouse Model of Prolonged Cerebral Hypoperfusion. Transl Stroke Res 2019; 11:496-502. [PMID: 31606888 DOI: 10.1007/s12975-019-00734-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 08/23/2019] [Accepted: 08/29/2019] [Indexed: 12/13/2022]
Abstract
Clinical evidence suggests that patients with subcortical ischemic vascular dementia (SIVD) perform better at cognitive tests after exercise. However, the underlying mechanism for this effect is largely unknown. Here, we examined how treadmill exercise changes the cognitive function and white matter cellular pathology in a mouse model of SIVD. Prolonged cerebral hypoperfusion was induced in 2-month-old male C57BL/6J mice by bilateral common carotid artery stenosis. A week later, the mice were randomly divided into a group that received 6-week treadmill exercise and a sedentary group for observation. In multiple behavioral tests (Y-maze, novel object recognition, and Morris water maze tests), the treadmill exercise training was shown to ameliorate cognitive decline in the hypoperfused SIVD mice. In addition, immunohistological analyses confirmed that there was a larger population of oligodendrocyte precursor cells in the subventricular zone of exercised versus sedentary mice. Although further investigations are needed to confirm a causal link between these findings, our study establishes a model and cellular foundation for investigating the mechanisms through which exercise preserves cognitive function in SIVD.
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16
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Nakagomi T, Takagi T, Beppu M, Yoshimura S, Matsuyama T. Neural regeneration by regionally induced stem cells within post-stroke brains: Novel therapy perspectives for stroke patients. World J Stem Cells 2019; 11:452-463. [PMID: 31523366 PMCID: PMC6716084 DOI: 10.4252/wjsc.v11.i8.452] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/04/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023] Open
Abstract
Ischemic stroke is a critical disease which causes serious neurological functional loss such as paresis. Hope for novel therapies is based on the increasing evidence of the presence of stem cell populations in the central nervous system (CNS) and the development of stem-cell-based therapies for stroke patients. Although mesenchymal stem cells (MSCs) represented initially a promising cell source, only a few transplanted MSCs were present near the injured areas of the CNS. Thus, regional stem cells that are present and/or induced in the CNS may be ideal when considering a treatment following ischemic stroke. In this context, we have recently showed that injury/ischemia-induced neural stem/progenitor cells (iNSPCs) and injury/ischemia-induced multipotent stem cells (iSCs) are present within post-stroke human brains and post-stroke mouse brains. This indicates that iNSPCs/iSCs could be developed for clinical applications treating patients with stroke. The present study introduces the traits of mouse and human iNSPCs, with a focus on the future perspective for CNS regenerative therapies using novel iNSPCs/iSCs.
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Affiliation(s)
- Takayuki Nakagomi
- Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
- Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Toshinori Takagi
- Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Mikiya Beppu
- Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Shinichi Yoshimura
- Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Tomohiro Matsuyama
- Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
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17
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Tuazon JP, Castelli V, Borlongan CV. Drug-like delivery methods of stem cells as biologics for stroke. Expert Opin Drug Deliv 2019; 16:823-833. [PMID: 31311344 DOI: 10.1080/17425247.2019.1645116] [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] [Indexed: 12/24/2022]
Abstract
Introduction: Stem cell therapy is an experimental treatment for brain disorders. Although a cellular product, stem cells can be classified as biologics based on the cells' secretion of therapeutic substances. Treatment with stem cell biologics may appeal to stroke because of the secondary cell death mechanisms, especially neuroinflammation, that are rampant from the onset and remain elevated during the progressive phase of the disease requiring multi-pronged biological targets to effectively abrogate the neurodegenerative pathology. However, the optimal delivery methods, among other logistical approaches (i.e. cell doses and timing of intervention), for stem cell therapy will need to be refined before stem cell biologics can be successfully utilized for stroke in large scale clinical trials. Areas covered: In this review, we discuss how the innate qualities of stem cells characterize them as biologics, how stem cell transplantation may be an ideal treatment for stroke, and the various routes of stem cell administration that have been employed in various preclinical and clinical investigations. Expert opinion: There is a need to optimize the delivery of stem cell biologics for stroke in order to guide the safe and effective translation of this therapy from the laboratory to the clinic.
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Affiliation(s)
- Julian P Tuazon
- a Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine , Tampa , FL , USA
| | - Vanessa Castelli
- a Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine , Tampa , FL , USA
| | - Cesar V Borlongan
- a Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine , Tampa , FL , USA
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18
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Li Q, Wang Y, Peng W, Jia Y, Tang J, Li W, Zhang JH, Yang J. MicroRNA-101a Regulates Autophagy Phenomenon via the MAPK Pathway to Modulate Alzheimer's-Associated Pathogenesis. Cell Transplant 2019; 28:1076-1084. [PMID: 31204500 PMCID: PMC6728707 DOI: 10.1177/0963689719857085] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Alzheimer’s disease (AD) is a type of neurodegenerative disorder and the most common form
of dementia. MicroRNA (miRNA) has been shown to play a role in various diseases, including
AD. It also has been reported to regulate autophagy. We extracted miRNA from blood samples
and constructed an miRNA-101a lentivirus vector. In this study we found the level of
miRNA-101a was significantly reduced in the plasma of patients with AD and APPswe/PS1ΔE9
transgenic mice. The relative expression of miRNA-101a exhibited a relatively high
diagnostic performance (area under receiver operating characteristic curve: 0.8725) in the
prediction of AD with a sensitivity of 0.913 and a specificity of 0.733 at the threshold
of 0.6463. Under electron microscopy, autophagic vacuoles in AD-related cells numbered
more than the cells up-regulating miRNA-101a in the in vitro experiments. Dual-luciferase
reporter assay and Western blot results proved that the MAPK1 pathway plays a role in the
formation of autophagic vacuoles in AD. This study found that the autophagy phenomenon
regulated by miRNA-101a via the MAPK pathway might be a new mechanism in AD. This could
provide new insights into AD formation and treatment.
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Affiliation(s)
- Qian Li
- 1 Department of Pediatrics, Daping Hospital, Army Medical University, Chongqing, China.,Both authors are the co-authors of this article
| | - Yu Wang
- 2 Department of Outpatient, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Both authors are the co-authors of this article
| | - Wenjie Peng
- 3 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yanjie Jia
- 4 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jinhua Tang
- 3 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wanwei Li
- 1 Department of Pediatrics, Daping Hospital, Army Medical University, Chongqing, China
| | - John H Zhang
- 5 Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Jun Yang
- 3 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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19
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Santos GSP, Magno LAV, Romano-Silva MA, Mintz A, Birbrair A. Pericyte Plasticity in the Brain. Neurosci Bull 2019; 35:551-560. [PMID: 30367336 PMCID: PMC6527663 DOI: 10.1007/s12264-018-0296-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 08/06/2018] [Indexed: 12/16/2022] Open
Abstract
Cerebral pericytes are perivascular cells that stabilize blood vessels. Little is known about the plasticity of pericytes in the adult brain in vivo. Recently, using state-of-the-art technologies, including two-photon microscopy in combination with sophisticated Cre/loxP in vivo tracing techniques, a novel role of pericytes was revealed in vascular remodeling in the adult brain. Strikingly, after pericyte ablation, neighboring pericytes expand their processes and prevent vascular dilatation. This new knowledge provides insights into pericyte plasticity in the adult brain.
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Affiliation(s)
- Gabryella S P Santos
- Departamento de Patologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil
| | - Luiz A V Magno
- Department of Mental Health, Federal University of Minas Gerais, Belo Horizonte, MG, 30130-100, Brazil
| | - Marco A Romano-Silva
- Department of Mental Health, Federal University of Minas Gerais, Belo Horizonte, MG, 30130-100, Brazil
| | - Akiva Mintz
- Department of Radiology, Columbia University Medical Center, New York, NY, 10032, USA
| | - Alexander Birbrair
- Departamento de Patologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
- Department of Radiology, Columbia University Medical Center, New York, NY, 10032, USA.
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20
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Modern Concepts in Regenerative Therapy for Ischemic Stroke: From Stem Cells for Promoting Angiogenesis to 3D-Bioprinted Scaffolds Customized via Carotid Shear Stress Analysis. Int J Mol Sci 2019; 20:ijms20102574. [PMID: 31130624 PMCID: PMC6566983 DOI: 10.3390/ijms20102574] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 05/20/2019] [Accepted: 05/22/2019] [Indexed: 02/06/2023] Open
Abstract
Ischemic stroke is associated with a tremendous economic and societal burden, and only a few therapies are currently available for the treatment of this devastating disease. The main therapeutic approaches used nowadays for the treatment of ischemic brain injury aim to achieve reperfusion, neuroprotection and neurorecovery. Therapeutic angiogenesis also seems to represent a promising tool to improve the prognosis of cerebral ischemia. This review aims to present the modern concepts and the current status of regenerative therapy for ischemic stroke and discuss the main results of major clinical trials addressing the effectiveness of stem cell therapy for achieving neuroregeneration in ischemic stroke. At the same time, as a glimpse into the future, this article describes modern concepts for stroke prevention, such as the implantation of bioprinted scaffolds seeded with stem cells, whose 3D geometry is customized according to carotid shear stress.
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21
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Beppu M, Nakagomi T, Takagi T, Nakano-Doi A, Sakuma R, Kuramoto Y, Tatebayashi K, Matsuyama T, Yoshimura S. Isolation and Characterization of Cerebellum-Derived Stem Cells in Poststroke Human Brain. Stem Cells Dev 2019; 28:528-542. [PMID: 30767605 DOI: 10.1089/scd.2018.0232] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
There is compelling evidence that the mature central nervous system (CNS) harbors stem cell populations outside conventional neurogenic regions. We previously demonstrated that brain pericytes (PCs) in both mouse and human exhibit multipotency to differentiate into various neural lineages following cerebral ischemia. PCs are found throughout the CNS, including cerebellum, but it remains unclear whether cerebellar PCs also form ischemia-induced multipotent stem cells (iSCs). In this study, we demonstrate that putative iSCs can be isolated from poststroke human cerebellum (cerebellar iSCs [cl-iSCs]). These cl-iSCs exhibited multipotency and differentiated into electrophysiologically active neurons. Neurogenic potential was also confirmed in single-cell suspensions. DNA microarray analysis revealed highly similar gene expression patterns between PCs and cl-iSCs, suggesting PC origin. Global gene expression comparison with cerebral iSCs revealed general similarity, but cl-iSCs differentially expressed certain cerebellum-specific genes. Thus, putative iSCs are present in poststroke cerebellum and possess region-specific traits, suggesting potential capacity to regenerate functional cerebellar neurons following ischemic stroke.
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Affiliation(s)
- Mikiya Beppu
- 1 Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takayuki Nakagomi
- 2 Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.,3 Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine, Nishinomiya, Japan
| | - Toshinori Takagi
- 1 Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Akiko Nakano-Doi
- 2 Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.,3 Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine, Nishinomiya, Japan
| | - Rika Sakuma
- 2 Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yoji Kuramoto
- 1 Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kotaro Tatebayashi
- 1 Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tomohiro Matsuyama
- 3 Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shinichi Yoshimura
- 1 Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Japan
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22
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Ostrowski RP, Zhang JH. The insights into molecular pathways of hypoxia-inducible factor in the brain. J Neurosci Res 2018; 98:57-76. [PMID: 30548473 DOI: 10.1002/jnr.24366] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 11/16/2018] [Accepted: 11/20/2018] [Indexed: 12/12/2022]
Abstract
The objectives of this present work were to review recent developments on the role of hypoxia-inducible factor (HIF) in the survival of cells under normoxic versus hypoxic and inflammatory brain conditions. The dual nature of HIF effects appears well established, based on the accumulated evidence of HIF playing both the role of adaptive factor and mediator of cell demise. Cellular HIF responses depend on pathophysiological conditions, developmental phase, comorbidities, and administered medications. In addition, HIF-1α and HIF-2α actions may vary in the same tissues. The multiple roles of HIF in stem cells are emerging. HIF not only regulates expression of target genes and thereby influences resultant protein levels but also contributes to epigenetic changes that may reciprocally provide feedback regulations loops. These HIF-dependent alterations in neurological diseases and its responses to treatments in vivo need to be examined alongside with a functional status of subjects involved in such studies. The knowledge of HIF pathways might be helpful in devising HIF-mimetics and modulating drugs, acting on the molecular level to improve clinical outcomes, as exemplified here by clinical and experimental data of selected brain diseases, occasionally corroborated by the data from disorders of other organs. Because of complex role of HIF in brain injuries, prospective therapeutic interventions need to differentially target HIF responses depending on their roles in the molecular mechanisms of neurologic diseases.
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Affiliation(s)
- Robert P Ostrowski
- Department of Experimental and Clinical Neuropathology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - John H Zhang
- Departments of Anesthesiology and Physiology, School of Medicine, Loma Linda University, Loma Linda, California
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23
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Hoshiba T, Sugano Y, Yokoyama N. Murine Neural Stem Cell (NSC) Line, MEB5-derived Decellularized Matrix as an In Vitro Extracellular Matrix Model in NSC Niche. CHEM LETT 2018. [DOI: 10.1246/cl.180788] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- Takashi Hoshiba
- Frontier Center for Organic Materials, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
- Innovative Flex Course for Frontier Organic Materials Systems, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
- Research Center for Functional Materials, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan
| | - Yuki Sugano
- Yamagata Prefectural Yonezawa Kojokan Senior High School, 1101 Oh-aza Sasano, Yonezawa, Yamagata 992-1443, Japan
| | - Natsumi Yokoyama
- Yamagata Prefectural Yonezawa Kojokan Senior High School, 1101 Oh-aza Sasano, Yonezawa, Yamagata 992-1443, Japan
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24
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Sakuma R, Takahashi A, Nakano-Doi A, Sawada R, Kamachi S, Beppu M, Takagi T, Yoshimura S, Matsuyama T, Nakagomi T. Comparative Characterization of Ischemia-Induced Brain Multipotent Stem Cells with Mesenchymal Stem Cells: Similarities and Differences. Stem Cells Dev 2018; 27:1322-1338. [PMID: 29999479 DOI: 10.1089/scd.2018.0075] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells localized to the perivascular regions of various organs, including bone marrow (BM). While MSC transplantation represents a promising stem cell-based therapy for ischemic stroke, increasing evidence indicates that exogenously administered MSCs rarely accumulate in the injured central nervous system (CNS). Therefore, compared with MSCs, regionally derived brain multipotent stem cells may be a superior source to elicit regeneration of the CNS following ischemic injury. We previously identified ischemia-induced multipotent stem cells (iSCs) as likely originating from brain pericytes/perivascular cells (PCs) within poststroke regions. However, detailed characteristics of iSCs and their comparison with MSCs remains to be investigated. In the present study, we compared iSCs with BM-derived MSCs, with a focus on the stemness and neuron-generating activity of each cell type. From our results, stem and undifferentiated cell markers, including c-myc and Klf4, were found to be expressed in iSCs and BM-MSCs. In addition, both cell types exhibited the ability to differentiate into mesoderm lineages, including as osteoblasts, adipocytes, and chondrocytes. However, compared with BM-MSCs, high expression of neural stem cell markers, including nestin and Sox2, were found in iSCs. In addition, iSCs, but not BM-MSCs, formed neurosphere-like cell clusters that differentiated into functional neurons. These results demonstrate that iSCs are likely multipotent stem cells with the ability to differentiate into not only mesoderm, but also neural, lineages. Collectively, our novel findings suggest that locally induced iSCs may contribute to CNS repair by producing neuronal cells following ischemic stroke.
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Affiliation(s)
- Rika Sakuma
- 1 Institute for Advanced Medical Sciences , Hyogo College of Medicine, Nishinomiya, Japan
| | - Ai Takahashi
- 1 Institute for Advanced Medical Sciences , Hyogo College of Medicine, Nishinomiya, Japan .,2 Graduate School of Science and Technology, Kwansei Gakuin University , Sanda, Japan
| | - Akiko Nakano-Doi
- 1 Institute for Advanced Medical Sciences , Hyogo College of Medicine, Nishinomiya, Japan .,3 Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine , Nishinomiya, Japan
| | - Rikako Sawada
- 1 Institute for Advanced Medical Sciences , Hyogo College of Medicine, Nishinomiya, Japan .,2 Graduate School of Science and Technology, Kwansei Gakuin University , Sanda, Japan
| | - Saeko Kamachi
- 3 Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine , Nishinomiya, Japan
| | - Mikiya Beppu
- 4 Department of Neurosurgery, Hyogo College of Medicine , Nishinomiya, Japan
| | - Toshinori Takagi
- 4 Department of Neurosurgery, Hyogo College of Medicine , Nishinomiya, Japan
| | - Shinichi Yoshimura
- 4 Department of Neurosurgery, Hyogo College of Medicine , Nishinomiya, Japan
| | - Tomohiro Matsuyama
- 3 Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine , Nishinomiya, Japan
| | - Takayuki Nakagomi
- 1 Institute for Advanced Medical Sciences , Hyogo College of Medicine, Nishinomiya, Japan .,3 Department of Therapeutic Progress in Brain Diseases, Hyogo College of Medicine , Nishinomiya, Japan
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25
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Nakano T, Kurimoto S, Kato S, Asano K, Hirata T, Kiyama H, Hirata H. Complete adult neurogenesis within a Wallerian degenerating nerve expressed as an ectopic ganglion. J Tissue Eng Regen Med 2018; 12:1469-1480. [DOI: 10.1002/term.2679] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Revised: 01/10/2018] [Accepted: 04/16/2018] [Indexed: 11/09/2022]
Affiliation(s)
- Tomonori Nakano
- Department of Hand Surgery; Nagoya University Graduate School of Medicine; Nagoya Aichi Japan
| | - Shigeru Kurimoto
- Department of Hand Surgery; Nagoya University Graduate School of Medicine; Nagoya Aichi Japan
| | - Shuichi Kato
- Department of Orthopaedic Surgery; Konan Kosei Hospital; Konan Aichi Japan
| | - Kenichi Asano
- Department of Hand Surgery; Nagoya University Graduate School of Medicine; Nagoya Aichi Japan
| | - Takuma Hirata
- Department of Hand Surgery; Nagoya University Graduate School of Medicine; Nagoya Aichi Japan
| | - Hiroshi Kiyama
- Department of Functional Anatomy and Neuroscience; Nagoya University Graduate School of Medicine; Nagoya Aichi Japan
| | - Hitoshi Hirata
- Department of Hand Surgery; Nagoya University Graduate School of Medicine; Nagoya Aichi Japan
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26
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Affiliation(s)
- Anica Dricu
- a Department of Biochemistry , University of Medicine and Pharmacy of Craiova , Craiova , Romania
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27
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Sarmah D, Kaur H, Saraf J, Pravalika K, Goswami A, Kalia K, Borah A, Wang X, Dave KR, Yavagal DR, Bhattacharya P. Getting Closer to an Effective Intervention of Ischemic Stroke: The Big Promise of Stem Cell. Transl Stroke Res 2017; 9:356-374. [PMID: 29075984 DOI: 10.1007/s12975-017-0580-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 10/12/2017] [Accepted: 10/17/2017] [Indexed: 12/13/2022]
Abstract
Stem cell therapy for ischemic stroke has widely been explored. Results from both preclinical and clinical studies have immensely supported the judicious use of stem cells as therapy. These provide an attractive means for preserving and replacing the damaged brain tissues following an ischemic attack. Since the past few years, researchers have used various types of stem cells to replenish insulted neuronal and glial cells in neurological disorders. In the present review, we discuss different types of stem cells employed for the treatment of ischemic stroke and mechanisms and challenges these cells face once introduced into the living system. Further, we also present different ways to maneuver and overcome challenges to translate the advances made at the preclinical level to clinics.
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Affiliation(s)
- Deepaneeta Sarmah
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Harpreet Kaur
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Jackson Saraf
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Kanta Pravalika
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Avirag Goswami
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kiran Kalia
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Xin Wang
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kunjan R Dave
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Dileep R Yavagal
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India.
- Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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