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Walia A, Kaur A, Singh R, Rani N, Swami R. Unveiling the Mysteries of the Blood-brain Barrier: The Problem of the Brain/spinal Pharmacotherapy. Cent Nerv Syst Agents Med Chem 2025; 25:91-108. [PMID: 39206486 DOI: 10.2174/0118715249297247240813104929] [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: 01/11/2024] [Revised: 06/03/2024] [Accepted: 06/20/2024] [Indexed: 09/04/2024]
Abstract
The most critical issue impeding the development of innovative cerebrospinal medications is the blood-brain barrier (BBB). The BBB limits the ability of most medications to penetrate the brain to the CNS. The BBB structure and functions are summarized, with the physical barrier generated by endothelial tight junctions and the transport barrier formed by transporters within the membrane and vesicular processes. The functions of connected cells, particularly the end feet of astrocytic glial cells, microglia, and pericytes, are described. The drugs that cross the blood brain barrier are explained below along with their mechanisms. Some of the associated conditions and problems are given.
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Affiliation(s)
- Aditya Walia
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Amandeep Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Randhir Singh
- Central University of Punjab, Bathinda, Punjab, India
| | - Nidhi Rani
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Rajan Swami
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Sun Z, Zhao H, Yang S, Liu R, Yi L, Gao J, Liu S, Chen Y, Zhang Z. Edaravone Dexborneol protects against blood-brain barrier disruption following cerebral ischemia/reperfusion by upregulating pericyte coverage via vitronectin-integrin and PDGFB/PDGFR-β signaling. Free Radic Biol Med 2024; 225:758-766. [PMID: 39486750 DOI: 10.1016/j.freeradbiomed.2024.10.309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/26/2024] [Accepted: 10/29/2024] [Indexed: 11/04/2024]
Abstract
BACKGROUND Recent advancements in brain cytoprotection therapies following cerebral ischemia-reperfusion (I/R) injury have become an emerging interest. Pericytes were vulnerable during the early stages of ischemia. This study aims to explore the protective effects of Edaravone dexborneol (Eda.B) on pericyte loss, as well as and the underlying mechanisms, given its potential in alleviating I/R injury. METHODS The rat transient middle cerebral artery occlusion (tMCAO) model was established. Rats were randomly divided into Sham group (Sham, n = 24), tMCAO group (tMCAO, n = 24), Edaravone group (Eda, n = 24), Dexborneol group (Dexborneol, n = 24), and Eda.B group (Eda.B, n = 24). Neurological function recovery, infarct volume, and blood-brain barrier (BBB) disruption were assessed using Zea-Longa scoring, TTC staining, and Evans Blue extravasation, respectively. Alterations in Basement membrane (BM) and pericyte coverage were assessed by transmission electron microscopy (TEM). The expression levels of pericyte marker NG2 and PDGFR-β in the ischemic region, as well as BBB transcellular transport-related proteins vitronectin (VTN), α5 and PDGFB were detected by western blotting. Furthermore, a specific inhibitor of PDGFB, MOR8457, was employed (Eda.B + MOR8457, n = 8) to explore the protective effects of Eda.B on pericyte injury via PDGFB/PDGFR-β. RESULTS Eda.B significantly reduced cerebral infarct volume and promoted neurological function recovery in comparison to the tMCAO, Eda and Dexborneol groups. Additionally, Eda.B significantly ameliorated BBB leakage, mitigated the decrease in pericyte coverage, and reduced vesicle density in endothelial cells and BM thickness following I/R. Mechanically, Eda.B inhibited the downregulation of NG2, PDGFB/PDGFR-β, VTN, while preventing upregulation of α5 protein expression in tMCAO rats. Blocking PDGFB with MOR8457 demonstrated that Eda.B improved pericyte loss and BBB permeability by activating PDGFB/PDGFR-β signaling. CONCLUSIONS We elucidated that vitronectin-integrin and PDGFB/PDGFR-β signaling contributed to Eda.B's protective effects against pericyte loss and BBB permeability following I/R injury, unraveling new insights into mechanisms of pericyte as a promising therapeutic target.
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Affiliation(s)
- Zhiyu Sun
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, China; Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Hanshu Zhao
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, China
| | - Shanshan Yang
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, China
| | - Ruijia Liu
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, China
| | - Lian Yi
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, China
| | - Jiadi Gao
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, China
| | - Sihan Liu
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, China
| | - Yilin Chen
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, China
| | - Zhongling Zhang
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, China.
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Sun F, Zhou J, Chen X, Yang T, Wang G, Ge J, Zhang Z, Mei Z. No-reflow after recanalization in ischemic stroke: From pathomechanisms to therapeutic strategies. J Cereb Blood Flow Metab 2024; 44:857-880. [PMID: 38420850 PMCID: PMC11318407 DOI: 10.1177/0271678x241237159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 01/07/2024] [Accepted: 02/18/2024] [Indexed: 03/02/2024]
Abstract
Endovascular reperfusion therapy is the primary strategy for acute ischemic stroke. No-reflow is a common phenomenon, which is defined as the failure of microcirculatory reperfusion despite clot removal by thrombolysis or mechanical embolization. It has been reported that up to 25% of ischemic strokes suffer from no-reflow, which strongly contributes to an increased risk of poor clinical outcomes. No-reflow is associated with functional and structural alterations of cerebrovascular microcirculation, and the injury to the microcirculation seriously hinders the neural functional recovery following macrovascular reperfusion. Accumulated evidence indicates that pathology of no-reflow is linked to adhesion, aggregation, and rolling of blood components along the endothelium, capillary stagnation with neutrophils, astrocytes end-feet, and endothelial cell edema, pericyte contraction, and vasoconstriction. Prevention or treatment strategies aim to alleviate or reverse these pathological changes, including targeted therapies such as cilostazol, adhesion molecule blocking antibodies, peroxisome proliferator-activated receptors (PPARs) activator, adenosine, pericyte regulators, as well as adjunctive therapies, such as extracorporeal counterpulsation, ischemic preconditioning, and alternative or complementary therapies. Herein, we provide an overview of pathomechanisms, predictive factors, diagnosis, and intervention strategies for no-reflow, and attempt to convey a new perspective on the clinical management of no-reflow post-ischemic stroke.
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Affiliation(s)
- Feiyue Sun
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Jing Zhou
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xiangyu Chen
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Tong Yang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Guozuo Wang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Jinwen Ge
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Academy of Chinese Medicine, Changsha, Hunan, China
| | - Zhanwei Zhang
- The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Zhigang Mei
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Third-Grade Pharmacological Laboratory on Chinese Medicine Approved by State Administration of Traditional Chinese Medicine, College of Medicine and Health Sciences, China Three Gorges University, Yichang, Hubei, China
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Sun Z, Shi C, Jin L. Mechanisms by Which SARS-CoV-2 Invades and Damages the Central Nervous System: Apart from the Immune Response and Inflammatory Storm, What Else Do We Know? Viruses 2024; 16:663. [PMID: 38793545 PMCID: PMC11125732 DOI: 10.3390/v16050663] [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: 01/30/2024] [Revised: 03/29/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Initially reported as pneumonia of unknown origin, COVID-19 is increasingly being recognized for its impact on the nervous system, despite nervous system invasions being extremely rare. As a result, numerous studies have been conducted to elucidate the mechanisms of nervous system damage and propose appropriate coping strategies. This review summarizes the mechanisms by which SARS-CoV-2 invades and damages the central nervous system, with a specific focus on aspects apart from the immune response and inflammatory storm. The latest research findings on these mechanisms are presented, providing new insights for further in-depth research.
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Affiliation(s)
- Zihan Sun
- Qingdao Medical College, Qingdao University, Qingdao 266071, China
| | - Chunying Shi
- Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Lixin Jin
- Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
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Sun Y, Jiang X, Gao J. Stem cell-based ischemic stroke therapy: Novel modifications and clinical challenges. Asian J Pharm Sci 2024; 19:100867. [PMID: 38357525 PMCID: PMC10864855 DOI: 10.1016/j.ajps.2023.100867] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/25/2023] [Accepted: 10/07/2023] [Indexed: 02/16/2024] Open
Abstract
Ischemic stroke (IS) causes severe disability and high mortality worldwide. Stem cell (SC) therapy exhibits unique therapeutic potential for IS that differs from current treatments. SC's cell homing, differentiation and paracrine abilities give hope for neuroprotection. Recent studies on SC modification have enhanced therapeutic effects for IS, including gene transfection, nanoparticle modification, biomaterial modification and pretreatment. These methods improve survival rate, homing, neural differentiation, and paracrine abilities in ischemic areas. However, many problems must be resolved before SC therapy can be clinically applied. These issues include production quality and quantity, stability during transportation and storage, as well as usage regulations. Herein, we reviewed the brief pathogenesis of IS, the "multi-mechanism" advantages of SCs for treating IS, various SC modification methods, and SC therapy challenges. We aim to uncover the potential and overcome the challenges of using SCs for treating IS and convey innovative ideas for modifying SCs.
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Affiliation(s)
- Yuankai Sun
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xinchi Jiang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jianqing Gao
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou 310058, China
- Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
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Shi X. Research advances in cochlear pericytes and hearing loss. Hear Res 2023; 438:108877. [PMID: 37651921 PMCID: PMC10538405 DOI: 10.1016/j.heares.2023.108877] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 08/03/2023] [Accepted: 08/18/2023] [Indexed: 09/02/2023]
Abstract
Pericytes are specialized mural cells surrounding endothelial cells in microvascular beds. They play a role in vascular development, blood flow regulation, maintenance of blood-tissue barrier integrity, and control of angiogenesis, tissue fibrosis, and wound healing. In recent decades, understanding of the critical role played by pericytes in retina, brain, lung, and kidney has seen significant progress. The cochlea contains a large population of pericytes. However, the role of cochlear pericytes in auditory pathophysiology is, by contrast, largely unknown. The present review discusses recent progress in identifying cochlear pericytes, mapping their distribution, and defining their role in regulating blood flow, controlling the blood-labyrinth barrier (BLB) and angiogenesis, and involvement in different types of hearing loss.
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Affiliation(s)
- Xiaorui Shi
- Department of Otolaryngology/Head & Neck Surgery, Oregon Hearing Research Center (NRC04), Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA.
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Wang N, Yang X, Zhao Z, Liu D, Wang X, Tang H, Zhong C, Chen X, Chen W, Meng Q. Cooperation between neurovascular dysfunction and Aβ in Alzheimer's disease. Front Mol Neurosci 2023; 16:1227493. [PMID: 37654789 PMCID: PMC10466809 DOI: 10.3389/fnmol.2023.1227493] [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: 05/23/2023] [Accepted: 08/02/2023] [Indexed: 09/02/2023] Open
Abstract
The amyloid-β (Aβ) hypothesis was once believed to represent the pathogenic process of Alzheimer's disease (AD). However, with the failure of clinical drug development and the increasing understanding of the disease, the Aβ hypothesis has been challenged. Numerous recent investigations have demonstrated that the vascular system plays a significant role in the course of AD, with vascular damage occurring prior to the deposition of Aβ and neurofibrillary tangles (NFTs). The question of how Aβ relates to neurovascular function and which is the trigger for AD has recently come into sharp focus. In this review, we outline the various vascular dysfunctions associated with AD, including changes in vascular hemodynamics, vascular cell function, vascular coverage, and blood-brain barrier (BBB) permeability. We reviewed the most recent findings about the complicated Aβ-neurovascular unit (NVU) interaction and highlighted its vital importance to understanding disease pathophysiology. Vascular defects may lead to Aβ deposition, neurotoxicity, glial cell activation, and metabolic dysfunction; In contrast, Aβ and oxidative stress can aggravate vascular damage, forming a vicious cycle loop.
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Affiliation(s)
- Niya Wang
- Department of Neurology, The First People’s Hospital of Yunnan Province, Kunming, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Xiang Yang
- Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhong Zhao
- Department of Neurology, The First People’s Hospital of Yunnan Province, Kunming, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Da Liu
- Department of Neurology, The First People’s Hospital of Yunnan Province, Kunming, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Xiaoyan Wang
- Department of Neurology, The First People’s Hospital of Yunnan Province, Kunming, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Hao Tang
- Department of Neurology, The First People’s Hospital of Yunnan Province, Kunming, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Chuyu Zhong
- Department of Neurology, The First People’s Hospital of Yunnan Province, Kunming, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Xinzhang Chen
- Department of Neurology, The First People’s Hospital of Yunnan Province, Kunming, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Wenli Chen
- Department of Neurology, The First People’s Hospital of Yunnan Province, Kunming, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Qiang Meng
- Department of Neurology, The First People’s Hospital of Yunnan Province, Kunming, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
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Benarroch E. What Are the Roles of Pericytes in the Neurovascular Unit and Its Disorders? Neurology 2023; 100:970-977. [PMID: 37188542 PMCID: PMC10186232 DOI: 10.1212/wnl.0000000000207379] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 03/15/2023] [Indexed: 05/17/2023] Open
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Łach A, Wnuk A, Wójtowicz AK. Experimental Models to Study the Functions of the Blood-Brain Barrier. Bioengineering (Basel) 2023; 10:bioengineering10050519. [PMID: 37237588 DOI: 10.3390/bioengineering10050519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/07/2023] [Accepted: 04/22/2023] [Indexed: 05/28/2023] Open
Abstract
The purpose of this paper was to discuss the achievements of in vitro modeling in terms of the blood-brain barrier [BBB] and to create a clear overview of this research area, which is useful in research planning. The text was divided into three main parts. The first part describes the BBB as a functional structure, its constitution, cellular and noncellular components, mechanisms of functioning and importance for the central nervous system, in terms of both protection and nourishment. The second part is an overview of parameters important in terms of establishing and maintaining a barrier phenotype that allows for formulating criteria of evaluation of the BBB in vitro models. The third and last part discusses certain techniques for developing the BBB in vitro models. It describes subsequent research approaches and models, as they underwent change alongside technological advancement. On the one hand, we discuss possibilities and limitations of different research approaches: primary cultures vs. cell lines and monocultures vs. multicultures. On the other hand, we review advantages and disadvantages of specific models, such as models-on-a-chip, 3D models or microfluidic models. We not only attempt to state the usefulness of specific models in different kinds of research on the BBB but also emphasize the significance of this area of research for advancement of neuroscience and the pharmaceutical industry.
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Affiliation(s)
- Andrzej Łach
- Laboratory of Neuropharmacology and Epigenetics, Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland
- Department of Nutrition, Animal Biotechnology and Fisheries, Faculty of Animal Sciences, University of Agriculture, 30-059 Kraków, Poland
| | - Agnieszka Wnuk
- Laboratory of Neuropharmacology and Epigenetics, Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland
| | - Anna Katarzyna Wójtowicz
- Department of Nutrition, Animal Biotechnology and Fisheries, Faculty of Animal Sciences, University of Agriculture, 30-059 Kraków, Poland
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Hu X, Geng P, Zhao X, Wang Q, Liu C, Guo C, Dong W, Jin X. The NG2-glia is a potential target to maintain the integrity of neurovascular unit after acute ischemic stroke. Neurobiol Dis 2023; 180:106076. [PMID: 36921779 DOI: 10.1016/j.nbd.2023.106076] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/07/2023] [Accepted: 03/07/2023] [Indexed: 03/18/2023] Open
Abstract
The neurovascular unit (NVU) plays a critical role in health and disease. In the current review, we discuss the critical role of a class of neural/glial antigen 2 (NG2)-expressing glial cells (NG2-glia) in regulating NVU after acute ischemic stroke (AIS). We first introduce the role of NG2-glia in the formation of NVU during development as well as aging-induced damage to NVU and accompanying NG2-glia change. We then discuss the reciprocal interactions between NG2-glia and the other component cells of NVU, emphasizing the factors that could influence NG2-glia. Damage to the NVU integrity is the pathological basis of edema and hemorrhagic transformation, the most dreaded complication after AIS. The role of NG2-glia in AIS-induced NVU damage and the effect of NG2-glia transplantation on AIS-induced NVU damage are summarized. We next discuss the role of NG2-glia and the effect of NG2-glia transplantation in oligodendrogenesis and white matter repair as well as angiogenesis which is associated with the outcome of the patients after AIS. Finally, we review the current strategies to promote NG2-glia proliferation and differentiation and propose to use the dental pulp stem cells (DPSC)-derived exosome as a promising strategy to reduce AIS-induced injury and promote repair through maintaining the integrity of NVU by regulating endogenous NG2-glia proliferation and differentiation.
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Affiliation(s)
- Xiaoyan Hu
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China
| | - Panpan Geng
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China
| | - Xiaoyun Zhao
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China
| | - Qian Wang
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China
| | - Changqing Liu
- Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Chun Guo
- School of Biosciences, University of Sheffield, Firth Court, Western Bank, Sheffield, UK
| | - Wen Dong
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
| | - Xinchun Jin
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China; Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
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Warrington JP, Jones-Muhammad M, Thompson RO, Pryor T, Shao Q, Gunturu M. Retinal Venule Coverage by Pericytes Decreases in Multiparous Mice in a Time-Dependent Manner Post-Delivery. Int J Mol Sci 2023; 24:3967. [PMID: 36835376 PMCID: PMC9958816 DOI: 10.3390/ijms24043967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
Structural changes in the retinal vasculature have been linked to increased cardiovascular risks and also change as a function of age. Because multiparity has been associated with poorer cardiovascular health scores, we hypothesized that changes in retinal vascular caliber would be observed in multiparous, compared to nulliparous, females and retired breeder males. Age-matched nulliparous (n = 6) and multiparous (n = 11, retired breeder females with 4 ± 1 litters), and male breeder (n = 7) SMA-GFP reporter mice were included for assessment of retinal vascular structure. Multiparous females had higher body mass, heart weight, and kidney weight compared to nulliparous mice, with lower kidney and higher brain weight compared to male breeders. There was no difference in number of retinal arterioles or venules, or arteriole or venule diameter among groups; however, venous pericyte density (number per venule area) decreased in multiparous vs. nulliparous mice and was negatively associated with the time since last litter and with age. Our results suggest that the time elapsed since delivery is an important factor to be considered in multiparity studies. Taken together, changes in vascular structure and potentially function, are time- and age-dependent. Ongoing and future work will determine whether structural changes are associated with functional consequences at the blood-retinal barrier.
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Affiliation(s)
- Junie P. Warrington
- Department of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Maria Jones-Muhammad
- Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Rachael O. Thompson
- Department of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Tyranny Pryor
- Department of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Qingmei Shao
- Department of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Manasa Gunturu
- Department of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, USA
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Ultrastructural Remodeling of the Blood-Brain Barrier and Neurovascular Unit by Lipopolysaccharide-Induced Neuroinflammation. Int J Mol Sci 2023; 24:ijms24021640. [PMID: 36675154 PMCID: PMC9862046 DOI: 10.3390/ijms24021640] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/09/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
The blood-brain barrier (BBB) is an interface primarily comprised of brain endothelial cells (BECs), separating the central nervous system (CNS) from the systemic circulation while carefully regulating the transport of molecules and inflammatory cells, and maintaining the required steady-state environment. Inflammation modulates many BBB functions, but the ultrastructural cytoarchitectural changes of the BBB with inflammation are understudied. Inflammation was induced in male 8-10-week-old CD-1 mice with intraperitoneal lipopolysaccharide (LPS), using a regimen (3 mg/kg at 0, 6, and 24 h) that caused robust BBB disruption but had minimal lethality at the study timepoint of 28 h. Perfusion-fixed brains were collected and the frontal cortical layer III regions were analyzed using a transmission electron microscopy (TEM). The LPS-treated mice had pronounced ultrastructural remodeling changes in BECs that included plasma membrane ruffling, increased numbers of extracellular microvesicles, small exosome formation, aberrant BEC mitochondria, increased BEC transcytosis, while tight junctions appeared to be unaltered. Aberrant pericytes were contracted with rounded nuclei and a loss of their elongated cytoplasmic processes. Surveilling microglial cells were attracted to the neurovascular unit (NVU) of BECs, and astrocyte detachment and separation were associated with the formation of a perivascular space and pericapillary edema. The LPS treatment resulted in numerous ultrastructural aberrant remodeling changes to the neurovascular unit's BECs, microglia, pericytes, and astrocytes. In summary, a disturbance of the NVU morphology is a consequence of LPS treatment.
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Chang SR, Liu JG, Li H, Liu MX, Shi DD, Zhou LJ. Pharmaceutical and pharmacological studies of Shen Ma Yi Zhi granule for prevention of vascular dementia: A review. Front Neurosci 2022; 16:1044572. [PMID: 36507350 PMCID: PMC9731835 DOI: 10.3389/fnins.2022.1044572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 11/04/2022] [Indexed: 11/25/2022] Open
Abstract
Background: With dementia significantly increasing hospitalization and disability rates, worldwide aging of the population presents major challenges to public health. The majority of cases of cognitive dysfunction among the elderly, however, are characterized by an identifiable, preventable and treatable vascular component. As such, increased study of preventative methods in the context of dementia is warranted. Traditional Chinese medicine compounds have been reported to be neuroprotective and improve cognitive function via a variety of mechanisms. Shen Ma Yi Zhi granule (SMYZG) is one such collection of compounds that has been proven clinically effective. Pharmacological mechanisms of action, pharmacokinetics and clinical applications of SMYZG have been previously studied using a variety of vascular dementia animal models. SMYZG activates and regulates four main signaling pathways relevant to vascular dementia including the AMPK/PPARα/PGC-1α/UCP2, Nrf2/HO-1, HIF-1/VEGF/Notch, and VEGF/Flk-1/p8 MAPK pathways. Furthermore, SMYZG influences anti-inflammatory and anti-oxidant stress responses, reverses demyelination of brain white matter and vascular endothelium, regulates pericyte function and normalizes mitochondrial metabolism. Neuroprotective effects of SMYZG, as well as those promoting regeneration of vascular endothelium, have also been reported in studies of rat models of vascular dementia. Future research concerning SMYG is warranted for development of vascular dementia preventative management strategies.
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Affiliation(s)
- Su-rui Chang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jian-gang Liu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China,*Correspondence: Jian-gang Liu,
| | - Hao Li
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Institute of Geriatrics of China Academy of Chinese Medical Sciences, Beijing, China,Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Hao Li,
| | - Mei-xia Liu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Institute of Geriatrics of China Academy of Chinese Medical Sciences, Beijing, China
| | - Dan-dan Shi
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Institute of Geriatrics of China Academy of Chinese Medical Sciences, Beijing, China
| | - Li-juan Zhou
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Institute of Geriatrics of China Academy of Chinese Medical Sciences, Beijing, China
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14
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Li GS, Wang XX, Tan RB, Wang KH, Hu XS, Hu Y. Ultrastructural destruction of neurovascular unit in experimental cervical spondylotic myelopathy. Front Neurosci 2022; 16:1031180. [PMID: 36466180 PMCID: PMC9709118 DOI: 10.3389/fnins.2022.1031180] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 10/25/2022] [Indexed: 08/30/2023] Open
Abstract
Background and purpose The pathogenesis of cervical spondylotic myelopathy (CSM) remains unclear. This study aimed to explore the ultrastructural pathology of neurovascular unit (NVU) during natural development of CSM. Methods A total of 24 rats were randomly allocated to the control group and the CSM group. Basso-Beattie-Bresnahan (BBB) scoring and somatosensory evoked potentials (SEP) were used as functional assessments. Hematoxylin-eosin (HE), toluidine blue (TB), and Luxol fast blue (LFB) stains were used for general structure observation. Transmission electron microscopy (TEM) was applied for investigating ultrastructural characteristics. Results The evident compression caused significant neurological dysfunction, which was confirmed by the decrease in BBB score and SEP amplitude, as well as the prolongation of SEP latency (P < 0.05). The histopathological findings verified a significant decrease in the amount of Nissl body and myelin area and an increase in vacuolation compared with the control group (P < 0.05). The TEM results revealed ultrastructural destruction of NVU in several forms, including: neuronal degeneration and apoptosis; disruption of axonal cytoskeleton (neurofilaments) and myelin sheath and dystrophy of axonal terminal with dysfunction mitochondria; degenerative oligodendrocyte, astrocyte, and microglial cell inclusions with degenerating axon and dystrophic dendrite; swollen microvascular endothelium and loss of tight junction integrity; corroded basement membrane and collapsed microvascular wall; and proliferated pericyte and perivascular astrocytic endfeet. In the CSM group, reduction was observed in the amount of mitochondria with normal appearance and the number of cristae per mitochondria (P < 0.05), while no substantial drop of synaptic vesicle number was seen (P > 0.05). Significant narrowing of microvascular lumen size was also observed, accompanied by growth in the vascular wall area, endothelial area, basement membrane thickness, astrocytic endfeet area, and pericyte coverage area (rate) (P < 0.05). Conclusion Altogether, the findings of this study demonstrated ultrastructural destruction of NVU in an experimental CSM model with dorsal-lateral compression, revealing one of the crucial pathophysiological mechanisms of CSM.
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Affiliation(s)
- Guang-Sheng Li
- Spinal Division of Orthopaedic and Traumatology Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Xu-Xiang Wang
- Spinal Division of Orthopaedic and Traumatology Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ron-Bang Tan
- Spinal Division of Orthopaedic and Traumatology Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Kang-Heng Wang
- Spinal Division of Orthopaedic and Traumatology Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Xiao-song Hu
- Spinal Division of Orthopaedic and Traumatology Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Yong Hu
- Spinal Division of Orthopaedic and Traumatology Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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15
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Yao F, Luo Y, Liu YC, Chen YH, Li YT, Hu XY, You XY, Yu SS, Li ZY, Chen L, Tian DS, Zheng MG, Cheng L, Jing JH. Imatinib inhibits pericyte-fibroblast transition and inflammation and promotes axon regeneration by blocking the PDGF-BB/PDGFRβ pathway in spinal cord injury. Inflamm Regen 2022; 42:44. [PMID: 36163271 PMCID: PMC9511779 DOI: 10.1186/s41232-022-00223-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 07/29/2022] [Indexed: 12/03/2022] Open
Abstract
Background Fibrotic scar formation and inflammation are characteristic pathologies of spinal cord injury (SCI) in the injured core, which has been widely regarded as the main barrier to axonal regeneration resulting in permanent functional recovery failure. Pericytes were shown to be the main source of fibroblasts that form fibrotic scar. However, the mechanism of pericyte-fibroblast transition after SCI remains elusive. Methods Fibrotic scarring and microvessels were assessed using immunofluorescence staining after establishing a crush SCI model. To study the process of pericyte-fibroblast transition, we analyzed pericyte marker and fibroblast marker expression using immunofluorescence. The distribution and cellular origin of platelet-derived growth factor (PDGF)-BB were examined with immunofluorescence. Pericyte-fibroblast transition was detected with immunohistochemistry and Western blot assays after PDGF-BB knockdown and blocking PDGF-BB/PDGFRβ signaling in vitro. Intrathecal injection of imatinib was used to selectively inhibit PDGF-BB/PDGFRβ signaling. The Basso mouse scale score and footprint analysis were performed to assess functional recovery. Subsequently, axonal regeneration, fibrotic scarring, fibroblast population, proliferation and apoptosis of PDGFRβ+ cells, microvessel leakage, and the inflammatory response were assessed with immunofluorescence. Results PDGFRβ+ pericytes detached from the blood vessel wall and transitioned into fibroblasts to form fibrotic scar after SCI. PDGF-BB was mainly distributed in the periphery of the injured core, and microvascular endothelial cells were one of the sources of PDGF-BB in the acute phase. Microvascular endothelial cells induced pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway in vitro. Pharmacologically blocking the PDGF-BB/PDGFRβ pathway promoted motor function recovery and axonal regeneration and inhibited fibrotic scar formation. After fibrotic scar formation, blocking the PDGFRβ receptor inhibited proliferation and promoted apoptosis of PDGFRβ+ cells. Imatinib did not alter pericyte coverage on microvessels, while microvessel leakage and inflammation were significantly decreased after imatinib treatment. Conclusions We reveal that the crosstalk between microvascular endothelial cells and pericytes promotes pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway. Our finding suggests that blocking the PDGF-BB/PDGFRβ signaling pathway with imatinib contributes to functional recovery, fibrotic scarring, and inflammatory attenuation after SCI and provides a potential target for the treatment of SCI. Supplementary Information The online version contains supplementary material available at 10.1186/s41232-022-00223-9.
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Affiliation(s)
- Fei Yao
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Yang Luo
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Yan-Chang Liu
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Yi-Hao Chen
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Yi-Teng Li
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Xu-Yang Hu
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Xing-Yu You
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Shui-Sheng Yu
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Zi-Yu Li
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Lei Chen
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Da-Sheng Tian
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Mei-Ge Zheng
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China.
| | - Li Cheng
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China. .,School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, China.
| | - Jue-Hua Jing
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui Province, China.
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16
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Schreiner TG, Romanescu C, Popescu BO. The Blood-Brain Barrier-A Key Player in Multiple Sclerosis Disease Mechanisms. Biomolecules 2022; 12:538. [PMID: 35454127 PMCID: PMC9025898 DOI: 10.3390/biom12040538] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 02/07/2023] Open
Abstract
Over the past decade, multiple sclerosis (MS), a chronic neuroinflammatory disease with severe personal and social consequences, has undergone a steady increase in incidence and prevalence rates worldwide. Despite ongoing research and the development of several novel therapies, MS pathology remains incompletely understood, and the prospect for a curative treatment continues to be unpromising in the near future. A sustained research effort, however, should contribute to a deeper understanding of underlying disease mechanisms, which will undoubtedly yield improved results in drug development. In recent years, the blood-brain barrier (BBB) has increasingly become the focus of many studies as it appears to be involved in both MS disease onset and progression. More specifically, neurovascular unit damage is believed to be involved in the critical process of CNS immune cell penetration, which subsequently favors the development of a CNS-specific immune response, leading to the classical pathological and clinical hallmarks of MS. The aim of the current narrative review is to merge the relevant evidence on the role of the BBB in MS pathology in a comprehensive and succinct manner. Firstly, the physiological structure and functions of the BBB as a component of the more complex neurovascular unit are presented. Subsequently, the authors review the specific alteration of the BBB encountered in different stages of MS, focusing on both the modifications of BBB cells in neuroinflammation and the CNS penetration of immune cells. Finally, the currently accepted theories on neurodegeneration in MS are summarized.
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Affiliation(s)
- Thomas Gabriel Schreiner
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Faculty of Medicine, “Gr. T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Department of Electrical Measurements and Materials, Faculty of Electrical Engineering and Information Technology, Gheorghe Asachi Technical University of Iasi, 21-23 Professor Dimitrie Mangeron Blvd., 700050 Iasi, Romania
| | - Constantin Romanescu
- Faculty of Medicine, “Gr. T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Section IV, “St. Parascheva” Infectious Disease Hospital, 700116 Iași, Romania
| | - Bogdan Ovidiu Popescu
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Neurology Department, Colentina Clinical Hospital, 020125 Bucharest, Romania
- Laboratory of Cell Biology, Neurosciences and Experimental Myology, “Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania
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Bernardes SS, Pinto MCX, Amorim JH, Azevedo VADC, Resende RR, Mintz A, Birbrair A. Glioma Pericytes Promote Angiogenesis by Producing Periostin. Cell Mol Neurobiol 2022; 42:557-564. [PMID: 33010018 PMCID: PMC8018985 DOI: 10.1007/s10571-020-00975-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 09/27/2020] [Indexed: 12/14/2022]
Abstract
Glioma is the prevalent aggressive primary brain tumor, with a very poor prognosis. The absence of advanced understanding of the roles played by the cells within the glioma microenvironment limits the development of effective drugs. A recent study indicates that periostin expressed by pericytes is crucial for glioma angiogenesis. Here, we describe succinctly the results and implications of this discovery in what we know about pericytes within the glioma microenvironment. The emerging knowledge from this work will benefit the development of therapies for gliomas.
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Affiliation(s)
- Sara Santos Bernardes
- Tissue Microenvironment Laboratory, Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Mauro Cunha Xavier Pinto
- Laboratory of Neuropharmacology and Neurochemistry, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil
| | - Jaime Henrique Amorim
- Center of Biological Sciences and Health, Federal University of West Bahia, Barreiras, BA, Brazil
| | - Vasco Ariston de Carvalho Azevedo
- Cellular and Molecular Genetics Laboratory, Department of Genetics, Ecology and Evolution, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Rodrigo Ribeiro Resende
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Akiva Mintz
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
| | - Alexander Birbrair
- Tissue Microenvironment Laboratory, 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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18
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Qiu M, Zong JB, He QW, Liu YX, Wan Y, Li M, Zhou YF, Wu JH, Hu B. Cell Heterogeneity Uncovered by Single-Cell RNA Sequencing Offers Potential Therapeutic Targets for Ischemic Stroke. Aging Dis 2022; 13:1436-1454. [PMID: 36186129 PMCID: PMC9466965 DOI: 10.14336/ad.2022.0212] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 02/12/2022] [Indexed: 11/06/2022] Open
Abstract
Ischemic stroke is a detrimental neurological disease characterized by an irreversible infarct core surrounded by an ischemic penumbra, a salvageable region of brain tissue. Unique roles of distinct brain cell subpopulations within the neurovascular unit and peripheral immune cells during ischemic stroke remain elusive due to the heterogeneity of cells in the brain. Single-cell RNA sequencing (scRNA-seq) allows for an unbiased determination of cellular heterogeneity at high-resolution and identification of cell markers, thereby unveiling the principal brain clusters within the cell-type-specific gene expression patterns as well as cell-specific subclusters and their functions in different pathways underlying ischemic stroke. In this review, we have summarized the changes in differentiation trajectories of distinct cell types and highlighted the specific pathways and genes in brain cells that are impacted by stroke. This review is expected to inspire new research and provide directions for investigating the potential pathological mechanisms and novel treatment strategies for ischemic stroke at the level of a single cell.
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Affiliation(s)
| | | | | | | | | | | | | | - Jie-hong Wu
- Correspondence should be addressed to: Dr. Bo Hu () and Dr. Jie-hong Wu (), Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Hu
- Correspondence should be addressed to: Dr. Bo Hu () and Dr. Jie-hong Wu (), Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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19
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Yuan M, Wang Y, Wang S, Huang Z, Jin F, Zou Q, Li J, Pu Y, Cai Z. Bioenergetic Impairment in the Neuro-Glia-Vascular Unit: An Emerging Physiopathology during Aging. Aging Dis 2021; 12:2080-2095. [PMID: 34881087 PMCID: PMC8612602 DOI: 10.14336/ad.2021.04017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 04/17/2021] [Indexed: 12/28/2022] Open
Abstract
An emerging concept termed the "neuro-glia-vascular unit" (NGVU) has been established in recent years to understand the complicated mechanism of multicellular interactions among vascular cells, glial cells, and neurons. It has been proverbially reported that the NGVU is significantly associated with neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Physiological aging is an inevitable progression associated with oxidative damage, bioenergetic alterations, mitochondrial dysfunction, and neuroinflammation, which is partially similar to the pathology of AD. Thus, senescence is regarded as the background for the development of neurodegenerative diseases. With the exacerbation of global aging, senescence is an increasingly serious problem in the medical field. In this review, the coupling of each component, including neurons, glial cells, and vascular cells, in the NGVU is described in detail. Then, various mechanisms of age-dependent impairment in each part of the NGVU are discussed. Moreover, the potential bioenergetic alterations between different cell types in the NGVU are highlighted, which seems to be an emerging physiopathology associated with the aged brain. Bioenergetic intervention in the NGVU may be a new direction for studies on delaying or diminishing aging in the future.
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Affiliation(s)
- Minghao Yuan
- 1Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, Chongqing, China.,2Chongqing School, University of Chinese Academy of Sciences, Chongqing, China.,3Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing, China.,4Chongqing Medical University, Chongqing, China
| | - Yangyang Wang
- 1Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, Chongqing, China.,3Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing, China
| | - Shengyuan Wang
- 1Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, Chongqing, China.,2Chongqing School, University of Chinese Academy of Sciences, Chongqing, China.,3Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing, China.,4Chongqing Medical University, Chongqing, China
| | - Zhenting Huang
- 1Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, Chongqing, China.,3Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing, China
| | - Feng Jin
- 1Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, Chongqing, China.,2Chongqing School, University of Chinese Academy of Sciences, Chongqing, China.,3Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing, China
| | - Qian Zou
- 1Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, Chongqing, China.,3Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing, China
| | - Jing Li
- 1Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, Chongqing, China.,3Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing, China
| | - Yinshuang Pu
- 1Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, Chongqing, China.,3Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing, China
| | - Zhiyou Cai
- 1Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400013, Chongqing, China.,2Chongqing School, University of Chinese Academy of Sciences, Chongqing, China.,3Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing, China.,4Chongqing Medical University, Chongqing, China
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20
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Yu H, Commander CW, Stavas JM. Stem Cell-Based Therapies: What Interventional Radiologists Need to Know. Semin Intervent Radiol 2021; 38:523-534. [PMID: 34853498 DOI: 10.1055/s-0041-1736657] [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: 10/19/2022]
Abstract
As the basic units of biological organization, stem cells and their progenitors are essential for developing and regenerating organs and tissue systems using their unique self-renewal capability and differentiation potential into multiple cell lineages. Stem cells are consistently present throughout the entire human development, from the zygote to adulthood. Over the past decades, significant efforts have been made in biology, genetics, and biotechnology to develop stem cell-based therapies using embryonic and adult autologous or allogeneic stem cells for diseases without therapies or difficult to treat. Stem cell-based therapies require optimum administration of stem cells into damaged organs to promote structural regeneration and improve function. Maximum clinical efficacy is highly dependent on the successful delivery of stem cells to the target tissue. Direct image-guided locoregional injections into target tissues offer an option to increase therapeutic outcomes. Interventional radiologists have the opportunity to perform a key role in delivering stem cells more efficiently using minimally invasive techniques. This review discusses the types and sources of stem cells and the current clinical applications of stem cell-based therapies. In addition, the regulatory considerations, logistics, and potential roles of interventional Radiology are also discussed with the review of the literature.
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Affiliation(s)
- Hyeon Yu
- Division of Vascular and Interventional Radiology, Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.,ProKidney LLC, Winston Salem, North Carolina
| | - Clayton W Commander
- Division of Vascular and Interventional Radiology, Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Joseph M Stavas
- Department of Radiology, Creighton University School of Medicine, Omaha, Nebraska
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21
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Wang Q, Liu N, Ni YS, Yang JM, Ma L, Lan XB, Wu J, Niu JG, Yu JQ. TRPM2 in ischemic stroke: Structure, molecular mechanisms, and drug intervention. Channels (Austin) 2021; 15:136-154. [PMID: 33455532 PMCID: PMC7833771 DOI: 10.1080/19336950.2020.1870088] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/23/2020] [Accepted: 12/23/2020] [Indexed: 01/14/2023] Open
Abstract
Ischemic stroke has a high lethality rate worldwide, and novel treatments are limited. Calcium overload is considered to be one of the mechanisms of cerebral ischemia. Transient receptor potential melastatin 2 (TRPM2) is a reactive oxygen species (ROS)-sensitive calcium channel. Cerebral ischemia-induced TRPM2 activation triggers abnormal intracellular Ca2+ accumulation and cell death, which in turn causes irreversible brain damage. Thus, TRPM2 has emerged as a new therapeutic target for ischemic stroke. This review provides data on the expression, structure, and function of TRPM2 and illustrates its cellular and molecular mechanisms in ischemic stroke. Natural and synthetic TRPM2 inhibitors (both specific and nonspecific) are also summarized. The three-dimensional protein structure of TRPM2 has been identified, and we speculate that molecular simulation techniques will be essential for developing new drugs that block TRPM2 channels. These insights about TRPM2 may be the key to find potent therapeutic approaches for the treatment of ischemic stroke.
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Affiliation(s)
- Qing Wang
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
| | - Ning Liu
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
| | - Yuan-Shu Ni
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
| | - Jia-Mei Yang
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
| | - Lin Ma
- Ningxia Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, China
| | - Xiao-Bing Lan
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
| | - Jing Wu
- Laboratory Animal Center, Ningxia Medical University, Yinchuan, China
| | - Jian-Guo Niu
- Ningxia Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, China
| | - Jian-Qiang Yu
- Department of Pharmacology, Ningxia Medical University, Yinchuan, China
- Ningxia Collaborative Innovation Center of Regional Characteristic Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
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22
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Shaheryar ZA, Khan MA, Adnan CS, Zaidi AA, Hänggi D, Muhammad S. Neuroinflammatory Triangle Presenting Novel Pharmacological Targets for Ischemic Brain Injury. Front Immunol 2021; 12:748663. [PMID: 34691061 PMCID: PMC8529160 DOI: 10.3389/fimmu.2021.748663] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/15/2021] [Indexed: 12/20/2022] Open
Abstract
Ischemic stroke is one of the leading causes of morbidity and mortality globally. Hundreds of clinical trials have proven ineffective in bringing forth a definitive and effective treatment for ischemic stroke, except a myopic class of thrombolytic drugs. That, too, has little to do with treating long-term post-stroke disabilities. These studies proposed diverse options to treat stroke, ranging from neurotropic interpolation to venting antioxidant activity, from blocking specific receptors to obstructing functional capacity of ion channels, and more recently the utilization of neuroprotective substances. However, state of the art knowledge suggests that more pragmatic focus in finding effective therapeutic remedy for stroke might be targeting intricate intracellular signaling pathways of the 'neuroinflammatory triangle': ROS burst, inflammatory cytokines, and BBB disruption. Experimental evidence reviewed here supports the notion that allowing neuroprotective mechanisms to advance, while limiting neuroinflammatory cascades, will help confine post-stroke damage and disabilities.
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Affiliation(s)
- Zaib A. Shaheryar
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
- Faculty of Pharmacy, University of Lahore, Lahore, Pakistan
| | - Mahtab A. Khan
- Faculty of Pharmacy, University of Central Punjab, Lahore, Pakistan
| | | | - Awais Ali Zaidi
- Faculty of Pharmacy, University of Lahore, Lahore, Pakistan
- Imran Idrees College of Pharmacy, Lahore, Pakistan
| | - Daniel Hänggi
- Department of Neurosurgery, Faculty of Medicine and University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Sajjad Muhammad
- Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Neurosurgery, Faculty of Medicine and University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
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Traditional Chinese Medicine Shenmayizhi Decoction Ameliorates Memory and Cognitive Impairment Induced by Multiple Cerebral Infarctions. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6648455. [PMID: 33859709 PMCID: PMC8026291 DOI: 10.1155/2021/6648455] [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: 10/12/2020] [Revised: 02/17/2021] [Accepted: 03/21/2021] [Indexed: 11/25/2022]
Abstract
This study aimed to illustrate the mechanism by which Shenmayizhi decoction (SMYZD) improves the learning memory of rats with vascular cognitive impairment (VCI). Fifty male and female Wistar rats of specific pathogen-free grade (SPF grade) were used to establish the model by the administration of a microsphere embolization. This was accomplished by injecting sterile, standardized, mass-produced microspheres of uniform particle size (100–200 µm in diameter) in a sodium alginate microsphere vascular embolic agent suspension to induce VCI. The VCI model was successfully established in 40 rats, including both male and female rats, and the rats were randomly divided into 4 groups of 10 rats each. The model group was administered an equal volume of distilled water. The donepezil group was administered 0.45 mg/kg/d donepezil, which is equivalent to the clinical dosage. The SMYZ-H group was administered 11.88 g/kg/d SMYZ, which is 4 times higher than the clinically equivalent dosage. The SMYZ-L group was administered 2.97 g/kg/d SMYZ, which is the clinically equivalent dosage. A sham-operated group was used as the control group and administered an equal volume of distilled water. The rats in the 4 groups were treated by gavage with equal volumes of liquid and the indicated concentration of drug diluted in distilled water for 8 consecutive weeks. Two months later, the Morris water maze (MWM) was used to evaluate the spatial memory of all the rats. Ultrastructural and ultrapathological changes in the capillaries of the cerebral cortex were observed by transmission electron microscopy. Furthermore, Western blot and RT-PCR analyses were used to assess the levels of platelet-derived growth factor receptor-β (PDGFR-β), neuron-glial antigen 2 (NG2), vascular endothelial growth factor A (VEGF-A), and angiopoietin 1 (Ang1) in the cerebral cortex of the rats. The results showed that SMYZD at concentrations of 11.88 g/kg/d and 2.97 g/kg/d (SMYZ-H and SMYZ-L) significantly shortened the escape latency (EL). In addition, SMYZ-H significantly prolonged the distance traveled and the time spent in the original platform quadrant by the rats with VCI. SMYZ-H significantly increased the NG2 and Ang1 protein expression levels and increased the PDGFR-β and Ang1 mRNA levels. These results demonstrated that Shenmayizhi decoction can improve the memory abilities of rats with VCI induced by multiple cerebral infarctions by preventing pericyte degeneration.
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Gao L, Song Z, Mi J, Hou P, Xie C, Shi J, Li Y, Manaenko A. The Effects and Underlying Mechanisms of Cell Therapy on Blood-Brain Barrier Integrity After Ischemic Stroke. Curr Neuropharmacol 2020; 18:1213-1226. [PMID: 32928089 PMCID: PMC7770640 DOI: 10.2174/1570159x18666200914162013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/10/2020] [Accepted: 09/01/2020] [Indexed: 12/11/2022] Open
Abstract
Ischemic stroke is one of the main causes of mortality and disability worldwide. However, efficient therapeutic strategies are still lacking. Stem/progenitor cell-based therapy, with its vigorous advantages, has emerged as a promising tool for the treatment of ischemic stroke. The mechanisms involve new neural cells and neuronal circuitry formation, antioxidation, inflammation alleviation, angiogenesis, and neurogenesis promotion. In the past decades, in-depth studies have suggested that cell therapy could promote vascular stabilization and decrease blood-brain barrier (BBB) leakage after ischemic stroke. However, the effects and underlying mechanisms on BBB integrity induced by the engrafted cells in ischemic stroke have not been reviewed yet. Herein, we will update the progress in research on the effects of cell therapy on BBB integrity after ischemic stroke and review the underlying mechanisms. First, we will present an overview of BBB dysfunction under the ischemic condition and cells engraftment for ischemic treatment. Then, we will summarize and discuss the current knowledge about the effects and underlying mechanisms of cell therapy on BBB integrity after ischemic stroke. In particular, we will review the most recent studies in regard to the relationship between cell therapy and BBB in tissue plasminogen activator (t-PA)-mediated therapy and diabetic stroke.
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Affiliation(s)
- Li Gao
- Department of Neurology, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201112, China
| | - Zhenghong Song
- Department of Neurology, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201112, China
| | - Jianhua Mi
- Department of Neurology, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201112, China
| | - Pinpin Hou
- Central Laboratory, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University,
Shanghai 201112, China
| | - Chong Xie
- Departmeng of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jianquan Shi
- Departmeng of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Yansheng Li
- Department of Neurology, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201112, China
| | - Anatol Manaenko
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China,NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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25
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Mesenchymal stem cell therapy for ischemic stroke: A look into treatment mechanism and therapeutic potential. J Neurol 2020; 268:4095-4107. [DOI: 10.1007/s00415-020-10138-5] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/30/2020] [Accepted: 07/31/2020] [Indexed: 12/13/2022]
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26
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Seo S, Kim H, Sung JH, Choi N, Lee K, Kim HN. Microphysiological systems for recapitulating physiology and function of blood-brain barrier. Biomaterials 2019; 232:119732. [PMID: 31901694 DOI: 10.1016/j.biomaterials.2019.119732] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 12/20/2019] [Accepted: 12/25/2019] [Indexed: 12/27/2022]
Abstract
Central nervous system (CNS) diseases are emerging as a major issue in an aging society. Although extensive research has focused on the development of CNS drugs, the limited transport of therapeutic agents across the blood-brain barrier (BBB) remains a major challenge. Conventional two-dimensional culture dishes do not recapitulate in vivo physiology and real-time observations of molecular transport are not possible in animal models. Recent advances in engineering techniques have enabled the generation of more physiologically relevant in vitro BBB models, and their applications have expanded from fundamental biological research to practical applications in the pharmaceutical industry. In this article, we provide an overview of recent advances in the development of in vitro BBB models, with a particular focus on the recapitulation of BBB function. The development of biomimetic BBB models is postulated to revolutionize not only fundamental biological studies but also drug screening.
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Affiliation(s)
- Suyeong Seo
- Center for BioMicrosystems, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Program in Nano Science and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hwieun Kim
- Center for BioMicrosystems, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Department of Chemical Engineering, Hongik University, Seoul, 04066, Republic of Korea
| | - Jong Hwan Sung
- Department of Chemical Engineering, Hongik University, Seoul, 04066, Republic of Korea
| | - Nakwon Choi
- Center for BioMicrosystems, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea
| | - Kangwon Lee
- Program in Nano Science and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea.
| | - Hong Nam Kim
- Center for BioMicrosystems, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea.
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27
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Li F, Liu WC, Wang Q, Sun Y, Wang H, Jin X. NG2-glia cell proliferation and differentiation by glial growth factor 2 (GGF2), a strategy to promote functional recovery after ischemic stroke. Biochem Pharmacol 2019; 171:113720. [PMID: 31751533 DOI: 10.1016/j.bcp.2019.113720] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 11/14/2019] [Indexed: 12/16/2022]
Abstract
Stroke is the leading cause of adult disability. Spontaneous functional recovery occurs after ischemic stroke, but it is very limited. Therefore, it is urgent to find a strategy to promote functional recovery after stroke in clinical setting. Gray matter damage has received extensive attention owing to the important roles of the gray matter in synaptic plasticity, cognitive, and motor function. However, stroke also causes white matter damage, which accounts for half of the infarct volume and can be aggravated by blood brain barrier damage. Disruption of white matter integrity, which is characterized by death of oligodendrocytes (OLs), loss of myelin, and axonal injury, greatly contributes to impaired neurological function. Impaired proliferation and differentiation of OL precursor cell (OPC, NG2-glia cells) play an important role in limited functional recovery after ischemic stroke and inhibitor of differentiation 2 (ID2) is a key factor controlling NG2-glia cells differentiation. It has been reported that the number of NG2-glia cells in the peri-infarction area significantly increases after ischemic stroke and glial growth factor (GGF2) administration promotes the proliferation and differentiation of NG2-glia cells as well as functional recovery after spinal cord injury. On the basis of the important roles of GGF2 in functional recovery and those of ID2 in NG2-glia cell proliferation and differentiation, we propose that after binding with the ErBb receptor on the surface of NG2-glia cells, GGF2 promotes NG2-glia cell proliferation and differentiation, thereby repairing BBB and white matter integrity and promoting neural functional recovery after ischemic stroke.
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Affiliation(s)
- Fei Li
- School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan 442000, China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China
| | - Wen-Cao Liu
- Shanxi Provincial People's Hospital, Taiyuan 030001, China
| | - Qi Wang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yanyun Sun
- Jiangsu Key Laboratory of Neuro-Psychiatry Research and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
| | - Hongbo Wang
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, School of Pharmacy, Yantai University, Yantai, China.
| | - Xinchun Jin
- Jiangsu Key Laboratory of Neuro-Psychiatry Research and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Key Laboratory of Molecular Pharmacology and Drug Evaluation, School of Pharmacy, Yantai University, Yantai, China.
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28
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Bordone MP, Salman MM, Titus HE, Amini E, Andersen JV, Chakraborti B, Diuba AV, Dubouskaya TG, Ehrke E, Espindola de Freitas A, Braga de Freitas G, Gonçalves RA, Gupta D, Gupta R, Ha SR, Hemming IA, Jaggar M, Jakobsen E, Kumari P, Lakkappa N, Marsh APL, Mitlöhner J, Ogawa Y, Paidi RK, Ribeiro FC, Salamian A, Saleem S, Sharma S, Silva JM, Singh S, Sulakhiya K, Tefera TW, Vafadari B, Yadav A, Yamazaki R, Seidenbecher CI. The energetic brain - A review from students to students. J Neurochem 2019; 151:139-165. [PMID: 31318452 DOI: 10.1111/jnc.14829] [Citation(s) in RCA: 145] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 07/03/2019] [Accepted: 07/08/2019] [Indexed: 12/12/2022]
Abstract
The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia-neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS. We cover neuronal energy consumption in neural transmission and basic ('housekeeping') cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies, and medium chain fatty acids. We discuss the multifaceted role of non-neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS.
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Affiliation(s)
- Melina Paula Bordone
- Facultad de Farmacia y Bioquímica, Instituto de Investigaciones Farmacológicas (ININFA), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Mootaz M Salman
- Department of Cell Biology, Harvard Medical School, and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Haley E Titus
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Elham Amini
- Department of Medicine, University Kebangsaan Malaysia Medical Centre (HUKM), Cheras, Kuala Lumpur, Malaysia
| | - Jens V Andersen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Artem V Diuba
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Tatsiana G Dubouskaya
- Institute of Biophysics and Cell Engineering, National Academy of Sciences of Belarus, Minsk, Belarus
| | - Eric Ehrke
- Centre for Biomolecular Interactions, University of Bremen, Bremen, Germany
| | - Andiara Espindola de Freitas
- Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, California, USA
| | | | | | | | - Richa Gupta
- CSIR-Indian Institute of Toxicology Research, Lucknow, India
| | - Sharon R Ha
- Baylor College of Medicine, Houston, Texas, USA
| | - Isabel A Hemming
- Brain Growth and Disease Laboratory, The Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia.,School of Medicine and Pharmacology, The University of Western Australia, Crawley, Australia
| | - Minal Jaggar
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Emil Jakobsen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Punita Kumari
- Defense Institute of Physiology and allied sciences, Defense Research and Development Organization, Timarpur, Delhi, India
| | - Navya Lakkappa
- Department of Pharmacology, JSS college of Pharmacy, Ooty, India
| | - Ashley P L Marsh
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Jessica Mitlöhner
- Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Magdeburg, Germany
| | - Yuki Ogawa
- The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | | | | | - Ahmad Salamian
- Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Suraiya Saleem
- CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Sorabh Sharma
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan, India
| | - Joana M Silva
- Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal
| | - Shripriya Singh
- CSIR-Indian Institute of Toxicology Research, Lucknow, India
| | - Kunjbihari Sulakhiya
- Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, India
| | - Tesfaye Wolde Tefera
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Behnam Vafadari
- Institute of environmental medicine, UNIKA-T, Technical University of Munich, Munich, Germany
| | - Anuradha Yadav
- CSIR-Indian Institute of Toxicology Research, Lucknow, India
| | - Reiji Yamazaki
- Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.,Center for Behavioral Brain Sciences (CBBS), Otto von Guericke University, Magdeburg, Germany
| | - Constanze I Seidenbecher
- Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Magdeburg, Germany.,Center for Behavioral Brain Sciences (CBBS), Otto von Guericke University, Magdeburg, Germany
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29
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Jha NK, Kar R, Niranjan R. ABC Transporters in Neurological Disorders: An Important Gateway for Botanical Compounds Mediated Neuro-Therapeutics. Curr Top Med Chem 2019; 19:795-811. [PMID: 30977450 DOI: 10.2174/1568026619666190412121811] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 02/27/2019] [Accepted: 03/07/2019] [Indexed: 12/13/2022]
Abstract
Neurodegeneration is a distinguishing feature of many age related disorders and other vector borne neuroinflammatory diseases. There are a number of factors that can modulate the pathology of these disorders. ATP-binding cassette (ABC) transporters are primarily involved in the maintenance of normal brain homeostasis by eliminating toxic peptides and compounds from the brain. Also, ABC transporters protect the brain from the unwanted effects of endogenous and exogenous toxins that can enter the brain parenchyma. Therefore, these transporters have the ability to determine the pathological outcomes of several neurological disorders. For instance, ABC transporters like P-glycoprotein (ABCB1), and BCRP (ABCG2) have been reported to facilitate the clearance of peptides such as amyloid-β (Aβ) that accumulate in the brain during Alzheimer's disease (AD) progression. Other members such as ABCA1, ABCA2, ABCC8, ABCC9, ABCG1 and ABCG4 also have been reported to be involved in the progression of various brain disorders such as HIV-associated dementia, Multiple sclerosis (MS), Ischemic stroke, Japanese encephalitis (JE) and Epilepsy. However, these defective transporters can be targeted by numerous botanical compounds such as Verapamil, Berberine and Fascalpsyn as a therapeutic target to treat these neurological outcomes. These compounds are already reported to modulate ABC transporter activity in the CNS. Nonetheless, the exact mechanisms involving the ABC transporters role in normal brain functioning, their role in neuronal dysfunction and how these botanical compounds ensure and facilitate their therapeutic action in association with defective transporters still remain elusive. This review therefore, summarizes the role of ABC transporters in neurological disorders, with a special emphasis on its role in AD brains. The prospect of using botanical/natural compounds as modulators of ABC transporters in neurological disorders is discussed in the latter half of the article.
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Affiliation(s)
- Niraj Kumar Jha
- Department of Biotechnology, Noida Institute of Engineering & Technology (NIET), Greater Noida, India
| | - Rohan Kar
- Department of Biotechnology, Noida Institute of Engineering & Technology (NIET), Greater Noida, India
| | - Rituraj Niranjan
- Unit of Microbiology and Molecular Biology, ICMR-Vector Control Research Center, Puducherry-605006, India
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Bhowmick S, D'Mello V, Caruso D, Wallerstein A, Muneer PMA. Impairment of pericyte-endothelium crosstalk leads to blood-brain barrier dysfunction following traumatic brain injury. Exp Neurol 2019; 317:260-270. [PMID: 30926390 DOI: 10.1016/j.expneurol.2019.03.014] [Citation(s) in RCA: 160] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 03/25/2019] [Accepted: 03/25/2019] [Indexed: 01/17/2023]
Abstract
The blood-brain barrier (BBB) constitutes a neurovascular unit formed by microvascular endothelial cells, pericytes, and astrocytes. Brain pericytes are important regulators of BBB integrity, permeability, and blood flow. Pericyte loss has been implicated in injury; however, how the crosstalk among pericytes, endothelial cells, and astrocytes ultimately leads to BBB dysfunction in traumatic brain injury (TBI) remains elusive. In this study, we demonstrate the importance of pericyte-endothelium interaction in maintaining the BBB function. TBI causes the platelet-derived growth factor-B (PDGF-B)/PDGF receptor-β signaling impairment that results in loss of interaction with endothelium and leads to neurovascular dysfunction. Using in vivo mild (7 psi) and moderate (15 psi) fluid percussion injury (FPI) in mice, we demonstrate the expression of various pericyte markers including PDGFR-β, NG2 and CD13 that were significantly reduced with a subsequent reduction in the expression of various integrins; adherent junction protein, N-cadherin; gap junction protein, connexin-43; and tight junction proteins such as occludin, claudin-5, ZO-1, and JAM-a. Impairment of pericyte-endothelium interaction increases the BBB permeability to water that is marked by a significant increase in aquaporin4 expression in injured animals. Similarly, pericyte-endothelium integrity impairment in FPI animals greatly increases the permeability of small-molecular-weight sodium fluorescein and high-molecular-weight-tracer Evans blue across the BBB. In addition, the injury-inflicted animals show significantly higher levels of S100β and NSE in the blood samples compared with controls. In conclusion, our data provide an insight that brain trauma causes an early impairment of pericyte-endothelium integrity and results in BBB dysregulation that initiates pathological consequences associated with TBI.
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Affiliation(s)
- Saurav Bhowmick
- Laboratory of CNS Injury and Molecular Therapy, JFK Neuroscience Institute, Hackensack Meridian Health JFK Medical Center, 65 James St, Edison, New Jersey 08820, United States
| | - Veera D'Mello
- Laboratory of CNS Injury and Molecular Therapy, JFK Neuroscience Institute, Hackensack Meridian Health JFK Medical Center, 65 James St, Edison, New Jersey 08820, United States
| | - Danielle Caruso
- Laboratory of CNS Injury and Molecular Therapy, JFK Neuroscience Institute, Hackensack Meridian Health JFK Medical Center, 65 James St, Edison, New Jersey 08820, United States
| | - Alex Wallerstein
- Laboratory of CNS Injury and Molecular Therapy, JFK Neuroscience Institute, Hackensack Meridian Health JFK Medical Center, 65 James St, Edison, New Jersey 08820, United States
| | - P M Abdul Muneer
- Laboratory of CNS Injury and Molecular Therapy, JFK Neuroscience Institute, Hackensack Meridian Health JFK Medical Center, 65 James St, Edison, New Jersey 08820, United States.
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31
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Kunze R, Marti HH. Angioneurins - Key regulators of blood-brain barrier integrity during hypoxic and ischemic brain injury. Prog Neurobiol 2019; 178:101611. [PMID: 30970273 DOI: 10.1016/j.pneurobio.2019.03.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 03/29/2019] [Indexed: 12/14/2022]
Abstract
The loss of blood-brain barrier (BBB) integrity leading to vasogenic edema and brain swelling is a common feature of hypoxic/ischemic brain diseases such as stroke, but is also central to the etiology of other CNS disorders. In the past decades, numerous proteins, belonging to the family of angioneurins, have gained increasing attention as potential therapeutic targets for ischemic stroke, but also other CNS diseases attributed to BBB dysfunction. Angioneurins encompass mediators that affect both neuronal and vascular function. Recently, increasing evidence has been accumulated that certain angioneurins critically determine disease progression and outcome in stroke among others through multifaceted effects on the compromised BBB. Here, we will give a concise overview about the family of angioneurins. We further describe the most important cellular and molecular components that contribute to structural integrity and low permeability of the BBB under steady-state conditions. We then discuss BBB alterations in ischemic stroke, and highlight underlying cellular and molecular mechanisms. For the most prominent angioneurin family members including vascular endothelial growth factors, angiopoietins, platelet-derived growth factors and erythropoietin, we will summarize current scientific literature from experimental studies in animal models, and if available from clinical trials, on the following points: (i) spatiotemporal expression of these factors in the healthy and hypoxic/ischemic CNS, (ii) impact of loss- or gain-of-function during cerebral hypoxia/ischemia for BBB integrity and beyond, and (iii) potential underlying molecular mechanisms. Moreover, we will highlight novel therapeutic strategies based on the activation of endogenous angioneurins that might improve BBB dysfuntion during ischemic stroke.
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Affiliation(s)
- Reiner Kunze
- Institute of Physiology and Pathophysiology, Heidelberg University, Germany.
| | - Hugo H Marti
- Institute of Physiology and Pathophysiology, Heidelberg University, Germany
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32
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Davidoff MS. The Pluripotent Microvascular Pericytes Are the Adult Stem Cells Even in the Testis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1122:235-267. [PMID: 30937872 DOI: 10.1007/978-3-030-11093-2_13] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The pericytes of the testis are part of the omnipresent population of pericytes in the vertebrate body and are the only true pluripotent adult stem cells able to produce structures typical for the tree primitive germ layers: ectoderm, mesoderm, and endoderm. They originate very early in the embryogenesis from the pluripotent epiblast. The pericytes become disseminated through the whole vertebrate organism by the growing and differentiating blood vessels where they remain in specialized periendothelial vascular niches as resting pluripotent adult stem cells for tissue generation, maintenance, repair, and regeneration. The pericytes are also the ancestors of the perivascular multipotent stromal cells (MSCs). The variable appearance of the pericytes and their progeny reflects the plasticity under the influence of their own epigenetic and the local environmental factors of the host organ. In the testis the pericytes are the ancestors of the neuroendocrine Leydig cells. After activation the pericytes start to proliferate, migrate, and build transit-amplifying cells that transdifferentiate into multipotent stromal cells. These represent progenitors for a number of different cell types in an organ. Finally, it becomes evident that the pericytes are a brilliant achievement of the biological nature aiming to supply every organ with an omnipresent population of pluripotent adult stem cells. Their fascinating features are prerequisites for future therapy concepts supporting cell systems of organs.
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Affiliation(s)
- Michail S Davidoff
- University Medical Center Hamburg-Eppendorf, Hamburg Museum of Medical History, Hamburg, Germany.
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Barreto RSN, Romagnolli P, Cereta AD, Coimbra-Campos LMC, Birbrair A, Miglino MA. Pericytes in the Placenta: Role in Placental Development and Homeostasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1122:125-151. [PMID: 30937867 DOI: 10.1007/978-3-030-11093-2_8] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The placenta is the most variable organ, in terms of structure, among the species. Besides it, all placental types have the same function: production of viable offspring, independent of pregnancy length, litter number, or invasion level. The angiogenesis is a central mechanism for placental functionality, due to proper maternal-fetal communication and exchanges. Much is known about the vasculature structure, but little is known about vasculature development and cellular interactions. Pericytes are perivascular cells that were described to control vasculature stability and permeability. Nowadays there are several new functions discovered, such as lymphocyte modulation and activation, macrophage-like phagocytic properties, tissue regenerative and repair processes, and also the ability to modulate stem cells, majorly the hematopoietic. In parallel, placental tissues are known to be a particularly immune microenvironment and a rich stem cell niche. The pericyte function plethora could be similar in the placental microenvironment and could have a central role in placental development and homeostasis.
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Affiliation(s)
- Rodrigo S N Barreto
- School of Veterinary Medicine and Animal Sciences, University of São Paulo, Butantã, Sao Paulo, Brazil
| | - Patricia Romagnolli
- School of Veterinary Medicine and Animal Sciences, University of São Paulo, Butantã, Sao Paulo, Brazil
| | - Andressa Daronco Cereta
- School of Veterinary Medicine and Animal Sciences, University of São Paulo, Butantã, Sao Paulo, Brazil
| | - Leda M C Coimbra-Campos
- Department of Pathology, Federal University of Minas Gerais, Pampulha, Belo Horizonte, Brazil
| | - Alexander Birbrair
- Department of Radiology, Columbia University Medical Center, New York, NY, USA.,Department of Pathology, Federal University of Minas Gerais, Pampulha, Belo Horizonte, Brazil
| | - Maria Angelica Miglino
- School of Veterinary Medicine and Animal Sciences, University of São Paulo, Butantã, Sao Paulo, Brazil.
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Guerra DAP, Paiva AE, Sena IFG, Azevedo PO, Silva WN, Mintz A, Birbrair A. Targeting glioblastoma-derived pericytes improves chemotherapeutic outcome. Angiogenesis 2018; 21:667-675. [PMID: 29761249 PMCID: PMC6238207 DOI: 10.1007/s10456-018-9621-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 05/08/2018] [Indexed: 12/12/2022]
Abstract
Glioblastoma is the most common malignant brain cancer in adults, with poor prognosis. The blood-brain barrier limits the arrival of several promising anti-glioblastoma drugs, and restricts the design of efficient therapies. Recently, by using state-of-the-art technologies, including thymidine kinase targeting system in combination with glioblastoma xenograft mouse models, it was revealed that targeting glioblastoma-derived pericytes improves chemotherapy efficiency. Strikingly, ibrutinib treatment enhances chemotherapeutic effectiveness, by targeting pericytes, improving blood-brain barrier permeability, and prolonging survival. This study identifies glioblastoma-derived pericyte as a novel target in the brain tumor microenvironment during carcinogenesis. Here, we summarize and evaluate recent advances in the understanding of pericyte's role in the glioblastoma microenvironment.
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Affiliation(s)
- Daniel A P Guerra
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Ana E Paiva
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Isadora F G Sena
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Patrick O Azevedo
- 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
| | - 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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Giurdanella G, Montalbano G, Gennuso F, Brancati S, Lo Furno D, Augello A, Bucolo C, Drago F, Salomone S. Isolation, cultivation, and characterization of primary bovine cochlear pericytes: A new in vitro model of stria vascularis. J Cell Physiol 2018; 234:1978-1986. [PMID: 30317595 DOI: 10.1002/jcp.27545] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 09/14/2018] [Indexed: 12/14/2022]
Abstract
The study of strial pericytes has gained great interest as they are pivotal for the physiology of stria vascularis. To provide an easily accessible in vitro model, here we described a growth medium-based approach to obtain and cultivate primary bovine cochlear pericytes (BCP) from the stria vascularis of explanted bovine cochleae. We obtained high-quality pericytes in 8-10 days with a > 90% purity after the second passage. Immunocytochemical analysis showed a homogeneous population of cells expressing typical pericyte markers, such as neural/glial antigen 2 (NG2), platelet-derived growth factor receptorβ (PDGFRβ), α-smooth muscle actin (α-SMA), and negative for the endothelial marker von Willebrand factor. When challenged with tumor necrosis factor or lipopolysaccharide, BCP changed their shape, similarly to human retinal pericytes (HRPC). The sensitivity of BCP to ototoxic drugs was evaluated by challenging with cisplatin or gentamicin for 48 hr. Compared to human retinal endothelial cells and HRPC, cell viability of BCP was significantly lower ( p < 0.05) after the treatment with gentamicin or cisplatin. These data indicate that our protocol provides a simple and reliable method to obtain highly pure strial BCP. Furthermore, BCP are suitable to assess the safety profile of molecules which supposedly exert ototoxic activity, and may represent a valid alternative to in vivo tests.
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Affiliation(s)
- Giovanni Giurdanella
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Giuseppe Montalbano
- Department of Veterinary Sciences and Zebrafish Neuromorphology Lab, University of Messina, Messina, Italia
| | - Florinda Gennuso
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Serena Brancati
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Debora Lo Furno
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Antonio Augello
- ASP Catania Dipartimento di Prevenzione Veterinaria, Servizio Igiene degli Alimenti di Origine Animale (SIAOA), Catania, Italy
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Salvatore Salomone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
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Ramirez SH, Andrews AM, Paul D, Pachter JS. Extracellular vesicles: mediators and biomarkers of pathology along CNS barriers. Fluids Barriers CNS 2018; 15:19. [PMID: 29960602 PMCID: PMC6026502 DOI: 10.1186/s12987-018-0104-7] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 05/28/2018] [Indexed: 02/07/2023] Open
Abstract
Extracellular vesicles (EVs) are heterogeneous, nano-sized vesicles that are shed into the blood and other body fluids, which disperse a variety of bioactive molecules (e.g., protein, mRNA, miRNA, DNA and lipids) to cellular targets over long and short distances. EVs are thought to be produced by nearly every cell type, however this review will focus specifically on EVs that originate from cells at the interface of CNS barriers. Highlighted topics include, EV biogenesis, the production of EVs in response to neuroinflammation, role in intercellular communication and their utility as a therapeutic platform. In this review, novel concepts regarding the use of EVs as biomarkers for BBB status and as facilitators for immune neuroinvasion are also discussed. Future directions and prospective are covered along with important unanswered questions in the field of CNS endothelial EV biology.
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Affiliation(s)
- Servio H Ramirez
- Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, 3500 N Broad St, Philadelphia, PA, 19140, USA. .,Shriners Hospital Pediatric Research Center, Philadelphia, PA, 19140, USA. .,Center for Substance Abuse Research, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
| | - Allison M Andrews
- Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, 3500 N Broad St, Philadelphia, PA, 19140, USA.,Center for Substance Abuse Research, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Debayon Paul
- Department of Immunology, Blood-Brain Barrier Laboratory & Laser Capture Microdissection Core, UConn Health, 263 Farmington Ave., Farmington, CT, 06070, USA
| | - Joel S Pachter
- Department of Immunology, Blood-Brain Barrier Laboratory & Laser Capture Microdissection Core, UConn Health, 263 Farmington Ave., Farmington, CT, 06070, USA.
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37
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Prazeres PHDM, Turquetti AOM, Azevedo PO, Barreto RSN, Miglino MA, Mintz A, Delbono O, Birbrair A. Perivascular cell αv integrins as a target to treat skeletal muscle fibrosis. Int J Biochem Cell Biol 2018; 99:109-113. [PMID: 29627438 PMCID: PMC6159891 DOI: 10.1016/j.biocel.2018.04.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 04/02/2018] [Accepted: 04/03/2018] [Indexed: 02/06/2023]
Abstract
Fibrosis following injury leads to aberrant regeneration and incomplete functional recovery of skeletal muscle, but the lack of detailed knowledge about the cellular and molecular mechanisms involved hampers the design of effective treatments. Using state-of-the-art technologies, Murray et al. (2017) found that perivascular PDGFRβ-expressing cells generate fibrotic cells in the skeletal muscle. Strikingly, genetic deletion of αv integrins from perivascular PDGFRβ-expressing cells significantly inhibited skeletal muscle fibrosis without affecting muscle vascularization or regeneration. In addition, the authors showed that a small molecule inhibitor of αv integrins, CWHM 12, attenuates skeletal muscle fibrosis. From a drug-development perspective, this study identifies a new cellular and molecular target to treat skeletal muscle fibrosis.
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Affiliation(s)
- Pedro H D M Prazeres
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Anaelise O M Turquetti
- Anatomy of Domestic and Wild Animals Program, Department of Surgery, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, SP, Brazil
| | - Patrick O Azevedo
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Rodrigo S N Barreto
- Anatomy of Domestic and Wild Animals Program, Department of Surgery, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, SP, Brazil
| | - Maria A Miglino
- Anatomy of Domestic and Wild Animals Program, Department of Surgery, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, SP, Brazil
| | - Akiva Mintz
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
| | - Osvaldo Delbono
- Department of Internal Medicine-Gerontology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Anatomy of Domestic and Wild Animals Program, Department of Surgery, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, SP, Brazil; Department of Radiology, Columbia University Medical Center, New York, NY, USA.
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38
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Use of functionalized liposomes loaded with antioxidants to permeate the blood–brain barrier and inhibit β-amyloid-induced neurodegeneration in the brain. J Taiwan Inst Chem Eng 2018. [DOI: 10.1016/j.jtice.2018.03.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Yang S, Jin H, Zhu Y, Wan Y, Opoku EN, Zhu L, Hu B. Diverse Functions and Mechanisms of Pericytes in Ischemic Stroke. Curr Neuropharmacol 2018; 15:892-905. [PMID: 28088914 PMCID: PMC5652032 DOI: 10.2174/1570159x15666170112170226] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 11/30/2016] [Accepted: 12/28/2016] [Indexed: 12/26/2022] Open
Abstract
Background: Every year, strokes take millions of lives and leave millions of individuals living with permanent disabilities. Recently more researchers embrace the concept of the neurovascular unit (NVU), which encompasses neurons, endothelial cells (ECs), pericytes, astrocyte, microglia, and the extracellular matrix. It has been well-documented that NVU emerged as a new paradigm for the exploration of mechanisms and therapies in ischemic stroke. To better understand the complex NVU and broaden therapeutic targets, we must probe the roles of multiple cell types in ischemic stroke. The aims of this paper are to introduce the biological characteristics of brain pericytes and the available evidence on the diverse functions and mechanisms involving the pericytes in the context of ischemic stroke. Methods: Research and online content related to the biological characteristics and pathophysiological roles of pericytes is review. The new research direction on the Pericytes in ischemic stroke, and the potential therapeutic targets are provided. Results: During the different stages of ischemic stroke, pericytes play different roles: 1) On the hyperacute phase of stroke, pericytes constriction and death may be a cause of the no-reflow phenomenon in brain capillaries; 2) During the acute phase, pericytes detach from microvessels and participate in inflammatory-immunological response, resulting in the BBB damage and brain edema. Pericytes also provide benefit for neuroprotection by protecting endothelium, stabilizing BBB and releasing neurotrophins; 3) Similarly, during the later recovery phase of stroke, pericytes also contribute to angiogenesis, neurogenesis, and thereby promote neurological recovery. Conclusion: This emphasis on the NVU concept has shifted the focus of ischemic stroke research from neuro-centric views to the complex interactions within NVU. With this new perspective, pericytes that are centrally positioned in the NVU have been widely studied in ischemic stroke. More work is needed to elucidate the beneficial and detrimental roles of brain pericytes in ischemic stroke that may serve as a basis for potential therapeutic targets.
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Affiliation(s)
- Shuai Yang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Huijuan Jin
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yiyi Zhu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yan Wan
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Elvis Nana Opoku
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lingqiang Zhu
- Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
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40
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Sena IFG, Paiva AE, Prazeres PHDM, Azevedo PO, Lousado L, Bhutia SK, Salmina AB, Mintz A, Birbrair A. Glioblastoma-activated pericytes support tumor growth via immunosuppression. Cancer Med 2018; 7:1232-1239. [PMID: 29479841 PMCID: PMC5911609 DOI: 10.1002/cam4.1375] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 12/26/2017] [Accepted: 01/10/2018] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma multiforme is the most common and aggressive primary brain tumor, with an extremely poor prognosis. The lack of detailed knowledge about the cellular and molecular mechanisms involved in glioblastoma development restricts the design of efficient therapies. A recent study using state-of-art technologies explores the role of pericytes in the glioblastoma microenvironment. Glioblastoma-activated pericytes develop an immunosuppressive phenotype, reducing T-cell activation through the induction of an anti-inflammatory response. Strikingly, pericytes support glioblastoma growth in vitro and in vivo. Here, we describe succinctly the results and implications of the findings reported in pericytes' and glioblastomas' biology. The emerging knowledge from this study will be essential for the treatment of brain tumors.
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Affiliation(s)
- Isadora F. G. Sena
- Department of PathologyFederal University of Minas Gerais (UFMG)Belo HorizonteMGBrazil
| | - Ana E. Paiva
- Department of PathologyFederal University of Minas Gerais (UFMG)Belo HorizonteMGBrazil
| | | | - Patrick O. Azevedo
- Department of PathologyFederal University of Minas Gerais (UFMG)Belo HorizonteMGBrazil
| | - Luiza Lousado
- Department of PathologyFederal University of Minas Gerais (UFMG)Belo HorizonteMGBrazil
| | - Sujit K. Bhutia
- Department of Life ScienceNational Institute of TechnologyRourkelaOdishaIndia
| | - Alla B. Salmina
- Department of BiochemistryKrasnoyarsk State Medical UniversityKrasnoyarskRussia
| | - Akiva Mintz
- Department of RadiologyColumbia University Medical CenterNew YorkNew York
| | - Alexander Birbrair
- Department of PathologyFederal University of Minas Gerais (UFMG)Belo HorizonteMGBrazil
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Azevedo PO, Sena IFG, Andreotti JP, Carvalho-Tavares J, Alves-Filho JC, Cunha TM, Cunha FQ, Mintz A, Birbrair A. Pericytes modulate myelination in the central nervous system. J Cell Physiol 2018; 233:5523-5529. [PMID: 29215724 DOI: 10.1002/jcp.26348] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 11/30/2017] [Indexed: 02/06/2023]
Abstract
Multiple sclerosis is a highly prevalent chronic demyelinating disease of the central nervous system. Remyelination is the major therapeutic goal for this disorder. The lack of detailed knowledge about the cellular and molecular mechanisms involved in myelination restricts the design of effective treatments. A recent study by using [De La Fuente et al. (2017) Cell Reports, 20(8): 1755-1764] by using state-of-the-art techniques, including pericyte-deficient mice in combination with induced demyelination, reveal that pericytes participate in central nervous system regeneration. Strikingly, pericytes presence is essential for oligodendrocyte progenitors differentiation and myelin formation during remyelination in the brain. The emerging knowledge from this research will be important for the treatment of multiple sclerosis.
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Affiliation(s)
- Patrick O Azevedo
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerias, Brazil
| | - Isadora F G Sena
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerias, Brazil
| | - Julia P Andreotti
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerias, Brazil
| | - Juliana Carvalho-Tavares
- Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerias, Brazil
| | - José C Alves-Filho
- Department of Pharmacology, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Thiago M Cunha
- Department of Pharmacology, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Fernando Q Cunha
- Department of Pharmacology, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Akiva Mintz
- Department of Radiology, Columbia University Medical Center, New York, New York
| | - Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerias, Brazil.,Department of Radiology, Columbia University Medical Center, New York, New York
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Peynshaert K, Devoldere J, De Smedt SC, Remaut K. In vitro and ex vivo models to study drug delivery barriers in the posterior segment of the eye. Adv Drug Deliv Rev 2018; 126:44-57. [PMID: 28939376 DOI: 10.1016/j.addr.2017.09.007] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 07/18/2017] [Accepted: 09/08/2017] [Indexed: 12/18/2022]
Abstract
Many ocular disorders leading to blindness could benefit from efficient delivery of therapeutics to the retina. However, despite extensive research into drug delivery vehicles and administration techniques, efficacy remains limited because of the many static and dynamic barriers present in the eye. Comprehension of the various barriers and especially how to overcome them can improve our ability to estimate the potential of existent drug delivery vectors and support the design of new ones. To this end, this review gives an overview of the most important ocular barriers for each administration route to the back of the eye. For each barrier, its biological composition and its role as an obstacle towards macromolecules, nanoparticles and viral vectors will be discussed; special attention will be paid to the influence of size, charge and lipophilicity of drug(s) (carrier) on their ability to overcome each barrier. Finally, the most significant available in vitro and ex vivo methods and models to test the potential of a therapeutic to cross each barrier are listed.
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Abstract
The role of pericytes seems to extend beyond their known function in angiogenesis, fibrosis and wound healing, blood-brain barrier maintenance, and blood flow regulation. More and more data are currently accumulating indicating that pericytes, uniquely positioned at the interface between blood and parenchyma, secrete a large plethora of different molecules in response to microenvironmental changes. Their secretome is tissue-specific and stimulus-specific and includes pro- and anti-inflammatory factors, growth factors, and extracellular matrix as well as microvesicles suggesting the important role of pericytes in the regulation of immune response and immune evasion of tumors. However, the angiogenic and trophic secretome of pericytes indicates that their secretome plays a role in physiological homeostasis but possibly also in disease progression or could be exploited for regenerative processes in the future. This book chapter summarizes the current data on the secretory properties of pericytes from different tissues in response to certain pathological stimuli such as inflammatory stimuli, hypoxia, high glucose, and others and thereby aims to provide insights into the possible role of pericytes in these conditions.
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Affiliation(s)
- Abderahim Gaceb
- Translational Neurology Group, Department of Clinical Sciences and Wallenberg Center for Molecular Medicine, Department of Neurology, Lund University, Lund, Sweden
| | - Gesine Paul
- Translational Neurology Group, Department of Clinical Sciences and Wallenberg Center for Molecular Medicine, Department of Neurology, Lund University, Lund, Sweden. .,Skåne University Hospital, Lund, Sweden.
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Jiang Q, Gao Y, Wang C, Tao R, Wu Y, Zhan K, Liao M, Lu N, Lu Y, Wilcox CS, Luo J, Jiang LH, Yang W, Han F. Nitration of TRPM2 as a Molecular Switch Induces Autophagy During Brain Pericyte Injury. Antioxid Redox Signal 2017; 27:1297-1316. [PMID: 28292196 DOI: 10.1089/ars.2016.6873] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
AIMS Dysfunction of neurovascular pericytes underlies breakdown of the blood-brain barrier, but the molecular mechanisms are largely unknown. In this study, we evaluated the role of the transient receptor potential melastatin-related 2 (TRPM2) channel and autophagy during brain pericyte injury both in vitro and in vivo. RESULTS A rapid induction in autophagy in human brain vascular pericytes, in the zinc oxide nanoparticles (ZnO-NP)-induced cell stress model, was paralleled with an increase in the expression of the TRPM2-S truncated isoform, which was abolished by treatment with a nitric oxide synthase inhibitor and a peroxynitrite scavenger. Furthermore, Y1485 in the C-terminus of the TRPM2 protein was identified as the tyrosine nitration substrate by mass spectrometry. Overexpression of the Y1485S TRPM2 mutant reduced LC3-II accumulation and pericyte injury induced by ZnO-NP. Consistently, LC3-II accumulation was reduced and pericytes were better preserved in intact brain microvessels of the TRPM2 knockout mice after ZnO-NP-induced vascular injury. Innovation and Conclusions: Our present study has revealed a novel mechanism of autophagy disturbance secondary to nitrosative stress-induced tyrosine nitration of TRPM2 during pericyte injury. Antioxid. Redox Signal. 27, 1297-1316.
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Affiliation(s)
- Quan Jiang
- 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China
| | - Yinping Gao
- 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China .,2 School of Medicine, Zhejiang University City College , Hangzhou, Zhejiang, China
| | - Chengkun Wang
- 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China
| | - Rongrong Tao
- 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China
| | - Yan Wu
- 3 Key Laboratory of Medical Neurobiology, Department of Neurobiology, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine , Hangzhou, Zhejiang, China
| | - Kaiyu Zhan
- 3 Key Laboratory of Medical Neurobiology, Department of Neurobiology, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine , Hangzhou, Zhejiang, China
| | - Meihua Liao
- 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China
| | - Nannan Lu
- 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China
| | - Yingmei Lu
- 2 School of Medicine, Zhejiang University City College , Hangzhou, Zhejiang, China
| | - Christopher S Wilcox
- 4 Hypertension, Kidney, and Vascular Research Center, Georgetown University Medical Center , Washington, District of Columbia
| | - Jianhong Luo
- 3 Key Laboratory of Medical Neurobiology, Department of Neurobiology, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine , Hangzhou, Zhejiang, China
| | - Lin-Hua Jiang
- 5 Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds , Leeds, United Kingdom .,6 Sino-UK Joint Laboratory of Brain Function and Injury, and Department of Physiology and Neurobiology, Xinxiang Medical University , Henan, China
| | - Wei Yang
- 3 Key Laboratory of Medical Neurobiology, Department of Neurobiology, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine , Hangzhou, Zhejiang, China
| | - Feng Han
- 1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang, China
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45
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Almeida VM, Paiva AE, Sena IFG, Mintz A, Magno LAV, Birbrair A. Pericytes Make Spinal Cord Breathless after Injury. Neuroscientist 2017; 24:440-447. [PMID: 29283016 DOI: 10.1177/1073858417731522] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Traumatic spinal cord injury is a devastating condition that leads to significant neurological deficits and reduced quality of life. Therapeutic interventions after spinal cord lesions are designed to address multiple aspects of the secondary damage. However, the lack of detailed knowledge about the cellular and molecular changes that occur after spinal cord injury restricts the design of effective treatments. Li and colleagues using a rat model of spinal cord injury and in vivo microscopy reveal that pericytes play a key role in the regulation of capillary tone and blood flow in the spinal cord below the site of the lesion. Strikingly, inhibition of specific proteins expressed by pericytes after spinal cord injury diminished hypoxia and improved motor function and locomotion of the injured rats. This work highlights a novel central cellular population that might be pharmacologically targeted in patients with spinal cord trauma. The emerging knowledge from this research may provide new approaches for the treatment of spinal cord injury.
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Affiliation(s)
- Viviani M Almeida
- 1 Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Ana E Paiva
- 1 Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Isadora F G Sena
- 1 Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Akiva Mintz
- 2 Department of Radiology, Columbia University Medical Center, New York, NY, USA
| | - Luiz Alexandre V Magno
- 3 Department of Mental Health, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Alexander Birbrair
- 1 Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.,4 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.,5 Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, USA
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46
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Birbrair A, Borges IDT, Gilson Sena IF, Almeida GG, da Silva Meirelles L, Gonçalves R, Mintz A, Delbono O. How Plastic Are Pericytes? Stem Cells Dev 2017; 26:1013-1019. [PMID: 28490256 PMCID: PMC5512298 DOI: 10.1089/scd.2017.0044] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 04/27/2017] [Indexed: 01/18/2023] Open
Abstract
Pericytes are defined by both their anatomical location and molecular markers. Numerous publications have reported their role as stem cells, contributing to the formation of tissues other than blood vessels. However, using cell-lineage tracing in a new transgenic mouse model, a recent study shows that in the context of aging and some pathologies, Tbx18+ pericytes do not function as stem cells in vivo. This study challenges the current view that pericytes can differentiate into other cells and reopen questions about their plasticity. This emerging knowledge is important not only for our understanding of development but may also inform treatments for diseases.
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Affiliation(s)
- Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York
| | | | | | | | | | - Ricardo Gonçalves
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Akiva Mintz
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Osvaldo Delbono
- Department of Internal Medicine-Gerontology, Wake Forest School of Medicine, Winston-Salem, North Carolina
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47
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Dias Moura Prazeres PH, Sena IFG, Borges IDT, de Azevedo PO, Andreotti JP, de Paiva AE, de Almeida VM, de Paula Guerra DA, Pinheiro Dos Santos GS, Mintz A, Delbono O, Birbrair A. Pericytes are heterogeneous in their origin within the same tissue. Dev Biol 2017; 427:6-11. [PMID: 28479340 PMCID: PMC6076854 DOI: 10.1016/j.ydbio.2017.05.001] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 05/03/2017] [Accepted: 05/03/2017] [Indexed: 12/16/2022]
Abstract
Pericytes heterogeneity is based on their morphology, distribution, and markers. It is well known that pericytes from different organs may have distinct embryonic sources. Yamazaki et al. (2017) using several transgenic mouse model reveal by cell-lineage tracing that pericytes are even more heterogeneous than previously appreciated. This study shows that pericytes from within the same tissue may be heterogeneous in their origin. Remarkably, a subpopulation of embryonic dermal pericytes derives from the hematopoietic lineage, an unexpected source. Reconstructing the lineage of pericytes is central to understanding development, and also for the diagnosis and treatment of diseases in which pericytes play important roles.
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Affiliation(s)
| | | | | | | | - Julia Peres Andreotti
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Ana Emília de Paiva
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | | | | | | | - Akiva Mintz
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Osvaldo Delbono
- Department of Internal Medicine-Gerontology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, USA.
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48
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Takeshita Y, Omoto M, Fujikawa S, Kanda T. Immunohistochemical analysis of laminin components in the blood-nerve barrier and blood-brain barrier. ACTA ACUST UNITED AC 2017. [DOI: 10.1111/cen3.12359] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Yukio Takeshita
- Department of Neurology and Clinical Neuroscience; Yamaguchi University Graduate School of Medicine; Yamaguchi Japan
| | - Masatoshi Omoto
- Department of Neurology and Clinical Neuroscience; Yamaguchi University Graduate School of Medicine; Yamaguchi Japan
| | - Susumu Fujikawa
- Department of Neurology and Clinical Neuroscience; Yamaguchi University Graduate School of Medicine; Yamaguchi Japan
| | - Takashi Kanda
- Department of Neurology and Clinical Neuroscience; Yamaguchi University Graduate School of Medicine; Yamaguchi Japan
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Hu X, De Silva TM, Chen J, Faraci FM. Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke. Circ Res 2017; 120:449-471. [PMID: 28154097 PMCID: PMC5313039 DOI: 10.1161/circresaha.116.308427] [Citation(s) in RCA: 299] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 10/13/2016] [Accepted: 10/26/2016] [Indexed: 12/13/2022]
Abstract
The consequences of cerebrovascular disease are among the leading health issues worldwide. Large and small cerebral vessel disease can trigger stroke and contribute to the vascular component of other forms of neurological dysfunction and degeneration. Both forms of vascular disease are driven by diverse risk factors, with hypertension as the leading contributor. Despite the importance of neurovascular disease and subsequent injury after ischemic events, fundamental knowledge in these areas lag behind our current understanding of neuroprotection and vascular biology in general. The goal of this review is to address select key structural and functional changes in the vasculature that promote hypoperfusion and ischemia, while also affecting the extent of injury and effectiveness of therapy. In addition, as damage to the blood-brain barrier is one of the major consequences of ischemia, we discuss cellular and molecular mechanisms underlying ischemia-induced changes in blood-brain barrier integrity and function, including alterations in endothelial cells and the contribution of pericytes, immune cells, and matrix metalloproteinases. Identification of cell types, pathways, and molecules that control vascular changes before and after ischemia may result in novel approaches to slow the progression of cerebrovascular disease and lessen both the frequency and impact of ischemic events.
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Affiliation(s)
- Xiaoming Hu
- Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - T. Michael De Silva
- Biomedicine Discovery Institute, Department of Pharmacology, 9 Ancora Imparo Way, Monash University, Clayton, Vic, Australia
| | - Jun Chen
- Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Frank M. Faraci
- Departments of Internal Medicine and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City Veterans Affairs Healthcare System, Iowa City, IA, USA
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Pericytes: The Role of Multipotent Stem Cells in Vascular Maintenance and Regenerative Medicine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1079:69-86. [PMID: 29282647 DOI: 10.1007/5584_2017_138] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Blood vessels consist of an inner endothelial cell layer lining the vessel wall and perivascular pericytes, also known as mural cells, which envelop the vascular tube surface. Pericytes have recently been recognized for their central role in blood vessel formation. Pericytes are multipotent cells that are heterogeneous in their origin, function, morphology and surface markers. Similar to other types of stem cells, pericytes act as a repair system in response to injury by maintaining the structural integrity of blood vessels. Several studies have shown that blood vessels lacking pericytes become hyperdilated and haemorrhagic, leading to vascular complications ranging from diabetic retinopathy to embryonic death. The role of pericytes is not restricted to the formation and development of the vasculature: they have been shown to possess stem cell-like characteristics and may differentiate into cell types from different lineages. Recent discoveries regarding the contribution of pericytes to tumour metastasis and the maintenance of tumour vascular supply and angiogenesis have led researchers to propose targeting pericytes with anti-angiogenic therapies. In this review, we will examine the different physiological roles of pericytes, their differentiation potential, and how they interact with surrounding cells to ensure the integrity of blood vessel formation and maintenance.
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