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Yin D, Wang C, Qi Y, Wang YC, Hagemann N, Mohamud Yusuf A, Dzyubenko E, Kaltwasser B, Tertel T, Giebel B, Gunzer M, Popa-Wagner A, Doeppner TR, Hermann DM. Neural precursor cell delivery induces acute post-ischemic cerebroprotection, but fails to promote long-term stroke recovery in hyperlipidemic mice due to mechanisms that include pro-inflammatory responses associated with brain hemorrhages. J Neuroinflammation 2023; 20:210. [PMID: 37715288 PMCID: PMC10504699 DOI: 10.1186/s12974-023-02894-8] [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] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 09/07/2023] [Indexed: 09/17/2023] Open
Abstract
BACKGROUND The intravenous delivery of adult neural precursor cells (NPC) has shown promising results in enabling cerebroprotection, brain tissue remodeling, and neurological recovery in young, healthy stroke mice. However, the translation of cell-based therapies to clinical settings has encountered challenges. It remained unclear if adult NPCs could induce brain tissue remodeling and recovery in mice with hyperlipidemia, a prevalent vascular risk factor in stroke patients. METHODS Male mice on a normal (regular) diet or on cholesterol-rich Western diet were exposed to 30 min intraluminal middle cerebral artery occlusion (MCAO). Vehicle or 106 NPCs were intravenously administered immediately after reperfusion, at 3 day and 7 day post-MCAO. Neurological recovery was evaluated using the Clark score, Rotarod and tight rope tests over up to 56 days. Histochemistry and light sheet microscopy were used to examine ischemic injury and brain tissue remodeling. Immunological responses in peripheral blood and brain were analyzed through flow cytometry. RESULTS NPC administration reduced infarct volume, blood-brain barrier permeability and the brain infiltration of neutrophils, monocytes, T cells and NK cells in the acute stroke phase in both normolipidemic and hyperlipidemic mice, but increased brain hemorrhage formation and neutrophil, monocyte and CD4+ and CD8+ T cell counts and activation in the blood of hyperlipidemic mice. While neurological deficits in hyperlipidemic mice were reduced by NPCs at 3 day post-MCAO, NPCs did not improve neurological deficits at later timepoints. Besides, NPCs did not influence microglia/macrophage abundance and activation (assessed by morphology analysis), astroglial scar formation, microvascular length or branching point density (evaluated using light sheet microscopy), long-term neuronal survival or brain atrophy in hyperlipidemic mice. CONCLUSIONS Intravenously administered NPCs did not have persistent effects on post-ischemic neurological recovery and brain remodeling in hyperlipidemic mice. These findings highlight the necessity of rigorous investigations in vascular risk factor models to fully assess the long-term restorative effects of cell-based therapies. Without comprehensive studies in such models, the clinical potential of cell-based therapies cannot be definitely determined.
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Affiliation(s)
- Dongpei Yin
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Chen Wang
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Yachao Qi
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Ya-Chao Wang
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
- Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Nina Hagemann
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Ayan Mohamud Yusuf
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Egor Dzyubenko
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Britta Kaltwasser
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
| | - Tobias Tertel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Matthias Gunzer
- Institute for Experimental Immunology and Imaging and Imaging Center Essen (IMCES), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Leibniz-Institut für Analytische Wissenschaften –ISAS– e.V., Dortmund, Germany
| | - Aurel Popa-Wagner
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
- Center of Experimental and Clinical Medicine, University of Medicine and Pharmacy, Craiova, Romania
| | - Thorsten R. Doeppner
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
- Department of Neurology, Justus-Liebig University Gießen, Giessen, Germany
| | - Dirk M. Hermann
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
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Medina JP, Bermejo-Álvarez I, Pérez-Baos S, Yáñez R, Fernández-García M, García-Olmo D, Mediero A, Herrero-Beaumont G, Largo R. MSC therapy ameliorates experimental gouty arthritis hinting an early COX-2 induction. Front Immunol 2023; 14:1193179. [PMID: 37533852 PMCID: PMC10391650 DOI: 10.3389/fimmu.2023.1193179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/03/2023] [Indexed: 08/04/2023] Open
Abstract
Objective The specific effect of Adipose-Derived Mesenchymal Stem Cells (Ad-MSC) on acute joint inflammation, where the response mostly depends on innate immunity activation, remains elusive. The pathogenesis of gouty arthritis, characterized by the deposition of monosodium urate (MSU) crystals in the joints, associated to acute flares, has been associated to NLRP3 inflammasome activation and subsequent amplification of the inflammatory response. Our aim was to study the effect of human Ad-MSC administration in the clinical inflammatory response of rabbits after MSU injection, and the molecular mechanisms involved. Methods Ad-MSC were administered by intraarterial route shortly after intraarticular MSU crystal injections. Joint and systemic inflammation was sequentially studied, and the mechanisms involved in NLRP3 inflammasome activation, and the synthesis of inflammatory mediators were assessed in the synovial membranes 72h after insult. Ad-MSC and THP-1-derived macrophages stimulated with MSU were co-cultured in transwell system. Results A single systemic dose of Ad-MSC accelerated the resolution of local and systemic inflammatory response. In the synovial membrane, Ad-MSC promoted alternatively M2 macrophage presence, inhibiting NLRP3 inflammasome and inducing the production of anti-inflammatory cytokines, such as IL-10 or TGF-β, and decreasing nuclear factor-κB activity. Ad-MSC induced a net anti-inflammatory balance in MSU-stimulated THP-1 cells, with a higher increase in IL-10 and IDO expression than that observed for IL-1β and TNF. Conclusion Our in vivo and in vitro results showed that a single systemic dose of Ad-MSC decrease the intensity and duration of the inflammatory response by an early local COX-2 upregulation and PGE2 release. Ad-MSCs suppressed NF-kB activity, NLRP3 inflammasome, and promoted the presence of M2 alternative macrophages in the synovium. Therefore, this therapeutic approach could be considered as a pharmacological alternative in patients with comorbidities that preclude conventional treatment.
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Affiliation(s)
- Juan Pablo Medina
- Bone and Joint Research Unit, Rheumatology Dept, IIS-Fundación Jiménez Díaz Universidad Autonoma de Madrid (UAM), Madrid, Spain
| | - Ismael Bermejo-Álvarez
- Bone and Joint Research Unit, Rheumatology Dept, IIS-Fundación Jiménez Díaz Universidad Autonoma de Madrid (UAM), Madrid, Spain
| | - Sandra Pérez-Baos
- Bone and Joint Research Unit, Rheumatology Dept, IIS-Fundación Jiménez Díaz Universidad Autonoma de Madrid (UAM), Madrid, Spain
| | - Rosa Yáñez
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain
- Advanced Therapies Dept, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain
| | - María Fernández-García
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain
- Advanced Therapies Dept, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain
| | - Damián García-Olmo
- New Therapies Laboratory, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain
- Department of Surgery, School of Medicine UAM, Madrid, Spain
| | - Aránzazu Mediero
- Bone and Joint Research Unit, Rheumatology Dept, IIS-Fundación Jiménez Díaz Universidad Autonoma de Madrid (UAM), Madrid, Spain
| | - Gabriel Herrero-Beaumont
- Bone and Joint Research Unit, Rheumatology Dept, IIS-Fundación Jiménez Díaz Universidad Autonoma de Madrid (UAM), Madrid, Spain
| | - Raquel Largo
- Bone and Joint Research Unit, Rheumatology Dept, IIS-Fundación Jiménez Díaz Universidad Autonoma de Madrid (UAM), Madrid, Spain
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Kurashiki Y, Kagusa H, Yagi K, Kinouchi T, Sumiyoshi M, Miyamoto T, Shimada K, Kitazato KT, Uto Y, Takagi Y. Role of post-ischemic phase-dependent modulation of anti-inflammatory M2-type macrophages against rat brain damage. J Cereb Blood Flow Metab 2023; 43:531-541. [PMID: 36545833 PMCID: PMC10063836 DOI: 10.1177/0271678x221147090] [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: 09/16/2022] [Revised: 10/21/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022]
Abstract
Cerebral ischemia triggers inflammatory changes, and early complications and unfavorable outcomes of endovascular thrombectomy for brain occlusion promote the recruitment of various cell types to the ischemic area. Although anti-inflammatory M2-type macrophages are thought to exert protective effects against cerebral ischemia, little has been clarified regarding the significance of post-ischemic phase-dependent modulation of M2-type macrophages. To test our hypothesis that post-ischemic phase-dependent modulation of macrophages represents a potential therapy against ischemic brain damage, the effects on rats of an M2-type macrophage-specific activator, Gc-protein macrophage-activating factor (GcMAF), were compared with vehicle-treated control rats in the acute (day 0-6) or subacute (day 7-13) phase after ischemia induction. Acute-phase GcMAF treatment augmented both anti-inflammatory CD163+ M2-type- and pro-inflammatory CD16+ M1-type macrophages, resulting in no beneficial effects. Conversely, subacute-phase GcMAF injection increased only CD163+ M2-type macrophages accompanied by elevated mRNA levels of arginase-1 and interleukin-4. M2-type macrophages co-localized with CD36+ phagocytic cells led to clearance of the infarct area, which were abrogated by clodronate-liposomes. Expression of survival-related molecules on day 28 at the infarct border was augmented by GcMAF. These data provide new and important insights into the significance of M2-type macrophage-specific activation as post-ischemic phase-dependent therapy.
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Affiliation(s)
- Yoshitaka Kurashiki
- Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan
| | - Hiroshi Kagusa
- Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan
| | - Kenji Yagi
- Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan
| | - Tomoya Kinouchi
- Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan
| | - Manabu Sumiyoshi
- Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan
| | - Takeshi Miyamoto
- Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan
| | - Kenji Shimada
- Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan
| | - Keiko T Kitazato
- Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan
| | - Yoshihiro Uto
- Department of Life Systems, Institute of Technology and Science, Tokushima University Graduate School, Japan
| | - Yasushi Takagi
- Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan
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Milczarek O, Swadźba J, Swadźba P, Starowicz-Filip A, Krzyżewski RM, Kwiatkowski S, Majka M. Comparative Analysis of the Results of Stroke Treatment With Multiple Administrations of Wharton's Jelly Mesenchymal Stem Cells-Derived HE-ATMP and Standard Conservative Treatment: Case Series Study. Cell Transplant 2023; 32:9636897231195145. [PMID: 37644776 PMCID: PMC10469225 DOI: 10.1177/09636897231195145] [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: 11/28/2022] [Revised: 07/25/2023] [Accepted: 08/01/2023] [Indexed: 08/31/2023] Open
Abstract
Stroke remains still the leading cause of long-term disability worldwide. Although interventions such as early reperfusion, intravenous thrombolysis, and endovascular revascularization have shown neurological benefit in stroke patients, there is still lack of effective treatment enabling regeneration of nervous tissue after cerebral ischemic episodes. Cell therapy is an evolving opportunity for stroke survivors with residual neurological deficits. The purpose of this study was to evaluate safety and potential efficacy of multiple administration of Hospital Exemption-Advanced Therapy Medicinal Product (HE-ATMP) comprising 3 × 107 Wharton's jelly mesenchymal stem cells (WJMSCs). A study group was composed of six patients-three women and three men. The patients were qualified to the treatment with diagnosis of chronic stroke (2-24 months after cerebral ischemic episode), during 2 years. All the patients undergone repeated rounds of HE-ATMP administration to the CSF (cerebrospinal fluid) via lumbar puncture. The control group consisted of six patients (two women and four men) who experienced stroke, treated at the same time (follow-up period: 24 months) using standard treatment methods, without endovascular treatment. To evaluate the results of the therapy, we used both impairment scales [National Institutes of Health Stroke Score (NIHSS)] and functional outcomes scales [Modified Rankin Scale (MRS) and Barthel Index (BI)]. In four patients, who received at least three repeated rounds of HE-ATMP, we reported neurological improvement and reduction of functional neurodeficiency. The biggest improvement concerned the reduction of speech disorders in two cases; significant improvement in the field of motor skills in three patients and reduction of apraxia and improvement of logical communication skills in two patients were also reported. All the patients became more independent. Significant improvement of the neurological condition using the same scales was registered only in two patients from the control group. We did not report any adverse events in the treated group during follow-up. At 1-year follow-up, we demonstrate safety and beneficial effect of WJMSC transplantation including neurological improvement and reduction of functional neurodeficiency. We are aware that the samples size of this study is relatively small. The treatment regimen needs to be further tested in larger group of patients.
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Affiliation(s)
- Olga Milczarek
- Department of Children’s Neurosurgery, Institute of Pediatrics, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Jakub Swadźba
- Department of Laboratory Medicine, Andrzej Frycz–Modrzewski Cracow University, Cracow, Poland
| | | | - Anna Starowicz-Filip
- Department of Psychology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Roger M. Krzyżewski
- Department of Neurosurgery and Neurotraumatology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Stanisław Kwiatkowski
- Department of Children’s Neurosurgery, Institute of Pediatrics, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Majka
- Department of Transplantation, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
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Femminò S, Bonelli F, Brizzi MF. Extracellular vesicles in cardiac repair and regeneration: Beyond stem-cell-based approaches. Front Cell Dev Biol 2022; 10:996887. [PMID: 36120584 PMCID: PMC9479097 DOI: 10.3389/fcell.2022.996887] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 08/16/2022] [Indexed: 11/13/2022] Open
Abstract
The adult human heart poorly regenerate after injury due to the low self-renewal capability retained by adult cardiomyocytes. In the last two decades, several clinical studies have reported the ability of stem cells to induce cardiac regeneration. However, low cell integration and survival into the tissue has limited stem-cell-based clinical approaches. More recently, the release of paracrine mediators including extracellular vesicles (EV) has been recognized as the most relevant mechanism driving benefits upon cell-based therapy. In particular, EV have emerged as key mediators of cardiac repair after damage, in terms of reduction of apoptosis, resolution of inflammation and new blood vessel formation. Herein, mechanisms involved in cardiac damage and regeneration, and current applications of EV and their small non-coding RNAs (miRNAs) in regenerative medicine are discussed.
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Zhou M, Li R, Venkat P, Qian Y, Chopp M, Zacharek A, Landschoot-Ward J, Powell B, Jiang Q, Cui X. Post-Stroke Administration of L-4F Promotes Neurovascular and White Matter Remodeling in Type-2 Diabetic Stroke Mice. Front Neurol 2022; 13:863934. [PMID: 35572941 PMCID: PMC9100936 DOI: 10.3389/fneur.2022.863934] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/21/2022] [Indexed: 02/02/2023] Open
Abstract
Patients with type 2 diabetes mellitus (T2DM) exhibit a distinct and high risk of ischemic stroke with worse post-stroke neurovascular and white matter (WM) prognosis than the non-diabetic population. In the central nervous system, the ATP-binding cassette transporter member A 1 (ABCA1), a reverse cholesterol transporter that efflux cellular cholesterol, plays an important role in high-density lipoprotein (HDL) biogenesis and in maintaining neurovascular stability and WM integrity. Our previous study shows that L-4F, an economical apolipoprotein A member I (ApoA-I) mimetic peptide, has neuroprotective effects via alleviating neurovascular and WM impairments in the brain of db/db-T2DM stroke mice. To further investigate whether L-4F has neurorestorative benefits in the ischemic brain after stroke in T2DM and elucidate the underlying molecular mechanisms, we subjected middle-aged, brain-ABCA1 deficient (ABCA1-B/-B), and ABCA1-floxed (ABCA1fl/fl) T2DM control mice to distal middle cerebral artery occlusion. L-4F (16 mg/kg, subcutaneous) treatment was initiated 24 h after stroke and administered once daily for 21 days. Treatment of T2DM-stroke with L-4F improved neurological functional outcome, and decreased hemorrhage, mortality, and BBB leakage identified by decreased albumin infiltration and increased tight-junction and astrocyte end-feet densities, increased cerebral arteriole diameter and smooth muscle cell number, and increased WM density and oligodendrogenesis in the ischemic brain in both ABCA1-B/-B and ABCA1fl/fl T2DM-stroke mice compared with vehicle-control mice, respectively (p < 0.05, n = 9 or 21/group). The L-4F treatment reduced macrophage infiltration and neuroinflammation identified by decreases in ED-1, monocyte chemoattractant protein-1 (MCP-1), and toll-like receptor 4 (TLR4) expression, and increases in anti-inflammatory factor Insulin-like growth factor 1 (IGF-1) and its receptor IGF-1 receptor β (IGF-1Rβ) in the ischemic brain (p < 0.05, n = 6/group). These results suggest that post-stroke administration of L-4F may provide a restorative strategy for T2DM-stroke by promoting neurovascular and WM remodeling. Reducing neuroinflammation in the injured brain may contribute at least partially to the restorative effects of L-4F independent of the ABCA1 signaling pathway.
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Affiliation(s)
- Min Zhou
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Rongwen Li
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Poornima Venkat
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Yu Qian
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
- Department of Physics, Oakland University, Rochester, MI, United States
| | - Alex Zacharek
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | | | - Brianna Powell
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Quan Jiang
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
- Department of Physics, Oakland University, Rochester, MI, United States
| | - Xu Cui
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
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Mesenchymal Stem Cells: Therapeutic Mechanisms for Stroke. Int J Mol Sci 2022; 23:ijms23052550. [PMID: 35269692 PMCID: PMC8910569 DOI: 10.3390/ijms23052550] [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: 01/22/2022] [Revised: 02/20/2022] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Due to aging of the world’s population, stroke has become increasingly prevalent, leading to a rise in socioeconomic burden. In the recent past, stroke research and treatment have become key scientific issues that need urgent solutions, with a sharp focus on stem cell transplantation, which is known to treat neurodegenerative diseases related to traumatic brain injuries, such as stroke. Indeed, stem cell therapy has brought hope to many stroke patients, both in animal and clinical trials. Mesenchymal stem cells (MSCs) are most commonly utilized in biological medical research, due to their pluripotency and universality. MSCs are often obtained from adipose tissue and bone marrow, and transplanted via intravenous injection. Therefore, this review will discuss the therapeutic mechanisms of MSCs and extracellular vehicles (EVs) secreted by MSCs for stroke, such as in attenuating inflammation through immunomodulation, releasing trophic factors to promote therapeutic effects, inducing angiogenesis, promoting neurogenesis, reducing the infarct volume, and replacing damaged cells.
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Zheng Z, Chen J, Chopp M. Mechanisms of Plasticity Remodeling and Recovery. Stroke 2022. [DOI: 10.1016/b978-0-323-69424-7.00011-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Hu J, Chang Y, Peng C, Huang S, Li G, Li H. Umbilical Cord Mesenchymal Stem Cells Derived Neurospheres Promote Long-term functional recovery But Aggravate Acute Phase Inflammation in Experimental Stroke. Neuroscience 2021; 480:217-228. [PMID: 34762983 DOI: 10.1016/j.neuroscience.2021.10.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 11/16/2022]
Abstract
Human umbilical cord mesenchymal stem cells (UC-MSCs) transplantation has been shown to ameliorate intracerebral hemorrhage (ICH) in animal and clinical studies. We previously reported an easy one-step method to induce UC-MSCs into neurospheres with much enhanced neurogenic and angiogenic potential. In the present study, we further evaluated the neuro-protective effects of these UC-MSCs derived neurospheres (UC-MSCs-NS) using a murine collagenase induced ICH model. We compared the effects of UC-MSCs or UC-MSCs-NS transplantation at two different time-points: 3 h after ICH induction (early transplantation) or three days after ICH induction (delayed transplantation). The results showed that UC-MSCs exhibited favorable effects at both time-points whereas UC-MSCs-NS early delivery led to increased cell apoptosis, exacerbated brain edema, enlarged ICH volume and deteriorated neurological function. In vivo inflammatory cytokine analysis indicated UC-MSCs transplantation was able to attenuate the acute phase secretion of inflammatory cytokines TNF-α and IL-1β whereas UC-MSCs-NS immediate transplantation led to increased levels of these cytokines. However, long-term follow-up experiment showed delayed UC-MSCs-NS transplantation was superior to UC-MSCs transplantation alone in terms of increased neurogenic reconstitution. Our results suggest both UC-MSCs and UC-MSCs-NS can exert favorable effects in ICH therapy but the infusion of UC-MSCs-NS should avoid the super-early phase of ICH. We believe UC-MSCs derived neurospheres should be further exploited for chronic refractory neurological disorders such as chronic phase of stroke and various neurodegenerative disorders such as Alzheimer's disease.
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Affiliation(s)
- Jingqiong Hu
- Stem Cell Center, Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
| | - Yanmin Chang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Chunyang Peng
- Emergency Internal Medicine Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Sui Huang
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Gang Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Huiyu Li
- Stem Cell Center, Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
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Ali AMEA, Ahmed AS, El-Yasergy DF, Abousarie MA, Elsayed RM, Mohammed YE, Mohammed RA. Therapeutic potential of mesenchymal stem cells for peripheral artery disease in a rat model of hindlimb ischemia. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:805-814. [PMID: 34630958 PMCID: PMC8487602 DOI: 10.22038/ijbms.2021.55861.12491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/19/2021] [Indexed: 11/11/2022]
Abstract
OBJECTIVES Mesenchymal stem cells are viewed as the first choice in regenerative medicine. This study aimed to elucidate the influence of BM-MSCs transplantation on angiogenesis in a rat model of unilateral peripheral vascular disease. MATERIALS AND METHODS Twenty-one rats were arbitrarily allocated into three groups (7/group). Group I: control sham-operated rats, Group II: control ischemic group: Rats were subjected to unilateral surgical ligation of the femoral artery, and Group III: ischemia group: Rats were induced as in group II, 24 hr after ligation, they were intramuscularly injected with BM-MSCs. After scarification, gastrocnemius muscle gene expression of stromal cell-derived factor-1 (SDF-1), CXC chemokine receptor 4 (CXCR4), vascular endothelial growth factor receptor 2 (VEGFR2), von Willebrand factor (vWF), and hypoxia-inducible factor-1α (HIF-1α) were analyzed by quantitative real-time PCR. Muscle regeneration and angiogenesis evaluation was assessed through H&E staining of the tissue. Furthermore, Pax3 and Pax7 nuclear expression was immunohistochemically assessed. RESULTS Rats treated with BM-MSCs showed significantly raised gene expression levels of SDF-1, CXCR4, VEGFR2, and vWF compared with control and ischemia groups. H&E staining of the gastrocnemius showed prominent new vessel formation. Granulation tissue within muscles of the ischemic treated group by BM-MSCs showed cells demonstrating nuclear expression of Pax3 and Pax7. CONCLUSION BM-MSCs transplantation has an ameliorating effect on muscle ischemia through promoting angiogenesis, detected by normal muscle architecture restoration and new blood vessel formations observed by H&E, confirmed by increased gene expression levels of SDF-1, CXCR4, VEGFR2, and vWF, decreased HIF-1α gene expression, and increased myogenic Pax7 gene expression.
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Affiliation(s)
- Amani M. El Amin Ali
- Department of Medical Physiology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Amira S. Ahmed
- Hormones Department, Medical Research Division, National Research Centre, Giza, Egypt
| | - Dina F. El-Yasergy
- Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Ramadan M. Elsayed
- Department of Medical Anatomy, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Yasmin E. Mohammed
- Department of Medical Anatomy, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Rahab A. Mohammed
- Department of Medical Physiology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
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Guo YS, Yuan M, Han Y, Shen XY, Gao ZK, Bi X. Therapeutic Potential of Cytokines in Demyelinating Lesions After Stroke. J Mol Neurosci 2021; 71:2035-2052. [PMID: 33970426 DOI: 10.1007/s12031-021-01851-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/26/2021] [Indexed: 12/15/2022]
Abstract
White matter damage is a component of most human stroke and usually accounts for at least half of the lesion volume. Subcortical white matter stroke (WMS) accounts for 25% of all strokes and causes severe motor and cognitive dysfunction. The adult brain has a very limited ability to repair white matter damage. Pathological analysis shows that demyelination or myelin loss is the main feature of white matter injury and plays an important role in long-term sensorimotor and cognitive dysfunction. This suggests that demyelination is a major therapeutic target for ischemic stroke injury. An acute inflammatory reaction is triggered by brain ischemia, which is accompanied by cytokine production. The production of cytokines is an important factor affecting demyelination and myelin regeneration. Different cytokines have different effects on myelin damage and myelin regeneration. Exploring the role of cytokines in demyelination and remyelination after stroke and the underlying molecular mechanisms of demyelination and myelin regeneration after ischemic injury is very important for the development of rehabilitation treatment strategies. This review focuses on recent findings on the effects of cytokines on myelin damage and remyelination as well as the progress of research on the role of cytokines in ischemic stroke prognosis to provide a new treatment approach for amelioration of white matter damage after stroke.
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Affiliation(s)
- Yi-Sha Guo
- Shanghai University of Sport, Shanghai, 200438, China
| | - Mei Yuan
- Shanghai University of Sport, Shanghai, 200438, China
| | - Yu Han
- Shanghai University of Sport, Shanghai, 200438, China
| | - Xin-Ya Shen
- Shanghai University of Traditional Chinese Medicine, Shanghai, 200438, China
| | - Zhen-Kun Gao
- Shanghai University of Traditional Chinese Medicine, Shanghai, 200438, China
| | - Xia Bi
- Department of Rehabilitation Medicine, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China.
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12
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Xu ZQ, Zhang JJ, Kong N, Zhang GY, Ke P, Han T, Su DF, Liu C. Autophagy is Involved in Neuroprotective Effect of Alpha7 Nicotinic Acetylcholine Receptor on Ischemic Stroke. Front Pharmacol 2021; 12:676589. [PMID: 33995108 PMCID: PMC8117007 DOI: 10.3389/fphar.2021.676589] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/14/2021] [Indexed: 01/14/2023] Open
Abstract
The α7 nicotinic acetylcholine receptor (α7nAChR) belongs to the superfamily of cys loop cationic ligand-gated channels, which consists of homogeneous α7 subunits. Although our lab found that activation of α7nAChR could alleviate ischemic stroke, the mechanism is still unknown. Herein, we explored whether autophagy is involved in the neuroprotective effect mediated by α7nAChR in ischemic stroke. Transient middle cerebral artery occlusion (tMCAO) and oxygen and glucose deprivation (OGD/R) exposure were applied to in vivo and in vitro models of ischemic stroke, respectively. Neurological deficit score and infarct volume were used to evaluate outcomes of tMCAO in the in vivo study. Autophagy-related proteins were detected by Western blot, and autophagy flux was detected by using tandem fluorescent mRFP-GFP-LC3 lentivirus. At 24 h after tMCAO, α7nAChR knockout mice showed worse neurological function and larger infarct volume than wild-type mice. PNU282987, an α7nAChR agonist, protected against OGD/R-induced neuronal injury, enhanced autophagy, and promoted autophagy flux. However, the beneficial effects of PNU282987 were eliminated by 3-methyladenine (3-MA), an autophagy inhibitor. Moreover, we found that PNU282987 treatment could activate the AMPK-mTOR-p70S6K signaling pathway in the in vitro study, while the effect was attenuated by compound C, an AMPK inhibitor. Our results demonstrated that the beneficial effect on neuronal survival via activation of α7nAChR was associated with enhanced autophagy, and the AMPK-mTOR-p70S6K signaling pathway was involved in α7nAChR activation-mediated neuroprotection.
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Affiliation(s)
- Zhe-Qi Xu
- Department of Pharmacy, Second Military Medical University, Shanghai, China
| | - Jing-Jing Zhang
- Department of Pharmacy, Second Military Medical University, Shanghai, China
| | - Ni Kong
- Department of Pharmacy, Second Military Medical University, Shanghai, China
| | - Guang-Yu Zhang
- Department of Pharmacy, Second Military Medical University, Shanghai, China
| | - Ping Ke
- Department of Pharmacy, Second Military Medical University, Shanghai, China
| | - Ting Han
- Department of Pharmacy, Second Military Medical University, Shanghai, China
| | - Ding-Feng Su
- Department of Pharmacy, Second Military Medical University, Shanghai, China
| | - Chong Liu
- Department of Pharmacy, Second Military Medical University, Shanghai, China
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13
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Wang M, Li Y, Zhang R, Zhang S, Feng H, Kong Z, Aiziretiaili N, Luo Z, Cai Q, Hong Y, Liu Y. Adiponectin-Transfected Endothelial Progenitor Cells Have Protective Effects After 2-Hour Middle-Cerebral Artery Occlusion in Rats With Type 2 Diabetes Mellitus. Front Neurol 2021; 12:630681. [PMID: 33746885 PMCID: PMC7966523 DOI: 10.3389/fneur.2021.630681] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 01/28/2021] [Indexed: 02/05/2023] Open
Abstract
Objectives: This present study aimed to examine the effects of adiponectin-transfected endothelial progenitor cells (LV-APN-EPCs) on cerebral ischemia-reperfusion injury in rats with type 2 diabetes mellitus (T2DM) and to explore the underlying mechanisms. Methods: Seventy male Sprague-Dawley rats with T2DM were randomly divided into sham, phosphate-buffered saline (PBS), LV-APN-EPCs, LV-EPCs, and EPCs groups. Transient middle cerebral artery occlusion (MCAO) was induced by the intraluminal suture method. After 1 h of reperfusion, the five interventions were performed by tail-vein injections. The modified neurological severity score (mNSS) was used to assess neurological function before and on days 1, 7, and 14 after MCAO. After 14 days, magnetic resonance imaging scanning, hematoxylin and eosin staining, terminal dUTP nick-end labeling staining, Western blotting analysis, cluster of differentiation (CD) 31 immunofluorescence, and enzyme-linked immunosorbent assay were used to evaluate infarct rate, morphological damage, cell apoptosis, and microvessel density. Results: Compared with PBS, LV-EPCs, and EPCs groups, the LV-APN-EPCs group showed significantly lower mNSS score, lower infarct rate, and less morphological damage (all P < 0.05). In addition, compared with other groups, the LV-APN-EPCs group had significantly increased levels of B cell lymphoma/leukemia-2 (Bcl-2) protein, CD31+ microvessels, endothelial nitric oxide synthase, and vascular endothelial growth factor, and decreased levels of Bcl-2-associated X protein and neuronal apoptosis in the peri-infarct cortex (all P < 0.05). Conclusion: These results suggest that LV-APN-EPCs exert protective effects against cerebral ischemia-reperfusion injury in T2DM rats by increasing angiogenesis.
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Affiliation(s)
- Meiyao Wang
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yan Li
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Renwei Zhang
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shuaimei Zhang
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hongliang Feng
- Guangdong Mental Health Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhaohong Kong
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Nadire Aiziretiaili
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhengjin Luo
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qi Cai
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yan Hong
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yumin Liu
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
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14
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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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15
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Chen Z, Wang X, Liao H, Sheng T, Chen P, Zhou H, Pan Y, Liu W, Yao H. Glycine attenuates cerebrovascular remodeling via glycine receptor alpha 2 and vascular endothelial growth factor receptor 2 after stroke. Am J Transl Res 2020; 12:6895-6907. [PMID: 33194080 PMCID: PMC7653569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 08/01/2020] [Indexed: 06/11/2023]
Abstract
As a dual-acting neurotransmitter, glycine plays critical roles in cerebral ischemia by activating both glycine receptors (GlyRs) and N-methyl-D-aspartate acid receptors (NMDARs). However, the involvement of glycine receptor alpha 2 (GlyRa2) in cerebral ischemia has not been explored. The objective of this study was to determine the mechanism of action of GlyRa2 in cerebrovascular remodeling. After induction of rat tMCAO, levels of the GLRA2 gene and GlyRa2 protein were examined using q-PCR, western blot, and immunohistochemical analyses. Blood-brain barrier permeability, and the presence of hemorrhage and arteriosclerosis were also analyzed. The underlying mechanism of vascular remodeling was examined using immunohistochemical and immunofluorescence analyses. Both the GLRA2 gene and GlyRa2 protein were altered sharply after stroke. GlyRa2 of vascular origin appears to play a protective role after glycine treatment for ischemia. Blockade of GlyRa2 by the addition of cyclothiazide was found to abolish previous improvements in cerebrovascular survival after glycine treatment for tMCAO in rats. GlyRa2-dependent neurovascular remodeling was found to be correlated with the vascular endothelial growth factor receptor 2 (VEGFR2) pathways. These results suggest that vascular-derived GlyRa2 protects against post-ischemic injury. Vascular protection via GlyRa2 is due to VEGFR2/pSTAT3 signaling.
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Affiliation(s)
- Zheng Chen
- Schools of Medicine, Huzhou University, Huzhou Central HospitalHuzhou, PR China
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou University, Huzhou Central HospitalHuzhou, PR China
- Division of Vascular Surgery, East Hospital, Tongji University School of MedicineShanghai, 200120, PR China
| | - Xiang Wang
- Division of Vascular Surgery, East Hospital, Tongji University School of MedicineShanghai, 200120, PR China
| | - Haikang Liao
- Institute of Life Sciences and Institute of Neuroscience, Wenzhou UniversityWenzhou, PR China
| | - Tao Sheng
- Schools of Medicine, Huzhou University, Huzhou Central HospitalHuzhou, PR China
| | - Panhong Chen
- Schools of Medicine, Huzhou University, Huzhou Central HospitalHuzhou, PR China
| | - Hongchang Zhou
- Schools of Medicine, Huzhou University, Huzhou Central HospitalHuzhou, PR China
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou University, Huzhou Central HospitalHuzhou, PR China
| | - Yongliang Pan
- Schools of Medicine, Huzhou University, Huzhou Central HospitalHuzhou, PR China
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou University, Huzhou Central HospitalHuzhou, PR China
| | - Weiqin Liu
- The Affiliated Ganzhou Hospital of Nanchang UniversityGanzhou, PR China
| | - Hua Yao
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical UniversityGuilin, PR China
- Institute of Life Sciences and Institute of Neuroscience, Wenzhou UniversityWenzhou, PR China
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16
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Ueno Y, Hira K, Miyamoto N, Kijima C, Inaba T, Hattori N. Pleiotropic Effects of Exosomes as a Therapy for Stroke Recovery. Int J Mol Sci 2020; 21:ijms21186894. [PMID: 32962207 PMCID: PMC7555640 DOI: 10.3390/ijms21186894] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/16/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Stroke is the leading cause of disability, and stroke survivors suffer from long-term sequelae even after receiving recombinant tissue plasminogen activator therapy and endovascular intracranial thrombectomy. Increasing evidence suggests that exosomes, nano-sized extracellular membrane vesicles, enhance neurogenesis, angiogenesis, and axonal outgrowth, all the while suppressing inflammatory reactions, thereby enhancing functional recovery after stroke. A systematic literature review to study the association of stroke recovery with exosome therapy was carried out, analyzing species, stroke model, source of exosomes, behavioral analyses, and outcome data, as well as molecular mechanisms. Thirteen studies were included in the present systematic review. In the majority of studies, exosomes derived from mesenchymal stromal cells or stem cells were administered intravenously within 24 h after transient middle cerebral artery occlusion, showing a significant improvement of neurological severity and motor functions. Specific microRNAs and molecules were identified by mechanistic investigations, and their amplification was shown to further enhance therapeutic effects, including neurogenesis, angiogenesis, axonal outgrowth, and synaptogenesis. Overall, this review addresses the current advances in exosome therapy for stroke recovery in preclinical studies, which can hopefully be preparatory steps for the future development of clinical trials involving stroke survivors to improve functional outcomes.
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Affiliation(s)
- Yuji Ueno
- Correspondence: ; Tel.: +81-3-3813-3111; Fax: +81-3-5800-0547
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17
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Exosomes derived from bone marrow mesenchymal stem cells harvested from type two diabetes rats promotes neurorestorative effects after stroke in type two diabetes rats. Exp Neurol 2020; 334:113456. [PMID: 32889008 DOI: 10.1016/j.expneurol.2020.113456] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 07/08/2020] [Accepted: 08/30/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND PURPOSE Diabetes elevates the risk of stroke, promotes inflammation, and exacerbates vascular and white matter damage post stroke, thereby hindering long term functional recovery. Here, we investigated the neurorestorative effects and the underlying therapeutic mechanisms of treatment of stroke in type 2 diabetic rats (T2DM) using exosomes harvested from bone marrow stromal cells obtained from T2DM rats (T2DM-MSC-Exo). METHODS T2DM was induced in adult male Wistar rats using a combination of high fat diet and Streptozotocin. Rats were subjected to transient 2 h middle cerebral artery occlusion (MCAo) and 3 days later randomized to one of the following treatment groups: 1) phosphate-buffered-saline (PBS, i.v), 2) T2DM-MSC-Exo, (3 × 1011, i.v), 3) T2DM-MSC-Exo with miR-9 over expression (miR9+/+-T2DM-MSC-Exo, 3 × 1011, i.v) or 4) MSC-Exo derived from normoglycemic rats (Nor-MSC-Exo) (3 × 1011, i.v). T2DM sham control group is included as reference. Rats were sacrificed 28 days after MCAo. RESULTS T2DM-MSC-Exo treatment does not alter blood glucose, lipid levels, or lesion volume, but significantly improves neurological function and attenuates post-stroke weight loss compared to PBS treated as well as Nor-MSC-Exo treated T2DM-stroke rats. Compared to PBS treatment, T2DM-MSC-Exo treatment of T2DM-stroke rats significantly 1) increases tight junction protein ZO-1 and improves blood brain barrier (BBB) integrity; 2) promotes white matter remodeling indicated by increased axon and myelin density, and increases oligodendrocytes and oligodendrocyte progenitor cell numbers in the ischemic border zone as well as increases primary cortical neuronal axonal outgrowth; 3) decreases activated microglia, M1 macrophages, and inflammatory factors MMP-9 (matrix mettaloproteinase-9) and MCP-1 (monocyte chemoattractant protein-1) expression in the ischemic brain; and 4) decreases miR-9 expression in serum, and increases miR-9 target ABCA1 (ATP-binding cassette transporter 1) and IGFR1 (Insulin-like growth factor 1 receptor) expression in the brain. MiR9+/+-T2DM-MSC-Exo treatment significantly increases serum miR-9 expression compared to PBS treated and T2DM-MSC-Exo treated T2DM stroke rats. Treatment of T2DM stroke with miR9+/+-T2DM-MSC-Exo fails to improve functional outcome and attenuates T2DM-MSC-Exo treatment induced white matter remodeling and anti-inflammatory effects in T2DM stroke rats. CONCLUSIONS T2DM-MSC-Exo treatment for stroke in T2DM rats promotes neurorestorative effects and improves functional outcome. Down regulation of miR-9 expression and increasing its target ABCA1 pathway may contribute partially to T2DM-MSC-Exo treatment induced white matter remodeling and anti-inflammatory responses.
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18
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Yang F, Li WB, Qu YW, Gao JX, Tang YS, Wang DJ, Pan YJ. Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling. World J Stem Cells 2020; 12:633-658. [PMID: 32843919 PMCID: PMC7415242 DOI: 10.4252/wjsc.v12.i7.633] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/04/2020] [Accepted: 05/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bone marrow mesenchymal stem cells (BMSCs) are capable of shifting the microglia/macrophages phenotype from M1 to M2, contributing to BMSCs-induced brain repair. However, the regulatory mechanism of BMSCs on microglia/macrophages after ischemic stroke is unclear. Recent evidence suggests that mesencephalic astrocyte–derived neurotrophic factor (MANF) and platelet-derived growth factor-AA (PDGF-AA)/MANF signaling regulate M1/M2 macrophage polarization.
AIM To investigate whether and how MANF or PDGF-AA/MANF signaling influences BMSCs-mediated M2 polarization.
METHODS We identified the secretion of MANF by BMSCs and developed transgenic BMSCs using a targeting small interfering RNA for knockdown of MANF expression. Using a rat middle cerebral artery occlusion (MCAO) model transplanted by BMSCs and BMSCs–microglia Transwell coculture system, the effect of BMSCs-induced downregulation of MANF expression on the phenotype of microglia/macrophages was tested by Western blot, quantitative reverse transcription-polymerase chain reaction, and immunofluorescence. Additionally, microglia were transfected with mimics of miR-30a*, which influenced expression of X-box binding protein (XBP) 1, a key transcription factor that synergized with activating transcription factor 6 (ATF6) to govern MANF expression. We examined the levels of miR-30a*, ATF6, XBP1, and MANF after PDGF-AA treatment in the activated microglia.
RESULTS Inhibition of MANF attenuated BMSCs-induced functional recovery and decreased M2 marker production, but increased M1 marker expression in vivo or in vitro. Furthermore, PDGF-AA treatment decreased miR-30a* expression, had no influence on the levels of ATF6, but enhanced expression of both XBP1 and MANF.
CONCLUSION BMSCs-mediated MANF paracrine signaling, in particular the PDGF-AA/miR-30a*/XBP1/MANF pathway, synergistically mediates BMSCs-induced M2 polarization.
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Affiliation(s)
- Fan Yang
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Wen-Bin Li
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ye-Wei Qu
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Jin-Xing Gao
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Shi Tang
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Dong-Jie Wang
- Department of Respiratory Medicine, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Jun Pan
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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19
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Opportunities and Limitations of Vascular Risk Factor Models in Studying Plasticity-Promoting and Restorative Ischemic Stroke Therapies. Neural Plast 2019; 2019:9785476. [PMID: 31827502 PMCID: PMC6885287 DOI: 10.1155/2019/9785476] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 10/02/2019] [Accepted: 10/24/2019] [Indexed: 12/24/2022] Open
Abstract
Major efforts are currently made promoting neuronal plasticity and brain remodeling in the postacute stroke phase. Experimental studies evaluating new stroke therapies are mostly performed in rodents, which compared to humans exhibit a short lifespan. These studies widely employ young, otherwise healthy, rodents that lack the vascular risk factors and comorbidities of stroke patients. These risk factors compromise postischemic neurological recovery and brain plasticity and in several contexts reduce the brain responsiveness to recovery-inducing plasticity-promoting treatments. By examining risk factor models, which have hitherto been used for studying experimentally induced ischemic stroke, this review outlines the possibilities and limitations of risk factor models in the evaluation of plasticity-promoting and restorative stroke treatments.
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20
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Gómez-de Frutos MC, Laso-García F, Diekhorst L, Otero-Ortega L, Fuentes B, Jolkkonen J, Detante O, Moisan A, Martínez-Arroyo A, Díez-Tejedor E, Gutiérrez-Fernández M. Intravenous delivery of adipose tissue-derived mesenchymal stem cells improves brain repair in hyperglycemic stroke rats. Stem Cell Res Ther 2019; 10:212. [PMID: 31315686 PMCID: PMC6637493 DOI: 10.1186/s13287-019-1322-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 05/14/2019] [Accepted: 07/02/2019] [Indexed: 12/11/2022] Open
Abstract
Background Over 50% of acute stroke patients have hyperglycemia, which is associated with a poorer prognosis and outcome. Our aim was to investigate the impact of hyperglycemia on behavioral recovery and brain repair of delivered human adipose tissue-derived mesenchymal stem cells (hAD-MSCs) in a rat model of permanent middle cerebral artery occlusion (pMCAO). Methods Hyperglycemia was induced in rats by the administration of nicotinamide and streptozotocin. The rats were then subjected to stroke by a pMCAO model. At 48 h post-stroke, 1 × 106 hAD-MSCs or saline were intravenously administered. We evaluated behavioral outcome, infarct size by MRI, and brain plasticity markers by immunohistochemistry (glial fibrillary acidic protein [GFAP], Iba-1, synaptophysin, doublecortin, CD-31, collagen-IV, and α-smooth muscle actin [α-SMA]). Results The hyperglycemic group exhibited more severe neurological deficits; lesion size and diffusion coefficient were larger compared with the non-hyperglycemic rats. GFAP, Iba-1, and α-SMA were increased in the hyperglycemic group. The hyperglycemic rats administered hAD-MSCs at 48 h after pMCAO had improved neurological impairment. Although T2-MRI did not show differences in lesion size between groups, the rADC values were lower in the treated group. Finally, the levels of GFAP, Iba-1, and arterial wall thickness were lower in the treated hyperglycemic group than in the nontreated hyperglycemic group at 6 weeks post-stroke. Conclusions Our data suggest that rats with hyperglycemic ischemic stroke exhibit increased lesion size and impaired brain repair processes, which lead to impairments in behavioral recovery after pMCAO. More importantly, hAD-MSC administration induced better anatomical tissue preservation, associated with a good behavioral outcome. Electronic supplementary material The online version of this article (10.1186/s13287-019-1322-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mari Carmen Gómez-de Frutos
- Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain
| | - Fernando Laso-García
- Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain
| | - Luke Diekhorst
- Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain
| | - Laura Otero-Ortega
- Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain
| | - Blanca Fuentes
- Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain
| | - Jukka Jolkkonen
- Department of Neurology, University of Eastern Finland, Kuopio, Finland.,NeuroCenter, Kuopio University Hospital, Kuopio, Finland
| | - Olivier Detante
- Neurology Department, Stroke Unit, Grenoble Hospital, Grenoble, France.,Grenoble Institute of Neurosciences, Inserm U1216, Grenoble Alpes University, Grenoble, France
| | - Anaick Moisan
- Grenoble Institute of Neurosciences, Inserm U1216, Grenoble Alpes University, Grenoble, France.,Cell Therapy and Engineering Unit, EFS Auvergne Rhône Alpes, Saint-Ismier, France
| | - Arturo Martínez-Arroyo
- Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain
| | - Exuperio Díez-Tejedor
- Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain
| | - María Gutiérrez-Fernández
- Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain.
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Hermann DM, Kleinschnitz C. Modeling Vascular Risk Factors for the Development of Ischemic Stroke Therapies. Stroke 2019; 50:1310-1317. [DOI: 10.1161/strokeaha.118.024673] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Dirk M. Hermann
- From the Department of Neurology, University Hospital Essen, Germany
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22
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Laso-García F, Diekhorst L, Gómez-de Frutos MC, Otero-Ortega L, Fuentes B, Ruiz-Ares G, Díez-Tejedor E, Gutiérrez-Fernández M. Cell-Based Therapies for Stroke: Promising Solution or Dead End? Mesenchymal Stem Cells and Comorbidities in Preclinical Stroke Research. Front Neurol 2019; 10:332. [PMID: 31024426 PMCID: PMC6467162 DOI: 10.3389/fneur.2019.00332] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 03/19/2019] [Indexed: 01/11/2023] Open
Abstract
Stroke is a major health problem worldwide. It has been estimated that 90% of the population attributable risk of stroke is due to risk factors such as aging, hypertension, hyperglycemia, diabetes mellitus and obesity, among others. However, most animal models of stroke use predominantly healthy and young animals. These models ignore the main comorbidities associated with cerebrovascular disease, which could be one explanation for the unsuccessful bench-to-bedside translation of protective and regenerative strategies by not taking the patient's situation into account. This lack of success makes it important to incorporate comorbidities into animal models of stroke in order to study the effects of the various therapeutic strategies tested. Regarding cell therapy, the administration of stem cells in the acute and chronic phases has been shown to be safe and effective in experimental animal models of stroke. This review aims to show the results of studies with promising new therapeutic strategies such as mesenchymal stem cells, which are being tested in preclinical models of stroke associated with comorbidities and in elderly animals.
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Affiliation(s)
- Fernando Laso-García
- Neuroscience and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Center, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Madrid, Spain
| | - Luke Diekhorst
- Neuroscience and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Center, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Madrid, Spain
| | - Mari Carmen Gómez-de Frutos
- Neuroscience and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Center, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Madrid, Spain
| | - Laura Otero-Ortega
- Neuroscience and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Center, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Madrid, Spain
| | - Blanca Fuentes
- Neuroscience and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Center, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Madrid, Spain
| | - Gerardo Ruiz-Ares
- Neuroscience and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Center, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Madrid, Spain
| | - Exuperio Díez-Tejedor
- Neuroscience and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Center, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Madrid, Spain
| | - María Gutiérrez-Fernández
- Neuroscience and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Center, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Madrid, Spain
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Hermann DM, Popa-Wagner A, Kleinschnitz C, Doeppner TR. Animal models of ischemic stroke and their impact on drug discovery. Expert Opin Drug Discov 2019; 14:315-326. [DOI: 10.1080/17460441.2019.1573984] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Dirk M. Hermann
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Center of Clinical and Experimental Medicine, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Aurel Popa-Wagner
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Center of Clinical and Experimental Medicine, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Christoph Kleinschnitz
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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24
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Venkat P, Chen J, Chopp M. Exosome-mediated amplification of endogenous brain repair mechanisms and brain and systemic organ interaction in modulating neurological outcome after stroke. J Cereb Blood Flow Metab 2018; 38:2165-2178. [PMID: 29888985 PMCID: PMC6282218 DOI: 10.1177/0271678x18782789] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Ischemic stroke is caused by a regional interruption of cerebral blood flow to the brain. Rigorous pre-clinical and clinical research has made landmark progress in stroke treatment using thrombolytics and endovascular thrombectomy. Although numerous successful neuroprotective therapeutic agents for ischemic stroke have been reported in pre-clinical studies, most of them failed in clinical testing. Persistent pre-clinical research has demonstrated that the ischemic brain is not only passively dying but is also actively recovering. Within the neurovascular niche in the peri-infarct tissue, repair mechanisms thrive on the interactions between the neural and vascular compartments. In this review, we discuss exogenous therapy using mesenchymal stromal cell-derived exosomes to amplify endogenous brain repair mechanisms and to induce neurorestorative effects after stroke. Emerging evidence indicates that multiple communication axes between the various organs such as the brain, heart, kidney and gut, and whole body immune response mediated by the spleen can also affect stroke outcome. Therefore, in this review, we summarize this evidence and initiate a discussion on the potential to improve stroke outcome by amplifying multiple brain repair mechanisms after stroke, and by targeting peripheral organs and downstream events to enhance recovery in the injured brain and promote over all well being.
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Affiliation(s)
- Poornima Venkat
- 1 Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
| | - Jieli Chen
- 1 Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
| | - Michael Chopp
- 1 Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.,2 Department of Physics, Oakland University, Rochester, MI, USA
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25
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Zheng H, Zhang B, Chhatbar PY, Dong Y, Alawieh A, Lowe F, Hu X, Feng W. Mesenchymal Stem Cell Therapy in Stroke: A Systematic Review of Literature in Pre-Clinical and Clinical Research. Cell Transplant 2018; 27:1723-1730. [PMID: 30343609 PMCID: PMC6300779 DOI: 10.1177/0963689718806846] [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: 03/13/2018] [Revised: 09/23/2018] [Accepted: 09/24/2018] [Indexed: 12/19/2022] Open
Abstract
Exogenous stem cell therapy (SCT) has been recognized recently as a promising neuroregenerative strategy to augment recovery in stroke survivors. Mesenchymal stem cells (MSCs) are the primary source of stem cells used in the majority of both pre-clinical and clinical studies in stroke. In the absence of evidence-based guidelines on the use of SCT in stroke patients, understanding the progress of MSC research across published studies will assist researchers and clinicians in better achieving success in translating research. We conducted a systematic review on published literature using MSCs in both pre-clinical studies and clinical trials between 2008 and 2017 using the public databases PubMed and Ovid Medline, and the clinical trial registry ( www.clinicaltrials.gov ). A total of 78 pre-clinical studies and eight clinical studies were identified. While majority of the pre-clinical and clinical studies demonstrated statistically significant effects, the clinical significance of these findings was still unclear. Effect sizes could not be measured mainly due to reporting issues in pre-clinical studies, thus limiting our ability to compare results across studies quantitatively. The overall quality of both pre-clinical and clinical studies was sub-optimal. By conducting a systematic review of both pre-clinical and clinical studies on MSCs therapy in stroke, we assessed the quality of current evidence and identified several issues and gaps in translating animal studies to human trials. Addressing these issues and incorporating changes into future animal studies and human trials may lead to better success of stem cells-based therapeutics in the near future.
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Affiliation(s)
- Haiqing Zheng
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Neurology, Medical University of South Carolina, Charleston, SC, USA
| | - Bin Zhang
- Department of Neurology, Medical University of South Carolina, Charleston, SC, USA
- Department of Neurology, Shanghai Jiaotong University Affiliated the Sixth People’s Hospital, Shanghai, China
| | - Pratik Y. Chhatbar
- Department of Neurology, Medical University of South Carolina, Charleston, SC, USA
| | - Yi Dong
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Ali Alawieh
- Department of Neurology, Medical University of South Carolina, Charleston, SC, USA
| | - Forrest Lowe
- Department of Neurology, Medical University of South Carolina, Charleston, SC, USA
| | - Xiquan Hu
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wuwei Feng
- Department of Neurology, Medical University of South Carolina, Charleston, SC, USA
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26
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Yong KW, Choi JR, Mohammadi M, Mitha AP, Sanati-Nezhad A, Sen A. Mesenchymal Stem Cell Therapy for Ischemic Tissues. Stem Cells Int 2018; 2018:8179075. [PMID: 30402112 PMCID: PMC6196793 DOI: 10.1155/2018/8179075] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 08/01/2018] [Accepted: 08/29/2018] [Indexed: 12/13/2022] Open
Abstract
Ischemic diseases such as myocardial infarction, ischemic stroke, and critical limb ischemia are immense public health challenges. Current pharmacotherapy and surgical approaches are insufficient to completely heal ischemic diseases and are associated with a considerable risk of adverse effects. Alternatively, human mesenchymal stem cells (hMSCs) have been shown to exhibit immunomodulation, angiogenesis, and paracrine secretion of bioactive factors that can attenuate inflammation and promote tissue regeneration, making them a promising cell source for ischemic disease therapy. This review summarizes the pathogenesis of ischemic diseases, discusses the potential therapeutic effects and mechanisms of hMSCs for these diseases, and provides an overview of challenges of using hMSCs clinically for treating ischemic diseases.
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Affiliation(s)
- Kar Wey Yong
- Pharmaceutical Production Research Facility, Department of Chemical and Petroleum Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
- BioMEMS and Bioinspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
| | - Jane Ru Choi
- Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, Vancouver, BC, V6T 1Z4, Canada
- Centre for Blood Research, Life Sciences Centre, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Mehdi Mohammadi
- BioMEMS and Bioinspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
- Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
| | - Alim P. Mitha
- Department of Clinical Neurosciences, Foothills Medical Centre, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Amir Sanati-Nezhad
- BioMEMS and Bioinspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
- Center of Bioengineering Research and Education, Schulich School of Engineering, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
| | - Arindom Sen
- Pharmaceutical Production Research Facility, Department of Chemical and Petroleum Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
- Center of Bioengineering Research and Education, Schulich School of Engineering, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
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27
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Yan T, Venkat P, Chopp M, Zacharek A, Yu P, Ning R, Qiao X, Kelley MR, Chen J. APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats. Aging Dis 2018; 9:453-466. [PMID: 29896433 PMCID: PMC5988600 DOI: 10.14336/ad.2017.1130] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 11/30/2017] [Indexed: 12/15/2022] Open
Abstract
APX3330 is a selective inhibitor of APE1/Ref-1 redox activity. In this study, we investigate the therapeutic effects and underlying mechanisms of APX3330 treatment in type one diabetes mellitus (T1DM) stroke rats. Adult male Wistar rats were induced with T1DM and subjected to transient middle cerebral artery occlusion (MCAo) and treated with either PBS or APX3330 (10mg/kg, oral gavage) starting at 24h after MCAo, and daily for 14 days. Rats were sacrificed at 14 days after MCAo and, blood brain barrier (BBB) permeability, ischemic lesion volume, immunohistochemistry, cell death assay, Western blot, real time PCR, and angiogenic ELISA array were performed. Compared to PBS treatment, APX3330 treatment of stroke in T1DM rats significantly improves neurological functional outcome, decreases lesion volume, and improves BBB integrity as well as decreases total vessel density and VEGF expression, while significantly increases arterial density in the ischemic border zone (IBZ). APX3330 significantly increases myelin density, oligodendrocyte number, oligodendrocyte progenitor cell number, synaptic protein expression, and induces M2 macrophage polarization in the IBZ of T1DM stroke rats. Compared to PBS treatment, APX3330 treatment significantly decreases plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 and matrix metalloproteinase 9 (MMP9) and receptor for advanced glycation endproducts expression in the ischemic brain of T1DM stroke rats. APX3330 treatment significantly decreases cell death and MMP9 and PAI-1 gene expression in cultured primary cortical neurons subjected to high glucose and oxygen glucose deprivation, compared to untreated control cells. APX3330 treatment increases M2 macrophage polarization and decreases inflammatory factor expression in the ischemic brain as well as promotes neuroprotective and neurorestorative effects after stroke in T1DM rats.
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Affiliation(s)
- Tao Yan
- 1Gerontology Institute, Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China.,2Department of Neurology, Henry Ford hospital, Detroit, MI, USA
| | - Poornima Venkat
- 2Department of Neurology, Henry Ford hospital, Detroit, MI, USA
| | - Michael Chopp
- 2Department of Neurology, Henry Ford hospital, Detroit, MI, USA.,3Department of Physics, Oakland University, Rochester, MI, USA
| | - Alex Zacharek
- 2Department of Neurology, Henry Ford hospital, Detroit, MI, USA
| | - Peng Yu
- 2Department of Neurology, Henry Ford hospital, Detroit, MI, USA
| | - Ruizhuo Ning
- 2Department of Neurology, Henry Ford hospital, Detroit, MI, USA.,4Department of Neurology, First Hospital Harbin, Harbin, China
| | - Xiaoxi Qiao
- 5Department of Ophthalmology, Henry Ford Hospital, Detroit, MI, USA
| | - Mark R Kelley
- 6Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jieli Chen
- 2Department of Neurology, Henry Ford hospital, Detroit, MI, USA
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28
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Venkat P, Chopp M, Chen J. Cell-Based and Exosome Therapy in Diabetic Stroke. Stem Cells Transl Med 2018; 7:451-455. [PMID: 29498242 PMCID: PMC5980126 DOI: 10.1002/sctm.18-0014] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 02/15/2018] [Indexed: 12/21/2022] Open
Abstract
Stroke is a global health concern and it is imperative that therapeutic strategies with wide treatment time frames be developed to improve neurological outcome in patients. Patients with diabetes mellitus who suffer a stroke have worse neurological outcomes and long‐term functional recovery than nondiabetic stroke patients. Diabetes induced vascular damage and enhanced inflammatory milieu likely contributes to worse post stroke outcomes. Diabetic stroke patients have an aggravated pathological cascade, and treatments that benefit nondiabetic stroke patients do not necessarily translate to diabetic stroke patients. Therefore, there is a critical need to develop therapeutics for stroke specifically in the diabetic population. Stem cell based therapy for stroke is an emerging treatment option with wide therapeutic time window. Cell‐based therapies for stroke promote endogenous central nervous system repair and neurorestorative mechanisms such as angiogenesis, neurogenesis, vascular remodeling, white matter remodeling, and also modulate inflammatory and immune responses at the local and systemic level. Emerging evidence suggests that exosomes and their cargo microRNA mediate cell therapy derived neurorestorative effects. Exosomes are small vesicles containing protein and RNA characteristic of its parent cell. Exosomes are transported by biological fluids and facilitate communication between neighboring and remote cells. MicroRNAs, a class of naturally occurring, small noncoding RNA sequences, contained within exosomes can regulate recipient cell's signaling pathways and alter protein expression either acting alone or in concert with other microRNAs. In this perspective article, we summarize current knowledge and highlight the promising future of cell based and exosome therapy for stroke and specifically for diabetic stroke. stemcellstranslationalmedicine2018;7:451–455
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Affiliation(s)
| | - Michael Chopp
- Neurology Henry Ford Hospital, Detroit, Michigan, USA.,Department of Physics, Oakland University, Rochester, Michigan, USA
| | - Jieli Chen
- Neurology Henry Ford Hospital, Detroit, Michigan, USA.,Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, People's Republic of China
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Sun J, Huang Q, Li S, Meng F, Li X, Gong X. miR-330-5p/Tim-3 axis regulates macrophage M2 polarization and insulin resistance in diabetes mice. Mol Immunol 2018; 95:107-113. [PMID: 29433065 DOI: 10.1016/j.molimm.2018.02.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 02/01/2018] [Accepted: 02/06/2018] [Indexed: 12/11/2022]
Abstract
Obesity is associated with a state of low-grade inflammatory response in adipose tissue, and contributes to the development of type 2 diabetes. Immune cells such as macrophages can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. Therefore, adipose tissue promotes macrophage infiltration, resulting in local inflammation and insulin resistance. Tim-3 negatively regulates IFN-γ secretion and influences the ability to induce T cell tolerance in diabetes. MicroRNA contributes to the development of immunological tolerance and involves in macrophage polarization. However, the potential of Tim-3 to regulate macrophage polarization and the related microRNA has not been reported. In this experiment, 8-week-old C57BL/6 mice were fed a high-fat diet for 8 weeks. The adipose tissue macrophages were isolated, miR-330-5p and Tim-3 levels, and M1/M2 polarization were analyzed. In addition, insulin tolerance tests was detected. The results demonstrated that miR-330-5p levels increased but Tim-3 levels decreased, leading to M1 polarization and insulin tolerance in diabetes mice. In addition, inhibition of miR-330-5p enhanced Tim-3 levels, leading to M2 polarization and insulin tolerance attenuation in diabetes mice. Furthermore, we detected the inverse relationship between miR-330-5p and Tim-3. We found that Tim-3 mRNA contained conserved miR-330-5p binding sites in its 3'UTR, and miR-330-5p could directly regulate Tim-3 expression through these 3'UTR sites. Our study demonstrated that miR-330-5p served as a regulator of the M2 polarization and miR-330-5p/Tim-3 axis potentially down-regulated insulin resistance in diabetes, probably through enhancing the M2 polarization of macrophage.
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Affiliation(s)
- Jiling Sun
- Department of Nurse, The People's Hospital of Linyi, Linyi, Shandong 276000, China
| | - Qiujing Huang
- Department of Endocrinology, The Third People's Hospital of Linyi, Linyi, Shandong 276023, China
| | - Shufa Li
- Department of Endocrinology, The Third People's Hospital of Linyi, Linyi, Shandong 276023, China.
| | - Fanqing Meng
- Department of Endocrinology, The Third People's Hospital of Linyi, Linyi, Shandong 276023, China
| | - Xunhua Li
- Department of Urology, The Third People's Hospital of Linyi, Linyi, Shandong 276023, China
| | - Xiaoyun Gong
- Department of Public Health, The Third People's Hospital of Linyi, Linyi, Shandong 276023, China
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30
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Cell Therapy in Stroke-Cautious Steps Towards a Clinical Treatment. Transl Stroke Res 2017; 9:321-332. [PMID: 29150739 DOI: 10.1007/s12975-017-0587-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 11/01/2017] [Accepted: 11/07/2017] [Indexed: 01/01/2023]
Abstract
In the future, stroke patients may receive stem cell therapy as this has the potential to restore lost functions. However, the development of clinically deliverable therapy has been slower and more challenging than expected. Despite recommendations by STAIR and STEPS consortiums, there remain flaws in experimental studies such as lack of animals with comorbidities, inconsistent approaches to experimental design, and concurrent rehabilitation that might lead to a bias towards positive results. Clinical studies have typically been small, lacking control groups as well as often without clear biological hypotheses to guide patient selection. Furthermore, they have used a wide range of cell types, doses, and delivery methods, and outcome measures. Although some ongoing and recent trial programs offer hints that these obstacles are now being tackled, the Horizon2020 funded RESSTORE trial will be given as an example of inconsistent regulatory requirements and challenges in harmonized cell production, logistic, and clinical criteria in an international multicenter study. The PISCES trials highlight the complex issues around intracerebral cell transplantation. Therefore, a better understanding of translational challenges is expected to pave the way to more successful help for stroke patients.
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31
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Venkat P, Shen Y, Chopp M, Chen J. Cell-based and pharmacological neurorestorative therapies for ischemic stroke. Neuropharmacology 2017; 134:310-322. [PMID: 28867364 DOI: 10.1016/j.neuropharm.2017.08.036] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 08/22/2017] [Accepted: 08/24/2017] [Indexed: 01/09/2023]
Abstract
Ischemic stroke remains one of most common causes of death and disability worldwide. Stroke triggers a cascade of events leading to rapid neuronal damage and death. Neuroprotective agents that showed promise in preclinical experiments have failed to translate to the clinic. Even after decades of research, tPA remains the only FDA approved drug for stroke treatment. However, tPA is effective when administered 3-4.5 h after stroke onset and the vast majority of stroke patients do not receive tPA therapy. Therefore, there is a pressing need for novel therapies for ischemic stroke. Since stroke induces rapid cell damage and death, neuroprotective strategies that aim to salvage or replace injured brain tissue are challenged by treatment time frames. To overcome the barriers of neuroprotective therapies, there is an increasing focus on neurorestorative therapies for stroke. In this review article, we provide an update on neurorestorative treatments for stroke using cell therapy such as bone marrow derived mesenchymal stromal cells (BMSCs), human umbilical cord blood cells (HUCBCs) and select pharmacological approaches including Minocycline and Candesartan that have been employed in clinical trials. This review article discusses the present understanding of mechanisms of neurorestorative therapies and summarizes ongoing clinical trials. This article is part of the Special Issue entitled 'Cerebral Ischemia'.
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Affiliation(s)
- Poornima Venkat
- Department of Neurology, Henry Ford Hospital, Detroit, MI, 48202, USA
| | - Yi Shen
- Department of Neurology, Henry Ford Hospital, Detroit, MI, 48202, USA; Gerontology Institute, Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, 300052, China
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, MI, 48202, USA; Department of Physics, Oakland University, Rochester, MI, 48309, USA
| | - Jieli Chen
- Department of Neurology, Henry Ford Hospital, Detroit, MI, 48202, USA; Gerontology Institute, Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, 300052, China.
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32
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Yamawaki I, Taguchi Y, Komasa S, Tanaka A, Umeda M. Effects of glucose concentration on osteogenic differentiation of type II diabetes mellitus rat bone marrow-derived mesenchymal stromal cells on a nano-scale modified titanium. J Periodontal Res 2017; 52:761-771. [PMID: 28321876 DOI: 10.1111/jre.12446] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2016] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND OBJECTIVE Diabetes mellitus (DM) is a common disease worldwide. Patients with DM have an increased risk of losing their teeth compared with other individuals. Dental implants are a standard of care for treating partial or full edentulism, and various implant surface treatments have recently been developed to increase dental implant stability. However, some studies have reported that DM reduces osseointegration and the success rate of dental implants. The purpose of this study was to determine the effects of high glucose levels for hard tissue formation on a nano-scale modified titanium surface. MATERIAL AND METHODS Titanium disks were heated at 600°C for 1 h after treatment with or without 10 m NaOH solution. All disks were incubated with type II DM rat bone marrow-derived mesenchymal stromal cells before exposure to one of four concentrations of glucose (5.5, 8.0, 12.0 or 24.0 mm). The effect of different glucose concentrations on bone marrow-derived mesenchymal stromal cell osteogenesis and inflammatory cytokines on the nano-scale modified titanium surface was evaluated. RESULTS Alkaline phosphatase activity decreased with increasing glucose concentration. In contrast, osteocalcin production and calcium deposition were significantly decreased at 8.0 mm glucose, but increased with glucose concentrations over 8.0 mm. Differences in calcium/phosphate ratio associated with the various glucose concentrations were similar to osteocalcin production and calcium deposition. Inflammatory cytokines were expressed at high glucose concentrations, but the nano-scale modified titanium surface inhibited the effect of high glucose concentrations. CONCLUSION High glucose concentration increased hard tissue formation, but the quality of the mineralized tissue decreased. Furthermore, the nano-scale modified titanium surface increased mineralized tissue formation and anti-inflammation, but the quality of hard tissue was dependent on glucose concentration.
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Affiliation(s)
- I Yamawaki
- Department of Periodontology, Osaka Dental University, Osaka, Japan
| | - Y Taguchi
- Department of Periodontology, Osaka Dental University, Osaka, Japan
| | - S Komasa
- Department of Removable Prosthodontics and Occlusion, Osaka Dental University, Osaka, Japan
| | - A Tanaka
- Department of Oral Pathology, Osaka Dental University, Osaka, Japan
| | - M Umeda
- Department of Periodontology, Osaka Dental University, Osaka, Japan
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Venkat P, Chopp M, Chen J. Blood-Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke. J Am Heart Assoc 2017; 6:e005819. [PMID: 28572280 PMCID: PMC5669184 DOI: 10.1161/jaha.117.005819] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Poornima Venkat
- Department of Neurology Research, Henry Ford Hospital, Detroit, MI
| | - Michael Chopp
- Department of Neurology Research, Henry Ford Hospital, Detroit, MI
- Department of Physics, Oakland University, Rochester, MI
| | - Jieli Chen
- Department of Neurology Research, Henry Ford Hospital, Detroit, MI
- Neurological & Gerontology Institute, Neurology, Tianjin Medical University General Hospital, Tianjin, China
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Boltze J, Nitzsche F, Jolkkonen J, Weise G, Pösel C, Nitzsche B, Wagner DC. Concise Review: Increasing the Validity of Cerebrovascular Disease Models and Experimental Methods for Translational Stem Cell Research. Stem Cells 2017; 35:1141-1153. [DOI: 10.1002/stem.2595] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 02/06/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Johannes Boltze
- Department of Translational Medicine and Cell Technology; Fraunhofer Research Institution for Marine Biotechnology and Cell Technology; Lübeck Germany
- Institute for Medical and Marine Biotechnology, University of Lübeck; Lübeck Germany
| | - Franziska Nitzsche
- Department of Cell Therapy; Fraunhofer Institute for Cell Therapy and Immunology; Leipzig Germany
- Department of Radiology; McGowan Institute for Regenerative Medicine, University of Pittsburgh; Pennsylvania USA
| | - Jukka Jolkkonen
- Department of Neurology; Institute of Clinical Medicine, University of Eastern Finland; Kuopio Finland
| | - Gesa Weise
- Department of Cell Therapy; Fraunhofer Institute for Cell Therapy and Immunology; Leipzig Germany
- Department of Neurology; University of Leipzig; Germany
| | - Claudia Pösel
- Department of Cell Therapy; Fraunhofer Institute for Cell Therapy and Immunology; Leipzig Germany
| | - Björn Nitzsche
- Department of Cell Therapy; Fraunhofer Institute for Cell Therapy and Immunology; Leipzig Germany
- Department of Nuclear Medicine; University Hospital Leipzig; Germany
| | - Daniel-Christoph Wagner
- Department of Cell Therapy; Fraunhofer Institute for Cell Therapy and Immunology; Leipzig Germany
- Institute of Pathology, University Medical Center Mainz; Germany
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