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Xue B, Xu Z, Li L, Guo K, Mi J, Wu H, Li Y, Xie C, Jin J, Xu J, Jiang C, Gu X, Qin M, Jiang Q, Cao Y, Wang W. Hydrogels with programmed spatiotemporal mechanical cues for stem cell-assisted bone regeneration. Nat Commun 2025; 16:3633. [PMID: 40240370 PMCID: PMC12003706 DOI: 10.1038/s41467-025-59016-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 04/08/2025] [Indexed: 04/18/2025] Open
Abstract
Hydrogels are extensively utilized in stem cell-based tissue regeneration, providing a supportive environment that facilitates cell survival, differentiation, and integration with surrounding tissues. However, designing hydrogels for regenerating hard tissues like bone presents significant challenges. Here, we introduce macroporous hydrogels with spatiotemporally programmed mechanical properties for stem cell-driven bone regeneration. Using liquid-liquid phase separation and interfacial supramolecular self-assembly of protein fibres, the macroporous structure of hydrogels provide ample space to prevent contact inhibition during proliferation. The rigid protein fibre-coated pore shell provides sustained mechanical cues for guiding osteodifferentiation and protecting against mechanical loads. Temporally, the hydrogel exhibits tunable degradation rates that can synchronize with new tissue deposition to some extent. By integrating localized mechanical heterogeneity, macroporous structures, surface chemistry, and regenerative degradability, we demonstrate the efficacy of these stem cell-encapsulated hydrogels in rabbit and porcine models. This marks a substantial advancement in tailoring the mechanical properties of hydrogels for stem cell-assisted tissue regeneration.
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Affiliation(s)
- Bin Xue
- Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, China.
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
- Institute for Brain Sciences, Nanjing University, Nanjing, China.
| | - Zhengyu Xu
- Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, China
- Chemistry and Biomedicine Innovation Center (ChemBIC), MOE Key Laboratory of High Performance Polymer Materials and Technology, and State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Lan Li
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Jiangsu Engineering Research Center for 3D Bioprinting, Nanjing, China
| | - Kaiqiang Guo
- Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, China
| | - Jing Mi
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Haipeng Wu
- Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, China
| | - Yiran Li
- Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, China
| | - Chunmei Xie
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jing Jin
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Juan Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chunping Jiang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
| | - Xiaosong Gu
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
| | - Meng Qin
- Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, China
| | - Qing Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
- Jiangsu Engineering Research Center for 3D Bioprinting, Nanjing, China.
| | - Yi Cao
- Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, China.
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
- Institute for Brain Sciences, Nanjing University, Nanjing, China.
- Chemistry and Biomedicine Innovation Center (ChemBIC), MOE Key Laboratory of High Performance Polymer Materials and Technology, and State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
| | - Wei Wang
- Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, China.
- Institute for Brain Sciences, Nanjing University, Nanjing, China.
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Sarmah D, Datta A, Rana N, Suthar P, Gupta V, Kaur H, Ghosh B, Levoux J, Rodriguez AM, Yavagal DR, Bhattacharya P. SIRT-1/RHOT-1/PGC-1α loop modulates mitochondrial biogenesis and transfer to offer resilience following endovascular stem cell therapy in ischemic stroke. Free Radic Biol Med 2024; 225:255-274. [PMID: 39306015 DOI: 10.1016/j.freeradbiomed.2024.09.022] [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: 06/19/2024] [Revised: 09/05/2024] [Accepted: 09/14/2024] [Indexed: 10/12/2024]
Abstract
Current clinical interventions for stroke majorly involve thrombolysis or thrombectomy, however, cessation of the progressive deleterious cellular cascades post-stroke and long-term neuroprotection are yet to be explored. Mitochondria are highly vulnerable organelles and their dysfunction is one of the detrimental consequences following stroke. Mitochondria dysregulation activate unfavourable cellular events over a period of time that leads to the collapse of neuronal machinery in the brain. Hence, strategies to protect and replenish mitochondria in injured neurons may be useful and needs to be explored. Stem cell therapy in ischemic stroke holds a great promise. Past studies have shown beneficial outcomes of endovascularly delivered stem cells in both pre-clinical and clinical settings. Intra-arterial (IA) administration can provide more cells to the stroke foci and affected brain regions than intravenous administration. Supplying new mitochondria to the stroke-compromised neurons either in the core or penumbra by infused stem cells can help increase their survival and longevity. Previously, our lab has demonstrated that IA 1∗105 mesenchymal stem cells (MSCs) in rats were safe, efficacious and rendered neuroprotection by regulating neuronal calcineurin, modulating sirtuin1(SIRT-1) mediated inflammasome signaling, ameliorating endoplasmic reticulum-stress, alleviation of post-stroke edema and reducing cellular apoptosis. To explore further, our present study aims to investigate the potential of IA MSCs in protecting and replenishing mitochondria in the injured neurons post-stroke and the involvement of SIRT-1/RHOT-1/PGC-1α loop towards mitochondria transfer, biogenesis, and neuroprotection. This study will open new avenues for using stem cells for ischemic stroke in clinics as one of the future adjunctive therapies.
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Affiliation(s)
- Deepaneeta Sarmah
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Aishika Datta
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Nikita Rana
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Pramod Suthar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Vishal Gupta
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Harpreet Kaur
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Bijoyani Ghosh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India
| | - Jennyfer Levoux
- Universite' Paris-Est Cre'teil, INSERM, IMRB, 94010, Cre'teil, France
| | - Anne-Marie Rodriguez
- UMR CNRS 8256, INSERM U1164, Biological Adaptation and Ageing, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 7, Quai St Bernard (case 256), 75005, Paris, France
| | - Dileep R Yavagal
- Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India.
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Masri JE, Afyouni A, Ghazi M, Hamideh K, Moubayed I, Jurjus A, Haidar H, Petrosyan R, Salameh P, Hosseini H. Stem cell transplantation in cerebrovascular accidents: A global bibliometric analysis (2000-2023). World J Stem Cells 2024; 16:832-841. [PMID: 39351261 PMCID: PMC11438731 DOI: 10.4252/wjsc.v16.i9.832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 08/01/2024] [Accepted: 09/18/2024] [Indexed: 09/24/2024] Open
Abstract
BACKGROUND Cerebrovascular accident (CVA) is a major global contributor to death and disability. As part of its medical management, researchers have recognized the importance of promising neuroprotective strategies, where stem cell transplantation (SCT) is thought to confer advantages via trophic and neuroprotective effects. AIM To evaluate the current state of research on SCT in patients with CVA, assess key trends and highlight literature gaps. METHODS PubMed was screened for SCT in CVA-related articles in October 2023, for each country during the period between 2000 and 2023. Using the World Bank data, total population and gross domestic product were collected for comparison. VOSviewer_1.6.19 was used to create the VOS figure using the results of the same query. Graphs and tables were obtained using Microsoft Office Excel. RESULTS A total of 6923 studies were identified on SCT in CVA, making 0.03% of all published studies worldwide. Approximately, 68% were conducted in high-income countries, with a significant focus on mesenchymal stem cells. The journal "Stroke" featured the largest share of these articles, with mesenchymal SCT having the highest rate of inclusion, followed by hematopoietic SCT. Over time, there has been a noticeable shift from in vitro studies, which assess stem cell proliferation and neurogenesis, to in vivo studies aimed at evaluating efficacy and safety. Additionally, the number of reviews increased along this approach. CONCLUSION This bibliometric analysis provides a comprehensive guide for physicians and researchers in the field through an objective overview of research activity, and highlights both current trends and gaps. Having a potential therapeutic role in CVA, more research is needed in the future to focus on different aspects of SCT, aiming to reach a better treatment strategy and improve life quality in patients.
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Affiliation(s)
- Jad El Masri
- École Doctorale Sciences de la Vie et de la Santé, Université Paris-Est Créteil, Créteil 94010, France
- INSERM U955-E01, Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, Créteil 94000, France
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon
| | - Ahmad Afyouni
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon
| | - Maya Ghazi
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon
- Department of Neurology, Faculty of Medicine, Lebanese American University, Beirut 1102, Lebanon
| | - Karim Hamideh
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon
| | - Israe Moubayed
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon
| | - Abdo Jurjus
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon.
| | - Hanine Haidar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon
| | - Ruzanna Petrosyan
- Department of Pathology, Faculty of Medicine, Lebanese American University, Beirut 1102, Lebanon
| | - Pascale Salameh
- Faculty of Pharmacy, Lebanese University, Beirut 1102, Lebanon
- Faculty of Medicine, Lebanese American University, Beirut 1102, Lebanon
- Department of Primary Care and Population Health, University of Nicosia Medical School, Nicosia 2408, Cyprus
- Institut National de Santé Publique d'Épidémiologie Clinique et de Toxicologie-Liban, Beirut 1103, Lebanon
| | - Hassan Hosseini
- INSERM U955-E01, Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, Créteil 94000, France
- Department of Neurology, Henri Mondor Hospital, AP-HP, Créteil 94000, France
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Gordon J, Borlongan CV. An update on stem cell therapy for stroke patients: Where are we now? J Cereb Blood Flow Metab 2024; 44:1469-1479. [PMID: 38639015 PMCID: PMC11418600 DOI: 10.1177/0271678x241227022] [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: 07/31/2023] [Revised: 10/17/2023] [Accepted: 11/29/2023] [Indexed: 04/20/2024]
Abstract
With a foundation built upon initial work from the 1980s demonstrating graft viability in cerebral ischemia, stem cell transplantation has shown immense promise in promoting survival, enhancing neuroprotection and inducing neuroregeneration, while mitigating both histological and behavioral deficits that frequently accompany ischemic stroke. These findings have led to a number of clinical trials that have thoroughly supported a strong safety profile for stem cell therapy in patients but have generated variable efficacy. As preclinical evidence continues to expand through the investigation of new cell lines and optimization of stem cell delivery, it remains critical for translational models to adhere to the protocols established through basic scientific research. With the recent shift in approach towards utilization of stem cells as a conjunctive therapy alongside standard thrombolytic treatments, key issues including timing, route of administration, and stem cell type must each be appropriately translated from the laboratory in order to resolve the question of stem cell efficacy for cerebral ischemia that ultimately will enhance therapeutics for stroke patients towards improving quality of life.
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Affiliation(s)
- Jonah Gordon
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Cesar V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
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Chae DS, An SJ, Han S, Kim SW. Synergistic Therapeutic Potential of Dual 3D Mesenchymal Stem Cell Therapy in an Ischemic Hind Limb Mouse Model. Int J Mol Sci 2023; 24:14620. [PMID: 37834069 PMCID: PMC10572732 DOI: 10.3390/ijms241914620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/15/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
Three-dimensional (3D) culture systems have been widely used to promote the viability and metabolic activity of mesenchymal stem cells (MSCs). The aim of this study was to explore the synergistic benefits of using dual 3D MSC culture systems to promote vascular regeneration and enhance therapeutic potential. We used various experimental assays, including dual 3D cultures of human adipose MSCs (hASCs), quantitative reverse transcription polymerase chain reaction (qRT-PCR), in vitro cell migration, Matrigel tube network formation, Matrigel plug assay, therapeutic assays using an ischemic hind limb mouse model, and immunohistochemical analysis. Our qRT-PCR results revealed that fibroblast growth factor 2 (FGF-2), granulocyte chemotactic protein-2 (GCP-2), and vascular endothelial growth factor-A (VEGF-A) were highly upregulated in conventional 3D-cultured hASCs (ASC-3D) than in two-dimensional (2D)-cultured hASCs. Hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), and stromal-cell-derived factor-1 (SDF-1) showed higher expression levels in cytokine-cocktail-based, 3D-cultured hASCs (ASC-3Dc). A conditioned medium (CM) mixture of dual 3D ASCs (D-3D; ASC-3D + ASC-3Dc) resulted in higher migration and Matrigel tube formation than the CM of single 3D ASCs (S-3D; ASC-3D). Matrigel plugs containing D-3D contained more red blood cells than those containing S-3D. D-3D transplantation into ischemic mouse hind limbs prevented limb loss and augmented blood perfusion when compared to S-3D transplantation. Transplanted D-3D also revealed a high capillary density and angiogenic cytokine levels and transdifferentiated into endothelial-like cells in the hind limb muscle. These findings highlight the benefits of using the dual 3D culture system to optimize stem-cell-based therapeutic strategies, thereby advancing the therapeutic strategy for ischemic vascular disease and tissue regeneration.
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Affiliation(s)
- Dong-Sik Chae
- Department of Orthopedic Surgery, College of Medicine, Catholic Kwandong University, International St. Mary’s Hospital, Incheon 22711, Republic of Korea
| | - Sang Joon An
- Department of Neurology, College of Medicine, Catholic Kwandong University, International St. Mary’s Hospital, Incheon 22711, Republic of Korea
| | - Seongho Han
- Department of Family Medicine, College of Medicine, Dong-A University, Busan 49236, Republic of Korea
| | - Sung-Whan Kim
- Department Medicine, College of Medicine, Catholic Kwandong University, Gangneung 25601, Republic of Korea
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Voloshin N, Tyurin-Kuzmin P, Karagyaur M, Akopyan Z, Kulebyakin K. Practical Use of Immortalized Cells in Medicine: Current Advances and Future Perspectives. Int J Mol Sci 2023; 24:12716. [PMID: 37628897 PMCID: PMC10454025 DOI: 10.3390/ijms241612716] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/23/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
In modern science, immortalized cells are not only a convenient tool in fundamental research, but they are also increasingly used in practical medicine. This happens due to their advantages compared to the primary cells, such as the possibility to produce larger amounts of cells and to use them for longer periods of time, the convenience of genetic modification, the absence of donor-to-donor variability when comparing the results of different experiments, etc. On the other hand, immortalization comes with drawbacks: possibilities of malignant transformation and/or major phenotype change due to genetic modification itself or upon long-term cultivation appear. At first glance, such issues are huge hurdles in the way of immortalized cells translation into medicine. However, there are certain ways to overcome such barriers that we describe in this review. We determined four major areas of usage of immortalized cells for practical medicinal purposes, and each has its own means to negate the drawbacks associated with immortalization. Moreover, here we describe specific fields of application of immortalized cells in which these problems are of much lesser concern, for example, in some cases where the possibility of malignant growth is not there at all. In general, we can conclude that immortalized cells have their niches in certain areas of practical medicine where they can successfully compete with other therapeutic approaches, and more preclinical and clinical trials with them should be expected.
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Affiliation(s)
- Nikita Voloshin
- Faculty of Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia; (N.V.); (P.T.-K.); (M.K.)
| | - Pyotr Tyurin-Kuzmin
- Faculty of Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia; (N.V.); (P.T.-K.); (M.K.)
| | - Maxim Karagyaur
- Faculty of Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia; (N.V.); (P.T.-K.); (M.K.)
| | - Zhanna Akopyan
- Medical Research and Education Center, Lomonosov Moscow State University, 119234 Moscow, Russia;
| | - Konstantin Kulebyakin
- Faculty of Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia; (N.V.); (P.T.-K.); (M.K.)
- Medical Research and Education Center, Lomonosov Moscow State University, 119234 Moscow, Russia;
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Yonesi M, Ramos M, Ramirez-Castillejo C, Fernández-Serra R, Panetsos F, Belarra A, Chevalier M, Rojo FJ, Pérez-Rigueiro J, Guinea GV, González-Nieto D. Resistance to Degradation of Silk Fibroin Hydrogels Exposed to Neuroinflammatory Environments. Polymers (Basel) 2023; 15:polym15112491. [PMID: 37299290 DOI: 10.3390/polym15112491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/18/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Central nervous system (CNS) diseases represent an extreme burden with significant social and economic costs. A common link in most brain pathologies is the appearance of inflammatory components that can jeopardize the stability of the implanted biomaterials and the effectiveness of therapies. Different silk fibroin scaffolds have been used in applications related to CNS disorders. Although some studies have analyzed the degradability of silk fibroin in non-cerebral tissues (almost exclusively upon non-inflammatory conditions), the stability of silk hydrogel scaffolds in the inflammatory nervous system has not been studied in depth. In this study, the stability of silk fibroin hydrogels exposed to different neuroinflammatory contexts has been explored using an in vitro microglial cell culture and two in vivo pathological models of cerebral stroke and Alzheimer's disease. This biomaterial was relatively stable and did not show signs of extensive degradation across time after implantation and during two weeks of in vivo analysis. This finding contrasted with the rapid degradation observed under the same in vivo conditions for other natural materials such as collagen. Our results support the suitability of silk fibroin hydrogels for intracerebral applications and highlight the potentiality of this vehicle for the release of molecules and cells for acute and chronic treatments in cerebral pathologies.
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Affiliation(s)
- Mahdi Yonesi
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain
| | - Milagros Ramos
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain
- Departamento de Tecnología Fotónica y Bioingeniería, ETSI Telecomunicaciones, Universidad Politécnica de Madrid, 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Carmen Ramirez-Castillejo
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain
| | - Rocío Fernández-Serra
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain
- Departamento de Tecnología Fotónica y Bioingeniería, ETSI Telecomunicaciones, Universidad Politécnica de Madrid, 28040 Madrid, Spain
- Departamento de Ciencia de Materiales, ETSI Caminos, Canales y Puertos, Universidad Politécnica de Madrid, 28040 Madrid, Spain
- Silk Biomed SL, Calle Navacerrada 18, Urb. Puerto Galapagar, 28260 Madrid, Spain
| | - Fivos Panetsos
- Silk Biomed SL, Calle Navacerrada 18, Urb. Puerto Galapagar, 28260 Madrid, Spain
- Bioactive Surfaces SL, Puerto de Navacerrada 18. Galapagar, 28260 Madrid, Spain
- Neurocomputing and Neurorobotics Research Group, Faculty of Biology and Faculty of Optics, Universidad Complutense de Madrid, 28040 Madrid, Spain
- Biomaterials and Regenerative Medicine Group, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Calle Prof. Martín Lagos s/n, 28040 Madrid, Spain
| | - Adrián Belarra
- Laboratorio Micro-CT UCM, Departamento de Radiología, Rehabilitación y Fisioterapia, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Margarita Chevalier
- Laboratorio Micro-CT UCM, Departamento de Radiología, Rehabilitación y Fisioterapia, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Francisco J Rojo
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain
- Departamento de Ciencia de Materiales, ETSI Caminos, Canales y Puertos, Universidad Politécnica de Madrid, 28040 Madrid, Spain
- Silk Biomed SL, Calle Navacerrada 18, Urb. Puerto Galapagar, 28260 Madrid, Spain
- Bioactive Surfaces SL, Puerto de Navacerrada 18. Galapagar, 28260 Madrid, Spain
- Biomaterials and Regenerative Medicine Group, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Calle Prof. Martín Lagos s/n, 28040 Madrid, Spain
| | - José Pérez-Rigueiro
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Departamento de Ciencia de Materiales, ETSI Caminos, Canales y Puertos, Universidad Politécnica de Madrid, 28040 Madrid, Spain
- Silk Biomed SL, Calle Navacerrada 18, Urb. Puerto Galapagar, 28260 Madrid, Spain
- Bioactive Surfaces SL, Puerto de Navacerrada 18. Galapagar, 28260 Madrid, Spain
- Biomaterials and Regenerative Medicine Group, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Calle Prof. Martín Lagos s/n, 28040 Madrid, Spain
| | - Gustavo V Guinea
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Departamento de Ciencia de Materiales, ETSI Caminos, Canales y Puertos, Universidad Politécnica de Madrid, 28040 Madrid, Spain
- Silk Biomed SL, Calle Navacerrada 18, Urb. Puerto Galapagar, 28260 Madrid, Spain
- Bioactive Surfaces SL, Puerto de Navacerrada 18. Galapagar, 28260 Madrid, Spain
- Biomaterials and Regenerative Medicine Group, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Calle Prof. Martín Lagos s/n, 28040 Madrid, Spain
| | - Daniel González-Nieto
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain
- Departamento de Tecnología Fotónica y Bioingeniería, ETSI Telecomunicaciones, Universidad Politécnica de Madrid, 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Silk Biomed SL, Calle Navacerrada 18, Urb. Puerto Galapagar, 28260 Madrid, Spain
- Bioactive Surfaces SL, Puerto de Navacerrada 18. Galapagar, 28260 Madrid, Spain
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Yang W, Wang H, Guo Q, Xu X, Guo T, Sun L. Roles of TRPV4 in Regulating Circulating Angiogenic Cells to Promote Coronary Microvascular Regeneration. J Cardiovasc Transl Res 2022; 16:414-426. [PMID: 36103035 DOI: 10.1007/s12265-022-10305-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/17/2022] [Indexed: 11/24/2022]
Abstract
To clarify the mechanisms underlying TRPV4 regulating angiogenesis by enhancing the activity of CACs, we detected the angiogenesis ability of HUVEC co-cultured with CACs, the effects of ILK on TRPV4 expression and CACs activity, and the impacts of TRPV4 agonist or inhibitor on cardio-protection of AMI rats with or without CAC transplantation. ILK overexpression or TRPV4 agonist promoted the angiogenesis in HUVEC co-cultured with CACs. ILK overexpression or activation upregulated TRPV4 expression in CACs, while TRPV4 agonist stimulation also regulated ILK expression. TRPV4 agonist effectively improved the myocardial function of AMI rats. Moreover, this effect could be strengthened when combined with CAC transplantation, as CAC transplantation dramatically upregulated the expression of ILK and TRPV4 in heart tissues of AMI rats. Thus, the application of TRPV4 agonist may maintain the activity of CACs to promote angiogenesis and microcirculation reconstruction in the area of myocardial infarction and substantially improve the therapeutic effect.
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Affiliation(s)
- Wenhui Yang
- Department of Cardiology, Fuwai Yunnan Cardiovascular Hospital, Kunming, China
| | - Haizhen Wang
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, 650201, China
| | - Qiuzhe Guo
- Department of Cardiology, Fuwai Yunnan Cardiovascular Hospital, Kunming, China
| | - Xiaocui Xu
- Kunming Medical University, Kunming, China
| | - Tao Guo
- Department of Cardiology, Fuwai Yunnan Cardiovascular Hospital, Kunming, China.
| | - Lin Sun
- Department of Cardiology, Fuwai Yunnan Cardiovascular Hospital, Kunming, China.
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9
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Genet N, Hirschi KK. Understanding neural stem cell regulation in vivo and applying the insights to cell therapy for strokes. Regen Med 2021; 16:861-870. [PMID: 34498495 PMCID: PMC8656322 DOI: 10.2217/rme-2021-0022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The use of neural stem cell (NSC) therapy for the treatment of stroke patients is successfully paving its way into advanced phases of large-scale clinical trials. To understand how to optimize NSC therapeutic approaches, it is fundamental to decipher the crosstalk between NSC and other cells that comprise the NSC microenvironment (niche) and regulate their function, in vivo; namely, the endothelial cells of the microvasculature. In this mini review, we first provide a concise summary of preclinical findings describing the signaling mechanisms between NSC and vascular endothelial cells and vice versa. Second, we describe the progress made in the development of NSC therapy for the treatment of strokes.
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Affiliation(s)
- Nafiisha Genet
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.,Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Karen K Hirschi
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.,Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.,Department of Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
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10
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Yonesi M, Garcia-Nieto M, Guinea GV, Panetsos F, Pérez-Rigueiro J, González-Nieto D. Silk Fibroin: An Ancient Material for Repairing the Injured Nervous System. Pharmaceutics 2021; 13:429. [PMID: 33806846 PMCID: PMC8004633 DOI: 10.3390/pharmaceutics13030429] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 12/25/2022] Open
Abstract
Silk refers to a family of natural fibers spun by several species of invertebrates such as spiders and silkworms. In particular, silkworm silk, the silk spun by Bombyx mori larvae, has been primarily used in the textile industry and in clinical settings as a main component of sutures for tissue repairing and wound ligation. The biocompatibility, remarkable mechanical performance, controllable degradation, and the possibility of producing silk-based materials in several formats, have laid the basic principles that have triggered and extended the use of this material in regenerative medicine. The field of neural soft tissue engineering is not an exception, as it has taken advantage of the properties of silk to promote neuronal growth and nerve guidance. In addition, silk has notable intrinsic properties and the by-products derived from its degradation show anti-inflammatory and antioxidant properties. Finally, this material can be employed for the controlled release of factors and drugs, as well as for the encapsulation and implantation of exogenous stem and progenitor cells with therapeutic capacity. In this article, we review the state of the art on manufacturing methodologies and properties of fiber-based and non-fiber-based formats, as well as the application of silk-based biomaterials to neuroprotect and regenerate the damaged nervous system. We review previous studies that strategically have used silk to enhance therapeutics dealing with highly prevalent central and peripheral disorders such as stroke, Alzheimer's disease, Parkinson's disease, and peripheral trauma. Finally, we discuss previous research focused on the modification of this biomaterial, through biofunctionalization techniques and/or the creation of novel composite formulations, that aim to transform silk, beyond its natural performance, into more efficient silk-based-polymers towards the clinical arena of neuroprotection and regeneration in nervous system diseases.
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Affiliation(s)
- Mahdi Yonesi
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain; (M.Y.); (G.V.G.)
- Silk Biomed SL, 28260 Madrid, Spain;
| | | | - Gustavo V. Guinea
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain; (M.Y.); (G.V.G.)
- Silk Biomed SL, 28260 Madrid, Spain;
- Departamento de Ciencia de Materiales, ETSI Caminos, Canales y Puertos, Universidad Politécnica de Madrid, 28040 Madrid, Spain
- Biomedical Research Networking Center in Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
| | - Fivos Panetsos
- Silk Biomed SL, 28260 Madrid, Spain;
- Neurocomputing and Neurorobotics Research Group, Faculty of Biology and Faculty of Optics, Universidad Complutense de Madrid, 28040 Madrid, Spain
- Innovation Group, Institute for Health Research San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain
| | - José Pérez-Rigueiro
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain; (M.Y.); (G.V.G.)
- Silk Biomed SL, 28260 Madrid, Spain;
- Departamento de Ciencia de Materiales, ETSI Caminos, Canales y Puertos, Universidad Politécnica de Madrid, 28040 Madrid, Spain
- Biomedical Research Networking Center in Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
| | - Daniel González-Nieto
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Spain; (M.Y.); (G.V.G.)
- Silk Biomed SL, 28260 Madrid, Spain;
- Biomedical Research Networking Center in Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
- Departamento de Tecnología Fotónica y Bioingeniería, ETSI Telecomunicaciones, Universidad Politécnica de Madrid, 28040 Madrid, Spain
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11
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Saft M, Gonzales-Portillo B, Park YJ, Cozene B, Sadanandan N, Cho J, Garbuzova-Davis S, Borlongan CV. Stem Cell Repair of the Microvascular Damage in Stroke. Cells 2020; 9:cells9092075. [PMID: 32932814 PMCID: PMC7563611 DOI: 10.3390/cells9092075] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 08/20/2020] [Accepted: 09/04/2020] [Indexed: 02/07/2023] Open
Abstract
Stroke is a life-threatening disease that leads to mortality, with survivors subjected to long-term disability. Microvascular damage is implicated as a key pathological feature, as well as a therapeutic target for stroke. In this review, we present evidence detailing subacute diaschisis in a focal ischemic stroke rat model with a focus on blood–brain barrier (BBB) integrity and related pathogenic processes in contralateral brain areas. Additionally, we discuss BBB competence in chronic diaschisis in a similar rat stroke model, highlighting the pathological changes in contralateral brain areas that indicate progressive morphological brain disturbances overtime after stroke onset. With diaschisis closely approximating stroke onset and progression, it stands as a treatment of interest for stroke. Indeed, the use of stem cell transplantation for the repair of microvascular damage has been investigated, demonstrating that bone marrow stem cells intravenously transplanted into rats 48 h post-stroke survive and integrate into the microvasculature. Ultrastructural analysis of transplanted stroke brains reveals that microvessels display a near-normal morphology of endothelial cells and their mitochondria. Cell-based therapeutics represent a new mechanism in BBB and microvascular repair for stroke.
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Affiliation(s)
| | | | - You Jeong Park
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA; (Y.J.P.); (J.C.); (S.G.-D.)
| | | | | | - Justin Cho
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA; (Y.J.P.); (J.C.); (S.G.-D.)
| | - Svitlana Garbuzova-Davis
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA; (Y.J.P.); (J.C.); (S.G.-D.)
| | - Cesar V. Borlongan
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA; (Y.J.P.); (J.C.); (S.G.-D.)
- Correspondence: ; Tel.: +813-974-3988
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12
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Egawa N, Suzuki H, Takahashi R, Hayakawa K, Li W, Lo EH, Arai K, Inoue H. From in vitro to in vivo reprogramming for neural transdifferentiation: An approach for CNS tissue remodeling using stem cell technology. J Cereb Blood Flow Metab 2020; 40:1739-1751. [PMID: 32423328 PMCID: PMC7446571 DOI: 10.1177/0271678x20910324] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Advances in stem cell technology have provided three approaches to address the demanding issue of the treatment of intractable neurological disease. One of the approaches is the screening of compounds attenuating pathological phenotypes in stem-cell based models. A second approach consists of exogenous-targeted cell supplementation to the lesion with stem cell-derived differentiated cells. A third approach involves in vivo direct programming to transdifferentiate endogenous somatic cells and to boost CNS tissue remodeling. In this review, we outline research advances in stem cell technology of direct reprogramming in vitro and in vivo and discuss the future challenge of tissue remodeling by neural transdifferentiation.
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Affiliation(s)
- Naohiro Egawa
- Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan.,Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Hidefumi Suzuki
- Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan.,Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Ryosuke Takahashi
- Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kazuhide Hayakawa
- Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Wenlu Li
- Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Eng H Lo
- Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ken Arai
- Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Haruhisa Inoue
- iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan.,Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.,Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan
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13
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Mitochondrial Transfer as a Therapeutic Strategy Against Ischemic Stroke. Transl Stroke Res 2020; 11:1214-1228. [PMID: 32592024 DOI: 10.1007/s12975-020-00828-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 06/08/2020] [Accepted: 06/09/2020] [Indexed: 12/21/2022]
Abstract
Stroke is a debilitating disease that remains the second leading cause of death and disability worldwide. Despite accumulating knowledge of the disease pathology, treatments for stroke are limited, and clinical translation of the neuroprotective agents has not been a complete success. Accumulating evidence links mitochondrial dysfunction to brain impairments after stroke. Recent studies have implicated the important roles of healthy mitochondria in neuroprotection and neural recovery following ischemic stroke. New and convincing studies have shown that mitochondrial transfer to the damaged cells can help revive cells energetic in the recipient cells. Hence, mitochondrial transplantation has shown to replace impaired or dysfunctional mitochondria with exogenous healthy mitochondria after ischemic stroke. We highlight the potential of mitochondrial transfer by stem cells as a therapeutic strategy for the treatment of ischemic stroke. This review captures the recent advances in the mitochondrial transfer as a novel and promising treatment for ischemic stroke.
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14
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Nucci MP, Filgueiras IS, Ferreira JM, de Oliveira FA, Nucci LP, Mamani JB, Rego GNA, Gamarra LF. Stem cell homing, tracking and therapeutic efficiency evaluation for stroke treatment using nanoparticles: A systematic review. World J Stem Cells 2020; 12:381-405. [PMID: 32547686 PMCID: PMC7280869 DOI: 10.4252/wjsc.v12.i5.381] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 04/02/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Stroke is the second leading cause of death worldwide. There is a real need to develop treatment strategies for reducing neurological deficits in stroke survivors, and stem cell (SC) therapeutics appear to be a promising alternative for stroke therapy that can be used in combination with approved thrombolytic or thrombectomy approaches. However, the efficacy of SC therapy depends on the SC homing ability and engraftment into the injury site over a long period of time. Nonetheless, tracking SCs from their niche to the target tissues is a complex process.
AIM To evaluate SC migration homing, tracking and therapeutic efficacy in the treatment of stroke using nanoparticles
METHODS A systematic literature search was performed to identify articles published prior to November 2019 that were indexed in PubMed and Scopus. The following inclusion criteria were used: (1) Studies that used in vivo models of stroke or ischemic brain lesions; (2) Studies of SCs labeled with some type of contrast agent for cell migration detection; and (3) Studies that involved in vivo cellular homing and tracking analysis.
RESULTS A total of 82 articles were identified by indexing in Scopus and PubMed. After the inclusion criteria were applied, 35 studies were selected, and the articles were assessed for eligibility; ultimately, only 25 studies were included. Most of the selected studies used SCs from human and mouse bone marrow labeled with magnetic nanoparticles alone or combined with fluorophore dyes. These cells were administered in the stroke model (to treat middle cerebral artery occlusion in 74% of studies and for photothrombotic induction in 26% of studies). Fifty-three percent of studies used xenogeneic grafts for cell therapy, and the migration homing and tracking evaluation was performed by magnetic resonance imaging as well as other techniques, such as near-infrared fluorescence imaging (12%) or bioluminescence assays (12%).
CONCLUSION Our systematic review provided an up-to-date evaluation of SC migration homing and the efficacy of cellular therapy for stroke treatment in terms of functional and structural improvements in the late stage.
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Affiliation(s)
- Mariana Penteado Nucci
- LIM44, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 05529-060, Brazil
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15
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Brown J, Park YJ, Lee JY, Chase TN, Koga M, Borlongan CV. Bone Marrow-Derived NCS-01 Cells Advance a Novel Cell-Based Therapy for Stroke. Int J Mol Sci 2020; 21:ijms21082845. [PMID: 32325813 PMCID: PMC7215343 DOI: 10.3390/ijms21082845] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/15/2020] [Accepted: 04/18/2020] [Indexed: 12/14/2022] Open
Abstract
Human mesenchymal stem cells have been explored for their application in cell-based therapies targeting stroke. Identifying cell lines that stand as safe, accessible, and effective for transplantation, while optimizing dosage, timing, and method of delivery remain critical translational steps towards clinical trials. Preclinical studies using bone marrow-derived NCS-01 cells show the cells' ability to confer functional recovery in ischemic stroke. Coculturing primary rat cortical cells or human neural progenitor cells with NCS-01 cells protects against oxygen-glucose deprivation. In the rodent middle cerebral artery occlusion model, intracarotid artery administration of NCS-01 cells demonstrate greater efficacy than other mesenchymal stem cells (MSCs) at improving motor and neurological function, as well as reducing infarct volume and peri-infarct cell loss. NCS-01 cells secrete therapeutic factors, including basic fibroblast growth factor and interleukin-6, while also demonstrating a potentially novel mechanism of extending filopodia towards the site of injury. In this review, we discuss recent preclinical advancements using in vitro and in vivo ischemia models that support the transplantation of NCS-01 in human stroke trials. These results, coupled with the recommendations put forth by the consortium of Stem cell Therapeutics as an Emerging Paradigm for Stroke (STEPS), highlight a framework for conducting preclinical research with the ultimate goal of initiating clinical trials.
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Affiliation(s)
- John Brown
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL 33612, USA; (J.B.); (Y.J.P.); (J.-Y.L.)
| | - You Jeong Park
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL 33612, USA; (J.B.); (Y.J.P.); (J.-Y.L.)
| | - Jea-Young Lee
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL 33612, USA; (J.B.); (Y.J.P.); (J.-Y.L.)
| | - Thomas N. Chase
- KM Pharmaceutical Consulting LLC, Washington, DC 20006, USA; (T.N.C.); (M.K.)
| | - Minako Koga
- KM Pharmaceutical Consulting LLC, Washington, DC 20006, USA; (T.N.C.); (M.K.)
| | - Cesar V. Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL 33612, USA; (J.B.); (Y.J.P.); (J.-Y.L.)
- Correspondence: ; Tel.: +1-813-974-3988
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16
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He Z, Ning N, Zhou Q, Khoshnam SE, Farzaneh M. Mitochondria as a therapeutic target for ischemic stroke. Free Radic Biol Med 2020; 146:45-58. [PMID: 31704373 DOI: 10.1016/j.freeradbiomed.2019.11.005] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 10/07/2019] [Accepted: 11/03/2019] [Indexed: 12/24/2022]
Abstract
Stroke is the leading cause of death and physical disability worldwide. Mitochondrial dysfunction has been considered as one of the hallmarks of ischemic stroke and contributes to the pathology of ischemia and reperfusion. Mitochondria is essential in promoting neural survival and neurological improvement following ischemic stroke. Therefore, mitochondria represent an important drug target for stroke treatment. This review discusses the mitochondrial molecular mechanisms underlying cerebral ischemia and involved in reactive oxygen species generation, mitochondrial electron transport dysfunction, mitochondria-mediated regulation of inflammasome activation, mitochondrial dynamics and biogenesis, and apoptotic cell death. We highlight the potential of mitochondrial transfer by stem cells as a therapeutic target for stroke treatment and provide valuable insights for clinical strategies. A better understanding of the roles of mitochondria in ischemia-induced cell death and protection may provide a rationale design of novel therapeutic interventions in the ischemic stroke.
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Affiliation(s)
- Zhi He
- Department of Pharmacy, Luohe Medical College, Luohe, 462000, China
| | - Niya Ning
- Department of Obstetrics and Gynecology, Shaoling District People's Hospital of Luohe City, Luohe, 462300, China
| | - Qiongxiu Zhou
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, 610052, China.
| | - Seyed Esmaeil Khoshnam
- Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Maryam Farzaneh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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17
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Hassanshahi M, Khabbazi S, Peymanfar Y, Hassanshahi A, Hosseini-Khah Z, Su YW, Xian CJ. Critical limb ischemia: Current and novel therapeutic strategies. J Cell Physiol 2019; 234:14445-14459. [PMID: 30637723 DOI: 10.1002/jcp.28141] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 01/02/2019] [Indexed: 01/24/2023]
Abstract
Critical limb ischemia (CLI) is the advanced stage of peripheral artery disease spectrum and is defined by limb pain or impending limb loss because of compromised blood flow to the affected extremity. Current conventional therapies for CLI include amputation, bypass surgery, endovascular therapy, and pharmacological approaches. Although these conventional therapeutic strategies still remain as the mainstay of treatments for CLI, novel and promising therapeutic approaches such as proangiogenic gene/protein therapies and stem cell-based therapies have emerged to overcome, at least partially, the limitations and disadvantages of current conventional therapeutic approaches. Such novel CLI treatment options may become even more effective when other complementary approaches such as utilizing proper bioscaffolds are used to increase the survival and engraftment of delivered genes and stem cells. Therefore, herein, we address the benefits and disadvantages of current therapeutic strategies for CLI treatment and summarize the novel and promising therapeutic approaches for CLI treatment. Our analyses also suggest that these novel CLI therapeutic strategies show considerable advantages to be used when current conventional methods have failed for CLI treatment.
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Affiliation(s)
- Mohammadhossein Hassanshahi
- School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia
| | - Samira Khabbazi
- School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia
| | - Yaser Peymanfar
- School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia
| | - Alireza Hassanshahi
- Department of Genetics, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Zahra Hosseini-Khah
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Yu-Wen Su
- School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia
| | - Cory J Xian
- School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia
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18
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MacPherson A, Kimmelman J. Ethical development of stem-cell-based interventions. Nat Med 2019; 25:1037-1044. [PMID: 31270501 DOI: 10.1038/s41591-019-0511-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 06/04/2019] [Indexed: 02/07/2023]
Abstract
The process of developing new and complex stem-cell-based therapeutics is incremental and requires decades of sustained collaboration among different stakeholders. In this Perspective, we address key ethical and policy challenges confronting the clinical translation of stem-cell-based interventions (SCBIs), including premature diffusion of SCBIs to clinical practice, assessment of risk in trials, obtaining valid informed consent for research participants, balanced and complete scientific reporting and public communications, regulation, and equitable access to treatment. We propose a way forward for translating these therapies with the above challenges in mind.
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Affiliation(s)
- Amanda MacPherson
- Biomedical Ethics Unit, STREAM Research Group, McGill University, Montreal, Canada
| | - Jonathan Kimmelman
- Biomedical Ethics Unit, STREAM Research Group, McGill University, Montreal, Canada.
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19
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Krause M, Phan TG, Ma H, Sobey CG, Lim R. Cell-Based Therapies for Stroke: Are We There Yet? Front Neurol 2019; 10:656. [PMID: 31293500 PMCID: PMC6603096 DOI: 10.3389/fneur.2019.00656] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 06/04/2019] [Indexed: 12/15/2022] Open
Abstract
Stroke is the second leading cause of death and physical disability, with a global lifetime incidence rate of 1 in 6. Currently, the only FDA approved treatment for ischemic stroke is the administration of tissue plasminogen activator (tPA). Stem cell clinical trials for stroke have been underway for close to two decades, with data suggesting that cell therapies are safe, feasible, and potentially efficacious. However, clinical trials for stroke account for <1% of all stem cell trials. Nevertheless, the resources devoted to clinical research to identify new treatments for stroke is still significant (53–64 million US$, Phase 1–4). Notably, a quarter of cell therapy clinical trials for stroke have been withdrawn (15.2%) or terminated (6.8%) to date. This review discusses the bottlenecks in delivering a successful cell therapy for stroke, and the cost-to-benefit ratio necessary to justify these expensive trials. Further, this review will critically assess the currently available data from completed stroke trials, the importance of standardization in outcome reporting, and the role of industry-led research in the development of cell therapies for stroke.
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Affiliation(s)
- Mirja Krause
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.,Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Thanh G Phan
- Department of Medicine, Monash University, Melbourne, VIC, Australia
| | - Henry Ma
- Department of Medicine, Monash University, Melbourne, VIC, Australia
| | - Christopher G Sobey
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC, Australia
| | - Rebecca Lim
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.,Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia.,Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
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20
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Borlongan CV. Concise Review: Stem Cell Therapy for Stroke Patients: Are We There Yet? Stem Cells Transl Med 2019; 8:983-988. [PMID: 31099181 PMCID: PMC6708064 DOI: 10.1002/sctm.19-0076] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 05/03/2019] [Indexed: 12/14/2022] Open
Abstract
Four decades of preclinical research demonstrating survival, functional integration, and behavioral effects of transplanted stem cells in experimental stroke models have provided ample scientific basis for initiating limited clinical trials of stem cell therapy in stroke patients. Although safety of the grafted cells has been overwhelmingly documented, efficacy has not been forthcoming. Two recently concluded stroke clinical trials on mesenchymal stem cells (MSCs) highlight the importance of strict adherence to the basic science findings of optimal transplant regimen of cell dose, timing, and route of delivery in enhancing the functional outcomes of cell therapy. Echoing the Stem Cell Therapeutics as an Emerging Paradigm for Stroke and Stroke Treatment Academic Industry Roundtable call for an NIH‐guided collaborative consortium of multiple laboratories in testing the safety and efficacy of stem cells and their derivatives, not just as stand‐alone but preferably in combination with approved thrombolytic or thrombectomy, may further increase the likelihood of successful fruition of translating stem cell therapy for stroke clinical application. The laboratory and clinical experience with MSC therapy for stroke may guide the future translational research on stem cell‐based regenerative medicine in neurological disorders. stem cells translational medicine2019;8:983&988
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Affiliation(s)
- Cesario V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida, USA
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21
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Boncoraglio GB, Ranieri M, Bersano A, Parati EA, Del Giovane C, Cochrane Stroke Group. Stem cell transplantation for ischemic stroke. Cochrane Database Syst Rev 2019; 5:CD007231. [PMID: 31055832 PMCID: PMC6500737 DOI: 10.1002/14651858.cd007231.pub3] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Stroke is a leading cause of morbidity and mortality worldwide, with very large healthcare and social costs, and a strong demand for alternative therapeutic approaches. Preclinical studies have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in people with ischemic stroke is lacking. This is the first update of the Cochrane review published in 2010. OBJECTIVES To assess the efficacy and safety of stem cell transplantation compared with control in people with ischemic stroke. SEARCH METHODS We searched the Cochrane Stroke Group Trials Register (last searched August 2018), CENTRAL (last searched August 2018), MEDLINE (1966 to August 2018), Embase (1980 to August 2018), and BIOSIS (1926 to August 2018). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched August 2018). We also contacted individuals active in the field and stem cell manufacturers (last contacted August 2018). SELECTION CRITERIA We included randomized controlled trials (RCTs) that recruited people with ischemic stroke, in any phase of the disease (acute, subacute or chronic), and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation, regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as neurologic impairment or functional outcome) at longer term follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections, and neoplastic transformation). DATA COLLECTION AND ANALYSIS Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data. If needed, we contacted study authors for additional information. We performed random effects meta-analyses when two or more RCTs were available for any outcome. We assessed the certainty of the evidence by using the GRADE approach. MAIN RESULTS In this updated review, we included seven completed RCTs with 401 participants. All tested adult human non-neural stem cells; cells were transplanted during the acute, subacute, or chronic phase of ischemic stroke; administered intravenously, intra-arterially, intracerebrally, or into the lumbar subarachnoid space. Follow-up ranged from six months to seven years. Efficacy outcomes were measured with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), or Barthel Index (BI). Safety outcomes included case fatality, and were measured at the end of the trial.Overall, stem cell transplantation was associated with a better clinical outcome when measured with the NIHSS (mean difference [MD] -1.49, 95% confidence interval [CI] -2.65 to -0.33; five studies, 319 participants; low-certainty evidence), but not with the mRS (MD -0.42, 95% CI -0.86 to 0.02; six studies, 371 participants; very low-certainty evidence), or the BI (MD 14.09, 95% CI -1.94 to 30.13; three studies, 170 participants; very low-certainty evidence). The studies in favor of stem cell transplantation had, on average, a higher risk of bias, and a sample size of 32 or fewer participants.No significant safety concerns associated with stem cell transplantation were raised with respect to death (risk ratio [RR] 0.66, 95% CI 0.39 to 1.14; six studies, participants; low-certainty evidence).We were not able to perform the sensitivity analysis according to the quality of studies, because all of them were at high risk of bias. AUTHORS' CONCLUSIONS Overall, in participants with ischemic stroke, stem cell transplantation was associated with a reduced neurological impairment, but not with a better functional outcome. No obvious safety concerns were raised. However, these conclusions came mostly from small RCTs with high risk of bias, and the certainty of the evidence ranged from low to very low. More well-designed trials are needed.
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Affiliation(s)
- Giorgio Battista Boncoraglio
- Fondazione IRCCS Istituto Neurologico "Carlo Besta"Department of NeurologyVia Celoria 11MilanoItaly20133
- Università di Milano – BicoccaPhD Program in NeuroscienceMonzaItaly
| | - Michela Ranieri
- Fondazione IRCCS Istituto Neurologico "Carlo Besta"Department of NeurologyVia Celoria 11MilanoItaly20133
| | - Anna Bersano
- Fondazione IRCCS Istituto Neurologico "Carlo Besta"Department of NeurologyVia Celoria 11MilanoItaly20133
| | - Eugenio A Parati
- Fondazione IRCCS Istituto Neurologico "Carlo Besta"Department of NeurologyVia Celoria 11MilanoItaly20133
| | - Cinzia Del Giovane
- University of BernInstitute of Primary Health Care (BIHAM)Gesellschaftsstrasse 49BernSwitzerland3012
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Intraparenchymal Neural Stem/Progenitor Cell Transplantation for Ischemic Stroke Animals: A Meta-Analysis and Systematic Review. Stem Cells Int 2018; 2018:4826407. [PMID: 30369951 PMCID: PMC6189667 DOI: 10.1155/2018/4826407] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 07/25/2018] [Indexed: 02/07/2023] Open
Abstract
Intraparenchymal transplantation of neural stem/progenitor cells (NSPCs) has been extensively investigated in animal models of ischemic stroke. However, the reported therapeutic efficacy was inconsistent among studies. To evaluate this situation, PubMed, Embase, and Web of Science databases were searched for preclinical studies using NSPC intraparenchymal transplantation in ischemic stroke animals. Data of study quality score, neurobehavioral (mNSS, rotarod test, and cylinder test) and histological (infarct volume) outcomes, cell therapy-related serious adverse events, and related cellular mechanisms were extracted for meta-analysis and systematic review. A total of 62 studies containing 73 treatment arms were included according to our criterion, with a mean quality score of 5.10 in 10. Among these studies, almost half of the studies claimed no adverse events of tumorigenesis. The finally pooled effect sizes for neurobehavioral and histological assessments were large (1.27 for mNSS, 1.63 for the rotarod test, 0.71 for the cylinder test, and 1.11 for infarct volume reduction). With further analysis, it was found that the administration time poststroke, NSPC donor species, and transplantation immunogenicity had close correlations with the degree of infarct volume reduction. The NSPC dosage delivered into the brain parenchyma was also negatively correlated with the effect of the cylinder test. Intriguingly, endogenous apoptosis inhibition and axonal regeneration played the most critical role in intraparenchymal NSPC transplantation among the cellular mechanisms. These results indicate that intraparenchymal NSPC transplantation is beneficial for neurobehavioral and histological improvement and is relatively safe for ischemic stroke animals. Therefore, intraparenchymal NSPC transplantation is a promising treatment for stroke patients.
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Zibara K, Ballout N, Mondello S, Karnib N, Ramadan N, Omais S, Nabbouh A, Caliz D, Clavijo A, Hu Z, Ghanem N, Gajavelli S, Kobeissy F. Combination of drug and stem cells neurotherapy: Potential interventions in neurotrauma and traumatic brain injury. Neuropharmacology 2018; 145:177-198. [PMID: 30267729 DOI: 10.1016/j.neuropharm.2018.09.032] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 09/17/2018] [Accepted: 09/21/2018] [Indexed: 12/12/2022]
Abstract
Traumatic brain injury (TBI) has been recognized as one of the major public health issues that leads to devastating neurological disability. As a consequence of primary and secondary injury phases, neuronal loss following brain trauma leads to pathophysiological alterations on the molecular and cellular levels that severely impact the neuropsycho-behavioral and motor outcomes. Thus, to mitigate the neuropathological sequelae post-TBI such as cerebral edema, inflammation and neural degeneration, several neurotherapeutic options have been investigated including drug intervention, stem cell use and combinational therapies. These treatments aim to ameliorate cellular degeneration, motor decline, cognitive and behavioral deficits. Recently, the use of neural stem cells (NSCs) coupled with selective drug therapy has emerged as an alternative treatment option for neural regeneration and behavioral rehabilitation post-neural injury. Given their neuroprotective abilities, NSC-based neurotherapy has been widely investigated and well-reported in numerous disease models, notably in trauma studies. In this review, we will elaborate on current updates in cell replacement therapy in the area of neurotrauma. In addition, we will discuss novel combination drug therapy treatments that have been investigated in conjunction with stem cells to overcome the limitations associated with stem cell transplantation. Understanding the regenerative capacities of stem cell and drug combination therapy will help improve functional recovery and brain repair post-TBI. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".
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Affiliation(s)
- Kazem Zibara
- ER045, Laboratory of Stem Cells, PRASE, Lebanese University, Beirut, Lebanon; Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Nissrine Ballout
- ER045, Laboratory of Stem Cells, PRASE, Lebanese University, Beirut, Lebanon
| | - Stefania Mondello
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Nabil Karnib
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon
| | - Naify Ramadan
- Department of Women's and Children's Health (KBH), Division of Clinical Pediatrics, Karolinska Institute, Sweden
| | - Saad Omais
- Department of Biology, American University of Beirut, Beirut, Lebanon
| | - Ali Nabbouh
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon
| | - Daniela Caliz
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA
| | - Angelica Clavijo
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA
| | - Zhen Hu
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA
| | - Noël Ghanem
- Department of Biology, American University of Beirut, Beirut, Lebanon
| | - Shyam Gajavelli
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA.
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon; Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Department of Emergency Medicine, University of Florida, Gainesville, FL, 32611, USA.
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HDAC4 in ischemic stroke: mechanisms and therapeutic potential. Clin Epigenetics 2018; 10:117. [PMID: 30208931 PMCID: PMC6136233 DOI: 10.1186/s13148-018-0549-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022] Open
Abstract
Stroke is one of the leading causes of death and disability worldwide, and the majority of the cases are ischemic stroke. However, it still lacks effective treatment except for thrombolytic therapy in an extremely narrow time window. Increased evidence suggests that histone deacetylase 4 (HDAC4) was dysregulated in ischemic stroke, which plays a key role in the pathogenesis of ischemic stroke and post-stroke recovery by affecting neuronal death, angiogenesis, and neurogenesis. Therefore, we aim to review the dysregulation of HDAC4 in ischemic stroke and the role of dysregulated HDAC4 in the pathogenesis of ischemic stroke. Furthermore, the therapeutic potential of modulating HDAC4 in ischemic stroke is discussed.
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25
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Zheng Z, Liu L, Zhan Y, Yu S, Kang T. Adipose-derived stem cell-derived microvesicle-released miR-210 promoted proliferation, migration and invasion of endothelial cells by regulating RUNX3. Cell Cycle 2018; 17:1026-1033. [PMID: 29912616 DOI: 10.1080/15384101.2018.1480207] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
Abstract
The potential mechanism of miRNA released from adipose-derived stem cell (ADSC)-derived micro vesicle (MV) onthe modulation of proliferation, migration and invasion of endothelial cells were explored. In this study, miR-210 level was detected by qT-PCR. Alix, VEGF and RUNX3 expressions were detected by Western blot. The proliferation, migration and invasion of human umbilical vein endothelial cells (HUVECs) were observed by MTT assay and Transwell assay. Luciferase reporter gene assay was conducted to validate the targeting activity of MVs-released miR-210 on RUNX3. We found hypoxia significantly increased the expression of MVs-released miR-210. MVs released from ADSCsin hypoxic group significantly promoted the proliferation, migration and invasion of HUVECs. Overexpression of miR-210 significantly upregulated VEGF expression, and promoted the proliferation, migration and invasion of HUVECs. Besides, RUNX3 was identified as the direct of miR-210 in HUVECs. Overexpression of miR-210 decreased RUNX3 expression and promoted the proliferation, migration and invasion of HUVECs, while overexpression of RUNX3 inhibited these promotion effects. In vivo experiment showed that MVs derived from ADSCs under hypoxia increased miR-210 level and capillary density, and inhibition of miR-210 decreased capillary density. We also found MVs downregulated RUNX3 expression, and inhibition of miR-210 upregulated RUNX3 expression. Therefore, miR-210 released from ADSCs-derived MVs promoted proliferation, migration and invasion of HUVECs by targeting RUNX3, which revealed one of the mechanisms of ADSCs-derived MVs on the promotion of proliferation, migration and invasion of HUVECs. ABBREVIATIONS ADSC, adipose-derived stem cell; MV, micro vesicle; HUVECs, human umbilical vein endothelial cells; RUNX3, Runtrelatedtranscription factor-3.
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Affiliation(s)
- Zeqi Zheng
- a Department of Cardiology , The First Affiliated Hospital of Nanchang University , Nanchang , China
| | - Lijuan Liu
- a Department of Cardiology , The First Affiliated Hospital of Nanchang University , Nanchang , China
| | - Yuliang Zhan
- b Department of Cardiology , Jiangxi Provincial People's Hospital , Nanchang , China
| | - Songping Yu
- b Department of Cardiology , Jiangxi Provincial People's Hospital , Nanchang , China
| | - Ting Kang
- a Department of Cardiology , The First Affiliated Hospital of Nanchang University , Nanchang , China
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Sarmah D, Kaur H, Saraf J, Vats K, Pravalika K, Wanve M, Kalia K, Borah A, Kumar A, Wang X, Yavagal DR, Dave KR, Bhattacharya P. Mitochondrial Dysfunction in Stroke: Implications of Stem Cell Therapy. Transl Stroke Res 2018; 10:10.1007/s12975-018-0642-y. [PMID: 29926383 DOI: 10.1007/s12975-018-0642-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 05/21/2018] [Accepted: 06/12/2018] [Indexed: 01/06/2023]
Abstract
Stroke is a debilitating condition which is also the second leading cause of death and disability worldwide. Despite the benefits and promises shown by numerous neuroprotective agents in animal stroke models, their clinical translation has not been a complete success. Hence, search for treatment options have directed researchers towards utilising stem cells. Mitochondria has a major involvement in the pathophysiology of stroke and a number of other conditions. Stem cells have shown the ability to transfer mitochondria to the damaged cells and to help revive cell energetics in the recipient cell. The present review discusses how stem cells could be employed to protect neurons and mitochondria in stroke and also the various mechanisms involved in neuroprotection.
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Affiliation(s)
- Deepaneeta Sarmah
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Harpreet Kaur
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Jackson Saraf
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Kanchan Vats
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Kanta Pravalika
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Madhuri Wanve
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Kiran Kalia
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Akhilesh Kumar
- Department of Botany, Banaras Hindu University, Varanasi, India
| | - Xin Wang
- Department of Neurosurgery, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | - Dileep R Yavagal
- Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Kunjan R Dave
- Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Pallab Bhattacharya
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India.
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27
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Wood CR, Al Delfi IRT, Innes JF, Myint P, Johnson WEB. Exposing mesenchymal stem cells to chondroitin sulphated proteoglycans reduces their angiogenic and neuro-adhesive paracrine activity. Biochimie 2018; 155:26-36. [PMID: 29680669 DOI: 10.1016/j.biochi.2018.04.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 04/13/2018] [Indexed: 01/04/2023]
Abstract
The multifactorial complexity of spinal cord injuries includes the formation of a glial scar, of which chondroitin sulphated proteoglycans (CSPG) are an integral component. Previous studies have shown CSPG to have inhibitory effects on endothelial and neuronal cell growth, highlighting the difficulty of spinal cord regeneration. Mesenchymal stem/stromal cells (MSC) are widely used as a cell therapy, and there is mounting evidence for their angiogenic and neurotrophic paracrine properties. However, in vivo studies have observed poor engraftment and survival of MSC when injected into SCI. Currently, it is not known whether increasing CSPG concentrations seen after SCI may affect MSC; therefore we have investigated the effects of CSPG exposure to MSC in vitro. CSPG-mediated inhibition of MSC adhesion was observed when MSC were cultured on substrates of increasing CSPG concentration, however MSC viability was not affected even up to five days of culture. Culture conditioned medium harvested from these cultures (primed MSC CM) was used as both culture substrata and soluble medium for EA.hy926 endothelial cells and SH-SY5Y neuronal cells. MSC CM was angiogenic, promoting endothelial cell adhesion, proliferation and tubule formation. However, exposing MSC to CSPG reduced the effects of CSPG-primed MSC CM on endothelial cell adhesion and proliferation, but did not reduce MSC-induced endothelial tubule formation. Primed MSC CM also promoted neuronal cell adhesion, which was reduced following exposure to CSPG. There were no marked differences in neurite outgrowth in MSC CM from CSPG primed MSC cultures versus control conditions, although non-primed MSC CM from the same donors was found to significantly enhance neurite outgrowth. Taken together, these studies demonstrate that MSC are resilient to CSPG exposure, but that there is a marked effect of CSPG on their paracrine regenerative activity. The findings increase our understanding of how the wound microenvironment after SCI can mitigate the beneficial effects of MSC transplantation.
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Affiliation(s)
- Chelsea R Wood
- Biological Sciences, Faculty of Medicine, Dentistry and Life Sciences, University of Chester, Parkgate Road, Chester, CH1 4BJ, United Kingdom.
| | - Ibtesam R T Al Delfi
- Centre for Experimental Medicine, Queen's University, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.
| | - John F Innes
- Veterinary Tissue Bank Ltd, Brynkinalt Business Centre, Wrexham, LL14 5NS, United Kingdom.
| | - Peter Myint
- Veterinary Tissue Bank Ltd, Brynkinalt Business Centre, Wrexham, LL14 5NS, United Kingdom.
| | - William E B Johnson
- Biological Sciences, Faculty of Medicine, Dentistry and Life Sciences, University of Chester, Parkgate Road, Chester, CH1 4BJ, United Kingdom.
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González-Nieto D, Fernández-García L, Pérez-Rigueiro J, Guinea GV, Panetsos F. Hydrogels-Assisted Cell Engraftment for Repairing the Stroke-Damaged Brain: Chimera or Reality. Polymers (Basel) 2018; 10:polym10020184. [PMID: 30966220 PMCID: PMC6415003 DOI: 10.3390/polym10020184] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 02/06/2018] [Accepted: 02/11/2018] [Indexed: 01/07/2023] Open
Abstract
The use of advanced biomaterials as a structural and functional support for stem cells-based therapeutic implants has boosted the development of tissue engineering applications in multiple clinical fields. In relation to neurological disorders, we are still far from the clinical reality of restoring normal brain function in neurodegenerative diseases and cerebrovascular disorders. Hydrogel polymers show unique mechanical stiffness properties in the range of living soft tissues such as nervous tissue. Furthermore, the use of these polymers drastically enhances the engraftment of stem cells as well as their capacity to produce and deliver neuroprotective and neuroregenerative factors in the host tissue. Along this article, we review past and current trends in experimental and translational research to understand the opportunities, benefits, and types of tentative hydrogel-based applications for the treatment of cerebral disorders. Although the use of hydrogels for brain disorders has been restricted to the experimental area, the current level of knowledge anticipates an intense development of this field to reach clinics in forthcoming years.
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Affiliation(s)
- Daniel González-Nieto
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28040 Madrid, Spain.
- Departamento de Tecnología Fotónica y Bioingeniería, ETSI Telecomunicaciones, Universidad Politécnica de Madrid, 28040 Madrid, Spain.
- Biomedical Research Networking Center in Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), 28040 Madrid, Spain.
| | - Laura Fernández-García
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28040 Madrid, Spain.
| | - José Pérez-Rigueiro
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28040 Madrid, Spain.
- Biomedical Research Networking Center in Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), 28040 Madrid, Spain.
- Departamento de Ciencia de Materiales, ETSI Caminos, Canales y Puertos, Universidad Politécnica de Madrid 28040 Madrid, Spain.
| | - Gustavo V Guinea
- Center for Biomedical Technology, Universidad Politécnica de Madrid, 28040 Madrid, Spain.
- Biomedical Research Networking Center in Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), 28040 Madrid, Spain.
- Departamento de Ciencia de Materiales, ETSI Caminos, Canales y Puertos, Universidad Politécnica de Madrid 28040 Madrid, Spain.
| | - Fivos Panetsos
- Neurocomputing and Neurorobotics Research Group: Faculty of Biology and Faculty of Optics, Universidad Complutense de Madrid, 28040 Madrid, Spain.
- Instituto de Investigación Sanitaria, Hospital Clínico San Carlos Madrid, IdISSC, 28040 Madrid, Spain.
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Borlongan CV. Preliminary Reports of Stereotaxic Stem Cell Transplants in Chronic Stroke Patients. Mol Ther 2018; 24:1710-1711. [PMID: 27818493 DOI: 10.1038/mt.2016.186] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Cesar V Borlongan
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida, USA
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30
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Napoli E, Lippert T, Borlongan CV. Stem Cell Therapy: Repurposing Cell-Based Regenerative Medicine Beyond Cell Replacement. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1079:87-91. [PMID: 29480446 DOI: 10.1007/5584_2018_174] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Stem cells exhibit simple and naive cellular features, yet their exact purpose for regenerative medicine continues to elude even the most elegantly designed research paradigms from developmental biology to clinical therapeutics. Based on their capacity to divide indefinitely and their dynamic differentiation into any type of tissue, the advent of transplantable stem cells has offered a potential treatment for aging-related and injury-mediated diseases. Recent laboratory evidence has demonstrated that transplanted human neural stem cells facilitate endogenous reparative mechanisms by initiating multiple regenerative processes in the brain neurogenic areas. Within these highly proliferative niches reside a myriad of potent regenerative molecules, including anti-inflammatory cytokines, proteomes, and neurotrophic factors, altogether representing a biochemical cocktail vital for restoring brain function in the aging and diseased brain. Here, we advance the concept of therapeutically repurposing stem cells not towards cell replacement per se, but rather exploiting the cells' intrinsic properties to serve as the host brain regenerative catalysts.
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Affiliation(s)
- Eleonora Napoli
- Department of Molecular Biosciences, University of California Davis, Davis, CA, USA.
| | - Trenton Lippert
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
| | - Cesar V Borlongan
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA.
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31
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Corey S, Ghanekar S, Sokol J, Zhang JH, Borlongan CV. An update on stem cell therapy for neurological disorders: cell death pathways as therapeutic targets. Chin Neurosurg J 2017. [DOI: 10.1186/s41016-016-0071-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
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32
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Napoli E, Borlongan CV. Stem Cell Recipes of Bone Marrow and Fish: Just What the Stroke Doctors Ordered. Stem Cell Rev Rep 2017; 13:192-197. [PMID: 28064388 DOI: 10.1007/s12015-016-9716-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Stem cell therapy for stroke has advanced from the laboratory to the clinic, but remains as an experimental treatment. Two lines of transplant regimens have emerged, namely the "early bird" peripheral injections in subacute stroke patients and the "late night" direct intracerebral treatments in chronic stroke patients. Autologous bone marrow-derived stem cells, which only required minimal manipulations during graft cell preparation, gained fast-track entry into the clinic, while gene modified stem cells necessitated overcoming more stringent regulatory criteria before they were approved for clinical use. Safety of the stem cell therapy can be declared from these clinical trials, but efficacy warrants further investigations. Here, we offer insights into the translation of cell therapy from the laboratory to the clinic, in the hopes that highlighting the lessons we learned from this experience will guide the optimization of functional outcomes of future clinical trials of stem cell therapy for stroke.
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Affiliation(s)
- Eleonora Napoli
- Department of Molecular Biosciences, University of California Davis, Davis, CA, 95616, USA
| | - Cesar V Borlongan
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, 33612, USA.
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Napoli E. Endogenous repair mechanisms enhanced in Parkinson's disease following stem cell therapy. Brain Circ 2017; 3:163-166. [PMID: 30276319 PMCID: PMC6057692 DOI: 10.4103/bc.bc_22_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Revised: 09/01/2017] [Accepted: 09/05/2017] [Indexed: 11/16/2022] Open
Abstract
This mini-review highlights the innovative observation that transplanted human neural stem cells can bring about endogenous brain repair through the stimulation of multiple regenerative processes in the neurogenic area (i.e., subventricular zone [SVZ]) in an animal model of Parkinson's disease (PD). In addition, we convey that identifying anti-inflammatory cytokines, therapeutic proteomes, and neurotrophic factors within the SVZ may be essential to induce brain repair and behavioral recovery. This work opens up a new area of research for further understanding the pathology and treatment of PD. This paper is a review article. Referred literature in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors’ experiences.
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Affiliation(s)
- Eleonora Napoli
- Department of Molecular Biosciences, University of California Davis, Davis, California, 95616 USA
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Zhao L, Johnson T, Liu D. Therapeutic angiogenesis of adipose-derived stem cells for ischemic diseases. Stem Cell Res Ther 2017; 8:125. [PMID: 28583178 PMCID: PMC5460534 DOI: 10.1186/s13287-017-0578-2] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ischemic diseases, the leading cause of disability and death, are caused by the stenosis or obstruction of arterioles/capillaries that is not compensated for by vessel dilatation or collateral circulation. Angiogenesis is a complex process leading to new blood vessel formation and is triggered by ischemic conditions. Adequate angiogenesis, as a compensatory mechanism in response to ischemia, may increase oxygen and nutrient supplies to tissues and protect their function. Therapeutic angiogenesis has been the most promising therapy for treating ischemic diseases. In recent years, stem cell transplantation has been recognized as a new technique with therapeutic angiogenic effects on ischemic diseases. Adipose-derived stem cells, characterized by their ease of acquisition, high yields, proliferative growth, and low immunogenicity, are an ideal cell source. In this review, the characterization of adipose-derived stem cells and the role of angiogenesis in ischemic attack are summarized. The angiogenic effects of adipose-derived stem cells are discussed from the perspectives of in-vitro, in-vivo, and clinical trial studies for the treatment of ischemic diseases, including ischemic cardiac, cerebral, and peripheral vascular diseases and wound healing. The microvesicles/exosomes released from adipose-derived stem cells are also presented as a novel therapeutic prospect for treating ischemic diseases.
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Affiliation(s)
- Lina Zhao
- Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA
| | - Takerra Johnson
- Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA
| | - Dong Liu
- Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA.
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Napoli E, Borlongan CV. Cell Therapy in Parkinson's Disease: Host Brain Repair Machinery Gets a Boost From Stem Cell Grafts. Stem Cells 2017; 35:1443-1445. [DOI: 10.1002/stem.2636] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 04/25/2017] [Indexed: 12/27/2022]
Affiliation(s)
- Eleonora Napoli
- Department of Molecular Biosciences; University of California Davis; Davis California USA
| | - Cesar V. Borlongan
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair; University of South Florida College of Medicine; Tampa Florida USA
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Sinden JD, Hicks C, Stroemer P, Vishnubhatla I, Corteling R. Human Neural Stem Cell Therapy for Chronic Ischemic Stroke: Charting Progress from Laboratory to Patients. Stem Cells Dev 2017; 26:933-947. [PMID: 28446071 PMCID: PMC5510676 DOI: 10.1089/scd.2017.0009] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Chronic disability after stroke represents a major unmet neurologic need. ReNeuron's development of a human neural stem cell (hNSC) therapy for chronic disability after stroke is progressing through early clinical studies. A Phase I trial has recently been published, showing no safety concerns and some promising signs of efficacy. A single-arm Phase II multicenter trial in patients with stable upper-limb paresis has recently completed recruitment. The hNSCs administrated are from a manufactured, conditionally immortalized hNSC line (ReNeuron's CTX0E03 or CTX), generated with c-mycERTAM technology. This technology has enabled CTX to be manufactured at large scale under cGMP conditions, ensuring sufficient supply to meets the demands of research, clinical development, and, eventually, the market. CTX has key pro-angiogenic, pro-neurogenic, and immunomodulatory characteristics that are mechanistically important in functional recovery poststroke. This review covers the progress of CTX cell therapy from its laboratory origins to the clinic, concluding with a look into the late stage clinical future.
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Ottoboni L, Merlini A, Martino G. Neural Stem Cell Plasticity: Advantages in Therapy for the Injured Central Nervous System. Front Cell Dev Biol 2017; 5:52. [PMID: 28553634 PMCID: PMC5427132 DOI: 10.3389/fcell.2017.00052] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 04/25/2017] [Indexed: 12/14/2022] Open
Abstract
The physiological and pathological properties of the neural germinal stem cell niche have been well-studied in the past 30 years, mainly in animals and within given limits in humans, and knowledge is available for the cyto-architectonic structure, the cellular components, the timing of development and the energetic maintenance of the niche, as well as for the therapeutic potential and the cross talk between neural and immune cells. In recent years we have gained detailed understanding of the potentiality of neural stem cells (NSCs), although we are only beginning to understand their molecular, metabolic, and epigenetic profile in physiopathology and, further, more can be invested to measure quantitatively the activity of those cells, to model in vitro their therapeutic responses or to predict interactions in silico. Information in this direction has been put forward for other organs but is still limited in the complex and very less accessible context of the brain. A comprehensive understanding of the behavior of endogenous NSCs will help to tune or model them toward a desired response in order to treat complex neurodegenerative diseases. NSCs have the ability to modulate multiple cellular functions and exploiting their plasticity might make them into potent and versatile cellular drugs.
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Affiliation(s)
- Linda Ottoboni
- Neuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific InstituteMilan, Italy
| | - Arianna Merlini
- Neuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific InstituteMilan, Italy
| | - Gianvito Martino
- Neuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific InstituteMilan, Italy
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Jin Y, Barnett A, Zhang Y, Yu X, Luo Y. Poststroke Sonic Hedgehog Agonist Treatment Improves Functional Recovery by Enhancing Neurogenesis and Angiogenesis. Stroke 2017; 48:1636-1645. [PMID: 28487338 DOI: 10.1161/strokeaha.117.016650] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 03/20/2017] [Accepted: 03/30/2017] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND PURPOSE Because of the limitation in treatment window of the r-tPA (recombinant tissue-type plasminogen activator), the development of delayed treatment for stroke is needed. In this study, we examined the efficacy of delayed poststroke treatment (post 3-8 days) of the sonic hedgehog pathway agonist on functional recovery and the underlying mechanisms. METHODS We evaluated functional recovery at 1 month after stroke using locomotion analysis and Barnes maze test for cognitive function. We used a genetically inducible neural stem cell-specific reporter mouse line (nestin-CreERT2-R26R-YFP) to label and track their proliferation, survival, and differentiation in ischemic brain. Brain tissue damage, angiogenesis, and cerebral blood flow recovery was evaluated using magnetic resonance imaging techniques and immunostaining. RESULTS Our results show that delayed treatment of sonic hedgehog pathway agonist in stroke mice results in enhanced functional recovery both in locomotor function and in cognitive function at 1 month after stroke. Furthermore, using the Nestincre-ERT2-YFP mice, we showed that poststroke sonic hedgehog pathway agonist treatment increased surviving newly born cells derived from both subventricular zone and subgranular zone neural stem cells, total surviving DCX+ (Doublecortin) neuroblast cells, and neurons (NeuN+/YFP+) in the ischemic brain. Sonic hedgehog pathway agonist treatment also improved the brain tissue repair in ischemic region supported by our T2-weighted magnetic resonance imaging, cerebral blood flow map by arterial spin labeling, and immunohistochemistry (α-smooth muscle actin and CD31 immunostaining). CONCLUSIONS These data confirm an important role for the hedgehog pathway in poststroke brain repair and functional recovery, suggesting a prolonged treatment window for potential treatment strategy to modulate sonic hedgehog pathway after stroke.
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Affiliation(s)
- Yongming Jin
- From the Department of Neurological Surgery (Y.J., A.B., Y.L.) and Department of Biomedical Engineering (Y.Z., X.Y.), Case Western Reserve University, Cleveland, OH
| | - Austin Barnett
- From the Department of Neurological Surgery (Y.J., A.B., Y.L.) and Department of Biomedical Engineering (Y.Z., X.Y.), Case Western Reserve University, Cleveland, OH
| | - Yifan Zhang
- From the Department of Neurological Surgery (Y.J., A.B., Y.L.) and Department of Biomedical Engineering (Y.Z., X.Y.), Case Western Reserve University, Cleveland, OH
| | - Xin Yu
- From the Department of Neurological Surgery (Y.J., A.B., Y.L.) and Department of Biomedical Engineering (Y.Z., X.Y.), Case Western Reserve University, Cleveland, OH
| | - Yu Luo
- From the Department of Neurological Surgery (Y.J., A.B., Y.L.) and Department of Biomedical Engineering (Y.Z., X.Y.), Case Western Reserve University, Cleveland, OH.
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Garbuzova-Davis S, Haller E, Lin R, Borlongan CV. Intravenously Transplanted Human Bone Marrow Endothelial Progenitor Cells Engraft Within Brain Capillaries, Preserve Mitochondrial Morphology, and Display Pinocytotic Activity Toward Blood-Brain Barrier Repair in Ischemic Stroke Rats. Stem Cells 2017; 35:1246-1258. [PMID: 28142208 DOI: 10.1002/stem.2578] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 01/05/2017] [Accepted: 01/12/2017] [Indexed: 01/01/2023]
Abstract
Stroke is a life-threatening disease with limited therapeutic options. Cell therapy has emerged as an experimental stroke treatment. Blood-brain barrier (BBB) impairment is a key pathological manifestation of ischemic stroke, and barrier repair is an innovative target for neurorestoration in stroke. Here, we evaluated via electron microscopy the ability of transplanted human bone marrow endothelial progenitor cells (hBMEPCs) to repair the BBB in adult Sprague-Dawley rats subjected to transient middle cerebral artery occlusion (tMCAO). β-galactosidase prelabeled hBMEPCs were intravenously transplanted 48 hours post-tMCAO. Ultrastructural analysis of microvessels in nontransplant stroke rats revealed typical BBB pathology. At 5 days post-transplantation with hBMEPCs, stroke rats displayed widespread vascular repair in bilateral striatum and motor cortex, characterized by robust cell engraftment within capillaries. hBMEPC transplanted stroke rats exhibited near normal morphology of endothelial cells (ECs), pericytes, and astrocytes, without detectable perivascular edema. Near normal morphology of mitochondria was also detected in ECs and perivascular astrocytes from transplanted stroke rats. Equally notable, we observed numerous pinocytic vesicles within engrafted cells. Robust engraftment and intricate functionality of transplanted hBMEPCs likely abrogated stroke-altered vasculature. Preserving mitochondria and augmenting pinocytosis in cell-based therapeutics represent a new neurorestorative mechanism in BBB repair for stroke. Stem Cells 2017;35:1246-1258.
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Affiliation(s)
- Svitlana Garbuzova-Davis
- Center of Excellence for Aging & Brain Repair.,Department of Neurosurgery and Brain Repair.,Department of Molecular Pharmacology and Physiology.,Department of Pathology and Cell Biology, Morsani College of Medicine
| | - Edward Haller
- Department of Integrative Biology, University of South Florida, Tampa, Florida, USA
| | - Roger Lin
- Center of Excellence for Aging & Brain Repair
| | - Cesario V Borlongan
- Center of Excellence for Aging & Brain Repair.,Department of Neurosurgery and Brain Repair
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Liska MG, Crowley MG, Borlongan CV. Regulated and Unregulated Clinical Trials of Stem Cell Therapies for Stroke. Transl Stroke Res 2017; 8:93-103. [PMID: 28127687 DOI: 10.1007/s12975-017-0522-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Accepted: 01/17/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Michael G Liska
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL, 33612, USA
| | - Marci G Crowley
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL, 33612, USA
| | - Cesar V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL, 33612, USA.
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