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Ding N, Luo R, Zhang Q, Li H, Zhang S, Chen H, Hu R. Current Status and Progress in Stem Cell Therapy for Intracerebral Hemorrhage. Transl Stroke Res 2025; 16:512-534. [PMID: 38001353 DOI: 10.1007/s12975-023-01216-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/23/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023]
Abstract
Intracerebral hemorrhage is a highly prevalent and prognostically poor disease, imposing immeasurable harm on human life and health. However, the treatment options for intracerebral hemorrhage are severely limited, particularly in terms of improving the microenvironment of the lesion, promoting neuronal cell survival, and enhancing neural function. This review comprehensively discussed the application of stem cell therapy for intracerebral hemorrhage, providing a systematic summary of its developmental history, types of transplants, transplantation routes, and transplantation timing. Moreover, this review presented the latest research progress in enhancing the efficacy of stem cell transplantation, including pretransplantation preconditioning, genetic modification, combined therapy, and other diverse strategies. Furthermore, this review pioneeringly elaborated on the barriers to clinical translation for stem cell therapy. These discussions were of significant importance for promoting stem cell therapy for intracerebral hemorrhage, facilitating its clinical translation, and improving patient prognosis.
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Affiliation(s)
- Ning Ding
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Ran Luo
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Qian Zhang
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Huanhuan Li
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Shuixian Zhang
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Huanran Chen
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Rong Hu
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
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2
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Adipose and Bone Marrow Derived-Mesenchymal Stromal Cells Express Similar Tenogenic Expression Levels when Subjected to Mechanical Uniaxial Stretching In Vitro. Stem Cells Int 2023; 2023:4907230. [PMID: 36756494 PMCID: PMC9902123 DOI: 10.1155/2023/4907230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 05/12/2022] [Accepted: 09/03/2022] [Indexed: 01/31/2023] Open
Abstract
The present study was conducted to determine whether adipose derived mesenchymal stromal cells (AD-MSCs) or bone marrow derived-MSCs (BM-MSCs) would provide superior tenogenic expressions when subjected to cyclical tensile loading. The results for this would indicate the best choice of MSCs source to be used for cell-based tendon repair strategies. Both AD-MSCs and BM-MSCs were obtained from ten adult donors (N = 10) and cultured in vitro. At passaged-2, cells from both groups were subjected to cyclical stretching at 1 Hz and 8% of strain. Cellular morphology, orientation, proliferation rate, protein, and gene expression levels were compared at 0, 24, and 48 hours of stretching. In both groups, mechanical stretching results in similar morphological changes, and the redirection of cell alignment is perpendicular to the direction of stretching. Loading at 8% strain did not significantly increase proliferation rates but caused an increase in total collagen expression and tenogenic gene expression levels. In both groups, these levels demonstrated no significant differences suggesting that in a similar loading environment, both cell types possess similar tenogenic potential. In conclusion, AD-MSCs and BM-MSCs both demonstrate similar tenogenic phenotypic and gene expression levels when subjected to cyclic tensile loading at 1 Hz and 8% strain, thus, suggesting that the use of either cell source may be suitable for tendon repair.
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3
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Takamiya S, Kawabori M, Fujimura M. Stem Cell Therapies for Intracerebral Hemorrhage: Review of Preclinical and Clinical Studies. Cell Transplant 2023; 32:9636897231158153. [PMID: 36823970 PMCID: PMC9969479 DOI: 10.1177/09636897231158153] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
Despite recent developments in the treatments for ischemic stroke, such as tissue plasminogen activator (t-PA) and thrombectomy, effective therapies for intracerebral hemorrhage (ICH) remain scarce. Stem cell therapies have attracted considerable attention owing to their potential neuro-regenerative ability; preclinical and clinical studies have been conducted to explore strategies for achieving functional recovery following ICH. In this review, we summarize the findings of preclinical studies on stem cell therapies of ICH, with a focus on different animal models, stem cell sources, transplantation methods, and their potential mechanisms of action. We also provide an overview of data from clinical trials to discuss the current status and future perspectives. Understanding the effectiveness and limitations of stem cell therapy and the future prospects could expand the applications of this novel therapeutic approach for ICH.
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Affiliation(s)
- Soichiro Takamiya
- Department of Neurosurgery, Hokkaido University Hospital, Sapporo, Japan
| | - Masahito Kawabori
- Department of Neurosurgery, Hokkaido University Hospital, Sapporo, Japan
| | - Miki Fujimura
- Department of Neurosurgery, Hokkaido University Hospital, Sapporo, Japan
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Jansen van Rensburg M, Crous A, Abrahamse H. Promoting Immortalized Adipose-Derived Stem Cell Transdifferentiation and Proliferation into Neuronal-Like Cells through Consecutive 525 nm and 825 nm Photobiomodulation. Stem Cells Int 2022; 2022:2744789. [PMID: 36106176 PMCID: PMC9467736 DOI: 10.1155/2022/2744789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/12/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
Neuronal cells can be generated from adipose-derived stem cells (ADSCs) through biological or chemical inducers. Research has shown that this process may be optimized by the introduction of laser irradiation in the form of photobiomodulation (PBM) to cells. This in vitro study is aimed at generating neuronal-like cells with inducers, chemical or biological, and at furthermore treating these transdifferentiating cells with consecutive PBM of a 525 nm green (G) laser and 825 nm near-infrared (NIR) laser light with a fluence of 10 J/cm2. Cells were exposed to induction type 1 (IT1): 3-isobutyl-1-methylxanthine (IBMX) (0.5 mM)+indomethacin (200 μM)+insulin (5 μg/ml) for 14 days, preinduced with β-mercaptoethanol (BME) (1 mM) for two days, and then incubated with IT2: β-hydroxyanisole (BHA) (100 μM)+retinoic acid (RA) (10-6 M)+epidermal growth factor (EGF) (10 ng/ml)+basic fibroblast growth factor (bFGF) (10 ng/ml) for 14 days and preinduced with β-mercaptoethanol (BME) (1 mM) for two days and then incubated with indomethacin (200 μM)+RA (1 μM)+forskolin (10 μM) for 14 days. The results were evaluated through morphological observations, viability, proliferation, and migration studies, 24 h, 48 h, and 7 days post-PBM. The protein detection of an early neuronal marker, neuron-specific enolase (NSE), and late, ciliary neurotrophic factor (CNTF), was determined with enzyme-linked immunosorbent assays (ELISAs). The genetic expression was also explored through real-time PCR. Results indicated differentiation in all experimental groups; however, cells that were preinduced showed higher proliferation and a higher differentiation rate than the group that was not preinduced. Within the preinduced groups, results indicated that cells treated with IT2 and consecutive PBM upregulated differentiation the most morphologically and physiologically.
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Affiliation(s)
- Madeleen Jansen van Rensburg
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg, South Africa 2028
| | - Anine Crous
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg, South Africa 2028
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg, South Africa 2028
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Zhou JF, Xiong Y, Kang X, Pan Z, Zhu Q, Goldbrunner R, Stavrinou L, Lin S, Hu W, Zheng F, Stavrinou P. Application of stem cells and exosomes in the treatment of intracerebral hemorrhage: an update. Stem Cell Res Ther 2022; 13:281. [PMID: 35765072 PMCID: PMC9241288 DOI: 10.1186/s13287-022-02965-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 06/19/2022] [Indexed: 12/14/2022] Open
Abstract
Non-traumatic intracerebral hemorrhage is a highly destructive intracranial disease with high mortality and morbidity rates. The main risk factors for cerebral hemorrhage include hypertension, amyloidosis, vasculitis, drug abuse, coagulation dysfunction, and genetic factors. Clinically, surviving patients with intracerebral hemorrhage exhibit different degrees of neurological deficits after discharge. In recent years, with the development of regenerative medicine, an increasing number of researchers have begun to pay attention to stem cell and exosome therapy as a new method for the treatment of intracerebral hemorrhage, owing to their intrinsic potential in neuroprotection and neurorestoration. Many animal studies have shown that stem cells can directly or indirectly participate in the treatment of intracerebral hemorrhage through regeneration, differentiation, or secretion. However, considering the uncertainty of its safety and efficacy, clinical studies are still lacking. This article reviews the treatment of intracerebral hemorrhage using stem cells and exosomes from both preclinical and clinical studies and summarizes the possible mechanisms of stem cell therapy. This review aims to provide a reference for future research and new strategies for clinical treatment.
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Affiliation(s)
- Jian-Feng Zhou
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Yu Xiong
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Xiaodong Kang
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Zhigang Pan
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Qiangbin Zhu
- Department of Neurosurgery, Hui'an County Hospital of Fujian Province, Quanzhou, Fujian, China
| | - Roland Goldbrunner
- Department of Neurosurgery, Faculty of Medicine and University Hospital, Center for Neurosurgery, University of Cologne, Cologne, Germany
| | - Lampis Stavrinou
- 2nd Department of Neurosurgery, Athens Medical School, "Attikon" University Hospital, National and Kapodistrian University, Athens, Greece
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China. .,Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia.
| | - Weipeng Hu
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China.
| | - Feng Zheng
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China.
| | - Pantelis Stavrinou
- Department of Neurosurgery, Faculty of Medicine and University Hospital, Center for Neurosurgery, University of Cologne, Cologne, Germany.,Neurosurgery, Metropolitan Hospital, Athens, Greece
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6
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Yang G, Fan X, Mazhar M, Yang S, Xu H, Dechsupa N, Wang L. Mesenchymal Stem Cell Application and Its Therapeutic Mechanisms in Intracerebral Hemorrhage. Front Cell Neurosci 2022; 16:898497. [PMID: 35769327 PMCID: PMC9234141 DOI: 10.3389/fncel.2022.898497] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/18/2022] [Indexed: 12/15/2022] Open
Abstract
Intracerebral hemorrhage (ICH), a common lethal subtype of stroke accounting for nearly 10–15% of the total stroke disease and affecting two million people worldwide, has a high mortality and disability rate and, thus, a major socioeconomic burden. However, there is no effective treatment available currently. The role of mesenchymal stem cells (MSCs) in regenerative medicine is well known owing to the simplicity of acquisition from various sources, low immunogenicity, adaptation to the autogenic and allogeneic systems, immunomodulation, self-recovery by secreting extracellular vesicles (EVs), regenerative repair, and antioxidative stress. MSC therapy provides an increasingly attractive therapeutic approach for ICH. Recently, the functions of MSCs such as neuroprotection, anti-inflammation, and improvement in synaptic plasticity have been widely researched in human and rodent models of ICH. MSC transplantation has been proven to improve ICH-induced injury, including the damage of nerve cells and oligodendrocytes, the activation of microglia and astrocytes, and the destruction of blood vessels. The improvement and recovery of neurological functions in rodent ICH models were demonstrated via the mechanisms such as neurogenesis, angiogenesis, anti-inflammation, anti-apoptosis, and synaptic plasticity. Here, we discuss the pathological mechanisms following ICH and the therapeutic mechanisms of MSC-based therapy to unravel new cues for future therapeutic strategies. Furthermore, some potential strategies for enhancing the therapeutic function of MSC transplantation have also been suggested.
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Affiliation(s)
- Guoqiang Yang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Department of Acupuncture and Rehabilitation, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xuehui Fan
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany
| | - Maryam Mazhar
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Sijin Yang
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Houping Xu
- Preventive Treatment Center, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- *Correspondence: Nathupakorn Dechsupa,
| | - Li Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
- Li Wang,
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7
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Magid-Bernstein J, Girard R, Polster S, Srinath A, Romanos S, Awad IA, Sansing LH. Cerebral Hemorrhage: Pathophysiology, Treatment, and Future Directions. Circ Res 2022; 130:1204-1229. [PMID: 35420918 PMCID: PMC10032582 DOI: 10.1161/circresaha.121.319949] [Citation(s) in RCA: 266] [Impact Index Per Article: 88.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Intracerebral hemorrhage (ICH) is a devastating form of stroke with high morbidity and mortality. This review article focuses on the epidemiology, cause, mechanisms of injury, current treatment strategies, and future research directions of ICH. Incidence of hemorrhagic stroke has increased worldwide over the past 40 years, with shifts in the cause over time as hypertension management has improved and anticoagulant use has increased. Preclinical and clinical trials have elucidated the underlying ICH cause and mechanisms of injury from ICH including the complex interaction between edema, inflammation, iron-induced injury, and oxidative stress. Several trials have investigated optimal medical and surgical management of ICH without clear improvement in survival and functional outcomes. Ongoing research into novel approaches for ICH management provide hope for reducing the devastating effect of this disease in the future. Areas of promise in ICH therapy include prognostic biomarkers and primary prevention based on disease pathobiology, ultra-early hemostatic therapy, minimally invasive surgery, and perihematomal protection against inflammatory brain injury.
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Affiliation(s)
| | - Romuald Girard
- Neurovascular Surgery Program, Department of Neurological Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA
| | - Sean Polster
- Neurovascular Surgery Program, Department of Neurological Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA
| | - Abhinav Srinath
- Neurovascular Surgery Program, Department of Neurological Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA
| | - Sharbel Romanos
- Neurovascular Surgery Program, Department of Neurological Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA
| | - Issam A. Awad
- Neurovascular Surgery Program, Department of Neurological Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA
| | - Lauren H. Sansing
- Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
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8
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Ma Y, Zhang Q, Yang K, Ma J, Pan R, Lu G. Ultra-structural morphology analysis of human cranial bone marrow mesenchymal stromal cells during neural differentiation. Neurosci Lett 2021; 763:136179. [PMID: 34416344 DOI: 10.1016/j.neulet.2021.136179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/31/2021] [Accepted: 08/15/2021] [Indexed: 10/20/2022]
Abstract
Neural differentiation of mesenchymal stromal cells has been widely studied. However, a comparative characterization of ultrastructural changes during neural differentiation has not been performed. In this study, we conducted scanning electron microscopy and transmission electron microscopy analysis to show the morphological changes in mesenchymal stromal cells upon induction of neural differentiation. In addition, transmission electron microscopy results demonstrated ultrastructural differences between human cranial bone marrow mesenchymal stromal cells and iliac crest bone marrow mesenchymal stromal cells. We propose that enriched microvesicles in cranial bone marrow mesenchymal stromal cells may be responsible for the increased efficiency of neural differentiation.
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Affiliation(s)
- Yuyuan Ma
- Department of Neurosurgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, PR China
| | - Qulin Zhang
- Department of Neurosurgery, Nanxun People's Hospital, Huzhou 313009, PR China
| | - Kaichuang Yang
- Department of Neurosurgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, PR China
| | - Jie Ma
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, P R China
| | - Ruolang Pan
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Hangzhou 311121, PR China; Institute for Cell-Based Drug Development of Zhejiang Province, S-Evans Biosciences, Hangzhou 311121, PR China.
| | - Gang Lu
- Department of Neurosurgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, PR China.
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Li J, Xiao L, He D, Luo Y, Sun H. Mechanism of White Matter Injury and Promising Therapeutic Strategies of MSCs After Intracerebral Hemorrhage. Front Aging Neurosci 2021; 13:632054. [PMID: 33927608 PMCID: PMC8078548 DOI: 10.3389/fnagi.2021.632054] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 03/18/2021] [Indexed: 12/15/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke with high disability and high mortality rates, and there is no effective treatment. The predilection site of ICH is in the area of the basal ganglia and internal capsule (IC), where exist abundant white matter (WM) fiber tracts, such as the corticospinal tract (CST) in the IC. Proximal or distal white matter injury (WMI) caused by intracerebral parenchymal hemorrhage is closely associated with poor prognosis after ICH, especially motor and sensory dysfunction. The pathophysiological mechanisms involved in WMI are quite complex and still far from clear. In recent years, the neuroprotection and repairment capacity of mesenchymal stem cells (MSCs) has been widely investigated after ICH. MSCs exert many unique biological effects, including self-recovery by producing growth factors and cytokines, regenerative repair, immunomodulation, and neuroprotection against oxidative stress, providing a promising cellular therapeutic approach for the treatment of WMI. Taken together, our goal is to discuss the characteristics of WMI following ICH, including the mechanism and potential promising therapeutic targets of MSCs, aiming at providing new clues for future therapeutic strategies.
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Affiliation(s)
- Jing Li
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Linglong Xiao
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Dian He
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yunhao Luo
- Division of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Sun
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Division of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Key Laboratory of Mental Health of The Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, China
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10
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Gong YH, Hao SL, Wang BC. Mesenchymal Stem Cells Transplantation in Intracerebral Hemorrhage: Application and Challenges. Front Cell Neurosci 2021; 15:653367. [PMID: 33841103 PMCID: PMC8024645 DOI: 10.3389/fncel.2021.653367] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 03/01/2021] [Indexed: 01/01/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is one of the leading causes of death and long-term disability worldwide. Mesenchymal stem cell (MSC) therapies have demonstrated improved outcomes for treating ICH-induced neuronal defects, and the neural network reconstruction and neurological function recovery were enhanced in rodent ICH models through the mechanisms of neurogenesis, angiogenesis, anti-inflammation, and anti-apoptosis. However, many key issues associated with the survival, differentiation, and safety of grafted MSCs after ICH remain to be resolved, which hinder the clinical translation of MSC therapy. Herein, we reviewed an overview of the research status of MSC transplantation after ICH in different species including rodents, swine, monkey, and human, and the challenges for MSC-mediated ICH recovery from pathological microenvironment have been summarized. Furthermore, some efficient strategies for the outcome improvement of MSC transplantation were proposed.
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Affiliation(s)
- Yu-Hua Gong
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Shi-Lei Hao
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Bo-Chu Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
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11
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Yang J, Ma K, Zhang C, Liu Y, Liang F, Hu W, Bian X, Yang S, Fu X. Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice. Front Immunol 2020; 11:578879. [PMID: 33240266 PMCID: PMC7677525 DOI: 10.3389/fimmu.2020.578879] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/07/2020] [Indexed: 12/17/2022] Open
Abstract
Neurological syndromes are observed in numerous patients who suffer burns, which add to the economic burden of societies and families. Recent studies have implied that blood-brain barrier (BBB) dysfunction is the key factor that induces these central nervous system (CNS) syndromes in peripheral traumatic disease, e.g., surgery and burns. However, the effect of burns on BBB and the underlying mechanism remains, largely, to be determined. The present study aimed to investigate the effect of burns on BBB and the potential of umbilical cord-derived mesenchymal stem cells (UC-MSCs), which have strong anti-inflammatory and repairing ability, to protect the integrity of BBB. BBB permeability was evaluated using dextran tracer (immunohistochemistry imaging and spectrophotometric quantification) and western blot, interleukin (IL)-6, and IL-1β levels in blood and brain were measured by enzyme-linked immunosorbent assay. Furthermore, transmission electron microscopy (TEM) was used to detect transcellular vesicular transport (transcytosis) in BBB. We found that burns increased mouse BBB permeability to both 10-kDa and 70-kDa dextran. IL-6 and IL-1β levels increased in peripheral blood and CNS after burns. In addition, burns decreased the level of tight junction proteins (TJs), including claudin-5, occludin, and ZO-1, which indicated increased BBB permeability due to paracellular pathway. Moreover, increased vesicular density after burns suggested increased transcytosis in brain microvascular endothelial cells. Finally, administering UC-MSCs at 1 h after burns effectively reversed these adverse effects and protected the integrity of BBB. These results suggest that burns increase BBB permeability through both paracellular pathway and transcytosis, the potential mechanism of which might be through increasing IL-6 and IL-1β levels and decreasing Mfsd2a level, and appropriate treatment with UC-MSCs can reverse these effects and protect the integrity of BBB after burns.
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Affiliation(s)
- Jie Yang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, Chinese People's Liberation Army (PLA) General Hospital and PLA Medical College, Beijing, China.,Department of Dermatology, Fourth Medical Center, PLA General Hospital, Beijing, China
| | - Kui Ma
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, Chinese People's Liberation Army (PLA) General Hospital and PLA Medical College, Beijing, China
| | - Cuiping Zhang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, Chinese People's Liberation Army (PLA) General Hospital and PLA Medical College, Beijing, China
| | - Yufan Liu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, Chinese People's Liberation Army (PLA) General Hospital and PLA Medical College, Beijing, China.,Department of Dermatology, Fourth Medical Center, PLA General Hospital, Beijing, China
| | - Feng Liang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, Chinese People's Liberation Army (PLA) General Hospital and PLA Medical College, Beijing, China
| | - Wenzhi Hu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, Chinese People's Liberation Army (PLA) General Hospital and PLA Medical College, Beijing, China
| | - Xiaowei Bian
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, Chinese People's Liberation Army (PLA) General Hospital and PLA Medical College, Beijing, China.,Tianjin Medical University, Tianjin, China
| | - Siming Yang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, Chinese People's Liberation Army (PLA) General Hospital and PLA Medical College, Beijing, China.,Department of Dermatology, Fourth Medical Center, PLA General Hospital, Beijing, China
| | - Xiaobing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, Chinese People's Liberation Army (PLA) General Hospital and PLA Medical College, Beijing, China.,Department of Dermatology, Fourth Medical Center, PLA General Hospital, Beijing, China
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12
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Singh M, Pandey PK, Bhasin A, Padma MV, Mohanty S. Application of Stem Cells in Stroke: A Multifactorial Approach. Front Neurosci 2020; 14:473. [PMID: 32581669 PMCID: PMC7296176 DOI: 10.3389/fnins.2020.00473] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 04/16/2020] [Indexed: 12/21/2022] Open
Abstract
Stroke has a debilitating effect on the human body and a serious negative effect on society, with a global incidence of one in every six people. According to the World Health Organization, 15 million people suffer stroke worldwide each year. Of these, 5 million die and another 5 million are permanently disabled. Motor and cognitive deficits like hemiparesis, paralysis, chronic pain, and psychomotor and behavioral symptoms can persist long term and prevent the patient from fully reintegrating into society, therefore continuing to add to the costly healthcare burden of stroke. Regenerative medicine using stem cells seems to be a panacea for sequelae after stroke. Stem cell-based therapy aids neuro-regeneration and neuroprotection for neurological recovery in patients. However, the use of stem cells as a therapy in stroke patients still needs a lot of research at both basic and translational levels. As well as the mode of action of stem cells in reversing the symptoms not being clear, there are several clinical parameters that need to be addressed before establishing stem cell therapy in stroke, such as the type of stem cells to be administered, the number of stem cells, the timing of dosage, whether dose-boosters are required, the route of administration, etc. There are upcoming prospects of cell-free therapy also by using exosomes derived from stem cells. There are several ongoing pre-clinical studies aiming to answer these questions. Despite still being in the development stage, stem cell therapy holds great potential for neurological rehabilitation in patients suffering from stroke.
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Affiliation(s)
- Manisha Singh
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, India
- Dr. Solomon H. Snyder Department of Neurosciences, Johns Hopkins University, Baltimore, MD, United States
| | - Pranav K. Pandey
- Dr. R.P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Ashu Bhasin
- Department of Neurosciences, All India Institute of Medical Sciences, New Delhi, India
| | - M. V. Padma
- Department of Neurosciences, All India Institute of Medical Sciences, New Delhi, India
| | - Sujata Mohanty
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, India
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13
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Zahra K, Turnbull MT, Zubair AC, Siegel JL, Venegas-Borsellino CP, Tawk RG, Freeman WD. A Combined Approach to Intracerebral Hemorrhage: Intravenous Mesenchymal Stem Cell Therapy with Minimally Invasive Hematoma Evacuation. J Stroke Cerebrovasc Dis 2020; 29:104931. [PMID: 32689636 DOI: 10.1016/j.jstrokecerebrovasdis.2020.104931] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 04/08/2020] [Accepted: 05/03/2020] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are multipotent stromal cells currently being tested as therapy for a variety of diseases. MSC therapy and hematoma evacuation using a minimally invasive approach are being studied separately to improve clinical outcomes after stroke. We report the first case of a patient with intracerebral hemorrhage (ICH) treated with combination MSC therapy and endoscopic hematoma evacuation. CASE REPORT A 36-year-old woman with a past medical history of essential chronic hypertension and right lung bronchial atresia presented to the emergency department with acute neurologic decline (National Institute of Health Stroke Scale [NIHSS] score, 22). Computed tomography showed a 4.4 × 3.5 × 3.5 cm right basal ganglia hemorrhage with intraventricular extension. An external ventricular drain was placed, and she was enrolled in a Phase I clinical trial investigating intravenous MSC therapy for acute ICH. Continued neurologic deterioration due to increased intracranial pressure led to minimally invasive hematoma evacuation using the Artemis Neuro Evacuation Device (Penumbra, Inc.) on hospital day 4. Follow-up scans showed decreased density and extent of hemorrhage. She was discharged on day 41 with improved neurologic function scores (NIHSS score, 2). At 3-month follow-up, she was walking on her own, but had residual left arm and hand weakness (modified Rankin Score, 2). CONCLUSIONS This case report suggests that the combination of MSC therapy and minimally invasive hematoma evacuation may be safe and well tolerated. Further larger randomized clinical trials are required to identify whether MSC therapy in combination with minimally invasive hematoma evacuation is safe, tolerable, and potentially improves outcomes than either alone.
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Affiliation(s)
- Kaneez Zahra
- Department of Neurology, Mayo Clinic, Jacksonville, FL, United States.
| | - Marion T Turnbull
- Department of Neurology, Mayo Clinic, Jacksonville, FL, United States.
| | - Abba C Zubair
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, United States.
| | - Jason L Siegel
- Department of Neurology, Department of Critical Care Medicine, and Department of Neurologic Surgery, Mayo Clinic, Jacksonville, FL, United States.
| | | | - Rabih G Tawk
- Department of Neurologic Surgery and Department of Radiology, Mayo Clinic, Jacksonville, FL, United States.
| | - William D Freeman
- Department of Neurology, Department of Critical Care Medicine, and Department of Neurologic Surgery, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, United States.
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14
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Hernández R, Jiménez-Luna C, Perales-Adán J, Perazzoli G, Melguizo C, Prados J. Differentiation of Human Mesenchymal Stem Cells towards Neuronal Lineage: Clinical Trials in Nervous System Disorders. Biomol Ther (Seoul) 2020; 28:34-44. [PMID: 31649208 PMCID: PMC6939692 DOI: 10.4062/biomolther.2019.065] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 08/12/2019] [Accepted: 08/12/2019] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been proposed as an alternative therapy to be applied into several pathologies of the nervous system. These cells can be obtained from adipose tissue, umbilical cord blood and bone marrow, among other tissues, and have remarkable therapeutic properties. MSCs can be isolated with high yield, which adds to their ability to differentiate into non-mesodermal cell types including neuronal lineage both in vivo and in vitro. They are able to restore damaged neural tissue, thus being suitable for the treatment of neural injuries, and possess immunosuppressive activity, which may be useful for the treatment of neurological disorders of inflammatory etiology. Although the long-term safety of MSC-based therapies remains unclear, a large amount of both pre-clinical and clinical trials have shown functional improvements in animal models of nervous system diseases following transplantation of MSCs. In fact, there are several ongoing clinical trials evaluating the possible benefits this cell-based therapy could provide to patients with neurological damage, as well as their clinical limitations. In this review we focus on the potential of MSCs as a therapeutic tool to treat neurological disorders, summarizing the state of the art of this topic and the most recent clinical studies.
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Affiliation(s)
- Rosa Hernández
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain.,Department of Anatomy and Embryology, University of Granada, Granada 18016, Spain.,Biosanitary Institute of Granada (ibs.GRANADA), Granada 18012, Spain
| | - Cristina Jiménez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain.,Department of Anatomy and Embryology, University of Granada, Granada 18016, Spain.,Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Epalinges 1066, Switzerland
| | - Jesús Perales-Adán
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
| | - Gloria Perazzoli
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain.,Biosanitary Institute of Granada (ibs.GRANADA), Granada 18012, Spain
| | - Consolación Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain.,Department of Anatomy and Embryology, University of Granada, Granada 18016, Spain.,Biosanitary Institute of Granada (ibs.GRANADA), Granada 18012, Spain
| | - José Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain.,Department of Anatomy and Embryology, University of Granada, Granada 18016, Spain.,Biosanitary Institute of Granada (ibs.GRANADA), Granada 18012, Spain
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15
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Mohammadi A, Maleki-Jamshid A, Milan PB, Ebrahimzadeh K, Faghihi F, Joghataei MT. Intrahippocampal Transplantation of Undifferentiated Human Chorionic- Derived Mesenchymal Stem Cells Does Not Improve Learning and Memory in the Rat Model of Sporadic Alzheimer Disease. Curr Stem Cell Res Ther 2019; 14:184-190. [PMID: 30033876 DOI: 10.2174/1574888x13666180723111249] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 05/22/2018] [Accepted: 06/19/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND OBJECTIVE Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with consequent cognitive impairment and behavioral deficits. AD is characterized by loss of cholinergic neurons and the presence of beta-amyloid protein deposits. Stem cell transplantation seems to be a promising strategy for regeneration of defects in the brain. METHOD One of the suitable type of stem cells originated from fetal membrane is Chorion-derived Mesenchymal Stem Cells (C-MSCs). MSCs were isolated from chorion and characterized by Flowcytometric analysis. Then C-MSCs labeled with DiI were transplanted into the STZ induced Alzheimer disease model in rat. RESULTS Nissl staining and behavior test were used to assess the efficacy of the transplanted cells. Phenotypic and Flowcytometric studies showed that isolated cells were positive for mesenchymal stem cell marker panel with spindle like morphology. CONCLUSION Learning and memory abilities were not improved after stem cell transplantation. C-MSCs transplantation can successfully engraft in injured site but the efficacy and function of transplanted cells were not clinically satisfied.
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Affiliation(s)
- Alireza Mohammadi
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ali Maleki-Jamshid
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.,Pars Advanced and Minimally Invasive medical Manners Research Center, Pars hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Peiman Brouki Milan
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Kaveh Ebrahimzadeh
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Faezeh Faghihi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghi Joghataei
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Neuroscience, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
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16
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Vitorino C, Silva S, Bicker J, Falcão A, Fortuna A. Antidepressants and nose-to-brain delivery: drivers, restraints, opportunities and challenges. Drug Discov Today 2019; 24:1911-1923. [PMID: 31181188 DOI: 10.1016/j.drudis.2019.06.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 05/07/2019] [Accepted: 06/04/2019] [Indexed: 12/17/2022]
Abstract
Why is nose-to-brain delivery considered to be a strategy that directly allows the access of antidepressants to the brain? In which circumstances can the intranasal pathway be applicable? Are there any requirements to follow? What triggers the antidepressant market? Which constraints are imposed during discovery programs? What opportunities can arise and what is their current status of development? Are they already translated into clinical practice? Which challenges are expected from recent development strategies? This review aims at providing a critical appraisal of nose-to-brain delivery of antidepressants, framed within a comprehensive analysis of drivers, restraints, opportunities and challenges.
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Affiliation(s)
- Carla Vitorino
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, Coimbra, Portugal
| | - Soraia Silva
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Joana Bicker
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Amílcar Falcão
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; CIBIT/ICNAS - Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Ana Fortuna
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; CIBIT/ICNAS - Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal.
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17
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Turnbull MT, Zubair AC, Meschia JF, Freeman WD. Mesenchymal stem cells for hemorrhagic stroke: status of preclinical and clinical research. NPJ Regen Med 2019; 4:10. [PMID: 31098299 PMCID: PMC6513857 DOI: 10.1038/s41536-019-0073-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 04/25/2019] [Indexed: 02/06/2023] Open
Abstract
Significant progress has been made during the past few decades in stem cell therapy research for various diseases and injury states; however this has not been overwhelmingly translated into approved therapies, despite much public attention and the rise in unregulated 'regenerative clinics'. In the last decade, preclinical research focusing on mesenchymal stem/stromal cell (MSC) therapy in experimental animal models of hemorrhagic stroke has gained momentum and has led to the development of a small number of human trials. Here we review the current studies focusing on MSC therapy for hemorrhagic stroke in an effort to summarize the status of preclinical and clinical research. Preliminary evidence indicates that MSCs are both safe and tolerable in patients, however future randomized controlled trials are required to translate the promising preclinical research into an effective therapy for hopeful patients.
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Affiliation(s)
| | - Abba C. Zubair
- Department of Laboratory Medicine and Pathology, Mayo Clinic Florida, Jacksonville, FL USA
| | - James F. Meschia
- Department of Neurology, Mayo Clinic Florida, Jacksonville, FL USA
| | - William D. Freeman
- Department of Neurology, Mayo Clinic Florida, Jacksonville, FL USA
- Department of Neurologic Surgery, Mayo Clinic Florida, Jacksonville, FL USA
- Department of Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL USA
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18
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Gao X, Wu D, Dou L, Zhang H, Huang L, Zeng J, Zhang Y, Yang C, Li H, Liu L, Ma B, Yuan Q. Protective effects of mesenchymal stem cells overexpressing extracellular regulating kinase 1/2 against stroke in rats. Brain Res Bull 2019; 149:42-52. [PMID: 31002912 DOI: 10.1016/j.brainresbull.2019.04.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 02/28/2019] [Accepted: 04/09/2019] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Although transplantation of bone marrow-derived mesenchymal stem cells (MSCs) has shown beneficial effects on stroke, lower survival of MSCs limits effects. Extracellular regulating kinase 1/2 signaling (ERK1/2) is crucial for cell survival, differentiation, and proliferation. This study was designed to explore whether MSCs modified by over-expressing ERK1/2 may reinforce beneficial effects on stroke in rats. METHODS rat MSCs transfected with ERK1/2 and empty lentivirus to generate MSCs overexpressing ERK1/2 (ERK/MSCs) and MSCs (as a control), respectively. In vitro, ERK/MSCs were plated and exposed to glutamate-induced condition, and viability of ERK/MSCs was measured. Furthermore, neural induction of ERK/MSCs was investigated in vitro. Cerebral ischemic rats were induced by occluding middle cerebral artery, and then were stereotaxically injected into ipsilateral right lateral ventricle with ERK/MSCs or MSCs 3 days after stroke and survived for 7 or 14 days after injection. RESULTS ERK/MSCs showed better viability in physiological and glutamate-induced neurotoxic conditions compared to MSCs. After neural induction, more neurons were be differentiated from ERK/MSCs than from MSCs. After transplantation, more numbers of grafted cells and improved functional recovery were observed in ERK/MSCs-treated rats compared with MSCs-treated rats. Compared with MSCs treatment, ERK/MSCs treatment significantly increased proliferation of neural stem cells in the subventricle zone (SVZ) and the MAP2/nestin double-labeled cells adjacent to the SVZ, enhanced the numbers of reactive astrocytes while suppressed microglial activation. Besides, TNF-α level was elevated in ERK/MSCs-treated rats. CONCLUSION ERK/MSCs transplantation showed better functional recovery after stroke in rats, likely in part through enhancing survival of MSCs and possibly by modulating the proliferation, neuronal de-differentiation and neuroinflammation.
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Affiliation(s)
- Xiaoqing Gao
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China; Department of Anatomy and Neurobiology, Southwest Medical University, Luzhou, 646000, China
| | - Dandan Wu
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Ling Dou
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Haibo Zhang
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Liang Huang
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Jiaqi Zeng
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Yiiie Zhang
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Chaoxian Yang
- Department of Anatomy and Neurobiology, Southwest Medical University, Luzhou, 646000, China
| | - Huanhuan Li
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Lifen Liu
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Bin Ma
- Department of Molecular and Biomedical Sciences, School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia
| | - Qionglan Yuan
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China.
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19
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Zappa Villar MF, Lehmann M, García MG, Mazzolini G, Morel GR, Cónsole GM, Podhajcer O, Reggiani PC, Goya RG. Mesenchymal stem cell therapy improves spatial memory and hippocampal structure in aging rats. Behav Brain Res 2019; 374:111887. [PMID: 30951751 DOI: 10.1016/j.bbr.2019.04.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 03/31/2019] [Accepted: 04/01/2019] [Indexed: 12/21/2022]
Abstract
There is a growing interest in the potential of mesenchymal stem cells (MSCs) for implementing regenerative medicine in the brain as they have shown neurogenic and immunomodulatory activities. We assessed the effect of intracerebroventricular (icv) administration of human bone marrow-derived MSCs (hBM-MSCs) on spatial memory and hippocampal morphology of senile (27 months) female rats, using 3-months-old counterparts as young controls. Half of the animals were injected in the lateral ventricles (LV) with a suspension containing 5 × 105hBM-MSCs in 8 μl per side. The other half received no treatment (senile controls). Spatial memory performance was assessed with a modified version of the Barnes maze test. We employed one probe trial, one day after training in order to evaluate learning ability as well as spatial memory retention. Neuroblast (DCX) and microglial (Iba-1 immunoreactive) markers were also immunohistochemically quantitated in the animals by means of an unbiased stereological approach. In addition, hippocampal presynaptic protein expression was assessed by immunoblotting analysis. After treatment, the senile MSC-treated group showed a significant improvement in spatial memory accuracy and extended permanence in a one- and 3-hole goal sectors as compared with senile controls. The MSC treatment increased the number of neuroblasts in the hippocampal dentate gyrus, reduced the number of reactive microglial cells, and restored presynaptic protein levels as compared to senile controls. We conclude that icv injected hBM-MSCs are effective in improving spatial memory in senile rats and that the strategy improves some functional and morphologic brain features typically altered in aging rats.
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Affiliation(s)
- Maria F Zappa Villar
- INIBIOLP-Pathology B, School of Medicine, National University of La Plata, Argentina; Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina
| | - Marianne Lehmann
- INIBIOLP-Pathology B, School of Medicine, National University of La Plata, Argentina; Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina
| | - Mariana G García
- Gene Therapy Laboratory, IIMT, School of Medical Science, Austral University, Buenos Aires, Argentina
| | - Guillermo Mazzolini
- Gene Therapy Laboratory, IIMT, School of Medical Science, Austral University, Buenos Aires, Argentina
| | - Gustavo R Morel
- INIBIOLP-Pathology B, School of Medicine, National University of La Plata, Argentina; Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina
| | - Gloria M Cónsole
- Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina
| | - Osvaldo Podhajcer
- Laboratory of Molecular and Cellular Therapy, Fundacion Instituto Leloir, Buenos Aires, Argentina
| | - Paula C Reggiani
- INIBIOLP-Pathology B, School of Medicine, National University of La Plata, Argentina; Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina
| | - Rodolfo G Goya
- INIBIOLP-Pathology B, School of Medicine, National University of La Plata, Argentina; Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina.
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20
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Zhou B, Liu HY, Zhu BL. Protective Role of SOCS3 Modified Bone Marrow Mesenchymal Stem Cells in Hypoxia-Induced Injury of PC12 Cells. J Mol Neurosci 2019; 67:400-410. [DOI: 10.1007/s12031-018-1243-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 12/11/2018] [Indexed: 01/01/2023]
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21
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Gao L, Xu W, Li T, Chen J, Shao A, Yan F, Chen G. Stem Cell Therapy: A Promising Therapeutic Method for Intracerebral Hemorrhage. Cell Transplant 2018; 27:1809-1824. [PMID: 29871521 PMCID: PMC6300771 DOI: 10.1177/0963689718773363] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 03/09/2018] [Accepted: 04/02/2018] [Indexed: 12/28/2022] Open
Abstract
Spontaneous intracerebral hemorrhage (ICH) is one type of the most devastating cerebrovascular diseases worldwide, which causes high morbidity and mortality. However, efficient treatment is still lacking. Stem cell therapy has shown good neuroprotective and neurorestorative effect in ICH and is a promising treatment. In this study, our aim was to review the therapeutic effects, strategies, related mechanisms and safety issues of various types of stem cell for ICH treatment. Numerous studies had demonstrated the therapeutic effects of diverse stem cell types in ICH. The potential mechanisms include tissue repair and replacement, neurotrophy, promotion of neurogenesis and angiogenesis, anti-apoptosis, immunoregulation and anti-inflammation and so forth. The microenvironment of the central nervous system (CNS) can also influence the effects of stem cell therapy. The detailed therapeutic strategies for ICH treatment such as cell type, the number of cells, time window, and the routes of medication delivery, varied greatly among different studies and had not been determined. Moreover, the safety issues of stem cell therapy for ICH should not be ignored. Stem cell therapy showed good therapeutic effect in ICH, making it a promising treatment. However, safety should be carefully evaluated, and more clinical trials are required before stem cell therapy can be extensively applied to clinical use.
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Affiliation(s)
- Liansheng Gao
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
| | - Weilin Xu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
| | - Tao Li
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
| | - Jingyin Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
| | - Anwen Shao
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
| | - Feng Yan
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
| | - Gao Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
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22
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Ye Y, Feng TT, Peng YR, Hu SQ, Xu T. The treatment of spinal cord injury in rats using bone marrow-derived neural-like cells induced by cerebrospinal fluid. Neurosci Lett 2017; 666:85-91. [PMID: 29274438 DOI: 10.1016/j.neulet.2017.12.043] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 12/15/2017] [Accepted: 12/19/2017] [Indexed: 12/13/2022]
Abstract
This study aimed to evaluate the effect of bone mesenchymal stem cells (BMSCs) and BMSC neural-like cells (BMSC-Ns) on the spinal cord injury (SCI) in the rat model of SCI. BMSC-Ns were prepared from the third passage of BMSCs by induction of healthy cerebrospinal fluid (CSF) of an adult human. The SCI rat model was established through a surgical procedure, and after 7 days the rats were randomly divided into 3 (A, B and C) groups. Groups A (BMSC-Ns) and B (BMSCs) were treated with 1 × 106/20 μl cells, while group C (saline) was treated with saline, all via intracerebroventricular injection. After transplantation, the BBB score of group A was significantly higher than that of group B, which in turn was significantly higher than that of group C (P < .05). The levels of Bdnf, Ngf, Ntf3 were statistically significantly higher in group A than those in groups B and C (P < .05). The levels of 5-HT, NA, Ach, DA, GABA in group A were significantly higher than those in groups B and C, whereas the level of Glu was significantly lower in group A than that in groups B and C (P < .05). The histopathological data showed remarkably less necrosis of the spinal cord in group A, compared to that in groups B and C. Transplanting BMSC-Ns or BMSCs into the lateral ventricles improved the neurological function of rats with SCI. Moreover, BMSC-Ns were significantly more effective than BMSCs, which provides a possible approach for the treatment of SCI.
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Affiliation(s)
- Ying Ye
- Institute of Emergency Rescue Medicine & Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Emergency Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
| | - Ting-Ting Feng
- Emergency Center, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, 222000, China
| | - Yi-Ran Peng
- Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
| | - Shu-Qun Hu
- Institute of Emergency Rescue Medicine & Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
| | - Tie Xu
- Institute of Emergency Rescue Medicine & Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Emergency Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China.
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Kovac M, Vasicek J, Kulikova B, Bauer M, Curlej J, Balazi A, Chrenek P. Different RNA and protein expression of surface markers in rabbit amniotic fluid-derived mesenchymal stem cells. Biotechnol Prog 2017; 33:1601-1613. [DOI: 10.1002/btpr.2519] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 05/25/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Michal Kovac
- Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture; Nitra Slovak Republic
- Research Inst. for Animal Production, National Agricultural and Food Centre; Lužianky Slovak Republic
| | - Jaromir Vasicek
- Research Inst. for Animal Production, National Agricultural and Food Centre; Lužianky Slovak Republic
- Research Centre AgroBioTech, Slovak University of Agriculture; Nitra Slovak Republic
| | - Barbora Kulikova
- Research Inst. for Animal Production, National Agricultural and Food Centre; Lužianky Slovak Republic
| | - Miroslav Bauer
- Research Inst. for Animal Production, National Agricultural and Food Centre; Lužianky Slovak Republic
- Faculty of Natural Sciences; Constantine the Philosopher University; Nitra Slovak republic
| | - Jozef Curlej
- Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture; Nitra Slovak Republic
| | - Andrej Balazi
- Research Inst. for Animal Production, National Agricultural and Food Centre; Lužianky Slovak Republic
| | - Peter Chrenek
- Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture; Nitra Slovak Republic
- Research Inst. for Animal Production, National Agricultural and Food Centre; Lužianky Slovak Republic
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Tang X, Qin H, Gu X, Fu X. China’s landscape in regenerative medicine. Biomaterials 2017; 124:78-94. [DOI: 10.1016/j.biomaterials.2017.01.044] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 01/24/2017] [Accepted: 01/28/2017] [Indexed: 12/15/2022]
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Hu Y, Liu N, Zhang P, Pan C, Zhang Y, Tang Y, Deng H, Aimaiti M, Zhang Y, Zhou H, Wu G, Tang Z. Preclinical Studies of Stem Cell Transplantation in Intracerebral Hemorrhage: a Systemic Review and Meta-Analysis. Mol Neurobiol 2016; 53:5269-77. [PMID: 26409481 PMCID: PMC5012148 DOI: 10.1007/s12035-015-9441-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 09/10/2015] [Indexed: 01/15/2023]
Abstract
To comprehensively evaluate the therapeutic effects on both functional and structural outcomes, we performed a meta-analysis of preclinical data on stem cell therapy in intracranial hemorrhage, thus providing optimal evidence and instruction for clinical translation. We searched online databases to identify eligible studies based on unmodified stem cell transplantation in intracranial hemorrhage (ICH). From each study, we extracted data regarding neurobehavioral and histological outcomes in order to analyze the comprehensive effective sizes according to the most important clinical parameters (seven indices) and to explore any potential correlation through meta-regression. We analyzed 40 eligible studies including 1021 animals and found a significant improvement in both behavioral and structural outcomes with the median effect size of 1.77 for modified Neurological Severity Score, 1.16 for the modified placement test, 1.82 for the rotarod test, and 1.24 for tissue loss reduction. The meta-regression results revealed that intracerebral administration was the most effective for behavioral and structural recovery post-ICH; mesenchymal stem cells shared comparable therapeutic effects with neural stem cells. Delayed therapy, applied more than 1 week after ICH, showed the greatest improvement of structural outcomes. Stem cell therapy showed significant improvement on behavioral and structural outcomes of ICH animals with relatively large effect sizes. However, the practical efficacy of the therapy is likely to be lower considering poor study quality and non-negligible publication bias. Further, future research should interpret animal results cautiously considering the limited internal and external validity when referring to the design of both animal studies and clinical trials.
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Affiliation(s)
- Yang Hu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Na Liu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Ping Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Chao Pan
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Youping Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Yingxin Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Hong Deng
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Miribanu Aimaiti
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Ye Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Houguang Zhou
- Department of Geriatrics Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Guofeng Wu
- Department of Neurology, Affiliated Hospital of Guizhou Medical University, Guizhou, 550004, People's Republic of China
| | - Zhouping Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
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Review of Preclinical and Clinical Studies of Bone Marrow-Derived Cell Therapies for Intracerebral Hemorrhage. Stem Cells Int 2016; 2016:4617983. [PMID: 27698671 PMCID: PMC5028871 DOI: 10.1155/2016/4617983] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Accepted: 06/01/2016] [Indexed: 12/22/2022] Open
Abstract
Stroke is the second leading cause of mortality worldwide, causing millions of deaths annually, and is also a major cause of disability-adjusted life years. Hemorrhagic stroke accounts for approximately 10 to 27% of all cases and has a fatality rate of about 50% in the first 30 days, with limited treatment possibilities. In the past two decades, the therapeutic potential of bone marrow-derived cells (particularly mesenchymal stem cells and mononuclear cells) has been intensively investigated in preclinical models of different neurological diseases, including models of intracerebral hemorrhage and subarachnoid hemorrhage. More recently, clinical studies, most of them small, unblinded, and nonrandomized, have suggested that the therapy with bone marrow-derived cells is safe and feasible in patients with ischemic or hemorrhagic stroke. This review discusses the available evidence on the use of bone marrow-derived cells to treat hemorrhagic strokes. Distinctive properties of animal studies are analyzed, including study design, cell dose, administration route, therapeutic time window, and possible mechanisms of action. Furthermore, clinical trials are also reviewed and discussed, with the objective of improving future studies in the field.
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Increased Endothelial Progenitor Cell Levels are Associated with Good Outcome in Intracerebral Hemorrhage. Sci Rep 2016; 6:28724. [PMID: 27346699 PMCID: PMC4921860 DOI: 10.1038/srep28724] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 06/08/2016] [Indexed: 01/25/2023] Open
Abstract
Circulating endothelial progenitor cells (EPCs) play a role in the regeneration of damaged brain tissue. However, the relationship between circulating EPC levels and functional recovery in intracerebral hemorrhage (ICH) has not yet been tested. Therefore, our aim was to study the influence of circulating EPCs on the outcome of ICH. Forty-six patients with primary ICH (males, 71.7%; age, 72.7 ± 10.8 years) were prospectively included in the study within 12 hours of symptom onset. The main outcome variable was good functional outcome at 12 months (modified Rankin scale ≤2), considering residual volume at 6 months as a secondary variable. Circulating EPC (CD34+/CD133+/KDR+) levels were measured by flow cytometry from blood samples obtained at admission, 72 hours and day 7. Our results indicate that patients with good outcome show higher EPC numbers at 72 hours and day 7 (all p < 0.001). However, only EPC levels at day 7 were independently associated with good functional outcome at 12 months (OR, 1.15; CI95%, 1.01–1.35) after adjustment by age, baseline stroke severity and ICH volume. Moreover, EPC levels at day 7 were negatively correlated to residual volume (r = −0.525; p = 0.005). In conclusion, these findings suggest that EPCs may play a role in the functional recovery of ICH patients.
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After Intracerebral Hemorrhage, Oligodendrocyte Precursors Proliferate and Differentiate Inside White-Matter Tracts in the Rat Striatum. Transl Stroke Res 2016; 7:192-208. [PMID: 26743212 PMCID: PMC4873533 DOI: 10.1007/s12975-015-0445-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 12/17/2015] [Accepted: 12/28/2015] [Indexed: 02/06/2023]
Abstract
Damage to myelinated axons contributes to neurological deficits after acute CNS injury, including ischemic and hemorrhagic stroke. Potential treatments to promote re-myelination will require fully differentiated oligodendrocytes, but almost nothing is known about their fate following intracerebral hemorrhage (ICH). Using a rat model of ICH in the striatum, we quantified survival, proliferation, and differentiation of oligodendrocyte precursor cells (OPCs) (at 1, 3, 7, 14, and 28 days) in the peri-hematoma region, surrounding striatum, and contralateral striatum. In the peri-hematoma, the density of Olig2+ cells increased dramatically over the first 7 days, and this coincided with disorganization and fragmentation of myelinated axon bundles. Very little proliferation (Ki67+) of Olig2+ cells was seen in the anterior subventricular zone from 1 to 28 days. However, by 3 days, many were proliferating in the peri-hematoma region, suggesting that local proliferation expands their population. By 14 days, the density of Olig2+ cells declined in the peri-hematoma region, and, by 28 days, it reached the low level seen in the contralateral striatum. At these later times, many surviving axons were aligned into white-matter bundles, which appeared less swollen or fragmented. Oligodendrocyte cell maturation was prevalent over the 28-day period. Densities of immature OPCs (NG2+Olig2+) and mature (CC-1+Olig2+) oligodendrocytes in the peri-hematoma increased dramatically over the first week. Regardless of the maturation state, they increased preferentially inside the white-matter bundles. These results provide evidence that endogenous oligodendrocyte precursors proliferate and differentiate in the peri-hematoma region and have the potential to re-myelinate axon tracts after hemorrhagic stroke.
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Mohammad M, Yaseen N, Al-Joubory A, Abdullah R, Mahmood N, Ahmed AA, Al-Shammari A. Production of Neural Progenitors from Bone Marrow Mesenchymal Stem Cells. ACTA ACUST UNITED AC 2016. [DOI: 10.4236/scd.2016.61001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Wharton's jelly derived mesenchymal stromal cells: Biological properties, induction of neuronal phenotype and current applications in neurodegeneration research. Acta Histochem 2015; 117:329-38. [PMID: 25747736 DOI: 10.1016/j.acthis.2015.02.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Revised: 01/31/2015] [Accepted: 02/08/2015] [Indexed: 02/06/2023]
Abstract
Multipotent mesenchymal stromal cells, also known as mesenchymal stem cells (MSC), can be isolated from bone marrow or other tissues, including fat, muscle and umbilical cord. It has been shown that MSC behave in vitro as stem cells: they self-renew and are able to differentiate into mature cells typical of several mesenchymal tissues. Moreover, the differentiation toward non-mesenchymal cell lineages (e.g. neurons) has been reported as well. The clinical relevance of these cells is mainly related to their ability to spontaneously migrate to the site of inflammation/damage, to their safety profile thanks to their low immunogenicity and to their immunomodulation capacities. To date, MSCs isolated from the post-natal bone marrow have represented the most extensively studied population of adult MSCs, in view of their possible use in various therapeutical applications. However, the bone marrow-derived MSCs exhibit a series of limitations, mainly related to their problematic isolation, culturing and use. In recent years, umbilical cord (UC) matrix (i.e. Wharton's jelly, WJ) stromal cells have therefore emerged as a more suitable alternative source of MSCs, thanks to their primitive nature and the easy isolation without relevant ethical concerns. This review seeks to provide an overview of the main biological properties of WJ-derived MSCs. Moreover, the potential application of these cells for the treatment of some known dysfunctions in the central and peripheral nervous system will also be discussed.
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Cordeiro MF, Horn AP. Stem cell therapy in intracerebral hemorrhage rat model. World J Stem Cells 2015; 7:618-629. [PMID: 25914768 PMCID: PMC4404396 DOI: 10.4252/wjsc.v7.i3.618] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 12/03/2014] [Accepted: 12/19/2014] [Indexed: 02/06/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is a very complex pathology, with many different not fully elucidated etiologies and prognostics. It is the most severe subtype of stroke, with high mortality and morbidity rates. Unfortunately, despite the numerous promising preclinical assays including neuroprotective, anti-hypertensive, and anti-inflammatory drugs, to this moment only symptomatic treatments are available, motivating the search for new alternatives. In this context, stem cell therapy emerged as a promising tool. However, more than a decade has passed, and there is still much to be learned not only about stem cells, but also about ICH itself, and how these two pieces come together. To date, rats have been the most widely used animal model in this research field, and there is much more to be learned from and about them. In this review, we first summarize ICH epidemiology, risk factors, and pathophysiology. We then present different methods utilized to induce ICH in rats, and examine how accurately they represent the human disease. Next, we discuss the different types of stem cells used in previous ICH studies, also taking into account the tested transplantation sites. Finally, we summarize what has been achieved in assays with stem cells in rat models of ICH, and point out some relevant issues where attention must be given in future efforts.
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Xin H, Li Y, Chopp M. Exosomes/miRNAs as mediating cell-based therapy of stroke. Front Cell Neurosci 2014; 8:377. [PMID: 25426026 PMCID: PMC4226157 DOI: 10.3389/fncel.2014.00377] [Citation(s) in RCA: 222] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 10/22/2014] [Indexed: 12/19/2022] Open
Abstract
Cell-based therapy, e.g., multipotent mesenchymal stromal cell (MSC) treatment, shows promise for the treatment of various diseases. The strong paracrine capacity of these cells and not their differentiation capacity, is the principal mechanism of therapeutic action. MSCs robustly release exosomes, membrane vesicles (~30–100 nm) originally derived in endosomes as intraluminal vesicles, which contain various molecular constituents including proteins and RNAs from maternal cells. Contained among these constituents, are small non-coding RNA molecules, microRNAs (miRNAs), which play a key role in mediating biological function due to their prominent role in gene regulation. The release as well as the content of the MSC generated exosomes are modified by environmental conditions. Via exosomes, MSCs transfer their therapeutic factors, especially miRNAs, to recipient cells, and therein alter gene expression and thereby promote therapeutic response. The present review focuses on the paracrine mechanism of MSC exosomes, and the regulation and transfer of exosome content, especially the packaging and transfer of miRNAs which enhance tissue repair and functional recovery. Perspectives on the developing role of MSC mediated transfer of exosomes as a therapeutic approach will also be discussed.
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Affiliation(s)
- Hongqi Xin
- Department of Neurology, Henry Ford Hospital Detroit, MI, USA
| | - Yi Li
- Department of Neurology, Henry Ford Hospital Detroit, MI, USA
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital Detroit, MI, USA ; Department of Physics, Oakland University Rochester, MI, USA
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Prakash A, Medhi B, Chopra K. Granulocyte colony stimulating factor (GCSF) improves memory and neurobehavior in an amyloid-β induced experimental model of Alzheimer's disease. Pharmacol Biochem Behav 2013; 110:46-57. [PMID: 23756182 DOI: 10.1016/j.pbb.2013.05.015] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2012] [Revised: 05/21/2013] [Accepted: 05/25/2013] [Indexed: 10/26/2022]
Abstract
GCSF is an endogenous neuronal hematopoietic factor that displays robust in vitro and in vivo neuroprotective activity. The present study aimed to evaluate the effect of GCSF on Aβ-induced memory loss in an Alzheimer's disease model of rats. A total of 42 male adult Wistar rats weighing 200-250 g were used in the study and were divided into 7 experimental groups. Animals were subjected to intracerebroventricular (ICV) injection stereotaxically at day 0 to instill amyloid-β(1-42) (Aβ(1-42)) or PBS (sham operated group) at 10 μl (5 μl bilaterally). GCSF treatment was given from day 7 to 12 of Aβ injection. On day 21, behavioral tests (short term memory, exploratory behavior and motor coordination) in all groups were evaluated. Biochemical parameters and RNA expression were measured to ensure the efficacy of GCSF. GCSF (35 and 70 μg/kg, s.c.) showed statistically significant improvement in memory as compared to control and sham operated groups (p<0.05). Mean time spent in the platform placed quadrant was found to be significantly increased in the GCSF (70 μg/kg, s.c.) as compared to GCSF (35 μg/kg, s.c.) and GCSF (10 μg/kg, s.c.) groups (p<0.001). GCSF (35 and 70 μg/kg, s.c.) also improved motor coordination and exploratory behavior significantly as compared to naïve sham operated and GCSF (10 μg/kg, s.c.) groups (p<0.05). Improvement in memory by GCSF (35 and 70 μg/kg, s.c.) was coupled with marked reduction of lipid peroxidation, acetylcholinesterase levels and a significant increase in antioxidant enzymes as well as total RNA expression in the brain. Additionally, GCSF (35 and 70 μg/kg, s.c.) significantly increased progenitor cells (iPSCs) and surface marker CD34+ in the brain and hence induced neurogenesis. The present findings demonstrate an improvement of memory and neurobehavioral function with GCSF in Aβ-induced Alzheimer's disease model in rats.
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Affiliation(s)
- Ajay Prakash
- Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
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Bao XJ, Liu FY, Lu S, Han Q, Feng M, Wei JJ, Li GL, Zhao RCH, Wang RZ. Transplantation of Flk-1+ human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and anti-inflammatory and angiogenesis effects in an intracerebral hemorrhage rat model. Int J Mol Med 2013; 31:1087-96. [PMID: 23468083 DOI: 10.3892/ijmm.2013.1290] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Accepted: 01/30/2013] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been successfully used for the treatment of experimental intracerebral hemorrhage (ICH). However, the neuroprotective mechanisms through which MSCs improve neurological functional recovery are not fully understood. In the present study, we tested the hypothesis that treatment with MSCs inhibits inflammation after ICH and reduces subsequent brain injury. Adult rats subjected to stereotaxic injection of collagenase VII were transplanted with a subpopulation of human bone marrow-derived MSCs (hBMSCs), termed fetal liver kinase (Flk)-1(+) hBMSCs, or saline into the ipsilateral brain parenchyma 1 day after ICH. Significant recovery of behavior was noted in the Flk-1(+) hBMSC-treated rats beginning 3 days after ICH compared with the control group. Brain water content was significantly decreased in the ipsilateral hemispheres of the Flk-1(+) hBMSC-treated rats when compared with the controls 3 days after ICH. The relative hemorrhage volume was reduced 55 days after Flk-1(+) hBMSC treatment. However, this change was not statistically significant. Flk-1(+) hBMSCs significantly inhibited the proliferation of rat peripheral blood mononuclear cells (rPBMCs) induced in a mixed lymphocyte reaction. Consistently, we found a significant anti-inflammatory effect of Flk-1(+) hBMSCs on the ICH brain, including a decrease in neutrophil infiltration and microglial activation in the peri-ICH area, and downregulation of inflammatory mediators, such as interleukin (IL)-1β, IL-2, IL-4, IL-6, and tumor necrosis factor (TNF)-α. In addition, Flk-1+ hBMSC treatment significantly increased vascular density in the peri-ICH area, and transplanted Flk-1(+) hBMSCs were found to be incorporated into the cerebral vasculature 55 days after transplantation. Overall, these data suggest an essential role for Flk-1(+) hBMSCs in reducing inflammatory infiltration, promoting angiogenesis, and improving functional recovery after ICH in rats.
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Affiliation(s)
- Xin-Jie Bao
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
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Seghatoleslam M, Jalali M, Nikravesh MR, Hamidi Alamdari D, Hosseini M, Fazel A. Intravenous administration of human umbilical cord blood-mononuclear cells dose-dependently relieve neurologic deficits in rat intracerebral hemorrhage model. Ann Anat 2013; 195:39-49. [PMID: 22770555 DOI: 10.1016/j.aanat.2012.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Revised: 05/05/2012] [Accepted: 05/07/2012] [Indexed: 01/01/2023]
Abstract
Human umbilical cord blood (HUCB) is now considered as a valuable source for stem cell-based therapies. Previous studies showed that intravascular injection of the HUCB significantly improves neurological functional recovery in a model of intracerebral hemorrhage (ICH). To extend these findings, we examined the behavioral recovery and injured volume in the presence of increasing doses of human umbilical cord blood derived mononuclear cells (HUC-MCs) after intracerebral hemorrhage in rats. The experimental ICH was induced by intrastriatal administration of bacterial collagenase IV in adult rats. One day after the surgery, the rats were randomly divided into 4 groups to receive intravenously either BrdU positive human UC-MCs (4 × 10(6), 8 × 10(6) and 16 × 10(6) cells in 1 ml saline, n=10, respectively) as treated groups or the same amount of saline as lesion group (n=10). There was also one group (control n=10) that received only the vehicle solution of collagenase. The animals were evaluated for 14 days with modified limb placing and corner turn tests. The transplanted human UC-MCs were also detected by immunohistochemistry with labeling of BrdU. Two weeks after infusion, there was a significant recovery in the behavioral performance when 4 × 10(6) or more UC-MCs were delivered (P<0.05-0.001). Injured volume measurements disclosed an inverse relationship between UC-MCs dose and damage reaching significance at the higher UC-MCs doses. Moreover, human UC-MCs were localized by immunohistochemistry only in the injured area. Intravenously transplanted UC-MCs can accelerate the neurological function recovery of ICH rat and diminish the striatum lesion size by demonstrating a dose relationship between them.
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Affiliation(s)
- Masoumeh Seghatoleslam
- Department of Anatomy & Cell Biology, Medical Faculty, Mashhad University of Medical Sciences, Khorasan Razavi, Iran
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Chen J, Tang YX, Liu YM, Chen J, Hu XQ, Liu N, Wang SX, Zhang Y, Zeng WG, Ni HJ, Zhao B, Chen YF, Tang ZP. Transplantation of adipose-derived stem cells is associated with neural differentiation and functional improvement in a rat model of intracerebral hemorrhage. CNS Neurosci Ther 2012; 18:847-54. [PMID: 22934896 DOI: 10.1111/j.1755-5949.2012.00382.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 06/27/2012] [Accepted: 07/05/2012] [Indexed: 12/14/2022] Open
Abstract
AIMS To examine whether transplantation of adipose-derived stem cells (ADSCs) induces neural differentiation and improves neural function in a rat intracerebral hemorrhage (ICH) model. METHODS Adipose-derived stem cells cells were isolated from inguinal fat pad of rat. ICH was induced by injection of collagenase type IV into the right basal ganglia of rat. Forty-eight hours after ICH, ADSCs cells (10 μL of 2-4 × 10(7) cells/mL) were injected into the right lateral cerebral ventricle. The differentiation of ADSCs was detected in vitro and in vivo. The neural function was evaluated with Zea Longa 5-grade scale at day 1, 3, 7, 14, or 28. RESULTS Our data demonstrated that ADSCs differentiated into cells that shared the similarities of neurons or astrocytes in vitro. Transplantation of ADSCs decreased cell apoptosis and the transplanted ADSCs were able to differentiate into neuron-like and astrocyte-like cells around the hematoma, accompanied with upregulation of vascular endothelial growth factor expression and improvement of neural function. CONCLUSIONS Our data suggest that transplantation of ADSCs could be a therapeutic approach for ICH stroke.
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Affiliation(s)
- Juan Chen
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Neurology, University Hospital of Hubei Institute for Nationalities, Enshi, China
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Wang SP, Wang ZH, Peng DY, Li SM, Wang H, Wang XH. Therapeutic effect of mesenchymal stem cells in rats with intracerebral hemorrhage: reduced apoptosis and enhanced neuroprotection. Mol Med Rep 2012; 6:848-54. [PMID: 22825663 DOI: 10.3892/mmr.2012.997] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2012] [Accepted: 06/21/2012] [Indexed: 01/27/2023] Open
Abstract
Stem cell transplantation has been used to improve neural function in intracerebral hemorrhage (ICH). However, reports on bone marrow-derived mesenchymal stem cell (MSC) transplantation in ICH are limited. We aimed to explore the therapeutic effect and related mechanisms by transplantation of MSCs in rats with ICH. An experimental rat ICH model was established by intrastriatal administration of collagenase. The rats were randomly divided to receive either rat MSCs or PBS solution intravenously. In addition, behavioral tests using the modified neurological severity score (mNSS) were performed following ICH. Immunohistochemistry was performed to detect the Brdu-labeled MSCs and the protein expression of caspase 2, NF200 and GFAP in neural tissues. Western blotting and ELISA were performed to measure the protein expression of Akt and bcl-2 or the protein content of G-CSF and BDNF. The MSC-transplanted group demonstrated better neural function on the mNSS test following ICH compared with the control group (P<0.05). The MSC-transplanted group also showed reduced hemorrhage volume at 24 and 72 h following ICH. In the perihematomal regions of rat brain with ICH, a substantial number of Brdu-labeled MSCs were observed, and a high protein expression of caspase 3, NF200 and GFAP was found in the MSC-transplanted group. The protein content of Akt, Bcl-2, G-CSF and BDNF were all elevated by MSC transplantation. Intravenously transplanted MSCs are capable of improving functional recovery and restoring neurological deficits in experimental ICH. The mechanisms are associated with enhanced survival and differentiation of neural cells, and increased expression of anti-apoptotic proteins and trophic factors.
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Affiliation(s)
- Su-Ping Wang
- The First Department of Neurology, Dalian Central Hospital, Dalian, Liaoning 116033, PR China.
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Li ZM, Zhang ZT, Guo CJ, Geng FY, Qiang F, Wang LX. Autologous bone marrow mononuclear cell implantation for intracerebral hemorrhage-a prospective clinical observation. Clin Neurol Neurosurg 2012; 115:72-6. [PMID: 22657095 DOI: 10.1016/j.clineuro.2012.04.030] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Revised: 04/06/2012] [Accepted: 04/28/2012] [Indexed: 01/01/2023]
Abstract
BACKGROUND This study was designed to assess the clinical effect of bone marrow mononuclear cells including mesenchymal stem cell (MSCs) in patients with intracerebral hemorrhage (ICH). METHODS One hundred patients were divided into a study (n=60) or a control group (n=40). Bone marrow mononuclear cells from the same patient were injected to the perihemorrhage area in the base ganglia through an intracranial drainage tube 5.9 days after ICH. National Institute Stroke Scale (NIHSSS) and Barthel index was used to assess neurologic impairment and daily activities, respectively, before and 6 months after intervention. RESULTS Six months after implantation, the NIHSS score in the study group was lower than in the control group (10.09 ± 8.86 vs 14.35 ± 10.14, P<0.01), whereas the Barthel scores were higher (57.39 ± 23.51 vs 46.90 ± 20.29, P<0.01). Neurological and functional improvement was observed in 52 (86.7%) of the study group patients, and in 17 (42.5%) of the control group patients (P=0.001). No allergic or other adverse effects were observed in the study group. CONCLUSION Autologous bone marrow mononuclear cell implantation reduced neurological impairment and improved activities of daily living in a selected group of ICH patients. Further studies are required to ascertain the long-term safety and efficacy of this treatment.
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Affiliation(s)
- Zhong-Min Li
- Department of Neurosurgery, Liaocheng People's Hospital of Taishan Medical University, Liaocheng, Shandong 252000, PR China.
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Markers for characterization of bone marrow multipotential stromal cells. Stem Cells Int 2012; 2012:975871. [PMID: 22666272 PMCID: PMC3361338 DOI: 10.1155/2012/975871] [Citation(s) in RCA: 193] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2012] [Accepted: 02/29/2012] [Indexed: 12/13/2022] Open
Abstract
Given the observed efficacy of culture-expanded multipotential stromal cells, also termed mesenchymal stem cells (MSCs), in the treatment of graft-versus host and cardiac disease, it remains surprising that purity and potency characterization of manufactured cell batches remains rather basic. In this paper, we will initially discuss surface and molecular markers that were proposed to serve as the indicators of the MSC potency, in terms of their proliferative potential or the ability to differentiate into desired lineages. The second part of this paper will be dedicated to a critical discussion of surface markers of uncultured (i.e., native) bone marrow (BM) MSCs. Although no formal consensus has yet been reached on which markers may be best suited for prospective BM MSC isolation, markers that cross-react with MSCs of animal models (such as CD271 and W8-B2/MSCA-1) may have the strongest translational value. Whereas small animal models are needed to discover the in vivo function on these markers, large animal models are required for safety and efficacy testing of isolated MSCs, particularly in the field of bone and cartilage tissue engineering.
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Yang C, Zhou L, Gao X, Chen B, Tu J, Sun H, Liu X, He J, Liu J, Yuan Q. Neuroprotective effects of bone marrow stem cells overexpressing glial cell line-derived neurotrophic factor on rats with intracerebral hemorrhage and neurons exposed to hypoxia/reoxygenation. Neurosurgery 2011; 68:691-704. [PMID: 21311297 DOI: 10.1227/neu.0b013e3182098a8a] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Intracerebral hemorrhage (ICH) represents at least 15% of all strokes in the Western population and a considerably higher proportion at 50% to 60% in the Oriental population. OBJECTIVE To investigate whether administration of bone marrow stem cells (BMSCs) overexpressing glial cell line-derived neurotrophic factor (GDNF) provides more efficient neuroprotection for rats with ICH and neurons exposed to hypoxia/reoxygenation. METHODS Primary rat BMSCs were transfected with rat GDNF gene using virus vector (GDNF/BMSCs) and blank virus plasmid (BVP/BMSCs). Primary rat cortical neurons of rats were exposed to hypoxia and then reoxygenated with GDNF/BMSCs (GDNF/BMSCs group) or BVP/BMSCs (BMSCs group) treatment for 12 hours and 1, 2, 3, and 5 days. Hoechst 33258 staining was used to evaluate apoptosis. GDNF/BMSCs, BVP/BMSCs, and saline (GDNF/BMSCs, BMSCs, and control groups) were injected into the right striatum 3 days after rat ICH induced by injecting collagenase. Modified neurological severity scores and hematoxylin and eosin staining were performed to evaluate neurological function and lesion volume at 1 and 2 weeks after transplantation. Immunostaining was used to observe differentiation of grafted cells (neurofilament-200 for neurons, glial fibrillary acidic protein for astrocytes). The GDNF level and apoptosis were evaluated by Western blotting and terminal deoxynucleotidyl transferase dUTP nick-end labeling, respectively. RESULTS The GDNF/BMSCs group had significantly lowered apoptosis compared with the BMSCs group at the given time. The GDNF/BMSCs group had significantly improved functional deficits and reduced lesion volume compared with the BMSCs group. Stable GDNF expression in the GDNF/BMSCs group was detected at the given time in the host brain. The neurofilament-positive grafted cells in the GDNF/BMSCs group were more numerous than in the BMSCs group. The GDNF/BMSCs group had significantly decreased apoptotic cells compared with the BMSCs group. CONCLUSION These results suggest that GDNF/BMSCs provide better neuroprotection for rats with ICH and neurons exposed to hypoxia/reoxygenation.
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Affiliation(s)
- Chaoxian Yang
- Department of Anatomy and Neurobiology, Tongji University School of Medicine, and Department of Plastic and Reconstructive Surgery, 9th People's Hospital, Shanghai, China
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Sobrino T, Arias S, Pérez-Mato M, Agulla J, Brea D, Rodríguez-Yáñez M, Castillo J. Cd34+ progenitor cells likely are involved in the good functional recovery after intracerebral hemorrhage in humans. J Neurosci Res 2011; 89:979-85. [PMID: 21488087 DOI: 10.1002/jnr.22627] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Revised: 01/12/2011] [Accepted: 01/19/2011] [Indexed: 11/09/2022]
Abstract
Bone marrow-derived stem/progenitor cells (CD34(+) progenitor cells) were demonstrated to play an important role in the regeneration of damaged brain tissue. Our aim was to study the influence of CD34(+) progenitor cells in the outcome of intracerebral hemorrhage (ICH). Thirty-two patients with primary ICH (64.0% male, mean age 67.1 ± 10.8 years) were prospectively included in the study within 12 hr of symptom onset. The main outcome variable was good functional outcome at 3 months (modified Rankin scale ≤ 2). Circulating CD34(+) progenitor cell levels were measured by flow cytometry at admission and at 7 ± 1 days, and serum levels of growth factors (determined by ELISA) were measured at admission and at 24 and 72 hr. Circulating levels of CD34(+) progenitor cells at day 7 were independently associated with good functional outcome at 3 months (OR 1.17, CI95% 1.06-1.39, P = 0.012). On the other hand, CD34(+) progenitor cells at day 7 were negatively correlated with residual cavity volume at 3 months (r = -0.607, P = 0.001). Serum levels of vascular endothelial growth factor (r = 0.386), angiopoietin 1 (r = 0.518), brain-derived neurotrophic factor (r = 0.484), and stromal cell-derived factor-1α (r = 0.837) but not granulocyte-colony stimulating factor (r = -0.038) at 72 hr showed a strong correlation with CD34(+) progenitor cell levels at day 7. These findings suggest that CD34(+) progenitor cells may participate in the functional recovery of ICH patients.
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Affiliation(s)
- Tomás Sobrino
- Department of Neurology, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.
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Liu AM, Lu G, Tsang KS, Li G, Wu Y, Huang ZS, Ng HK, Kung HF, Poon WS. Umbilical cord-derived mesenchymal stem cells with forced expression of hepatocyte growth factor enhance remyelination and functional recovery in a rat intracerebral hemorrhage model. Neurosurgery 2011; 67:357-65; discussion 365-6. [PMID: 20644422 DOI: 10.1227/01.neu.0000371983.06278.b3] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Spontaneous intracerebral hemorrhage (ICH) carries a high mortality rate, with survivors commonly left with permanent neurological deficits. Mesenchymal stem cell (MSC) transplantation promotes functional recovery in experimental ICH, and treatment with hepatocyte growth factor (HGF) is beneficial in ischemic stroke. OBJECTIVE We hypothesize that transplantation of MSCs with previous transduction of HGF has an additive effect in promoting neurological recovery through myelin and axonal regeneration. METHODS HGF transduction to human umbilical cord-derived MSCs using lentiviral plasmid pWPI-HGF-GFP was prepared. One week after a collagenase-induced ICH, 80 male Sprague-Dawley rats were divided into 3 groups for stereotactic injection of phosphate-buffered saline (group I), MSC transplant (group II), and HGF-transduced MSC transplant (group III), respectively, into the left ventricle. The animals were assessed weekly for 5 weeks using the Rotarod motor function test, at which time they were killed for Luxol fast blue myelin staining and appropriate immunohistochemistry and Western blotting. RESULTS Animals receiving transplanted HGF-transduced MSCs (group III) exhibited significantly better motor function recovery than animals treated with MSCs alone (group II), which in turn performed better than the phosphate-buffered saline controls at 2 weeks after transplantation. Luxol fast blue staining of myelin displayed significantly less demyelination and significantly higher reactivity in myelin basic protein and growth-associated protein-43 in immunohistochemistry and Western blotting and significantly reduced myelin-associated glycoprotein activity in group III animals. CONCLUSION Animals transplanted with HGF-transduced MSCs 1 week after experimental ICH were shown to achieve a better neurological recovery. This improved neurological recovery from ICH is attributed to nerve fiber remyelination and axonal regeneration.
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Affiliation(s)
- An Min Liu
- Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
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Feng M, Zhu H, Zhu Z, Wei J, Lu S, Li Q, Zhang N, Li G, Li F, Ma W, An Y, Zhao RC, Qin C, Wang R. Serial 18F-FDG PET demonstrates benefit of human mesenchymal stem cells in treatment of intracerebral hematoma: a translational study in a primate model. J Nucl Med 2011; 52:90-97. [PMID: 21149480 DOI: 10.2967/jnumed.110.080325] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED This study evaluated the efficacy of human mesenchymal stem cells (hMSCs) in the treatment of intracerebral hematoma (ICH) using a primate model and serial 18F-FDG PET scans. METHODS Twenty-four Macaca fascicularis monkeys (male, 4.2±0.2 kg) were enrolled. The ICH models were established using a stereo-guided injection of 1.5 mL of autologous arterial blood between the right cortex and basal ganglia. One week (early treatment group, n=8) or 4 wk (late treatment group, n=8) after an ICH was established, (1-5)×10(6) hMSCs were transplanted near the hematoma using a stereotactic method. Control monkeys received saline only, either 1 or 4 wk (n=4 for each subgroup) after ICH establishment. The efficacy of treatment was evaluated by serial 18F-FDG PET scans (n=19) and neurologic deficit scoring weekly or biweekly. Pathologic analysis was performed 8 wk after hMSC transplantation. RESULTS One week after hMSC injection, higher 18F-FDG accumulated at the ipsilateral basal ganglia in both early and late hMSC-treated groups, indicating an early response to the treatment. When recovery reached a plateau, 18F-FDG uptake in the adjacent cortex was significantly higher in the early treatment group (P<0.05). The neurologic deficit scoring was significantly lower in the hMSC-treated groups, which also indicated better recovery. Pathologic analysis revealed higher vessel density surrounding the remains of hematoma in the hMSC-treated groups. CONCLUSION This preliminary study indicates that transplantation of hMSCs may improve the recovery from ICH in a primate model, and early treatment may lead to better results.
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Affiliation(s)
- Ming Feng
- Department of Neurosurgery of Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior. Mol Psychiatry 2010; 15:1164-75. [PMID: 19859069 DOI: 10.1038/mp.2009.110] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Adult bone marrow-derived mesenchymal stem cells (MSCs) are regarded as potential candidates for treatment of neurodegenerative disorders, because of their ability to promote neurogenesis. MSCs promote neurogenesis by differentiating into neural lineages as well as by expressing neurotrophic factors that enhance the survival and differentiation of neural progenitor cells. Depression has been associated with impaired neurogenesis in the hippocampus and dentate gyrus. Therefore, the aim of this study was to analyze the therapeutic potential of MSCs in the Flinders sensitive line (FSL), a rat animal model for depression. Rats received an intracerebroventricular injection of culture-expanded and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled bone marrow-derived MSCs (10⁵ cells). MSC-transplanted FSL rats showed significant improvement in their behavioral performance, as measured by the forced swim test and the dominant-submissive relationship (DSR) paradigm. After transplantation, MSCs migrated mainly to the ipsilateral dentate gyrus, CA1 and CA3 regions of the hippocampus, and to a lesser extent to the thalamus, hypothalamus, cortex and contralateral hippocampus. Neurogenesis was increased in the ipsilateral dentate gyrus and hippocampus of engrafted rats (granular cell layer) and was correlated with MSC engraftment and behavioral performance. We therefore postulate that MSCs may serve as a novel modality for treating depressive disorders.
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Intravenous infusion of bone marrow mesenchymal stem cells improves brain function after resuscitation from cardiac arrest. Crit Care Med 2010; 36:S486-91. [PMID: 20449915 DOI: 10.1097/ccm.0b013e31818a8ff0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Allogeneic bone marrow mesenchymal stem cells were previously shown to improve myocardial function when administered intravenously after resuscitation from cardiac arrest in rats. Coincidental evidence of improved brain function prompted the present study. DESIGN Prospective, randomized, controlled study. SETTING University-affiliated research institute. SUBJECTS Male Sprague-Dawley rats. INTERVENTIONS Using an established model in 20 male Sprague-Dawley rats in which 6 mins of untreated cardiac arrest was followed by cardiopulmonary resuscitation, animals were randomized to receive 5 x 10(6) mesenchymal stem cells labeled with PKH26 in phosphate buffer solution or phosphate buffer solution alone as a placebo at 2 hrs after restoration of spontaneous circulation. The stem cells or buffer diluent were injected into a catheter advanced from the jugular vein into the right atrium. MEASUREMENTS AND MAIN RESULTS Outcome measurements in addition to 35-day survival included somatosensor testing of capability for removal of an adhesive patch applied to both front paws, testing of motor function using a rotating cylinder, and observational scoring of the severity of neurologic impairment. Labeled mesenchymal stem cells were subsequently identified and counted in 5 microm sections obtained from defined sites in the harvested brain. Immunohistochemistry was used to identify neural cells differentiation of mesenchymal stem cells. Adhesive removal, motor function test, neurologic severity score, and 35-day survival were each significantly improved in comparison with control animals. Labeled mesenchymal stem cells were identified in the hippocampus, cortex, pons, medulla, and cerebellum and expressed protein markers phenotypic neural cells. CONCLUSIONS Mesenchymal stem cells injected into the right atrium of rats after resuscitation from cardiac arrest were identified in brains harvested 35 days later. Brain function was significantly improved. Accordingly, venous injection of mesenchymal stem cells after cardiopulmonary resuscitation has promise of minimizing the severity of postresuscitation neurologic impairment.
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Siniscalco D, Giordano C, Galderisi U, Luongo L, Alessio N, Di Bernardo G, de Novellis V, Rossi F, Maione S. Intra-brain microinjection of human mesenchymal stem cells decreases allodynia in neuropathic mice. Cell Mol Life Sci 2010; 67:655-669. [PMID: 19937263 PMCID: PMC11115751 DOI: 10.1007/s00018-009-0202-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2009] [Revised: 10/30/2009] [Accepted: 11/03/2009] [Indexed: 12/16/2022]
Abstract
Neuropathic pain is a very complex disease, involving several molecular pathways. Current available drugs are usually not acting on the several mechanisms underlying the generation and propagation of pain. We used spared nerve injury model of neuropathic pain to assess the possible use of human mesenchymal stem cells (hMSCs) as anti-neuropathic tool. Human MSCs were transplanted in the mouse lateral cerebral ventricle. Stem cells injection was performed 4 days after sciatic nerve surgery. Neuropathic mice were monitored 7, 10, 14, 17, and 21 days after surgery. hMSCs were able to reduce pain-like behaviors, such as mechanical allodynia and thermal hyperalgesia, once transplanted in cerebral ventricle. Anti-nociceptive effect was detectable from day 10 after surgery (6 days post cell injection). Human MSCs reduced the mRNA levels of the pro-inflammatory interleukin IL-1beta mouse gene, as well as the neural beta-galactosidase over-activation in prefrontal cortex of SNI mice. Transplanted hMSCs were able to reduce astrocytic and microglial cell activation.
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Affiliation(s)
- Dario Siniscalco
- Division of Pharmacology L. Donatelli, Department of Experimental Medicine, Second University of Naples, 80138 Naples, Italy.
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Lee JK, Lee JH. A study on differentiation potency of adult stem cells from pulp, periodontal ligament, and dental follicle to osteoblast. J Korean Assoc Oral Maxillofac Surg 2010. [DOI: 10.5125/jkaoms.2010.36.1.7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Affiliation(s)
- Joong-Kyou Lee
- Department of Oral and Maxillofacial Surgery, College of Dentistry, Dankook University, Korea
| | - Jae-Hoon Lee
- Department of Oral and Maxillofacial Surgery, College of Dentistry, Dankook University, Korea
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Bonilla C, Zurita M, Otero L, Aguayo C, Vaquero J. Delayed intralesional transplantation of bone marrow stromal cells increases endogenous neurogenesis and promotes functional recovery after severe traumatic brain injury. Brain Inj 2009; 23:760-9. [DOI: 10.1080/02699050903133970] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Kuo TK, Ho JH, Lee OK. Mesenchymal Stem Cell Therapy for Nonmusculoskeletal Diseases: Emerging Applications. Cell Transplant 2009; 18:1013-28. [DOI: 10.3727/096368909x471206] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Mesenchymal stem cells are stem/progenitor cells originated from the mesoderm and can different into multiple cell types of the musculoskeletal system. The vast differentiation potential and the relative ease for culture expansion have established mesenchymal stem cells as the building blocks in cell therapy and tissue engineering applications for a variety of musculoskeletal diseases, including repair of fractures and bone defects, cartilage regeneration, treatment of osteonecrosis of the femoral head, and correction of genetic diseases such as osteogenesis imperfect. However, research in the past decade has revealed differentiation potentials of mesenchymal stem cells beyond lineages of the mesoderm, suggesting broader applications than originally perceived. In this article, we review the recent developments in mesenchymal stem cell research with respect to their emerging properties and applications in nonmusculoskeletal diseases.
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Affiliation(s)
- Tom K. Kuo
- Stem Cell Research Center, National Yang-Ming University, Taiwan
| | - Jennifer H. Ho
- Graduate Institute of Clinical Medicine, Taipei Medical University, Taiwan
- Department of Ophthalmology, Taipei Medical University-Wan Fang Hospital, Taiwan
| | - Oscar K. Lee
- Stem Cell Research Center, National Yang-Ming University, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan
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Plaschke K. Human adult mesenchymal stem cells improve rat spatial cognitive function after systemic hemorrhagic shock. Behav Brain Res 2009; 201:332-7. [PMID: 19428653 DOI: 10.1016/j.bbr.2009.03.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Revised: 02/27/2009] [Accepted: 03/06/2009] [Indexed: 01/14/2023]
Abstract
The aim of the present study was to examine whether a single infusion of human adult mesenchymal stem cells (hMSC) has protective effects on rat cognitive functions after systemic hemorrhagic shock. Systemic hemorrhagic rat shock model of pronounced (30 min) systemic hypotension [30-40 mmHg mean arterial blood pressure (MABP) reduction] was used to induce cerebral oligemia. Immediately after the experimental transient hypotension period ended, human processed lipoaspirate-derived mesenchymal stem cells (hMSC, 1 x 10(6)) were administered via the femoral vein. Rats were tested in relation to their cognitive spatial abilities using the Morris water maze before and 3 days after transient oligemia and with/without hMSC transplantation. Immunohistological investigations were performed with respect to apoptosis and BrdU staining. A clear functional improvement was observed in the rats' spatial cognitive abilities after hypotension and subsequent hMSC transplantation. In the hypotension group, hMSC infusion reduced the mortality from 50% to 25%. Six days after hMSC administration and hypotension, we did not detect any BrdU-labeled cells in rat brain, lung, and liver; however, BrdU-positive cells were found in spleen. No signs of cerebral apoptosis were observed. We conclude from this study that hMSCs derived from peripheral blood could be an important cell source to improve functional outcome after transient cerebral oligemia. Identifying the underlying mechanism for this, however, should be the subject of further investigations.
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Affiliation(s)
- Konstanze Plaschke
- Clinic of Anesthesiology, University of Heidelberg Medical School, Heidelberg D-69120, Germany.
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