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1
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Yang C, Du XY, Luo W. Clinical application prospects and transformation value of dental follicle stem cells in oral and neurological diseases. World J Stem Cells 2023; 15:136-149. [PMID: 37181000 PMCID: PMC10173814 DOI: 10.4252/wjsc.v15.i4.136] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/18/2023] [Accepted: 03/21/2023] [Indexed: 04/26/2023] Open
Abstract
Since dental pulp stem cells (DPSCs) were first reported, six types of dental SCs (DSCs) have been isolated and identified. DSCs originating from the craniofacial neural crest exhibit dental-like tissue differentiation potential and neuro-ectodermal features. As a member of DSCs, dental follicle SCs (DFSCs) are the only cell type obtained at the early developing stage of the tooth prior to eruption. Dental follicle tissue has the distinct advantage of large tissue volume compared with other dental tissues, which is a prerequisite for obtaining a sufficient number of cells to meet the needs of clinical applications. Furthermore, DFSCs exhibit a significantly higher cell proliferation rate, higher colony-formation capacity, and more primitive and better anti-inflammatory effects than other DSCs. In this respect, DFSCs have the potential to be of great clinical significance and translational value in oral and neurological diseases, with natural advantages based on their origin. Lastly, cryopreservation preserves the biological properties of DFSCs and enables them to be used as off-shelf products for clinical applications. This review summarizes and comments on the properties, application potential, and clinical transformation value of DFSCs, thereby inspiring novel perspectives in the future treatment of oral and neurological diseases.
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Affiliation(s)
- Chao Yang
- Research and Development Department, Shenzhen Uni-medica Technology Co., Ltd, Shenzhen 518051, Guangdong Province, China
- Department of Stomatology, The People’s Hospital of Longhua, Shenzhen 518109, Guangdong Province, China
| | - Xin-Ya Du
- Department of Stomatology, The People’s Hospital of Longhua, Shenzhen 518109, Guangdong Province, China
| | - Wen Luo
- Department of Stomatology, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, Hainan Province, China
- School of Stomatology, Hainan Medical University, Haikou 571199, Hainan Province, China
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2
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Yang G, Kim YN, Kim H, Lee BK. Effect of Human Umbilical Cord Matrix-Derived Mesenchymal Stem Cells on Bisphosphonate-Related Osteonecrosis of the Jaw. Tissue Eng Regen Med 2021; 18:975-988. [PMID: 34347277 DOI: 10.1007/s13770-021-00372-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/17/2021] [Accepted: 06/25/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe sequela caused by bisphosphonates (BPs), which are widely used to treat osteoporosis or other malignancies. However, the mechanism underlying BRONJ remains unclear. Recently, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been studied for treatment of diverse diseases and injuries. This study aimed to investigate the therapeutic effects of hUC-MSCs in BRONJ. METHODS The therapeutic effects of hUC-MSCs were examined in rat bone marrow (rBM)-derived cells using cell viability, colony-forming, and real-time PCR assays and FACS for analyzing essential proinflammatory and bone regeneration markers in vitro. To demonstrate the in vivo therapeutic and adverse effects of transfused hUC-MSCs, micro-CT, H&E staining, IHC (Angiogenesis marker gene expression) staining, and parathyroid hormone (PTH)/calcium assay were conducted in a BRONJ-induced animal model. RESULTS BP-induced cytotoxicity and inflammation in rBM-derived cells decreased, after co-culture with hUC-MSCs. The expression levels of bone regeneration markers (RUNX2, OSX, and BMP-2) significantly increased in BP-treated rBM-derived cells, after co-culture with hUC-MSCs. The BP-induced abnormal shift in RANKL/OPG expression ratio in rBM-derived cells was normalized by hUC-MSCs. Consistent with these in vitro results, transfused hUC-MSCs markedly decreased BRONJ and significantly healed injured mucosa in the BRONJ-induced animal model. The animals exhibited serious destruction of the kidney structure and increases in serum PTH and calcium levels, which were significantly normalized by hUC-MSC transfusion. CONCLUSION hUC-MSCs exerted therapeutic effects on BRONJ in vitro and in vivo through their anti-cytotoxicity, anti-inflammatory activity and ability to recover bone regeneration.
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Affiliation(s)
- Gwanghyun Yang
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea
| | - Young-Nam Kim
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea
| | - Hyunjeong Kim
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea
| | - Bu-Kyu Lee
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea. .,Department of Oral and Maxillofacial Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
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3
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Guo X, Tang L, Tang X. Current Developments in Cell Replacement Therapy for Parkinson's Disease. Neuroscience 2021; 463:370-382. [PMID: 33774124 DOI: 10.1016/j.neuroscience.2021.03.022] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023]
Abstract
Parkinson's disease (PD) is characterized by tremor, rigidity, and bradykinesia. PD is caused mainly by depletion of the nigrostriatal pathway. Conventional medications such as levodopa are highly effective in the early stage of PD; however, these medications fail to prevent the underlying neurodegeneration. Cell replacement therapy (CRT) is a strategy to achieve long-term motor improvements by preventing or slowing disease progression. Replacement therapy can also increase the number of surviving dopaminergic neurons, an outcome confirmed by positron emission tomography and immunostaining. Several promising cell sources offer authentic and functional dopaminergic replacement neurons. These cell sources include fetal ventral mesencephalic tissue, embryonic stem cells (ESCs), neural stem cells (NSCs), mesenchymal stem cells (MSCs) from various tissues, induced pluripotent stem cells (iPSCs), and induced neural cells. To fully develop the potential of CRT, we need to recognize the advantages and limitations of these cell sources. For example, although fetal ventral midbrain is efficacious in some patients, its ethical issues and the existence of graft-induced dyskinesias (GID) have prevented its use in large-scale clinical applications. ESCs have reliable isolation protocols and the potential to differentiate into dopaminergic progenitors. iPSCs and induced neural cells are suitable for autologous grafting. Here we review milestone improvements and emerging sources for cell-based PD therapy to serve as a framework for clinicians and a key reference to develop replacement therapy for other neurological disorders.
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Affiliation(s)
- Xiaoqian Guo
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Lisha Tang
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Xiangqi Tang
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
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4
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Fričová D, Korchak JA, Zubair AC. Challenges and translational considerations of mesenchymal stem/stromal cell therapy for Parkinson's disease. NPJ Regen Med 2020; 5:20. [PMID: 33298940 PMCID: PMC7641157 DOI: 10.1038/s41536-020-00106-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 08/31/2020] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies, which gives rise to motor and non-motor symptoms. Unfortunately, current therapeutic strategies for PD merely treat the symptoms of the disease, only temporarily improve the patients' quality of life, and are not sufficient for completely alleviating the symptoms. Therefore, cell-based therapies have emerged as a novel promising therapeutic approach in PD treatment. Mesenchymal stem/stromal cells (MSCs) have arisen as a leading contender for cell sources due to their regenerative and immunomodulatory capabilities, limited ethical concerns, and low risk of tumor formation. Although several studies have shown that MSCs have the potential to mitigate the neurodegenerative pathology of PD, variabilities in preclinical and clinical trials have resulted in inconsistent therapeutic outcomes. In this review, we strive to highlight the sources of variability in studies using MSCs in PD therapy, including MSC sources, the use of autologous or allogenic MSCs, dose, delivery methods, patient factors, and measures of clinical outcome. Available evidence indicates that while the use of MSCs in PD has largely been promising, conditions need to be standardized so that studies can be effectively compared with one another and experimental designs can be improved upon, such that this body of science can continue to move forward.
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Affiliation(s)
- Dominika Fričová
- Department of Laboratory Medicine and Pathology and Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Jennifer A Korchak
- Department of Laboratory Medicine and Pathology and Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Abba C Zubair
- Department of Laboratory Medicine and Pathology and Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA.
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5
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Ebrahimi V, Eskandarian Boroujeni M, Aliaghaei A, Abdollahifar MA, Piryaei A, Haghir H, Sadeghi Y. Functional dopaminergic neurons derived from human chorionic mesenchymal stem cells ameliorate striatal atrophy and improve behavioral deficits in Parkinsonian rat model. Anat Rec (Hoboken) 2020; 303:2274-2289. [PMID: 31642188 DOI: 10.1002/ar.24301] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 08/17/2019] [Accepted: 09/22/2019] [Indexed: 12/15/2022]
Abstract
Human chorionic mesenchymal stem cells (HCMSCs) have been recognized as a desirable choice for cell therapy in neurological disorders such as Parkinson's disease (PD). Due to invaluable features of HCMSCs including their immunomodulatory and immunosuppressive properties, easily accessible and less differentiated compared to other types of MSCs, HCMSCs provide a great hope for regenerative medicine. Thus, the purpose of this study was to determine the in vitro and in vivo efficacy of HCMSCs-derived dopaminergic (DA) neuron-like cells with regard to PD. Initially, HCMSCs were isolated and underwent a 2-week DA differentiation, followed by in vitro assessments, using quantitative real-time polymerase chain reaction, immunocytochemistry, patch clamp recording, and high-performance liquid chromatography. In addition, the effects of implanted HCMSCs-derived DA neuron-like cells on the motor coordination along with stereological alterations in the striatum of rat models of PD were investigated. Our results showed that under neuronal induction, HCMSCs revealed neuron-like morphology, and expressed neuronal and DA-specific genes, together with DA release. Furthermore, transplantation of HCMSCs-derived DA neurons into the striatum of rat models of PD, augmented performance. Besides, it prevented reduction of striatal volume, dendritic length, and the total number of neurons, coupled with a diminished level of cleaved caspase-3. Altogether, these findings suggest that HCMSCs could be considered as an attractive strategy for cell-based therapies in PD.
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Affiliation(s)
- Vahid Ebrahimi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Eskandarian Boroujeni
- Department of Stem Cells and Regenerative Medicine, Faculty of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Abbas Aliaghaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Abdollahifar
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Haghir
- Department of Anatomy, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetic Research Center (MGRC), Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yousef Sadeghi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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6
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Santaella A, Wessels HJCT, Kulkarni P, Gloerich J, Kuiperij B, Bloem BR, van Gool AJ, Cabré S, Alamilla V, Verbeek MM. Proteomic profiling of striatal tissue of a rat model of Parkinson's disease after implantation of collagen-encapsulated human umbilical cord mesenchymal stem cells. J Tissue Eng Regen Med 2020; 14:1077-1086. [PMID: 32548924 PMCID: PMC7496133 DOI: 10.1002/term.3081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 06/04/2020] [Accepted: 06/15/2020] [Indexed: 12/29/2022]
Abstract
Parkinson's disease (PD) is the most common neurodegenerative disorder of movement worldwide. To date, only symptomatic treatments are available. Implantation of collagen‐encapsulated human umbilical cord mesenchymal stem cells (hUC‐MSCs) is being developed as a novel therapeutic approach to potentially modify PD progression. However, implanted collagen scaffolds may induce a host tissue response. To gain insight into such response, hUC‐MSCs were encapsulated into collagen hydrogels and implanted into the striatum of hemi‐Parkinsonian male Sprague–Dawley rats. One or 14 days after implantation, the area of interest was dissected using a cryostat. Total protein extracts were subjected to tryptic digestion and subsequent LC–MS/MS analyses for protein expression profiling. Univariate and multivariate analyses were performed to identify differentially expressed protein profiles with subsequent gene ontology and pathway analysis for biological interpretation of the data; 2,219 proteins were identified by MaxQuant at 1% false discovery rate. A high correlation of label‐free quantification (LFQ) protein values between biological replicates (r = .95) was observed. No significant differences were observed between brains treated with encapsulated hUC‐MSCs compared to appropriate controls. Proteomic data were highly robust and reproducible, indicating the suitability of this approach to map differential protein expression caused by the implants. The lack of differences between conditions suggests that the effects of implantation may be minimal. Alternatively, effects may only have been focal and/or could have been masked by nonrelevant high‐abundant proteins. For follow‐up assessment of local changes, a more accurate dissection technique, such as laser micro dissection, and analysis method are recommended.
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Affiliation(s)
- Anna Santaella
- Departments of Neurology and Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.,Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.,Center of Expertise for Parkinson & Movement Disorders, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hans J C T Wessels
- Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Purva Kulkarni
- Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jolein Gloerich
- Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bea Kuiperij
- Departments of Neurology and Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.,Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bastiaan R Bloem
- Departments of Neurology and Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.,Center of Expertise for Parkinson & Movement Disorders, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Alain J van Gool
- Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Silvia Cabré
- Pharmacology & Therapeutics and CÚRAM Centre for Research in Medical Devices, National University of Ireland, Galway, Ireland.,CÚRAM Centre for Research in Medical Devices, National University of Ireland, Galway, Ireland
| | - Verónica Alamilla
- Pharmacology & Therapeutics and CÚRAM Centre for Research in Medical Devices, National University of Ireland, Galway, Ireland.,CÚRAM Centre for Research in Medical Devices, National University of Ireland, Galway, Ireland
| | - Marcel M Verbeek
- Departments of Neurology and Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.,Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.,Center of Expertise for Parkinson & Movement Disorders, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
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7
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Reyhani S, Abbaspanah B, Mousavi SH. Umbilical cord-derived mesenchymal stem cells in neurodegenerative disorders: from literature to clinical practice. Regen Med 2020; 15:1561-1578. [PMID: 32479211 DOI: 10.2217/rme-2019-0119] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 04/29/2020] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have provided a promising tool for cell therapy. Umbilical cord (UC) is one of the best sources of MSCs since its collection is noninvasive, and effortless, and the cells from this source are more capable and prolific. It has been proven that the differentiation, migration and protective properties of UC-MSCs are superior compared with other kinds of stem cells. Moreover, incurable neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and Huntington, encourage scientists to apply UC-MSCs transplantation in order to find a definite treatment. This review will focus on the preclinical and clinical use of mesenchymal stem cells derived from human umbilical cord in the treatment of neurodegenerative disorders.
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Affiliation(s)
- Samira Reyhani
- Department of Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran 14177-44361, Iran
| | - Bahareh Abbaspanah
- Royan Stem Cell Technology Company, Cord Blood Bank, Tehran 14177-44361, Iran
| | - Seyed Hadi Mousavi
- Department of Hematology, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran 14177-44361, Iran
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8
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Staff NP, Jones DT, Singer W. Mesenchymal Stromal Cell Therapies for Neurodegenerative Diseases. Mayo Clin Proc 2019; 94:892-905. [PMID: 31054608 PMCID: PMC6643282 DOI: 10.1016/j.mayocp.2019.01.001] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 10/17/2018] [Accepted: 01/02/2019] [Indexed: 12/13/2022]
Abstract
Mesenchymal stromal cells are multipotent cells that are being used to treat a variety of medical conditions. Over the past decade, there has been considerable excitement about using MSCs to treat neurodegenerative diseases, which are diseases that are typically fatal and without other robust therapies. In this review, we discuss the proposed MSC mechanisms of action in neurodegenerative diseases, which include growth factor secretion, exosome secretion, and attenuation of neuroinflammation. We then provide a summary of preclinical and early clinical work on MSC therapies in amyotrophic lateral sclerosis, multiple system atrophy, Parkinson disease, and Alzheimer disease. Continued rigorous and controlled studies of MSC therapies will be critical in order to establish efficacy and protect patients from possible untoward effects.
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9
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Chang YH, Wu KC, Harn HJ, Lin SZ, Ding DC. Exosomes and Stem Cells in Degenerative Disease Diagnosis and Therapy. Cell Transplant 2018; 27:349-363. [PMID: 29692195 PMCID: PMC6038041 DOI: 10.1177/0963689717723636] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Stroke can cause death and disability, resulting in a huge burden on society. Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by motor dysfunction. Osteoarthritis (OA) is a progressive degenerative joint disease characterized by cartilage destruction and osteophyte formation in the joints. Stem cell therapy may provide a biological treatment alternative to traditional pharmacological therapy. Mesenchymal stem cells (MSCs) are preferred because of their differentiation ability and possible derivation from many adult tissues. In addition, the paracrine effects of MSCs play crucial anti-inflammatory and immunosuppressive roles in immune cells. Extracellular vesicles (EVs) are vital mediators of cell-to-cell communication. Exosomes contain various molecules such as microRNA (miRNA), which mediates biological functions through gene regulation. Therefore, exosomes carrying miRNA or other molecules can enhance the therapeutic effects of MSC transplantation. MSC-derived exosomes have been investigated in various animal models representing stroke, PD, and OA. Exosomes are a subtype of EVs. This review article focuses on the mechanism and therapeutic potential of MSC-derived exosomes in stroke, PD, and OA in basic and clinical aspects.
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Affiliation(s)
- Yu-Hsun Chang
- 1 Department of Pediatrics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.,2 Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
| | - Kung-Chi Wu
- 3 Department of Orthopedics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
| | - Horng-Jyh Harn
- 4 Department of Pathology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
| | - Shinn-Zong Lin
- 5 Department of Neurosurgery, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
| | - Dah-Ching Ding
- 2 Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.,6 Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
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10
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Chen X, Wang S, Cao W. Mesenchymal stem cell-mediated immunomodulation in cell therapy of neurodegenerative diseases. Cell Immunol 2017; 326:8-14. [PMID: 28778534 DOI: 10.1016/j.cellimm.2017.06.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 06/21/2017] [Accepted: 06/23/2017] [Indexed: 12/19/2022]
Abstract
Dysfunction of immune responses has been identified to involve in the pathogenesis of various neurodegenerative diseases. Abnormal activation of glia cells and/or infiltration of peripheral adaptive immune cells always sustains neuroinflammation and the disease progression. Obviously, the regulation of neuroinflammation has become a potential therapeutic strategy against neurodegenerative diseases. Mesenchymal stem cells (MSCs) exhibit complex interactions with various immune cells including T cells, macrophages and especially resident glia cells in the central nervous system. In response to tissue injury signals, MSCs adopt specific phenotype to suppress or promote immune responses depending on the inflammatory microenvironment they reside. Therefore, manipulation of MSCs may hold great potentials to improve MSC-based therapy on neurodegenerative diseases. Here we review MSC-mediated immunomodulation in cell therapy of neurodegenerative diseases, providing fundamental information for guiding appropriate applications of MSCs in clinical settings.
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Affiliation(s)
- Xiaodong Chen
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiaotong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China
| | - Shijia Wang
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiaotong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China
| | - Wei Cao
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiaotong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China.
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11
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Boroujeni ME, Gardaneh M. Umbilical cord: an unlimited source of cells differentiable towards dopaminergic neurons. Neural Regen Res 2017; 12:1186-1192. [PMID: 28852404 PMCID: PMC5558501 DOI: 10.4103/1673-5374.211201] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2017] [Indexed: 12/14/2022] Open
Abstract
Cell replacement therapy utilizing mesenchymal stem cells as its main resource holds great promise for ultimate treatment of human neurological disorders. Parkinson's disease (PD) is a common, chronic neurodegenerative disorder hallmarked by localized degeneration of a specific set of dopaminergic neurons within a midbrain sub-region. The specific cell type and confined location of degenerating neurons make cell replacement therapy ideal for PD treatment since it mainly requires replenishment of lost dopaminergic neurons with fresh and functional ones. Endogenous as well as exogenous cell sources have been identified as candidate targets for cell replacement therapy in PD. In this review, umbilical cord mesenchymal stem cells (UCMSCs) are discussed as they provide an inexpensive unlimited reservoir differentiable towards functional dopaminergic neurons that potentially lead to long-lasting behavioral recovery in PD patients. We also present miRNAs-mediated neuronal differentiation of UCMSCs. The UCMSCs bear a number of outstanding characteristics including their non-tumorigenic, low-immunogenic properties that make them ideal for cell replacement therapy purposes. Nevertheless, more investigations as well as controlled clinical trials are required to thoroughly confirm the efficacy of UCMSCs for therapeutic medical-grade applications in PD.
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Affiliation(s)
- Mahdi Eskandarian Boroujeni
- Department of Stem Cells and Regenerative Medicine, Faculty of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Mossa Gardaneh
- Department of Stem Cells and Regenerative Medicine, Faculty of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
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12
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Oh SH, Lee SC, Kim DY, Kim HN, Shin JY, Ye BS, Lee PH. Mesenchymal Stem Cells Stabilize Axonal Transports for Autophagic Clearance of α-Synuclein in Parkinsonian Models. Stem Cells 2017; 35:1934-1947. [PMID: 28580639 DOI: 10.1002/stem.2650] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 05/04/2017] [Accepted: 05/14/2017] [Indexed: 12/25/2022]
Abstract
Genome-wide association studies have identified two loci, SNCA and the microtubule (MT)-associated protein tau, as common risk factors for Parkinson's disease (PD). Specifically, α-synuclein directly destabilizes MT via tau phosphorylation and induces axonal transport deficits that are the primary events leading to an abnormal accumulation of α-synuclein that causes nigral dopaminergic cell loss. In this study, we demonstrated that mesenchymal stem cells (MSCs) could modulate cytoskeletal networks and trafficking to exert neuroprotective properties in wild-type or A53T α-synuclein overexpressing cells and mice. Moreover, we found that eukaryotic elongation factor 1A-2, a soluble factor derived from MSCs, stabilized MT assembly by decreasing calcium/calmodulin-dependent tau phosphorylation and induced autophagolysosome fusion, which was accompanied by an increase in the axonal motor proteins and increased neuronal survival. Our data suggest that MSCs have beneficial effects on axonal transports via MT stability by controlling α-synuclein-induced tau phosphorylation, indicating that MSCs may exert a protective role in the early stages of axonal transport defects in α-synucleinopathies. Stem Cells 2017;35:1934-1947.
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Affiliation(s)
- Se Hee Oh
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Seok Cheol Lee
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.,Severance Biomedical Science Institute, Yonsei University, Seoul, South Korea
| | - Dong Yeol Kim
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Ha Na Kim
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Jin Young Shin
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.,Severance Biomedical Science Institute, Yonsei University, Seoul, South Korea
| | - Byoung Seok Ye
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Phil Hyu Lee
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.,Severance Biomedical Science Institute, Yonsei University, Seoul, South Korea
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13
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Caprnda M, Kubatka P, Gazdikova K, Gasparova I, Valentova V, Stollarova N, La Rocca G, Kobyliak N, Dragasek J, Mozos I, Prosecky R, Siniscalco D, Büsselberg D, Rodrigo L, Kruzliak P. Immunomodulatory effects of stem cells: Therapeutic option for neurodegenerative disorders. Biomed Pharmacother 2017; 91:60-69. [PMID: 28448871 DOI: 10.1016/j.biopha.2017.04.034] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/04/2017] [Accepted: 04/10/2017] [Indexed: 12/14/2022] Open
Abstract
Stem cells have the capability of self-renewal and can differentiate into different cell types that might be used in regenerative medicine. Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) currently lack effective treatments. Although stem cell therapy is still on the way from bench to bedside, we consider that it might provide new hope for patients suffering with neurodegenerative diseases. In this article, we will give an overview of recent studies on the potential therapeutic use of mesenchymal stem cells (MSCs), neural stem cells (NSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and perinatal stem cells to neurodegenerative disorders and we will describe their immunomodulatory mechanisms of action in specific therapeutic modalities.
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Affiliation(s)
- Martin Caprnda
- 1st Department of Internal Medicine, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia; Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Katarina Gazdikova
- Department of Nutrition, Faculty of Nursing and Professional Health Studies, Slovak Medical University, Bratislava, Slovakia; Department of General Medicine, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia.
| | - Iveta Gasparova
- Institute of Biology, Genetics and Medical Genetics, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia
| | - Vanda Valentova
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia
| | - Nadezda Stollarova
- Catholic University in Ružomberok, Faculty of Pedagogy, Department of Biology and Ecology, Ružomberok, Slovakia
| | - Giampiero La Rocca
- Human Anatomy Section, Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo and Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
| | - Nazarii Kobyliak
- Endocrinology Department, Bogomolets National Medical University, Kyiv, Ukraine
| | - Jozef Dragasek
- 1st Department of Psychiatry, Faculty of Medicine, Pavol Jozef Safarik University and University Hospital, Kosice, Slovakia
| | - Ioana Mozos
- Department of Functional Sciences, Discipline of Pathophysiology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Robert Prosecky
- Department of Internal Medicine, Merciful Brotherś Hospital, Brno, Czech Republic
| | - Dario Siniscalco
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Dietrich Büsselberg
- Weill Cornell Medical College in Qatar, Qatar Foundation - Education City, Doha, Qatar
| | - Luis Rodrigo
- University of Oviedo, Central University Hospital of Asturias (HUCA), Oviedo, Spain
| | - Peter Kruzliak
- Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic; 2nd Department of Surgery, Faculty of Medicine,St. Annés University Hospital, Brno, Czech Republic.
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14
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Pires AO, Teixeira FG, Mendes-Pinheiro B, Serra SC, Sousa N, Salgado AJ. Old and new challenges in Parkinson's disease therapeutics. Prog Neurobiol 2017; 156:69-89. [PMID: 28457671 DOI: 10.1016/j.pneurobio.2017.04.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 03/15/2017] [Accepted: 04/20/2017] [Indexed: 02/06/2023]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons and/or loss od neuronal projections, in several dopaminergic networks. Current treatments for idiopathic PD rely mainly on the use of pharmacologic agents to improve motor symptomatology of PD patients. Nevertheless, so far PD remains an incurable disease. Therefore, it is of utmost importance to establish new therapeutic strategies for PD treatment. Over the last 20 years, several molecular, gene and cell/stem-cell therapeutic approaches have been developed with the aim of counteracting or retarding PD progression. The scope of this review is to provide an overview of PD related therapies and major breakthroughs achieved within this field. In order to do so, this review will start by focusing on PD characterization and current treatment options covering thereafter molecular, gene and cell/stem cell-based therapies that are currently being studied in animal models of PD or have recently been tested in clinical trials. Among stem cell-based therapies, those using MSCs as possible disease modifying agents for PD therapy and, specifically, the MSCs secretome contribution to meet the clinical challenge of counteracting or retarding PD progression, will be more deeply explored.
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Affiliation(s)
- Ana O Pires
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
| | - F G Teixeira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
| | - B Mendes-Pinheiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
| | - Sofia C Serra
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
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15
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Földes A, Kádár K, Kerémi B, Zsembery Á, Gyires K, S Zádori Z, Varga G. Mesenchymal Stem Cells of Dental Origin-Their Potential for Antiinflammatory and Regenerative Actions in Brain and Gut Damage. Curr Neuropharmacol 2017; 14:914-934. [PMID: 26791480 PMCID: PMC5333580 DOI: 10.2174/1570159x14666160121115210] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 12/14/2015] [Accepted: 01/20/2016] [Indexed: 02/07/2023] Open
Abstract
Alzheimer’s disease, Parkinson’s disease, traumatic brain and spinal cord injury and neuroinflammatory multiple sclerosis are diverse disorders of the central nervous system. However, they are all characterized by various levels of inappropriate inflammatory/immune response along with tissue destruction. In the gastrointestinal system, inflammatory bowel disease (IBD) is also a consequence of tissue destruction resulting from an uncontrolled inflammation. Interestingly, there are many similarities in the immunopathomechanisms of these CNS disorders and the various forms of IBD. Since it is very hard or impossible to cure them by conventional manner, novel therapeutic approaches such as the use of mesenchymal stem cells, are needed. Mesenchymal stem cells have already been isolated from various tissues including the dental pulp and periodontal ligament. Such cells possess transdifferentiating capabilities for different tissue specific cells to serve as new building blocks for regeneration. But more importantly, they are also potent immunomodulators inhibiting proinflammatory processes and stimulating anti-inflammatory mechanisms. The present review was prepared to compare the immunopathomechanisms of the above mentioned neurodegenerative, neurotraumatic and neuroinflammatory diseases with IBD. Additionally, we considered the potential use of mesenchymal stem cells, especially those from dental origin to treat such disorders. We conceive that such efforts will yield considerable advance in treatment options for central and peripheral disorders related to inflammatory degeneration.
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Affiliation(s)
| | | | | | | | | | | | - Gábor Varga
- Departments of Oral Biology, Semmelweis University, Budapest, Hungary
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16
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Gugliandolo A, Bramanti P, Mazzon E. Mesenchymal stem cell therapy in Parkinson's disease animal models. Curr Res Transl Med 2016; 65:51-60. [PMID: 28466824 DOI: 10.1016/j.retram.2016.10.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 10/14/2016] [Accepted: 10/14/2016] [Indexed: 12/14/2022]
Abstract
Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, and as a consequence, by decreased dopamine levels in the striatum. Currently available therapies are not able to stop or reverse the progression of the disease. A novel therapeutic approach is based on cell therapy with stem cells, in order to replace degenerated neurons. Among stem cells, mesenchymal stem cells seemed the most promising thanks to their capacities to differentiate toward dopaminergic neurons and to release neurotrophic factors. Indeed, mesenchymal stem cells are able to produce different molecules with immunomodulatory, neuroprotective, angiogenic, chemotactic effects and that stimulate differentiation of resident stem cells. Mesenchymal stem cells were isolated for the first time from bone marrow, but can be collected also from adipose tissue, umbilical cord and other tissues. In this review, we focused our attention on mesenchymal stem cells derived from different sources and their application in Parkinson's disease animal models.
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Affiliation(s)
- A Gugliandolo
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
| | - P Bramanti
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
| | - E Mazzon
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.
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17
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Park HJ, Oh SH, Kim HN, Jung YJ, Lee PH. Mesenchymal stem cells enhance α-synuclein clearance via M2 microglia polarization in experimental and human parkinsonian disorder. Acta Neuropathol 2016; 132:685-701. [PMID: 27497943 DOI: 10.1007/s00401-016-1605-6] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 07/31/2016] [Accepted: 08/01/2016] [Indexed: 11/26/2022]
Abstract
Microglia in the brain show distinctive phenotypes that serve different functions. In particular, M2-polarized microglia are anti-inflammatory and phagocytic cells that serve a restorative function. In this study, we investigated whether mesenchymal stem cells (MSCs) enhance the phagocytic clearance of α-synuclein via M2 microglia polarization, and thereby exert neuroprotective effects in α-synuclein-enriched experimental models and patients with multiple system atrophy (MSA). Treatment of BV2 cells with α-synuclein induced an inflammatory phenotype, whereas co-culture of α-synuclein-treated BV2 cells with MSCs induced an anti-inflammatory M2 phenotype, with decreased α-synuclein levels and increased lysosomal activity, leading to greater viability of neuronal cells co-cultured with BV2 cells. Using IL-4 receptor siRNA in BV2 cells and IL-4 siRNA in MSCs, we found that M2 microglia polarization was induced by IL-4 secreted from MSCs. In α-synuclein-inoculated mice, MSC treatment induced M2 microglia polarization decreased α-synuclein levels, and had a prosurvival effect on neurons. Using IL-4 and IL-4 receptor knockout mice, we further confirmed that IL-4 secreted from MSCs induced phagocytic clearance of α-synuclein through M2 microglia polarization. Next, we found that the cerebrospinal fluid (CSF) from MSC-transplanted MSA patients induced microglia M2 polarization and had a prosurvival effect via enhanced clearance of α-synuclein in α-synuclein-treated BV2 cells. Finally, a serial CSF study demonstrated that changes in oligomeric α-synuclein from baseline to 1-year follow-up were greater in the CSF of MSC-transplanted MSA patients than in placebo-transplanted MSA patients. These findings indicate that MSCs exert a neuroprotective effect via the clearance of extracellular α-synuclein by controlling microglia M2 polarization, suggesting that MSCs could be used as a disease-modifying therapy for patients with α-synucleinopathies.
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Affiliation(s)
- Hyun Jung Park
- Department of Neurology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea
| | - Se Hee Oh
- Department of Neurology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea
| | - Ha Na Kim
- Department of Neurology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea
| | - Yu Ju Jung
- Department of Neurology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea
| | - Phil Hyu Lee
- Department of Neurology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea.
- Severance Biomedical Science Institute, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea.
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18
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Oh SH, Kim HN, Park HJ, Shin JY, Kim DY, Lee PH. The Cleavage Effect of Mesenchymal Stem Cell and Its Derived Matrix Metalloproteinase-2 on Extracellular α-Synuclein Aggregates in Parkinsonian Models. Stem Cells Transl Med 2016; 6:949-961. [PMID: 28297586 PMCID: PMC5442774 DOI: 10.5966/sctm.2016-0111] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 08/29/2016] [Indexed: 01/01/2023] Open
Abstract
Ample evidence has suggested that extracellular α‐synuclein aggregates would play key roles in the pathogenesis and progression of Parkinsonian disorders (PDs). In the present study, we investigated whether mesenchymal stem cells (MSCs) and their derived soluble factors could exert neuroprotective effects via proteolysis of extracellular α‐synuclein. When preformed α‐synuclein aggregates were incubated with MSC‐conditioned medium, α‐synuclein aggregates were disassembled, and insoluble and oligomeric forms of α‐synuclein were markedly decreased, thus leading to a significant increase in neuronal viability. In an animal study, MSC or MSC‐conditioned medium treatment decreased the expression of α‐synuclein oligomers and the induction of pathogenic α‐synuclein with an attenuation of apoptotic cell death signaling. Furthermore, we identified that matrix metalloproteinase‐2 (MMP‐2), a soluble factor derived from MSCs, played an important role in the degradation of extracellular α‐synuclein. Our data demonstrated that MSCs and their derived MMP‐2 exert neuroprotective properties through proteolysis of aggregated α‐synuclein in PD‐related microenvironments. Stem Cells Translational Medicine2017;6:949–961
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Affiliation(s)
- Se Hee Oh
- Department of Neurology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ha Na Kim
- Department of Neurology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyun Jung Park
- Department of Neurology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Severance Biomedical Science Institute, Yonsei University, Seoul, Republic of Korea
| | - Jin Young Shin
- Department of Pharmacology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Dong Yeol Kim
- Department of Neurology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Phil Hyu Lee
- Department of Neurology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Severance Biomedical Science Institute, Yonsei University, Seoul, Republic of Korea
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19
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Neuroprotective and Therapeutic Strategies against Parkinson's Disease: Recent Perspectives. Int J Mol Sci 2016; 17:ijms17060904. [PMID: 27338353 PMCID: PMC4926438 DOI: 10.3390/ijms17060904] [Citation(s) in RCA: 120] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 05/27/2016] [Accepted: 05/30/2016] [Indexed: 12/18/2022] Open
Abstract
Parkinsonism is a progressive motor disease that affects 1.5 million Americans and is the second most common neurodegenerative disease after Alzheimer’s. Typical neuropathological features of Parkinson’s disease (PD) include degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra that project to the striatum (nigro-striatal pathway) and depositions of cytoplasmic fibrillary inclusions (Lewy bodies) which contain ubiquitin and α-synuclein. The cardinal motor signs of PD are tremors, rigidity, slow movement (bradykinesia), poor balance, and difficulty in walking (Parkinsonian gait). In addition to motor symptoms, non-motor symptoms that include autonomic and psychiatric as well as cognitive impairments are pressing issues that need to be addressed. Several different mechanisms play an important role in generation of Lewy bodies; endoplasmic reticulum (ER) stress induced unfolded proteins, neuroinflammation and eventual loss of dopaminergic neurons in the substantia nigra of mid brain in PD. Moreover, these diverse processes that result in PD make modeling of the disease and evaluation of therapeutics against this devastating disease difficult. Here, we will discuss diverse mechanisms that are involved in PD, neuroprotective and therapeutic strategies currently in clinical trial or in preclinical stages, and impart views about strategies that are promising to mitigate PD pathology.
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20
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Shen Y, Huang J, Liu L, Xu X, Han C, Zhang G, Jiang H, Li J, Lin Z, Xiong N, Wang T. A Compendium of Preparation and Application of Stem Cells in Parkinson's Disease: Current Status and Future Prospects. Front Aging Neurosci 2016; 8:117. [PMID: 27303288 PMCID: PMC4885841 DOI: 10.3389/fnagi.2016.00117] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 05/09/2016] [Indexed: 12/22/2022] Open
Abstract
Parkinson's Disease (PD) is a progressively neurodegenerative disorder, implicitly characterized by a stepwise loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and explicitly marked by bradykinesia, rigidity, resting tremor and postural instability. Currently, therapeutic approaches available are mainly palliative strategies, including L-3,4-dihydroxy-phenylalanine (L-DOPA) replacement therapy, DA receptor agonist and deep brain stimulation (DBS) procedures. As the disease proceeds, however, the pharmacotherapeutic efficacy is inevitably worn off, worse still, implicated by side effects of motor response oscillations as well as L-DOPA induced dyskinesia (LID). Therefore, the frustrating status above has propeled the shift to cell replacement therapy (CRT), a promising restorative therapy intending to secure a long-lasting relief of patients' symptoms. By far, stem cell lines of multifarious origins have been established, which can be further categorized into embryonic stem cells (ESCs), neural stem cells (NSCs), induced neural stem cells (iNSCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs). In this review, we intend to present a compendium of preparation and application of multifarious stem cells, especially in relation to PD research and therapy. In addition, the current status, potential challenges and future prospects for practical CRT in PD patients will be elaborated as well.
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Affiliation(s)
- Yan Shen
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Jinsha Huang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Ling Liu
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Xiaoyun Xu
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Chao Han
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Guoxin Zhang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Haiyang Jiang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Jie Li
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Zhicheng Lin
- Department of Psychiatry, Harvard Medical School, Division of Alcohol and Drug Abuse, and Mailman Neuroscience Research Center, McLean Hospital Belmont, MA, USA
| | - Nian Xiong
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Tao Wang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
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21
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Zhu B, Caldwell M, Song B. Development of stem cell-based therapies for Parkinson's disease. Int J Neurosci 2016; 126:955-62. [DOI: 10.3109/00207454.2016.1148034] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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22
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Oh SH, Kim HN, Park HJ, Shin JY, Bae EJ, Sunwoo MK, Lee SJ, Lee PH. Mesenchymal Stem Cells Inhibit Transmission of α-Synuclein by Modulating Clathrin-Mediated Endocytosis in a Parkinsonian Model. Cell Rep 2016; 14:835-849. [DOI: 10.1016/j.celrep.2015.12.075] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 09/11/2015] [Accepted: 12/15/2015] [Indexed: 02/06/2023] Open
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23
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Fu MH, Li CL, Lin HL, Chen PC, Calkins MJ, Chang YF, Cheng PH, Yang SH. Stem cell transplantation therapy in Parkinson's disease. SPRINGERPLUS 2015; 4:597. [PMID: 26543732 PMCID: PMC4628010 DOI: 10.1186/s40064-015-1400-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Accepted: 10/06/2015] [Indexed: 02/06/2023]
Abstract
Ineffective therapeutic treatments and inadequate repair ability in the central nervous system are disturbing problems for several neurological diseases. Fortunately, the development of clinically applicable populations of stem cells has provided an avenue to overcome the failure of endogenous repair systems and substitute new cells into the damaged brain. However, there are still several existing obstacles to translating into clinical application. Here we review the stem-cell based therapies for Parkinson’s disease and discuss the potential advantages and drawbacks. We hope this review may provide suggestions for viable strategies to overcome the current technical and biological issues associated with the application of stem cells in Parkinson’s disease.
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Affiliation(s)
- Mu-Hui Fu
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101 Taiwan.,Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301 Taiwan
| | - Chia-Ling Li
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101 Taiwan
| | - Hsiu-Lien Lin
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101 Taiwan.,Division of Breeding and Genetics, Livestock Research Institute, Council of Agriculture, Tainan, 71246 Taiwan
| | - Pei-Chun Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101 Taiwan.,Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101 Taiwan
| | - Marcus J Calkins
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101 Taiwan
| | - Yu-Fan Chang
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101 Taiwan
| | - Pei-Hsun Cheng
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101 Taiwan
| | - Shang-Hsun Yang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101 Taiwan.,Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101 Taiwan
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24
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Joerger-Messerli MS, Marx C, Oppliger B, Mueller M, Surbek DV, Schoeberlein A. Mesenchymal Stem Cells from Wharton's Jelly and Amniotic Fluid. Best Pract Res Clin Obstet Gynaecol 2015; 31:30-44. [PMID: 26482184 DOI: 10.1016/j.bpobgyn.2015.07.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 07/20/2015] [Indexed: 12/15/2022]
Abstract
The discovery of mesenchymal stem cells (MSCs) in perinatal sources, such as the amniotic fluid (AF) and the umbilical connective tissue, the so-called Wharton's jelly (WJ), has transformed them into promising stem cell grafts for the application in regenerative medicine. The advantages of AF-MSCs and WJ-MSCs over adult MSCs, such as bone marrow-derived mesenchymal stem cells (BM-MSCs), include their minimally invasive isolation procedure, their more primitive cell character without being tumourigenic, their low immunogenicity and their potential autologous application in congenital disorders and when cryopreserved in adulthood. This chapter gives an overview of the biology of AF-MSCs and WJ-MSCs, and their regenerative potential based on the results of recent preclinical and clinical studies. In the end, open questions concerning the use of WJ-MSCs and AF-MSCs in regenerative medicine will be emphasized.
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Affiliation(s)
- Marianne S Joerger-Messerli
- Department of Obstetrics and Gynecology, University Hospital Bern, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland.
| | - Caterina Marx
- Department of Obstetrics and Gynecology, University Hospital Bern, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland.
| | - Byron Oppliger
- Department of Obstetrics and Gynecology, University Hospital Bern, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland.
| | - Martin Mueller
- Department of Obstetrics and Gynecology, University Hospital Bern, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
| | - Daniel V Surbek
- Department of Obstetrics and Gynecology, University Hospital Bern, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland.
| | - Andreina Schoeberlein
- Department of Obstetrics and Gynecology, University Hospital Bern, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland.
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25
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Riecke J, Johns KM, Cai C, Vahidy FS, Parsha K, Furr-Stimming E, Schiess M, Savitz SI. A Meta-Analysis of Mesenchymal Stem Cells in Animal Models of Parkinson's Disease. Stem Cells Dev 2015; 24:2082-90. [PMID: 26134374 DOI: 10.1089/scd.2015.0127] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Multiple studies have been performed to evaluate the effects of mesenchymal stem cells (MSCs) in animal models of Parkinson's disease (PD). We performed a meta-analysis to estimate the treatment effect of unmodified MSCs on behavioral outcomes in preclinical studies of PD. We performed a systematic literature search to identify studies that used behavioral testing to evaluate the treatment effect of unmodified MSCs in PD models. Meta-analysis was used to determine pooled effect size for rotational behavior and limb function, and meta-regression was performed to explore sources of heterogeneity. Twenty-five studies, including three delivery routes, a wide range of doses, and multiple PD models, were examined. Significant improvement was seen in the pooled standardized mean difference (SMD) for both rotational behavior [SMD: 1.24, 95% confidence interval (95% CI): 0.84, 1.64] and limb function (SMD: 0.84, 95% CI: 0.01, 1.66). Using meta-regression, intravenous administration and higher dose had a larger effect on limb function. Treatment with MSCs improves behavioral outcomes in PD models. Our analyses suggest that MSCs could be considered for early-stage clinical trials in the treatment of PD.
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Affiliation(s)
- Jenny Riecke
- 1 Department of Neurology, University of Texas-Houston Medical School , Houston, Texas
| | - Katherine M Johns
- 1 Department of Neurology, University of Texas-Houston Medical School , Houston, Texas
| | - Chunyan Cai
- 2 Division of Clinical and Translational Sciences, Department of Internal Medicine, University of Texas-Houston Medical School , Houston, Texas
| | | | - Kaushik Parsha
- 1 Department of Neurology, University of Texas-Houston Medical School , Houston, Texas
| | - Erin Furr-Stimming
- 1 Department of Neurology, University of Texas-Houston Medical School , Houston, Texas
| | - Mya Schiess
- 1 Department of Neurology, University of Texas-Houston Medical School , Houston, Texas
| | - Sean I Savitz
- 1 Department of Neurology, University of Texas-Houston Medical School , Houston, Texas
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Anisimov SV, Paul G. Transplantation of mesenchymal stem cells: a future therapy for Parkinson’s disease? FUTURE NEUROLOGY 2014. [DOI: 10.2217/fnl.14.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
ABSTRACT: Parkinson’s disease (PD) is a common, progressive neurodegenerative disorder associated with a loss of dopaminergic cells in the substantia nigra pars compacta and a lack of dopamine in the striatum. To halt or reverse this disease, neurorestorative approaches or neuroprotective treatments are urgently needed. Recently, the first clinical trials transplanting mesenchymal stem cells (MSCs) have been performed in PD. MSCs are adult stem cells abundant in several tissues, such as the umbilical cord, the bone marrow, the adipose tissue and other tissues. These cells are multipotent, and able to synthesize and secrete a wide spectrum of biologically active factors. MSCs of various origins have been explored as possible substrates for cell therapy in PD animal models. In this review, we summarize MSC-based experimental transplantation studies in PD, and discuss biological mechanisms that may explain the effects of MSC seen in PD models. Furthermore, we critically evaluate the recent clinical transplantation trials using MSCs in patients with PD.
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Affiliation(s)
- Sergey V Anisimov
- Research Unit of Cellular & Genetic Engineering, Federal V.A. Almazov Medical Research Center, Saint-Petersburg, Russia
- Department of Intracellular Signaling & Transport, Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, Russia
| | - Gesine Paul
- Division of Neurology, Department of Clinical Sciences, Translational Neurology Group, Lund University, Lund, Sweden
- Department of Neurology, Scania University Hospital, Lund, Sweden
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Glavaski-Joksimovic A, Bohn MC. Mesenchymal stem cells and neuroregeneration in Parkinson's disease. Exp Neurol 2013; 247:25-38. [DOI: 10.1016/j.expneurol.2013.03.016] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 03/14/2013] [Indexed: 02/06/2023]
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Paul G, Anisimov SV. The secretome of mesenchymal stem cells: potential implications for neuroregeneration. Biochimie 2013; 95:2246-56. [PMID: 23871834 DOI: 10.1016/j.biochi.2013.07.013] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Accepted: 07/10/2013] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cells have shown regenerative properties in many tissues. This feature had originally been ascribed to their multipotency and thus their ability to differentiate into tissue-specific cells. However, many researchers consider the secretome of mesenchymal stem cells the most important player in the observed reparative effects of these cells. In this review, we specifically focus on the potential neuroregenerative effect of mesenchymal stem cells, summarize several possible mechanisms of neuroregeneration and list key factors mediating this effect. We illustrate examples of mesenchymal stem cell treatment in central nervous system disorders including stroke, neurodegenerative disorders (such as Parkinson's disease, Huntington's disease, multiple system atrophy and cerebellar ataxia) and inflammatory disease (such as multiple sclerosis). We specifically highlight studies where mesenchymal stem cells have entered clinical trials.
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Affiliation(s)
- Gesine Paul
- Translational Neurology Group, Division of Neurology, Department of Clinical Sciences, Lund University, Lund, Sweden; Department of Neurology, Scania University Hospital, Lund, Sweden.
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