|
1
|
Ballion B, Bonnet ML, Brot S, Gaillard A. Electrophysiological characterisation of intranigral-grafted hiPSC-derived dopaminergic neurons in a mouse model of Parkinson's disease. Stem Cell Res Ther 2025; 16:232. [PMID: 40346597 PMCID: PMC12065326 DOI: 10.1186/s13287-025-04344-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 04/15/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND Parkinson's disease (PD) is a complex neurological disorder characterized by the progressive degeneration of midbrain dopaminergic (mDA) neurons in the substantia nigra (SN). This degeneration disrupts the basal ganglia loops, leading to both motor and non-motor dysfunctions. Cell therapy for PD aims to replace lost mDA neurons to restore the DA neurotransmission in the denervated forebrain targets. In clinical trials for PD, mDA neurons are implanted into the target area, the striatum, and not in the SN where they are normally located. This ectopic localisation of cells may affect the functionality of transplanted neurons due to the absence of appropriate host afferent regulation. We recently demonstrated that human induced pluripotent stem cells (hiPSCs) derived mDA progenitors grafted into the substantia nigra pars compacta (SNpc) in a mouse model of PD, differentiated into mature mDA neurons, restored the degenerated nigrostriatal pathway, and induced motor recovery. The objective of the present study was to evaluate the long-term functionality of these intranigral-grafted mDA neurons by assessing their electrophysiological properties. METHODS We performed intranigral transplantation of hiPSC-derived mDA progenitors in a 6-hydroxydopamine RAG2-KO mouse model of PD. We recorded in vivo unit extracellular activity of grafted mDA neurons in anesthetised mice from 9 to 12 months post-transplantation. Their electrophysiological properties, including firing rates, patterns and spike characteristics, were analysed and compared with those of native nigral dopaminergic neurons from control mice. RESULTS We demonstrated that these grafted mDA neurons exhibited functional characteristics similar to those of native nigral dopaminergic neurons, such as large bi- or triphasic spike waveforms, low firing rates, pacemaker-like properties, and two single-spike firing patterns. Although grafted mDA neurons also displayed low discharge frequencies below 10 Hz, their mean frequency was significantly lower than that of nigral mDA neurons, with a differential pattern distribution. CONCLUSIONS Our findings indicate that grafted mDA neurons exhibit dopaminergic-like functional properties, including intrinsic membrane potential oscillations leading to regular firing patterns. Additionally, they demonstrated irregular and burst firing patterns, suggesting they receive modulatory inputs. However, grafted mDA neurons displayed distinct properties, potentially related to their human origin or the incomplete maturation one year after transplantation.
Collapse
Affiliation(s)
- Bérengère Ballion
- Laboratoire des neurosciences expérimentales et cliniques (LNEC), Université de Poitiers- INSERM 1084, Poitiers Cedex 9, 86073, France.
| | - Marie-Laure Bonnet
- Laboratoire des neurosciences expérimentales et cliniques (LNEC), Université de Poitiers- INSERM 1084, Poitiers Cedex 9, 86073, France
- Centre hospitalier universitaire (CHU) de Poitiers, Poitiers, 86021, France
| | - Sébastien Brot
- Laboratoire des neurosciences expérimentales et cliniques (LNEC), Université de Poitiers- INSERM 1084, Poitiers Cedex 9, 86073, France
| | - Afsaneh Gaillard
- Laboratoire des neurosciences expérimentales et cliniques (LNEC), Université de Poitiers- INSERM 1084, Poitiers Cedex 9, 86073, France.
| |
Collapse
|
|
2
|
Dong W, Liu S, Li S, Wang Z. Cell reprogramming therapy for Parkinson's disease. Neural Regen Res 2024; 19:2444-2455. [PMID: 38526281 PMCID: PMC11090434 DOI: 10.4103/1673-5374.390965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/23/2023] [Accepted: 10/08/2023] [Indexed: 03/26/2024] Open
Abstract
Parkinson's disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson's disease. The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson's disease, which could substantially alleviate the symptoms of Parkinson's disease in clinical practice. However, ethical issues and tumor formation were limitations of its clinical application. Induced pluripotent stem cells can be acquired without sacrificing human embryos, which eliminates the huge ethical barriers of human stem cell therapy. Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons, without the need for intermediate proliferation states, thus avoiding issues of immune rejection and tumor formation. Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson's disease. However, there are also ethical concerns and the risk of tumor formation that need to be addressed. This review highlights the current application status of cell reprogramming in the treatment of Parkinson's disease, focusing on the use of induced pluripotent stem cells in cell replacement therapy, including preclinical animal models and progress in clinical research. The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson's disease, as well as the controversy surrounding in vivo reprogramming. These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson's disease.
Collapse
Affiliation(s)
- Wenjing Dong
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| | - Shuyi Liu
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| | - Shangang Li
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| | - Zhengbo Wang
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| |
Collapse
|
|
3
|
Galgani A, Scotto M, Giorgi FS. The Neuroanatomy of Induced Pluripotent Stem Cells: In Vitro Models of Subcortical Nuclei in Neurodegenerative Disorders. Curr Issues Mol Biol 2024; 46:10180-10199. [PMID: 39329959 PMCID: PMC11430477 DOI: 10.3390/cimb46090607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/07/2024] [Accepted: 09/10/2024] [Indexed: 09/28/2024] Open
Abstract
Neuromodulatory subcortical systems (NSSs) are monoaminergic and cholinergic neuronal groups that are markedly and precociously involved in the pathogenesis of many neurodegenerative disorders (NDDs), including Parkinson's and Alzheimer's diseases. In humans, although many tools have been developed to infer information on these nuclei, encompassing neuroimaging and neurophysiological methods, a detailed and specific direct evaluation of their cellular features in vivo has been difficult to obtain until recent years. The development of induced pluripotent stem cell (iPSC) models has allowed research to deeply delve into the cellular and molecular biology of NSS neurons. In fact, iPSCs can be produced easily and non-invasively from patients' fibroblasts or circulating blood monocytes, by de-differentiating those cells using specific protocols, and then be re-differentiated towards neural phenotypes, which may reproduce the specific features of the correspondent brain neurons (including NSS ones) from the same patient. In this review, we summarized findings obtained in the field of NDDs using iPSCs, with the aim to understand how reliably these might represent in vitro models of NSS. We found that most of the current literature in the field of iPSCs and NSSs in NDDs has focused on midbrain dopaminergic neurons in Parkinson's disease, providing interesting results on cellular pathophysiology and even leading to the first human autologous transplantation. Differentiation protocols for noradrenergic, cholinergic, and serotoninergic neurons have also been recently defined and published. Thus, it might be expected that in the near future, this approach could extend to other NSSs and other NDDs.
Collapse
Affiliation(s)
- Alessandro Galgani
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy
| | - Marco Scotto
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy
- Istituto Italiano di Tecnologia, 16163 Genova, Italy
| | - Filippo S. Giorgi
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy
- IRCCS Stella Maris Foundation, 56128 Pisa, Italy
| |
Collapse
|
|
4
|
Kaewda C, Sriwichai S. Label-Free Electrochemical Dopamine Biosensor Based on Electrospun Nanofibers of Polyaniline/Carbon Nanotube Composites. BIOSENSORS 2024; 14:349. [PMID: 39056625 PMCID: PMC11275224 DOI: 10.3390/bios14070349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/11/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024]
Abstract
The development of conducting polymer incorporated with carbon materials-based electrochemical biosensors has been intensively studied due to their excellent electrical, optical, thermal, physical and chemical properties. In this work, a label-free electrochemical dopamine (DA) biosensor based on polyaniline (PANI) and its aminated derivative, i.e., poly(3-aminobenzylamine) (PABA), composited with functionalized multi-walled carbon nanotubes (f-CNTs), was developed to utilize a conducting polymer as a transducing material. The electrospun nanofibers of the composites were fabricated on the surface of fluorine-doped tin oxide (FTO)-coated glass substrate under the optimized condition. The PANI/f-CNTs and PABA/f-CNTs electrospun nanofibers were characterized by attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), which confirmed the existence of f-CNTs in the composites. The electroactivity of the electrospun nanofibers was investigated in phosphate buffer saline solution using cyclic voltammetry (CV) before being employed for label-free electrochemical detection of DA using differential pulse voltammetry (DPV). The sensing performances including sensitivity, selectivity, stability, repeatability and reproducibility of the fabricated electrospun nanofiber films were also electrochemically evaluated. The electrochemical DA biosensor based on PANI/f-CNTs and PABA/f-CNTs electrospun nanofibers exhibited a sensitivity of 6.88 µA·cm-2·µM-1 and 7.27 µA·cm-2·µM-1 in the linear range of 50-500 nM (R2 = 0.98) with a limit of detection (LOD) of 0.0974 µM and 0.1554 µM, respectively. The obtained DA biosensor showed great stability, repeatability and reproducibility with precious selectivity under the common interferences, i.e., glucose, ascorbic acid and uric acid. Moreover, the developed electrochemical DA biosensor also showed the good reliability under detection of DA in artificial urine.
Collapse
Affiliation(s)
| | - Saengrawee Sriwichai
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
| |
Collapse
|
|
5
|
Park JM, Rahmati M, Lee SC, Shin JI, Kim YW. Effects of mesenchymal stem cell on dopaminergic neurons, motor and memory functions in animal models of Parkinson's disease: a systematic review and meta-analysis. Neural Regen Res 2024; 19:1584-1592. [PMID: 38051903 PMCID: PMC10883506 DOI: 10.4103/1673-5374.387976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 10/09/2023] [Indexed: 12/07/2023] Open
Abstract
ABSTRACT Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, and although restoring striatal dopamine levels may improve symptoms, no treatment can cure or reverse the disease itself. Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson's disease. Mesenchymal stem cells are considered a promising option due to fewer ethical concerns, a lower risk of immune rejection, and a lower risk of teratogenicity. We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function, memory, and preservation of dopaminergic neurons in a Parkinson's disease animal model. We searched bibliographic databases (PubMed/MEDLINE, Embase, CENTRAL, Scopus, and Web of Science) to identify articles and included only peer-reviewed in vivo interventional animal studies published in any language through June 28, 2023. The study utilized the random-effect model to estimate the 95% confidence intervals (CI) of the standard mean differences (SMD) between the treatment and control groups. We use the systematic review center for laboratory animal experimentation's risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment. A total of 33 studies with data from 840 Parkinson's disease model animals were included in the meta-analysis. Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test. Among the stem cell types, the bone marrow MSCs with neurotrophic factor group showed largest effect size (SMD [95% CI] = -6.21 [-9.50 to -2.93], P = 0.0001, I2 = 0.0 %). The stem cell treatment group had significantly more tyrosine hydroxylase positive dopaminergic neurons in the striatum ([95% CI] = 1.04 [0.59 to 1.49], P = 0.0001, I2 = 65.1 %) and substantia nigra (SMD [95% CI] = 1.38 [0.89 to 1.87], P = 0.0001, I2 = 75.3 %), indicating a protective effect on dopaminergic neurons. Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route (SMD [95% CI] = -2.59 [-3.25 to -1.94], P = 0.0001, I2 = 74.4 %). The memory test showed significant improvement only in the intravenous route (SMD [95% CI] = 4.80 [1.84 to 7.76], P = 0.027, I2 = 79.6 %). Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson's disease. Further research is required to determine the optimal stem cell types, modifications, transplanted cell numbers, and delivery methods for these protocols.
Collapse
Affiliation(s)
- Jong Mi Park
- Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Masoud Rahmati
- Department of Physical Education and Sport Sciences, Faculty of Literature and Human Sciences, Lorestan University, Khoramabad, Iran
| | - Sang Chul Lee
- Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, South Korea
| | - Yong Wook Kim
- Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, South Korea
| |
Collapse
|
|
6
|
Cao Z, Kong F, Ding J, Chen C, He F, Deng W. Promoting Alzheimer's disease research and therapy with stem cell technology. Stem Cell Res Ther 2024; 15:136. [PMID: 38715083 PMCID: PMC11077895 DOI: 10.1186/s13287-024-03737-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 04/17/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD treatments aim to relieve symptoms and slow disease progression, but a cure is elusive due to limited understanding of the underlying disease mechanisms. MAIN CONTENT Stem cell technology has the potential to revolutionize AD research. With the ability to self-renew and differentiate into various cell types, stem cells are valuable tools for disease modeling, drug screening, and cell therapy. Recent advances have broadened our understanding beyond the deposition of amyloidβ (Aβ) or tau proteins in AD to encompass risk genes, immune system disorders, and neuron-glia mis-communication, relying heavily on stem cell-derived disease models. These stem cell-based models (e.g., organoids and microfluidic chips) simulate in vivo pathological processes with extraordinary spatial and temporal resolution. Stem cell technologies have the potential to alleviate AD pathology through various pathways, including immunomodulation, replacement of damaged neurons, and neurotrophic support. In recent years, transplantation of glial cells like oligodendrocytes and the infusion of exosomes have become hot research topics. CONCLUSION Although stem cell-based models and therapies for AD face several challenges, such as extended culture time and low differentiation efficiency, they still show considerable potential for AD treatment and are likely to become preferred tools for AD research.
Collapse
Affiliation(s)
- Zimeng Cao
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Fanshu Kong
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Jiaqi Ding
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Chunxia Chen
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China.
| | - Fumei He
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China.
- School of Pharmaceutical Sciences, Dali University, Dali, 671000, China.
| | - Wenbin Deng
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China.
| |
Collapse
|
|
7
|
Liao YJ, Liao CH, Chen LR, Yang JR. Dopaminergic neurons derived from porcine induced pluripotent stem cell like cells function in the Lanyu pig model of Parkinson's disease. Anim Biotechnol 2023; 34:1283-1294. [PMID: 35152856 DOI: 10.1080/10495398.2021.2020130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
The induced pluripotent stem cells (iPSCs) are able to differentiate into dopaminergic neurons and execute the therapeutic effects for Parkinson's disease (PD). Here, we established a animal model of PD in Lanyu pigs by injecting 5 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP). Next, the porcine iPSC-like cells (piPSC-like cells) were differentiated into D18 neuronal progenitors (D18 NPs) that were transplanted into the striatum to evaluate their therapeutic effects of PD. We showed that after 8 weeks of cell transplantation, the behavior score was significantly ameliorated and fully recovered at the 14th week of cell transplantation. The number of dopaminergic neurons was also significantly improved at the end of the experiment although the number was still about 50% lower than that in the control group. Our findings suggest that piPSC-like cell-derived D18 NPs exhibit a potential for the treatment of PD in the Lanyu pig model.
Collapse
Affiliation(s)
- Yu-Jing Liao
- Division of Physiology, Livestock Research Institute, Council of Agriculture, Tainan, Taiwan
| | - Chia-Hsin Liao
- Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
- Holistic Education Center, Tzu Chi University of Science and Technology, Hualien, Taiwan
| | - Lih-Ren Chen
- Division of Physiology, Livestock Research Institute, Council of Agriculture, Tainan, Taiwan
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan
| | - Jenn-Rong Yang
- Kaohsiung Animal Propagation Station, Livestock Research Institute, Council of Agriculture, Neipu, Pingtung, Taiwan
| |
Collapse
|
|
8
|
Moon H, Kim B, Kwon I, Oh Y. Challenges involved in cell therapy for Parkinson's disease using human pluripotent stem cells. Front Cell Dev Biol 2023; 11:1288168. [PMID: 37886394 PMCID: PMC10598731 DOI: 10.3389/fcell.2023.1288168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 09/25/2023] [Indexed: 10/28/2023] Open
Abstract
Neurons derived from human pluripotent stem cells (hPSCs) provide a valuable tool for studying human neural development and neurodegenerative diseases. The investigation of hPSC-based cell therapy, involving the differentiation of hPSCs into target cells and their transplantation into affected regions, is of particular interest. One neurodegenerative disease that is being extensively studied for hPSC-based cell therapy is Parkinson's disease (PD), the second most common among humans. Various research groups are focused on differentiating hPSCs into ventral midbrain dopaminergic (vmDA) progenitors, which have the potential to further differentiate into neurons closely resembling DA neurons found in the substantia nigra pars compacta (SNpc) after transplantation, providing a promising treatment option for PD. In vivo experiments, where hPSC-derived vmDA progenitor cells were transplanted into the striatum or SNpc of animal PD models, the transplanted cells demonstrated stable engraftment and resulted in behavioral recovery in the transplanted animals. Several differentiation protocols have been developed for this specific cell therapy. However, the lack of a reliable live-cell lineage identification method presents a significant obstacle in confirming the precise lineage of the differentiated cells intended for transplantation, as well as identifying potential contamination by non-vmDA progenitors. This deficiency increases the risk of adverse effects such as dyskinesias and tumorigenicity, highlighting the importance of addressing this issue before proceeding with transplantation. Ensuring the differentiation of hPSCs into the target cell lineage is a crucial step to guarantee precise therapeutic effects in cell therapy. To underscore the significance of lineage identification, this review focuses on the differentiation protocols of hPSC-derived vmDA progenitors developed by various research groups for PD treatment. Moreover, in vivo experimental results following transplantation were carefully analyzed. The encouraging outcomes from these experiments demonstrate the potential efficacy and safety of hPSC-derived vmDA progenitors for PD cell therapy. Additionally, the results of clinical trials involving the use of hPSC-derived vmDA progenitors for PD treatment were briefly reviewed, shedding light on the progress and challenges faced in translating this promising therapy into clinical practice.
Collapse
Affiliation(s)
- Heechang Moon
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea
| | - Bokwang Kim
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea
| | - Inbeom Kwon
- Department of Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Yohan Oh
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Advanced BioConvergence, Hanyang University, Seoul, Republic of Korea
| |
Collapse
|
|
9
|
Zheng X, Han D, Liu W, Wang X, Pan N, Wang Y, Chen Z. Human iPSC-derived midbrain organoids functionally integrate into striatum circuits and restore motor function in a mouse model of Parkinson's disease. Theranostics 2023; 13:2673-2692. [PMID: 37215566 PMCID: PMC10196819 DOI: 10.7150/thno.80271] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 04/15/2023] [Indexed: 05/24/2023] Open
Abstract
Rationale: Parkinson's disease (PD) is a prevalent neurodegenerative disorder that is characterized by degeneration of dopaminergic neurons (DA) at the substantia nigra pas compacta (SNpc). Cell therapy has been proposed as a potential treatment option for PD, with the aim of replenishing the lost DA neurons and restoring motor function. Fetal ventral mesencephalon tissues (fVM) and stem cell-derived DA precursors cultured in 2-dimentional (2-D) culture conditions have shown promising therapeutic outcomes in animal models and clinical trials. Recently, human induced pluripotent stem cells (hiPSC)-derived human midbrain organoids (hMOs) cultured in 3-dimentional (3-D) culture conditions have emerged as a novel source of graft that combines the strengths of fVM tissues and 2-D DA cells. Methods: 3-D hMOs were induced from three distinct hiPSC lines. hMOs at various stages of differentiation were transplanted as tissue pieces into the striatum of naïve immunodeficient mouse brains, with the aim of identifying the most suitable stage of hMOs for cellular therapy. The hMOs at Day 15 were determined to be the most appropriate stage and were transplanted into a PD mouse model to assess cell survival, differentiation, and axonal innervation in vivo. Behavioral tests were conducted to evaluate functional restoration following hMO treatment and to compare the therapeutic effects between 2-D and 3-D cultures. Rabies virus were introduced to identify the host presynaptic input onto the transplanted cells. Results: hMOs showed a relatively homogeneous cell composition, mostly consisting of dopaminergic cells of midbrain lineage. Analysis conducted 12 weeks post-transplantation of day 15 hMOs revealed that 14.11% of the engrafted cells expressed TH+ and over 90% of these cells were co-labeled with GIRK2+, indicating the survival and maturation of A9 mDA neurons in the striatum of PD mice. Transplantation of hMOs led to a reversal of motor function and establishment of bidirectional connections with natural brain target regions, without any incidence of tumor formation or graft overgrowth. Conclusion: The findings of this study highlight the potential of hMOs as safe and efficacious donor graft sources for cell therapy to treat PD.
Collapse
Affiliation(s)
- Xin Zheng
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Deqiang Han
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Weihua Liu
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Xueyao Wang
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Na Pan
- The Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing 100053, China
| | - Yuping Wang
- The Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing 100053, China
| | - Zhiguo Chen
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| |
Collapse
|
|
10
|
Skidmore S, Barker RA. Challenges in the clinical advancement of cell therapies for Parkinson's disease. Nat Biomed Eng 2023; 7:370-386. [PMID: 36635420 PMCID: PMC7615223 DOI: 10.1038/s41551-022-00987-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 11/04/2022] [Indexed: 01/14/2023]
Abstract
Cell therapies as potential treatments for Parkinson's disease first gained traction in the 1980s, owing to the clinical success of trials that used transplants of foetal midbrain dopaminergic tissue. However, the poor standardization of the tissue for grafting, and constraints on its availability and ethical use, have hindered this treatment strategy. Recent advances in stem-cell technologies and in the understanding of the development of dopaminergic neurons have enabled preclinical advancements of promising stem-cell therapies. To move these therapies to the clinic, appropriate levels of safety screening, as well as optimization of the cell products and the scalability of their manufacturing, will be required. In this Review, we discuss how challenges pertaining to cell sources, functional and safety testing, manufacturing and storage, and clinical-trial design are being addressed to advance the translational and clinical development of cell therapies for Parkinson's disease.
Collapse
Affiliation(s)
- Sophie Skidmore
- Wellcome and MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre Cambridge Biomedical Campus, Cambridge, UK
| | - Roger A Barker
- Wellcome and MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre Cambridge Biomedical Campus, Cambridge, UK.
- John van Geest Centre for Brain Repair, Department of Clinical Neuroscience, For vie Site, Cambridge, UK.
| |
Collapse
|
|
11
|
Chen J, Huang L, Yang Y, Xu W, Qin Q, Qin R, Liang X, Lai X, Huang X, Xie M, Chen L. Somatic Cell Reprogramming for Nervous System Diseases: Techniques, Mechanisms, Potential Applications, and Challenges. Brain Sci 2023; 13:brainsci13030524. [PMID: 36979334 PMCID: PMC10046178 DOI: 10.3390/brainsci13030524] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Nervous system diseases present significant challenges to the neuroscience community due to ethical and practical constraints that limit access to appropriate research materials. Somatic cell reprogramming has been proposed as a novel way to obtain neurons. Various emerging techniques have been used to reprogram mature and differentiated cells into neurons. This review provides an overview of somatic cell reprogramming for neurological research and therapy, focusing on neural reprogramming and generating different neural cell types. We examine the mechanisms involved in reprogramming and the challenges that arise. We herein summarize cell reprogramming strategies to generate neurons, including transcription factors, small molecules, and microRNAs, with a focus on different types of cells.. While reprogramming somatic cells into neurons holds the potential for understanding neurological diseases and developing therapeutic applications, its limitations and risks must be carefully considered. Here, we highlight the potential benefits of somatic cell reprogramming for neurological disease research and therapy. This review contributes to the field by providing a comprehensive overview of the various techniques used to generate neurons by cellular reprogramming and discussing their potential applications.
Collapse
Affiliation(s)
- Jiafeng Chen
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Lijuan Huang
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Yue Yang
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Wei Xu
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Qingchun Qin
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Rongxing Qin
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Xiaojun Liang
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Xinyu Lai
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Nanning 530021, China
| | - Xiaoying Huang
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Minshan Xie
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Li Chen
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Nanning 530021, China
| |
Collapse
|
|
12
|
Su QS, Zhuang DL, Nasser MI, Sai X, Deng G, Li G, Zhu P. Stem Cell Therapies for Restorative Treatments of Central Nervous System Ischemia-Reperfusion Injury. Cell Mol Neurobiol 2023; 43:491-510. [PMID: 35129759 PMCID: PMC11415191 DOI: 10.1007/s10571-022-01204-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 02/01/2022] [Indexed: 11/27/2022]
Abstract
Ischemic damage to the central nervous system (CNS) is a catastrophic postoperative complication of aortic occlusion subsequent to cardiovascular surgery that can cause brain impairment and sometimes even paraplegia. Over recent years, numerous studies have investigated techniques for protecting and revascularizing the nervous system during intraoperative ischemia; however, owing to a lack of knowledge of the physiological distinctions between the brain and spinal cord, as well as the limited availability of testing techniques and treatments for ischemia-reperfusion injury, the cause of brain and spinal cord ischemia-reperfusion injury remains poorly understood, and no adequate response steps are currently available in the clinic. Given the limited ability of the CNS to repair itself, it is of great clinical value to make full use of the proliferative and differentiation potential of stem cells to repair nerves in degenerated and necrotic regions by stem cell transplantation or mobilization, thereby introducing a novel concept for the treatment of severe CNS ischemia-reperfusion injury. This review summarizes the most recent advances in stem cell therapy for ischemia-reperfusion injury in the brain and spinal cord, aiming to advance basic research and the clinical use of stem cell therapy as a promising treatment for this condition.
Collapse
Affiliation(s)
- Qi-Song Su
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510080, Guangdong, China
| | - Dong-Lin Zhuang
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
- College of Medicine, Shantou University, Shantou, 515063, Guangdong, China
| | - Moussa Ide Nasser
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
| | - Xiyalatu Sai
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao City, 028000, Inner Mongolia, China
| | - Gang Deng
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Ge Li
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China.
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510080, Guangdong, China.
| | - Ping Zhu
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China.
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510080, Guangdong, China.
- College of Medicine, Shantou University, Shantou, 515063, Guangdong, China.
- Guangdong Provincial Key Laboratory of Structural Heart Disease, Guangzhou, 510100, Guangdong, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao City, 028000, Inner Mongolia, China.
| |
Collapse
|
|
13
|
Stem Cell-derived Extracellular Vesicles: A Promising Nano Delivery Platform to the Brain? Stem Cell Rev Rep 2023; 19:285-308. [PMID: 36173500 DOI: 10.1007/s12015-022-10455-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/22/2022] [Indexed: 02/07/2023]
Abstract
A very important cause of the frustration with drug therapy for central nervous system (CNS) diseases is the failure of drug delivery. The blood-brain barrier (BBB) prevents most therapeutic molecules from entering the brain while maintaining CNS homeostasis. Scientists are keen to develop new brain drug delivery systems to solve this dilemma. Extracellular vesicles (EVs), as a class of naturally derived nanoscale vesicles, have been extensively studied in drug delivery due to their superior properties. This review will briefly present current brain drug delivery strategies, including invasive and non-invasive techniques that target the brain, and the application of nanocarriers developed for brain drug delivery in recent years, especially EVs. The cellular origin of EVs affects the surface protein, size, yield, luminal composition, and other properties of EVs, which are also crucial in determining whether EVs are useful as drug carriers. Stem cell-derived EVs, which inherit the properties of parental cells and avoid the drawbacks of cell therapy, have always been favored by researchers. Thus, in this review, we will focus on the application of stem cell-derived EVs for drug delivery in the CNS. Various nucleic acids, proteins, and small-molecule drugs are loaded into EVs with or without modification and undergo targeted delivery to the brain to achieve their therapeutic effects. In addition, the challenges facing the clinical application of EVs as drug carriers will also be discussed. The directions of future efforts may be to improve drug loading efficiency and precise targeting.
Collapse
|
|
14
|
Behl T, Kaur I, Sehgal A, Singh S, Sharma N, Chigurupati S, Felemban SG, Alsubayiel AM, Iqbal MS, Bhatia S, Al-Harrasi A, Bungau S, Mostafavi E. "Cutting the Mustard" with Induced Pluripotent Stem Cells: An Overview and Applications in Healthcare Paradigm. Stem Cell Rev Rep 2022; 18:2757-2780. [PMID: 35793037 DOI: 10.1007/s12015-022-10390-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2022] [Indexed: 12/09/2022]
Abstract
Treatment of numerous ailments has been made accessible by the advent of genetic engineering, where the self-renewal property has unfolded the mysteries of regeneration, i.e., stem cells. This is narrowed down to pluripotency, the cell property of differentiating into other adult cells. The generation of induced pluripotent stem cells (iPSCs) was a major breakthrough in 2006, which was generated by a cocktail of 4 Yamanaka Factors, following which significant advancements have been reported in medical science and therapeutics. The iPSCs are reprogrammed from somatic cells, and the fascinating results focused on developing authentic techniques for their generation via molecular reprogramming mechanisms, with a plethora of molecules, like NANOG, miRNAs, and DNA modifying agents, etc. The iPSCs have exhibited reliable results in assessing the etiology and molecular mechanisms of diseases, followed by the development of possible treatments and the elimination of risks of immune rejection. The authors formulate a comprehensive review to develop a clear understanding of iPSC generation, their advantages and limitations, with potential challenges associated with their medical utility. In addition, a wide compendium of applications of iPSCs in regenerative medicine and disease modeling has been discussed, alongside bioengineering technologies for iPSC reprogramming, expansion, isolation, and differentiation. The manuscript aims to provide a holistic picture of the booming advancement of iPSC therapy, to attract the attention of global researchers, to investigate this versatile approach in treatment of multiple disorders, subsequently overcoming the challenges, in order to effectively expand its therapeutic window.
Collapse
Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
| | - Ishnoor Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Sridevi Chigurupati
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah, Kingdom of Saudi Arabia
| | - Shatha Ghazi Felemban
- Department of Medical Laboratory Science, Fakeeh College for Medical Sciences, Jeddah, Kingdom of Saudi Arabia
| | - Amal M Alsubayiel
- Department of Pharmaceutics, College of Pharmacy, Qassim University, Buraydah, Kingdom of Saudi Arabia
| | - Muhammad Shahid Iqbal
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
- School of Health Science, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
| | - Ebrahim Mostafavi
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
| |
Collapse
|
|
15
|
Li D, Huang LT, Zhang CP, Li Q, Wang JH. Insights Into the Role of Platelet-Derived Growth Factors: Implications for Parkinson’s Disease Pathogenesis and Treatment. Front Aging Neurosci 2022; 14:890509. [PMID: 35847662 PMCID: PMC9283766 DOI: 10.3389/fnagi.2022.890509] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Parkinson’s disease (PD), the second most common neurodegenerative disease after Alzheimer’s disease, commonly occurs in the elderly population, causing a significant medical and economic burden to the aging society worldwide. At present, there are few effective methods that achieve satisfactory clinical results in the treatment of PD. Platelet-derived growth factors (PDGFs) and platelet-derived growth factor receptors (PDGFRs) are important neurotrophic factors that are expressed in various cell types. Their unique structures allow for specific binding that can effectively regulate vital functions in the nervous system. In this review, we summarized the possible mechanisms by which PDGFs/PDGFRs regulate the occurrence and development of PD by affecting oxidative stress, mitochondrial function, protein folding and aggregation, Ca2+ homeostasis, and cell neuroinflammation. These modes of action mainly depend on the type and distribution of PDGFs in different nerve cells. We also summarized the possible clinical applications and prospects for PDGF in the treatment of PD, especially in genetic treatment. Recent advances have shown that PDGFs have contradictory roles within the central nervous system (CNS). Although they exert neuroprotective effects through multiple pathways, they are also associated with the disruption of the blood–brain barrier (BBB). Our recommendations based on our findings include further investigation of the contradictory neurotrophic and neurotoxic effects of the PDGFs acting on the CNS.
Collapse
Affiliation(s)
- Dan Li
- Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Le-Tian Huang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Cheng-pu Zhang
- Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qiang Li
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Qiang Li,
| | - Jia-He Wang
- Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, China
- Jia-He Wang,
| |
Collapse
|
|
16
|
Brot S, Thamrin NP, Bonnet ML, Francheteau M, Patrigeon M, Belnoue L, Gaillard A. Long-Term Evaluation of Intranigral Transplantation of Human iPSC-Derived Dopamine Neurons in a Parkinson's Disease Mouse Model. Cells 2022; 11:cells11101596. [PMID: 35626637 PMCID: PMC9140181 DOI: 10.3390/cells11101596] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/04/2022] [Accepted: 05/05/2022] [Indexed: 11/16/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder associated with loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). One strategy for treating PD is transplantation of DA neuroblasts. Significant advances have been made in generating midbrain DA neurons from human pluripotent stem cells. Before these cells can be routinely used in clinical trials, extensive preclinical safety studies are required. One of the main issues to be addressed is the long-term therapeutic effectiveness of these cells. In most transplantation studies using human cells, the maturation of DA neurons has been analyzed over a relatively short period not exceeding 6 months. In present study, we generated midbrain DA neurons from human induced pluripotent stem cells (hiPSCs) and grafted these neurons into the SNpc in an animal model of PD. Graft survival and maturation were analyzed from 1 to 12 months post-transplantation (mpt). We observed long-term survival and functionality of the grafted neurons. However, at 12 mpt, we observed a decrease in the proportion of SNpc DA neuron subtype compared with that at 6 mpt. In addition, at 12 mpt, grafts still contained immature neurons. Our results suggest that longer-term evaluation of the maturation of neurons derived from human stem cells is mandatory for the safe application of cell therapy for PD.
Collapse
Affiliation(s)
- Sébastien Brot
- Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, INSERM 1084, 86022 Poitiers, France; (S.B.); (N.P.T.); (M.-L.B.); (M.F.); (M.P.); (L.B.)
| | - Nabila Pyrenina Thamrin
- Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, INSERM 1084, 86022 Poitiers, France; (S.B.); (N.P.T.); (M.-L.B.); (M.F.); (M.P.); (L.B.)
| | - Marie-Laure Bonnet
- Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, INSERM 1084, 86022 Poitiers, France; (S.B.); (N.P.T.); (M.-L.B.); (M.F.); (M.P.); (L.B.)
- CHU Poitiers, 86022 Poitiers, France
| | - Maureen Francheteau
- Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, INSERM 1084, 86022 Poitiers, France; (S.B.); (N.P.T.); (M.-L.B.); (M.F.); (M.P.); (L.B.)
| | - Maëlig Patrigeon
- Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, INSERM 1084, 86022 Poitiers, France; (S.B.); (N.P.T.); (M.-L.B.); (M.F.); (M.P.); (L.B.)
| | - Laure Belnoue
- Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, INSERM 1084, 86022 Poitiers, France; (S.B.); (N.P.T.); (M.-L.B.); (M.F.); (M.P.); (L.B.)
- CHU Poitiers, 86022 Poitiers, France
| | - Afsaneh Gaillard
- Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, INSERM 1084, 86022 Poitiers, France; (S.B.); (N.P.T.); (M.-L.B.); (M.F.); (M.P.); (L.B.)
- Correspondence: ; Tel.: +33-54-945-3873
| |
Collapse
|
|
17
|
Grinand L, Takahashi J. Automated measurement of fluorescence signals reveals a significant increase of the graft-derived neurite extension in neonates compared to aged rats. Regen Ther 2022; 19:97-106. [PMID: 35155722 PMCID: PMC8810554 DOI: 10.1016/j.reth.2022.01.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/12/2022] [Indexed: 01/03/2023] Open
Abstract
Background – Neural tissue grafting is an acceptable form of cell therapy for brain injury and diseases. However, methods that can evaluate the graft integration and measure axonal extensions in a 3D environment are limited in scale, inconvenient, and operator intensive. Method – We stained grafts with a fluorescent antibody and then quantified the amount of fluorescence through the entire brain. To achieve this, we created an automated computer program designed to sort out authentic staining from background noise without any user input, enabling the analysis of thousands of images. Results – Our program could compensate for variations in the background brightness between images in all animals. Using this program, we show that human induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) progenitor cells integrate better into the striatum of neonates than older rats. Conclusion – Our program can quantify quickly and conveniently the integration of neural grafts in a 3D environment without depending on a blinded human operator. We expect this method to be a useful tool to assess the efficiency of graft-enhancing treatments for neurodegenerative diseases or other neural reconstruction attempts.
Collapse
|
|
18
|
Kim CK, Sachdev PS, Braidy N. Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet? Aging Dis 2022; 13:175-214. [PMID: 35111369 PMCID: PMC8782556 DOI: 10.14336/ad.2021.0705] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/05/2021] [Indexed: 12/21/2022] Open
Abstract
Owing to the global exponential increase in population ageing, there is an urgent unmet need to develop reliable strategies to slow down and delay the ageing process. Age-related neurodegenerative diseases are among the main causes of morbidity and mortality in our contemporary society and represent a major socio-economic burden. There are several controversial factors that are thought to play a causal role in brain ageing which are continuously being examined in experimental models. Among them are oxidative stress and brain inflammation which are empirical to brain ageing. Although some candidate drugs have been developed which reduce the ageing phenotype, their clinical translation is limited. There are several strategies currently in development to improve brain ageing. These include strategies such as caloric restriction, ketogenic diet, promotion of cellular nicotinamide adenine dinucleotide (NAD+) levels, removal of senescent cells, 'young blood' transfusions, enhancement of adult neurogenesis, stem cell therapy, vascular risk reduction, and non-pharmacological lifestyle strategies. Several studies have shown that these strategies can not only improve brain ageing by attenuating age-related neurodegenerative disease mechanisms, but also maintain cognitive function in a variety of pre-clinical experimental murine models. However, clinical evidence is limited and many of these strategies are awaiting findings from large-scale clinical trials which are nascent in the current literature. Further studies are needed to determine their long-term efficacy and lack of adverse effects in various tissues and organs to gain a greater understanding of their potential beneficial effects on brain ageing and health span in humans.
Collapse
Affiliation(s)
- Chul-Kyu Kim
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Perminder S Sachdev
- Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Sydney, Australia
| | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| |
Collapse
|
|
19
|
Mirzaei S, Kulkarni K, Zhou K, Crack PJ, Aguilar MI, Finkelstein DI, Forsythe JS. Biomaterial Strategies for Restorative Therapies in Parkinson's Disease. ACS Chem Neurosci 2021; 12:4224-4235. [PMID: 34634903 DOI: 10.1021/acschemneuro.1c00484] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Parkinson's disease (PD) is a progressive neurological disorder, in which dopaminergic midbrain neurons degenerate, leading to dopamine depletion that is associated with neuronal death. In this Review, we initially describe the pathogenesis of PD and established therapies that unfortunately only delay progression of the disease. With a rapidly escalating incidence in PD, there is an urgent need to develop new therapies that not only halt progression but even reverse degeneration. Biomaterials are playing critical roles in these new therapies which include controlled and site-specific delivery of neurotrophins, increased engraftment of implanted neural stem cells, and redirection of endogenous stem cell populations away from their niche to encourage reparative mechanisms. This Review will therefore cover important design features of biomaterials used in regenerative medicine and tissue engineering strategies targeted at PD.
Collapse
Affiliation(s)
- Samaneh Mirzaei
- Department of Materials Science and Engineering, Monash Institute of Medical Engineering, Monash University, Clayton, Victoria 3800, Australia
- Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Ketav Kulkarni
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
| | - Kun Zhou
- Department of Materials Science and Engineering, Monash Institute of Medical Engineering, Monash University, Clayton, Victoria 3800, Australia
| | - Peter J. Crack
- Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Marie-Isabel Aguilar
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
| | - David I. Finkelstein
- Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - John S. Forsythe
- Department of Materials Science and Engineering, Monash Institute of Medical Engineering, Monash University, Clayton, Victoria 3800, Australia
| |
Collapse
|
|
20
|
Aishwarya L, Arun D, Kannan S. Stem cells as a potential therapeutic option for treating neurodegenerative diseases. Curr Stem Cell Res Ther 2021; 17:590-605. [PMID: 35135464 DOI: 10.2174/1574888x16666210810105136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 11/22/2022]
Abstract
In future, neurodegenerative diseases will take over cancer's place and become the major cause of death in the world, especially in developed countries. Advancements in the medical field and its facilities have led to an increase in the old age population, and thus contributing to the increase in number of people suffering from neurodegenerative diseases. Economically it is of a great burden to society and the affected family. No current treatment aims to replace, protect, and regenerate lost neurons; instead, it alleviates the symptoms, extends the life span by a few months and creates severe side effects. Moreover, people who are affected are physically dependent for performing their basic activities, which makes their life miserable. There is an urgent need for therapy that could be able to overcome the deficits of conventional therapy for neurodegenerative diseases. Stem cells, the unspecialized cells with the properties of self-renewing and potency to differentiate into various cells types can become a potent therapeutic option for neurodegenerative diseases. Stem cells have been widely used in clinical trials to evaluate their potential in curing different types of ailments. In this review, we discuss the various types of stem cells and their potential use in the treatment of neurodegenerative disease based on published preclinical and clinical studies.
Collapse
Affiliation(s)
- Aishwarya L
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Chennai-600 116. India
| | - Dharmarajan Arun
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Chennai-600 116. India
| | - Suresh Kannan
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Chennai-600 116. India
| |
Collapse
|
|
21
|
Mukherjee S, Yadav G, Kumar R. Recent trends in stem cell-based therapies and applications of artificial intelligence in regenerative medicine. World J Stem Cells 2021; 13:521-541. [PMID: 34249226 PMCID: PMC8246250 DOI: 10.4252/wjsc.v13.i6.521] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/22/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cells are undifferentiated cells that can self-renew and differentiate into diverse types of mature and functional cells while maintaining their original identity. This profound potential of stem cells has been thoroughly investigated for its significance in regenerative medicine and has laid the foundation for cell-based therapies. Regenerative medicine is rapidly progressing in healthcare with the prospect of repair and restoration of specific organs or tissue injuries or chronic disease conditions where the body’s regenerative process is not sufficient to heal. In this review, the recent advances in stem cell-based therapies in regenerative medicine are discussed, emphasizing mesenchymal stem cell-based therapies as these cells have been extensively studied for clinical use. Recent applications of artificial intelligence algorithms in stem cell-based therapies, their limitation, and future prospects are highlighted.
Collapse
Affiliation(s)
- Sayali Mukherjee
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
| | - Garima Yadav
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
| | - Rajnish Kumar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
| |
Collapse
|
|
22
|
Duan R, Gao Y, He R, Jing L, Li Y, Gong Z, Yao Y, Luan T, Zhang C, Li L, Jia Y. Induced Pluripotent Stem Cells for Ischemic Stroke Treatment. Front Neurosci 2021; 15:628663. [PMID: 34135724 PMCID: PMC8202685 DOI: 10.3389/fnins.2021.628663] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 05/06/2021] [Indexed: 12/17/2022] Open
Abstract
Ischemic stroke is one of the main central nervous system diseases and is associated with high disability and mortality rates. Recombinant tissue plasminogen activator (rt-PA) and mechanical thrombectomy are the optimal therapies available currently to restore blood flow in patients with stroke; however, their limitations are well recognized. Therefore, new treatments are urgently required to overcome these shortcomings. Recently, stem cell transplantation technology, involving the transplantation of induced pluripotent stem cells (iPSCs), has drawn the interest of neuroscientists and is considered to be a promising alternative for ischemic stroke treatment. iPSCs are a class of cells produced by introducing specific transcription factors into somatic cells, and are similar to embryonic stem cells in biological function. Here, we have reviewed the current applications of stem cells with a focus on iPSC therapy in ischemic stroke, including the neuroprotective mechanisms, development constraints, major challenges to overcome, and clinical prospects. Based on the current state of research, we believe that stem cells, especially iPSCs, will pave the way for future stroke treatment.
Collapse
Affiliation(s)
- Ranran Duan
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yang Gao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ruya He
- The International Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lijun Jing
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanfei Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhe Gong
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yaobing Yao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Tingting Luan
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chaopeng Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Li Li
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yanjie Jia
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| |
Collapse
|
|
23
|
Li C, Xue L, Liu Y, Yang Z, Chi S, Xie A. Zonisamide for the Treatment of Parkinson Disease: A Current Update. Front Neurosci 2020; 14:574652. [PMID: 33408605 PMCID: PMC7779619 DOI: 10.3389/fnins.2020.574652] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 11/20/2020] [Indexed: 12/17/2022] Open
Abstract
Zonisamide has been used as an add-on treatment in order to overcome the deficiencies of the general therapies currently used to resolve the motor complications and non-motor symptoms of Parkinson disease. Various trials have been designed to investigate the mechanism of action and treatment effects of zonisamide in this condition. Most clinical trials of zonisamide in Parkinson disease were from Japan. The vast majority of studies used changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) scores and daily “OFF” time as primary endpoints. Based on adequate randomized controlled trials, zonisamide is considered a safe and efficacious add-on treatment in Parkinson disease. The most convincing proof is available for a dosage of 25–50 mg, which was shown to lead to a significant reduction in the UPDRS III score and daily “OFF” time, without increasing disabling dyskinesia. Furthermore, zonisamide may play a beneficial role in improving non-motor symptoms in PD, including impulsive–compulsive disorder, rapid eye movement sleep behavior disorder, and dementia. Among the various mechanisms reported, inhibition of monoamine oxidase-B, blocking of T-type calcium channels, modulation of the levodopa–dopamine metabolism, modulation of receptor expression, and neuroprotection are the most often cited. The mechanisms underlying neuroprotection, including modulation of dopamine turnover, induction of neurotrophic factor expression, inhibition of oxidative stress and apoptosis, inhibition of neuroinflammation, modulation of synaptic transmission, and modulation of gene expression, have been most extensively studied. This review focuses on structure, pharmacokinetics, mechanisms, therapeutic effectiveness, and safety and tolerability of zonisamide in patients with Parkinson disease.
Collapse
Affiliation(s)
- Chengqian Li
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Li Xue
- Department of Medical Record, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yumei Liu
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhengjie Yang
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Song Chi
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Anmu Xie
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|
|
24
|
Ford E, Pearlman J, Ruan T, Manion J, Waller M, Neely GG, Caron L. Human Pluripotent Stem Cells-Based Therapies for Neurodegenerative Diseases: Current Status and Challenges. Cells 2020; 9:E2517. [PMID: 33233861 PMCID: PMC7699962 DOI: 10.3390/cells9112517] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 11/13/2020] [Accepted: 11/17/2020] [Indexed: 12/11/2022] Open
Abstract
Neurodegenerative diseases are characterized by irreversible cell damage, loss of neuronal cells and limited regeneration potential of the adult nervous system. Pluripotent stem cells are capable of differentiating into the multitude of cell types that compose the central and peripheral nervous systems and so have become the major focus of cell replacement therapies for the treatment of neurological disorders. Human embryonic stem cell (hESC) and human induced pluripotent stem cell (hiPSC)-derived cells have both been extensively studied as cell therapies in a wide range of neurodegenerative disease models in rodents and non-human primates, including Parkinson's disease, stroke, epilepsy, spinal cord injury, Alzheimer's disease, multiple sclerosis and pain. In this review, we discuss the latest progress made with stem cell therapies targeting these pathologies. We also evaluate the challenges in clinical application of human pluripotent stem cell (hPSC)-based therapies including risk of oncogenesis and tumor formation, immune rejection and difficulty in regeneration of the heterogeneous cell types composing the central nervous system.
Collapse
Affiliation(s)
- Elizabeth Ford
- Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, Centenary Institute, University of Sydney, Camperdown, NSW 2006, Australia; (E.F.); (J.P.); (T.R.); (J.M.); (M.W.); (G.G.N.)
- School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia
- Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK
| | - Jodie Pearlman
- Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, Centenary Institute, University of Sydney, Camperdown, NSW 2006, Australia; (E.F.); (J.P.); (T.R.); (J.M.); (M.W.); (G.G.N.)
- School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia
- Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK
| | - Travis Ruan
- Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, Centenary Institute, University of Sydney, Camperdown, NSW 2006, Australia; (E.F.); (J.P.); (T.R.); (J.M.); (M.W.); (G.G.N.)
- School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia
| | - John Manion
- Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, Centenary Institute, University of Sydney, Camperdown, NSW 2006, Australia; (E.F.); (J.P.); (T.R.); (J.M.); (M.W.); (G.G.N.)
- School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia
- Department of Urology, Boston Children’s Hospital, Boston, MA 02115, USA
- Departments of Surgery and Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | - Matthew Waller
- Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, Centenary Institute, University of Sydney, Camperdown, NSW 2006, Australia; (E.F.); (J.P.); (T.R.); (J.M.); (M.W.); (G.G.N.)
- School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia
| | - Gregory G. Neely
- Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, Centenary Institute, University of Sydney, Camperdown, NSW 2006, Australia; (E.F.); (J.P.); (T.R.); (J.M.); (M.W.); (G.G.N.)
- School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia
| | - Leslie Caron
- Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, Centenary Institute, University of Sydney, Camperdown, NSW 2006, Australia; (E.F.); (J.P.); (T.R.); (J.M.); (M.W.); (G.G.N.)
- School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia
| |
Collapse
|
|
25
|
Jia N, Chong J, Sun L. Application of stem cell biology in treating neurodegenerative diseases. Int J Neurosci 2020; 132:815-825. [PMID: 33081549 DOI: 10.1080/00207454.2020.1840376] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND The appropriate strategies are needed for stimulating the endogenous neurogenesis or introducing extrinsic neural progenitors, which could be harnessed as the regenerative resources for cueing the neurodegenerations. Adult neurogenesis is the endogenous continuing physiology in limited brain regions such as hippocampus, olfactory system, and hypothalamus. Besides adult neurogenesis, induced pluripotent stem cells (iPSCs) induced functional neurons could be another option for regenerative therapies. OBJECTIVE Current studies are trying to improve the adult neurogenesis and enable the iPSCs induced neurons into neural regeneration. Methods: Here in this review, we mainly introduced the recent progress in neural stem cell biology and its application in the treatment of the neurodegenerations. We main separated the strategy in summarizing the mediators and potential targets to promoting endogenous neural regeneration and transplantation of neural progenitors. CONCLUSION By collecting and comparing the advantages disadvantages between above-mentioned two strategies, we will offer the insight on future development of stem cell therapy in treating neurodegenerative patients.
Collapse
Affiliation(s)
- Na Jia
- Beijing University of Posts and Telecommunications, Beijing, China
| | - Jingping Chong
- Beijing University of Posts and Telecommunications, Beijing, China.,Shanghai University of Engineering Science, Shanghai, China
| | - Lina Sun
- Beijing University of Posts and Telecommunications, Beijing, China.,College of PE and Sport, Beijing Normal University, Beijing, China
| |
Collapse
|
|
26
|
Song B, Cha Y, Ko S, Jeon J, Lee N, Seo H, Park KJ, Lee IH, Lopes C, Feitosa M, Luna MJ, Jung JH, Kim J, Hwang D, Cohen BM, Teicher MH, Leblanc P, Carter BS, Kordower JH, Bolshakov VY, Kong SW, Schweitzer JS, Kim KS. Human autologous iPSC-derived dopaminergic progenitors restore motor function in Parkinson's disease models. J Clin Invest 2020; 130:904-920. [PMID: 31714896 DOI: 10.1172/jci130767] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 10/30/2019] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder associated with loss of striatal dopamine, secondary to degeneration of midbrain dopamine (mDA) neurons in the substantia nigra, rendering cell transplantation a promising therapeutic strategy. To establish human induced pluripotent stem cell-based (hiPSC-based) autologous cell therapy, we report a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, we developed a method to more efficiently generate clinical-grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential. Second, we established a "spotting"-based in vitro differentiation methodology to generate functional and healthy mDA cells in a scalable manner. Third, we developed a chemical method that safely eliminates undifferentiated cells from the final product. Dopaminergic cells thus express high levels of characteristic mDA markers, produce and secrete dopamine, and exhibit electrophysiological features typical of mDA cells. Transplantation of these cells into rodent models of PD robustly restores motor function and reinnervates host brain, while showing no evidence of tumor formation or redistribution of the implanted cells. We propose that this platform is suitable for the successful implementation of human personalized autologous cell therapy for PD.
Collapse
Affiliation(s)
- Bin Song
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | - Young Cha
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | - Sanghyeok Ko
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | - Jeha Jeon
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | - Nayeon Lee
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | - Hyemyung Seo
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA.,Department of Molecular and Life Sciences, Hanyang University, Ansan, Korea
| | | | - In-Hee Lee
- Department of Pediatrics.,Computational Health Informatics Program, Boston Children's Hospital, and
| | - Claudia Lopes
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | - Melissa Feitosa
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | - María José Luna
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | - Jin Hyuk Jung
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | - Jisun Kim
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA.,Department of Molecular and Life Sciences, Hanyang University, Ansan, Korea
| | - Dabin Hwang
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | | | | | - Pierre Leblanc
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | - Bob S Carter
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jeffrey H Kordower
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
| | | | - Sek Won Kong
- Department of Pediatrics.,Computational Health Informatics Program, Boston Children's Hospital, and
| | - Jeffrey S Schweitzer
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kwang-Soo Kim
- Department of Psychiatry and.,Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| |
Collapse
|
|
27
|
Induced Pluripotent Stem Cells: Hope in the Treatment of Diseases, including Muscular Dystrophies. Int J Mol Sci 2020; 21:ijms21155467. [PMID: 32751747 PMCID: PMC7432218 DOI: 10.3390/ijms21155467] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 04/22/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Abstract
Induced pluripotent stem (iPS) cells are laboratory-produced cells that combine the biological advantages of somatic adult and stem cells for cell-based therapy. The reprogramming of cells, such as fibroblasts, to an embryonic stem cell-like state is done by the ectopic expression of transcription factors responsible for generating embryonic stem cell properties. These primary factors are octamer-binding transcription factor 4 (Oct3/4), sex-determining region Y-box 2 (Sox2), Krüppel-like factor 4 (Klf4), and the proto-oncogene protein homolog of avian myelocytomatosis (c-Myc). The somatic cells can be easily obtained from the patient who will be subjected to cellular therapy and be reprogrammed to acquire the necessary high plasticity of embryonic stem cells. These cells have no ethical limitations involved, as in the case of embryonic stem cells, and display minimal immunological rejection risks after transplant. Currently, several clinical trials are in progress, most of them in phase I or II. Still, some inherent risks, such as chromosomal instability, insertional tumors, and teratoma formation, must be overcome to reach full clinical translation. However, with the clinical trials and extensive basic research studying the biology of these cells, a promising future for human cell-based therapies using iPS cells seems to be increasingly clear and close.
Collapse
|
|
28
|
Marotta N, Kim S, Krainc D. Organoid and pluripotent stem cells in Parkinson's disease modeling: an expert view on their value to drug discovery. Expert Opin Drug Discov 2020; 15:427-441. [PMID: 31899983 DOI: 10.1080/17460441.2020.1703671] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Introduction: Parkinson's disease is a devastating neurodegenerative disorder preferentially involving loss of dopaminergic neurons in the substantia nigra, leading to typical motor symptoms. While there are still no therapeutics to modify disease course, recent work using induced pluripotent stem cell (iPSC) and 3D brain organoid models have provided further insight into Parkinson's disease pathogenesis and potential therapeutic targets.Areas covered: This review highlights the generation of iPSC neurons and neural organoids as models for studying Parkinson's disease. It further discusses the recent work using patient-derived neurons from both familial and sporadic forms of Parkinson's to study disease pathogenic phenotypes and pathways. It additionally provides an evaluation of iPSC neurons and organoid models for therapeutic development in Parkinson's.Expert opinion: The use of Parkinson's disease patient-derived neurons and organoids provides us with the exciting opportunity to directly investigate pathogenic mechanisms and test drug compounds in human neurons. Future studies will involve generating more sophisticated models of brain organoids, studying neuronal pathways using larger patient cohorts, and routinely assessing therapeutics in these models.
Collapse
Affiliation(s)
- Nick Marotta
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Soojin Kim
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Dimitri Krainc
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| |
Collapse
|
|
29
|
Chang M, Oh B, Choi J, Sulistio YA, Woo H, Jo A, Kim J, Kim E, Kim SW, Hwang J, Park J, Song J, Kwon O, Henry Kim H, Kim Y, Ko JY, Heo JY, Lee MJ, Lee M, Choi M, Chung SJ, Lee H, Lee S. LIN28A loss of function is associated with Parkinson's disease pathogenesis. EMBO J 2019; 38:e101196. [PMID: 31750563 PMCID: PMC6912061 DOI: 10.15252/embj.2018101196] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 10/01/2019] [Accepted: 10/15/2019] [Indexed: 12/18/2022] Open
Abstract
Parkinson's disease (PD) is neurodegenerative movement disorder characterized by degeneration of midbrain-type dopamine (mDA) neurons in the substantia nigra (SN). The RNA-binding protein Lin28 plays a role in neuronal stem cell development and neuronal differentiation. In this study, we reveal that Lin28 conditional knockout (cKO) mice show degeneration of mDA neurons in the SN, as well as PD-related behavioral deficits. We identify a loss-of-function variant of LIN28A (R192G substitution) in two early-onset PD patients. Using an isogenic human embryonic stem cell (hESC)/human induced pluripotent stem cell (hiPSC)-based disease model, we find that the Lin28 R192G variant leads to developmental defects and PD-related phenotypes in mDA neuronal cells that can be rescued by expression of wild-type Lin28A. Cell transplantation experiments in PD model rats show that correction of the LIN28A variant in the donor patient (pt)-hiPSCs leads to improved behavioral phenotypes. Our data link LIN28A to PD pathogenesis and suggest future personalized medicine targeting this variant in patients.
Collapse
|
|
30
|
Neurodegeneration and Neuro-Regeneration-Alzheimer's Disease and Stem Cell Therapy. Int J Mol Sci 2019; 20:ijms20174272. [PMID: 31480448 PMCID: PMC6747457 DOI: 10.3390/ijms20174272] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/27/2019] [Accepted: 08/28/2019] [Indexed: 12/17/2022] Open
Abstract
Aging causes many changes in the human body, and is a high risk for various diseases. Dementia, a common age-related disease, is a clinical disorder triggered by neurodegeneration. Brain damage caused by neuronal death leads to cognitive decline, memory loss, learning inabilities and mood changes. Numerous disease conditions may cause dementia; however, the most common one is Alzheimer’s disease (AD), a futile and yet untreatable illness. Adult neurogenesis carries the potential of brain self-repair by an endogenous formation of newly-born neurons in the adult brain; however it also declines with age. Strategies to improve the symptoms of aging and age-related diseases have included different means to stimulate neurogenesis, both pharmacologically and naturally. Finally, the regulatory mechanisms of stem cells neurogenesis or a functional integration of newborn neurons have been explored to provide the basis for grafted stem cell therapy. This review aims to provide an overview of AD pathology of different neural and glial cell types and summarizes current strategies of experimental stem cell treatments and their putative future use in clinical settings.
Collapse
|
|
31
|
The selective electrochemical detection of dopamine in the presence of ascorbic acid and uric acid using electro-polymerised-β-cyclodextrin incorporated f-MWCNTs/polyaniline modified glassy carbon electrode. Microchem J 2019. [DOI: 10.1016/j.microc.2019.04.081] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
|
|
32
|
Moon JI, Han MJ, Yu SH, Lee EH, Kim SM, Han K, Park CH, Kim CH. Enhanced delivery of protein fused to cell penetrating peptides to mammalian cells. BMB Rep 2019. [PMID: 30293549 PMCID: PMC6549919 DOI: 10.5483/bmbrep.2019.52.5.195] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Recent progress in cellular reprogramming technology and lineage-specific cell differentiation has provided great opportunities for translational research. Because virus-based gene delivery is not a practical reprogramming protocol, protein-based reprogramming has been receiving attention as a safe way to generate reprogrammed cells. However, the poor efficiency of the cellular uptake of reprogramming proteins is still a major obstacle. Here, we reported key factors which improve the cellular uptake of these proteins. Purified red fluorescent proteins fused with 9xLysine (dsRED-9K) as a cell penetrating peptide were efficiently delivered into the diverse primary cells. Protein delivery was improved by the addition of amodiaquine. Furthermore, purified dsRED-9K was able to penetrate all cell lineages derived from mouse embryonic stem cells efficiently. Our data may provide important insights into the design of protein-based reprogramming or differentiation protocols.
Collapse
Affiliation(s)
- Jung-Il Moon
- Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47906, USA
| | - Min-Joon Han
- Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Shin-Hye Yu
- Paean Biotechnology, Inc., Daejeon 34028, Hanyang University, Seoul 04763, Korea
| | - Eun-Hye Lee
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea
| | - Sang-Mi Kim
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea
| | - Kyuboem Han
- Paean Biotechnology, Inc., Daejeon 34028, Hanyang University, Seoul 04763, Korea
| | - Chang-Hwan Park
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea
- Department of Microbiology, College of Medicine, Hanyang University, Seoul 04763, Korea
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Chun-Hyung Kim
- Paean Biotechnology, Inc., Daejeon 34028, Hanyang University, Seoul 04763, Korea
| |
Collapse
|
|
33
|
Rhee YH, Puspita L, Sulistio YA, Kim SW, Vidyawan V, Elvira R, Chang MY, Shim JW, Lee SH. Efficient Neural Differentiation of hPSCs by Extrinsic Signals Derived from Co-cultured Neural Stem or Precursor Cells. Mol Ther 2019; 27:1299-1312. [PMID: 31043343 DOI: 10.1016/j.ymthe.2019.04.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Revised: 04/09/2019] [Accepted: 04/09/2019] [Indexed: 01/06/2023] Open
Abstract
In this study, we found that undifferentiated human pluripotent stem cells (hPSCs; up to 30% of total cells) present in the cultures of neural stem or precursor cells (NPCs) completely disappeared within several days when cultured under neural differentiation culture conditions. Intriguingly, the disappearance of undifferentiated cells was not due to cell death but was instead mediated by neural conversion of hPSCs. Based on these findings, we propose pre-conditioning of donor NPC cultures under terminal differentiation culture conditions as a simple but efficient method of eliminating undifferentiated cells to treat neurologic disorders. In addition, we could establish a new neural differentiation protocol, in which undifferentiated hPSCs co-cultured with NPCs become differentiated neurons or NPCs in an extremely efficient, fast, and reproducible manner across the hESC and human-induced pluripotent stem cell (hiPSC) lines.
Collapse
Affiliation(s)
- Yong-Hee Rhee
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 04763, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Lesly Puspita
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si 31151, Korea
| | - Yanuar Alan Sulistio
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 04763, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Seung Won Kim
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 04763, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Vincencius Vidyawan
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si 31151, Korea
| | - Rosalie Elvira
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si 31151, Korea
| | - Mi-Yoon Chang
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 04763, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Jae-Won Shim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si 31151, Korea.
| | - Sang-Hun Lee
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 04763, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea.
| |
Collapse
|
|
34
|
Ryu J, Park BC, Lee DH. A proteomic analysis of differentiating dopamine neurons derived from human embryonic stem cells. Anim Cells Syst (Seoul) 2019; 23:219-227. [PMID: 31231586 PMCID: PMC6566932 DOI: 10.1080/19768354.2019.1595140] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 02/23/2019] [Accepted: 03/03/2019] [Indexed: 11/08/2022] Open
Abstract
Human embryonic stem cells (hESC) are being exploited for potential use in cell transplantation due to their capacity for self-renewal and pluripotency. Dopamine (DA) neurons derived from hESC represent a promising source of cell replacement therapy for Parkinson’s disease (PD). While gene expression on the transcriptome level has been extensively studied, limited information is available for the proteome-level changes associated with DA neuron differentiation. Here we analyzed the proteome of differentiating DA neurons to search for the potential biomarkers to assess the efficiency of differentiation. Although the proteome profile of DA neurons did not exhibit significant changes, a number of cytoskeletal proteins including nuclear lamin, tropomyosin 1, and myosin light chain 1 were specifically up-regulated during differentiation. Expression analysis of the respective genes was also consistent with the proteome results. In addition, these differentially expressed proteins form protein interaction network with several PD-related proteins suggesting that they may play roles in PD pathogenesis as well as the maturation of DA neurons.
Collapse
Affiliation(s)
- Joohyun Ryu
- Department of Cellular and Molecular Biology, The Hormel Institute, University of Minnesota, Austin, MN, USA
| | - Byoung Chul Park
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Do Hee Lee
- Department of Bio and Environmental Technology, Seoul Women's University, Seoul, Korea
| |
Collapse
|
|
35
|
Large-Scale Generation and Characterization of Homogeneous Populations of Migratory Cortical Interneurons from Human Pluripotent Stem Cells. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2019; 13:414-430. [PMID: 31061832 PMCID: PMC6495066 DOI: 10.1016/j.omtm.2019.04.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 04/01/2019] [Indexed: 02/05/2023]
Abstract
During development, cortical interneurons (cINs) are generated from the ventral telencephalon, robustly migrate to the dorsal telencephalon, make local synaptic connections, and critically regulate brain circuitry by inhibiting other neurons. Thus, their abnormality is associated with various brain disorders. Human pluripotent stem cell (hPSC)-derived cINs can provide unlimited sources with which to study the pathogenesis mechanism of these disorders as well as provide a platform to develop novel therapeutics. By employing spinner culture, we could obtain a >10-fold higher yield of cIN progenitors compared to conventional culture without affecting their phenotype. Generated cIN spheres can be maintained feeder-free up to 10 months and are optimized for passaging and cryopreservation. In addition, we identified a combination of chemicals that synchronously matures generated progenitors into SOX6+KI67− migratory cINs and extensively characterized their maturation in terms of metabolism, migration, arborization, and electrophysiology. When transplanted into mouse brains, chemically matured migratory cINs generated grafts that efficiently disperse and integrate into the host circuitry without uncontrolled growth, making them an optimal cell population for cell therapy. Efficient large-scale generation of homogeneous migratory cINs without the need of feeder cells will play a critical role in the full realization of hPSC-derived cINs for development of novel therapeutics.
Collapse
|
|
36
|
Dong Y, Han LL, Xu ZX. Suppressed microRNA-96 inhibits iNOS expression and dopaminergic neuron apoptosis through inactivating the MAPK signaling pathway by targeting CACNG5 in mice with Parkinson's disease. Mol Med 2018; 24:61. [PMID: 30486773 PMCID: PMC6263543 DOI: 10.1186/s10020-018-0059-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 11/04/2018] [Indexed: 12/15/2022] Open
Abstract
Background There have been a number of reports implicating the association of microRNAs (miRs) and the MAPK signaling pathway with the dopaminergic neuron, which is involved in the development of Parkinson’s disease (PD). The present study was conducted with aims of exploring the role of miR-96 in the activation of iNOS and apoptosis of dopaminergic neuron through the MAPK signaling pathway in mice with PD. Methods The miR and the differentially expressed gene in PD were screened out and the relationship between them was verified. A mouse model of PD induced by MPTP and was then constructed and treated with miR-96 mimic/inhibitor and CACNG5 overexpression plasmid to extract nigral dopaminergic neuron for the purpose of detecting the effect of miR-96 on PD. The TH and iNOS positive neuronal cells, the apoptotic neuronal cells by TUNEL staining, and expression of miR-96, CACNG5, iNOS, p38MAPK, p-p38MAPK, c-Fos, Bax, and Bcl-2 in substantia nigra dopaminergic neuronal tissues were evaluated. Results The results obtained from the aforementioned procedure were then verified by cell culture of the SH-SY5Y cells, followed by treatment with miR-96 mimic/inhibitor, CACNG5 overexpression plasmid and the inhibitor of the MAPK signaling pathway. CACNG5 was confirmed as a target gene of miR-96. The inhibition of miR-96 resulted in a substantial increase in nigral cells, TH positive cells and expression of CACNG5 and Bcl-2 in nigral dopaminergic neuronal tissues, and a decrease in iNOS positive cells, apoptotic neuronal cells, and expression of iNOS, p38MAPK, p-p38MAPK, c-Fos, and Bax. Conclusion The above results implicated that the downregulation of miR-96 inhibits the activation of iNOS and apoptosis of dopaminergic neuron through the blockade of the MAPK signaling pathway by promoting CACNG5 in mice with PD.
Collapse
Affiliation(s)
- Yue Dong
- Department of Neurology , China-Japan Union Hospital, Jilin University, No. 126, Xiantai Street, Erdao District, Changchun, 130012, Jilin Province, People's Republic of China
| | - Li-Li Han
- Department of Neurology, Cangzhou Central Hospital, Cangzhou, 061000, People's Republic of China
| | - Zhong-Xin Xu
- Department of Neurology , China-Japan Union Hospital, Jilin University, No. 126, Xiantai Street, Erdao District, Changchun, 130012, Jilin Province, People's Republic of China.
| |
Collapse
|
|
37
|
Hou Y, Li C. Stem/Progenitor Cells and Their Therapeutic Application in Cardiovascular Disease. Front Cell Dev Biol 2018; 6:139. [PMID: 30406100 PMCID: PMC6200850 DOI: 10.3389/fcell.2018.00139] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 09/28/2018] [Indexed: 12/26/2022] Open
Abstract
Cardiovascular disease is the leading cause of death in the world. The stem/progenitor cell-based therapy has emerged as a promising approach for the treatment of a variety of cardiovascular diseases including myocardial infarction, stroke, peripheral arterial disease, and diabetes. An increasing number of evidence has shown that stem/progenitor cell transplantation could replenish damaged cells, improve cardiac and vascular functions, and repair injured tissues in many pre-clinical studies and clinical trials. In this review, we have outlined the major types of stem/progenitor cells, and summarized the studies in applying these cells, especially endothelial stem/progenitor cells and their derivatives, in the treatment of cardiovascular disease. Here the strategies used to improve the stem/progenitor cell-based therapies in cardiovascular disease and the challenges with these therapies in clinical applications are also reviewed.
Collapse
Affiliation(s)
| | - Chunying Li
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, United States
| |
Collapse
|
|
38
|
Sonntag KC, Song B, Lee N, Jung JH, Cha Y, Leblanc P, Neff C, Kong SW, Carter BS, Schweitzer J, Kim KS. Pluripotent stem cell-based therapy for Parkinson's disease: Current status and future prospects. Prog Neurobiol 2018; 168:1-20. [PMID: 29653250 PMCID: PMC6077089 DOI: 10.1016/j.pneurobio.2018.04.005] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 03/13/2018] [Accepted: 04/05/2018] [Indexed: 12/11/2022]
Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative disorders, which affects about 0.3% of the general population. As the population in the developed world ages, this creates an escalating burden on society both in economic terms and in quality of life for these patients and for the families that support them. Although currently available pharmacological or surgical treatments may significantly improve the quality of life of many patients with PD, these are symptomatic treatments that do not slow or stop the progressive course of the disease. Because motor impairments in PD largely result from loss of midbrain dopamine neurons in the substantia nigra pars compacta, PD has long been considered to be one of the most promising target diseases for cell-based therapy. Indeed, numerous clinical and preclinical studies using fetal cell transplantation have provided proof of concept that cell replacement therapy may be a viable therapeutic approach for PD. However, the use of human fetal cells as a standardized therapeutic regimen has been fraught with fundamental ethical, practical, and clinical issues, prompting scientists to explore alternative cell sources. Based on groundbreaking establishments of human embryonic stem cells and induced pluripotent stem cells, these human pluripotent stem cells have been the subject of extensive research, leading to tremendous advancement in our understanding of these novel classes of stem cells and promising great potential for regenerative medicine. In this review, we discuss the prospects and challenges of human pluripotent stem cell-based cell therapy for PD.
Collapse
Affiliation(s)
- Kai-C Sonntag
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Laboratory for Translational Research on Neurodegeneration, 115 Mill Street, Belmont, MA, 02478, United States; Program for Neuropsychiatric Research, 115 Mill Street, Belmont, MA, 02478, United States
| | - Bin Song
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States
| | - Nayeon Lee
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States
| | - Jin Hyuk Jung
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States
| | - Young Cha
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States
| | - Pierre Leblanc
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States
| | - Carolyn Neff
- Kaiser Permanente Medical Group, Irvine, CA, 92618, United States
| | - Sek Won Kong
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, United States; Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, 02115, United States
| | - Bob S Carter
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, 02114, United States
| | - Jeffrey Schweitzer
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, 02114, United States.
| | - Kwang-Soo Kim
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States.
| |
Collapse
|
|
39
|
Li J, Sun Y, Chen J. Identification of Critical Genes and miRNAs Associated with the Development of Parkinson's Disease. J Mol Neurosci 2018; 65:527-535. [PMID: 30083784 DOI: 10.1007/s12031-018-1129-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 07/18/2018] [Indexed: 01/18/2023]
Abstract
The purpose of this study was to explore the key mechanism involved in the pathogenesis of Parkinson's disease (PD) based on microarray analysis. The expression profile data of GSE7621, which contained 9 substantia nigra tissues isolated from normals and 16 substantia nigra tissues isolated from PD patients, was obtained from Gene Expression Omnibus. The differentially expressed genes (DEGs) were screened, followed by functional enrichment analysis and protein-protein interaction (PPI) network construction. After the miRNAs regulating the DEGs were predicted, the miRNA-DEG regulatory network was then constructed. Besides, the 6-hydroxydopamine rat model of PD was established and the expression of key DEGs and miRNA was detected. A total of 388 DEGs were identified, including 218 upregulated genes and 170 downregulated ones. Tyrosine hydroxylase (TH) and solute carrier family 6 member 3 (SLC6A3) were significantly related to the functional terms of catecholamine biosynthetic process and dopamine biosynthetic process. TH and SLC6A3 were hub nodes in the PPI network. EBF3 could be targeted by miR-218. Moreover, TH and SLC6A3 were found downregulated in the 6-OHDA rat model of PD, while miR-218 was markedly upregulated. Our results reveal that SLC6A3, TH, and EBF3 targeted by miR-218 could be involved in PD. These molecules might provide a new insight into the development of therapeutic strategies for PD.
Collapse
Affiliation(s)
- Jia Li
- Department of Neurology, China-Japan Union Hospital of Jilin University, Xiantai Road, Erdao District, Changchun, 130033, Jilin, China
| | - Yajuan Sun
- Department of Neurology, China-Japan Union Hospital of Jilin University, Xiantai Road, Erdao District, Changchun, 130033, Jilin, China
| | - Jiajun Chen
- Department of Neurology, China-Japan Union Hospital of Jilin University, Xiantai Road, Erdao District, Changchun, 130033, Jilin, China.
| |
Collapse
|
|
40
|
Grochowski C, Radzikowska E, Maciejewski R. Neural stem cell therapy-Brief review. Clin Neurol Neurosurg 2018; 173:8-14. [PMID: 30053745 DOI: 10.1016/j.clineuro.2018.07.013] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 07/09/2018] [Accepted: 07/17/2018] [Indexed: 12/23/2022]
Abstract
Adult mammalian neural stem cells are unique because of their properties, such as differentiation capacity, self-renewal, quiescence, and also because they exist in specific niches, which are the subventricular zone (SVZ) and subgranular zone (SGZ) - the dentate gyrus of the hippocampus. SVZ is situated along the ependymal cell layer, dividing the ventricular area and subventricular zone. There are several sources of neural stem cells such as human embryonic stem cells, human fetal brain-derived neural stem/progenitor cells, human induced pluripotent stem cells, direct reprogrammed astrocytes. Stem cell sciences are a promising tool for research purposes as well as therapy. Induced pluripotent stem cells appear to be very useful for human neuron studies, allowing the creation of defined neuron populations, particularly for neurodevelopmental and neurodegenerative diseases as well as ischemic events. Neural stem cell sciences have a promising future in terms of stem cell therapy as well as research. There is, however, still a great need for further research to overcome obstacles.
Collapse
Affiliation(s)
- Cezary Grochowski
- Department of Anatomy, Medical University of Lublin, Doktora Kazimierza Jaczewskiego 4, 20-400, Lublin, Poland; Department of Neurosurgery and Pediatric Neurosurgery in Lublin, Medical University of Lublin, Poland.
| | - Elżbieta Radzikowska
- Department of Plastic Surgery, Central Clinical Hospital of the MSWiA in Warsaw, Poland
| | - Ryszard Maciejewski
- Department of Anatomy, Medical University of Lublin, Doktora Kazimierza Jaczewskiego 4, 20-400, Lublin, Poland
| |
Collapse
|
|
41
|
Cell reprogramming approaches in gene- and cell-based therapies for Parkinson's disease. J Control Release 2018; 286:114-124. [PMID: 30026082 DOI: 10.1016/j.jconrel.2018.07.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 06/26/2018] [Accepted: 07/10/2018] [Indexed: 12/17/2022]
Abstract
Degeneration of dopamine (DA) neurons in the substantia nigra pars compacta is the pathological hallmark of Parkinson's disease (PD). In PD multiple pathogenic mechanisms initiate and drive this neurodegenerative process, making the development of effective treatments challenging. To date, PD patients are primarily treated with dopaminergic drugs able to temporarily enhance DA levels, therefore relieving motor symptoms. However, the drawbacks of these therapies including the inability to alter disease progression are constantly supporting the search for alternative treatment approaches. Over the past years efforts have been put into the development of new therapeutic strategies based on the delivery of therapeutic genes using viral vectors or transplantation of DA neurons for cell-based DA replacement. Here, past achievements and recent advances in gene- and cell-based therapies for PD are outlined. We discuss how current gene and cell therapy strategies hold great promise for the treatment of PD and how the use of stem cells and recent developments in cellular reprogramming could contribute to open a new avenue in PD therapy.
Collapse
|
|
42
|
Huang H, Young W, Chen L, Feng S, Zoubi ZMA, Sharma HS, Saberi H, Moviglia GA, He X, Muresanu DF, Sharma A, Otom A, Andrews RJ, Al-Zoubi A, Bryukhovetskiy AS, Chernykh ER, Domańska-Janik K, Jafar E, Johnson WE, Li Y, Li D, Luan Z, Mao G, Shetty AK, Siniscalco D, Skaper S, Sun T, Wang Y, Wiklund L, Xue Q, You SW, Zheng Z, Dimitrijevic MR, Masri WSE, Sanberg PR, Xu Q, Luan G, Chopp M, Cho KS, Zhou XF, Wu P, Liu K, Mobasheri H, Ohtori S, Tanaka H, Han F, Feng Y, Zhang S, Lu Y, Zhang Z, Rao Y, Tang Z, Xi H, Wu L, Shen S, Xue M, Xiang G, Guo X, Yang X, Hao Y, Hu Y, Li J, AO Q, Wang B, Zhang Z, Lu M, Li T. Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017). Cell Transplant 2018; 27:310-324. [PMID: 29637817 PMCID: PMC5898693 DOI: 10.1177/0963689717746999] [Citation(s) in RCA: 34] [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: 04/28/2017] [Revised: 07/22/2017] [Accepted: 11/13/2017] [Indexed: 12/11/2022] Open
Abstract
Cell therapy has been shown to be a key clinical therapeutic option for central nervous system diseases or damage. Standardization of clinical cell therapy procedures is an important task for professional associations devoted to cell therapy. The Chinese Branch of the International Association of Neurorestoratology (IANR) completed the first set of guidelines governing the clinical application of neurorestoration in 2011. The IANR and the Chinese Association of Neurorestoratology (CANR) collaborated to propose the current version "Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)". The IANR council board members and CANR committee members approved this proposal on September 1, 2016, and recommend it to clinical practitioners of cellular therapy. These guidelines include items of cell type nomenclature, cell quality control, minimal suggested cell doses, patient-informed consent, indications for undergoing cell therapy, contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility.
Collapse
Affiliation(s)
- Hongyun Huang
- Institute of Neurorestoratology, General Hospital of Armed Police Forces, Beijing, People’s Republic of China
| | - Wise Young
- W. M. Keck Center for Collaborative Neuroscience, Rutgers, State University of New Jersey, Piscataway, NJ, USA
| | - Lin Chen
- Department of Neurosurgery, Tsinghua University Yuquan Hospital, Beijing, People’s Republic of China
| | - Shiqing Feng
- Department of Orthopaedics, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
| | - Ziad M. Al Zoubi
- Jordan Ortho and Spinal Centre, Al-Saif Medical Center, Amman, Jordan
| | - Hari Shanker Sharma
- Intensive Experimental CNS Injury and Repair, University Hospital, Uppsala University, Uppsala, Sweden
| | - Hooshang Saberi
- Department of Neurosurgery, Brain and Spinal Injury Research center, Tehran University of Medical Sciences, Tehran, Iran
| | - Gustavo A. Moviglia
- Center of Research and Engineer of Tissues and Cellular Therapy, Maimonides University, Buenos Aires, Argentina
| | - Xijing He
- Department of Orthopaedics, Second Affiliated Hospital of Xi’an Jiaotong University, Xian, People’s Republic of China
| | - Dafin F. Muresanu
- Department of Neurosciences “Iuliu Hatieganu,” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Alok Sharma
- Department of Neurosurgery, LTM Medical College, LTMG Hospital, Mumbai, Mumbai, India
| | - Ali Otom
- Royal Rehabilitation Center, King Hussein Medical Centre-RJRC Amman, Jordan
| | - Russell J. Andrews
- Nanotechnology & Smart Systems, NASA Ames Research Center, Silicon Valley, CA, USA
| | - Adeeb Al-Zoubi
- The University of Illinois College of Medicine in Peoria, Peoria, IL, USA
| | - Andrey S. Bryukhovetskiy
- NeuroVita Clinic of Interventional and Restorative Neurology and Therapy, Kashirskoye shosse, Moscow, Russia
| | - Elena R. Chernykh
- Lab of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | | | - Emad Jafar
- Jordan Ortho and Spinal Centre, Al-Saif Medical Center, Amman, Jordan
| | - W. Eustace Johnson
- Stem Cells and Regenerative Biology, Faculty of Medicine Dentistry and Life Sciences, University of Chester, Chester, United Kingdom
| | - Ying Li
- Spinal Repair Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, United Kingdom
| | - Daqing Li
- Spinal Repair Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, United Kingdom
| | - Zuo Luan
- Department of Pediatrics, Navy General Hospital of PLA, Beijing, People’s Republic of China
| | - Gengsheng Mao
- Institute of Neurorestoratology, General Hospital of Armed Police Forces, Beijing, People’s Republic of China
| | - Ashok K. Shetty
- Department of Molecular and Cellular Medicine, Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA
| | - Dario Siniscalco
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli,” Naples, Italy
| | - Stephen Skaper
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
| | - Tiansheng Sun
- Department of orthopedics, PLA Army General Hospital, Beijing, People’s Republic of China
| | - Yunliang Wang
- Department of Neurology, 148th Hospital, Zibo, Shandong, People’s Republic of China
| | - Lars Wiklund
- Unit of Neurology, Department of Pharmacology and Clinical Neuroscience, Umea University, Ostersund, Sweden
| | - Qun Xue
- Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou Jiangsu, People’s Republic of China
| | - Si-Wei You
- Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China
| | - Zuncheng Zheng
- Department of Rehabilitation Medicine, The Central Hospital of Taian, Taian, Shandong, People’s Republic of China
| | | | - W. S. El Masri
- Spinal Injuries Unit, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, United Kingdom
| | - Paul R. Sanberg
- Center of Excellence for Aging & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Qunyuan Xu
- Institute of Neuroscience, Capital Medical University, Beijing, People’s Republic of China
| | - Guoming Luan
- Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Michael Chopp
- Henry Ford Hospital, Henry Ford Health System, Neurology Research, Detroit, MI, USA
| | - Kyoung-Suok Cho
- Department of Neurosurgery, Uijongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijongbu, South Korea
| | - Xin-Fu Zhou
- Division of Health Sciences, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia
| | - Ping Wu
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA
| | - Kai Liu
- Division of Life Science, The Hong Kong University of Science and Technology, Kowloon, Hong Kong
| | - Hamid Mobasheri
- Biomaterials Research Center, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Seiji Ohtori
- Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroyuki Tanaka
- Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Fabin Han
- Centre for Stem Cells and Regenerative Medicine, Liaocheng University/Liaocheng People’s Hospital, Liaocheng, Shandong, People’s Republic of China
| | - Yaping Feng
- Department of Neurosurgery, Kunming General Hospital of Chengdu Military Command of Chinese PLA, Kunming, Yunnan, People’s Republic of China
| | - Shaocheng Zhang
- Department of Orthopedics, Changhai Hospital, The Second Military Medical University, Shanghai, People’s Republic of China
| | - Yingjie Lu
- Department of Neurosurgery, Chengde Dadu Hospital, Weichang, Hebei, People’s Republic of China
| | - Zhicheng Zhang
- Department of orthopedics, PLA Army General Hospital, Beijing, People’s Republic of China
| | - Yaojian Rao
- Department of Spinal Surgery, Luoyang Orthopedic Hospital of Henan Province, Luoyang, Henan, People’s Republic of China
| | - Zhouping Tang
- Department of Neurology, Tongji Medical College of HUST, Tongji Hospital, Wuhan, People’s Republic of China
| | - Haitao Xi
- Department of Neurology, Beijing Rehabilitation Hospital of Capital Medical University, Beijing, People’s Republic of China
| | - Liang Wu
- Center of Rehabilitation, Beijing Xiaotangshan Rehabilitation Hospital, Beijing, People’s Republic of China
| | - Shunji Shen
- Department of Rehabilitation, Weihai Municipal Hospital, Weihai, Shandong, People’s Republic of China
| | - Mengzhou Xue
- Department of Neurorehabilitation, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Guanghong Xiang
- Brain Hospital of Hunan Province, Changsha, Hunan, People’s Republic of China
| | - Xiaoling Guo
- Department of Neurology, PLA Army 266 Hospital, Chengde, Hebei, People’s Republic of China
| | - Xiaofeng Yang
- Department of Neurosurgery, The First Affiliated Hospital of Zhejiang University Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Yujun Hao
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Yong Hu
- Department of Orthopaedic and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong
| | - Jinfeng Li
- Unit of Neurology, Department of Pharmacology and Clinical Neuroscience, Umea University, Ostersund, Sweden
| | - Qiang AO
- Department of tissue engineering, China Medical University, Shenyang, Liaoning, People’s Republic of China
| | - Bin Wang
- Department of Traumatology, The Second Affiliated Hospital of Guangzhou Medical University, Haizhu District, Guangzhou, People’s Republic of China
| | - Zhiwen Zhang
- Department of Neurosurgery, First Affiliated Hospital of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Ming Lu
- Department of Neurosurgery, Second Affiliated Hospital of Hunan Normal University (163 Hospital of PLA), Changsha, Hunan, People’s Republic of China
| | - Tong Li
- Department of Neurology, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
| |
Collapse
|
|
43
|
Zhang Y, Ge M, Hao Q, Dong B. Induced pluripotent stem cells in rat models of Parkinson's disease: A systematic review and meta-analysis. Biomed Rep 2018; 8:289-296. [PMID: 29564126 DOI: 10.3892/br.2018.1049] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 09/21/2017] [Indexed: 02/05/2023] Open
Abstract
The effects of induced pluripotent stem cells (iPSCs) in 6-hydroxydopamine-lesioned rat models of Parkinson's disease (PD) have been evaluated in multiple studies. However, the results evaluating the effectiveness of iPSCs in animal models of PD are mixed, primarily due to their low statistical power. In the current study, a meta-analysis was performed to describe the treatment effect of unsorted iPSCs on behavioral testing in experimental rat models of PD. Databases searched included PubMed, EMBASE, MEDLINE and the Cochrane Library from inception to March 2017. Data were extracted for rotation behavior tests (induced by amphetamine and apomorphine) and limb function tests. A total of eight studies were included in the current meta-analysis, and iPSCs were identified to be efficacious according to the pooled standardized mean differences (SMDs) for improving amphetamine-induced rotational behavior [SMD, -2.16; 95% confidence interval (95% CI), -2.93, -1.40; P<0.00001] and apomorphine-induced rotational test (SMD, -1.45; 95% CI, -2.16, -0.73; P<0.0001). The pooled evidence indicated that iPSCs improve rotational behavior in rat models of PD. It was concluded that iPSCs provide a potential approach for developing novel treatment strategies for PD, and the results of this meta-analysis may guide future preclinical and clinical studies.
Collapse
Affiliation(s)
- Yunxia Zhang
- Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China.,The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Meiling Ge
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qiukui Hao
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Birong Dong
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| |
Collapse
|
|
44
|
Ulasov AV, Rosenkranz AA, Sobolev AS. Transcription factors: Time to deliver. J Control Release 2017; 269:24-35. [PMID: 29113792 DOI: 10.1016/j.jconrel.2017.11.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 11/02/2017] [Accepted: 11/03/2017] [Indexed: 12/17/2022]
Abstract
Transcription factors (TFs) are at the center of the broad regulatory network orchestrating gene expression programs that elicit different biological responses. For a long time, TFs have been considered as potent drug targets due to their implications in the pathogenesis of a variety of diseases. At the same time, TFs, located at convergence points of cellular regulatory pathways, are powerful tools providing opportunities both for cell type change and for managing the state of cells. This task formulation requires the TF modulation problem to come to the fore. We review several ways to manage TF activity (small molecules, transfection, nanocarriers, protein-based approaches), analyzing their limitations and the possibilities to overcome them. Delivery of TFs could revolutionize the biomedical field. Whether this forecast comes true will depend on the ability to develop convenient technologies for targeted delivery of TFs.
Collapse
Affiliation(s)
- Alexey V Ulasov
- Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia
| | - Andrey A Rosenkranz
- Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia; Faculty of Biology, Moscow State University, 1-12 Leninskiye Gory St., 119234 Moscow, Russia
| | - Alexander S Sobolev
- Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia; Faculty of Biology, Moscow State University, 1-12 Leninskiye Gory St., 119234 Moscow, Russia.
| |
Collapse
|
|
45
|
López-León M, Outeiro TF, Goya RG. Cell reprogramming: Therapeutic potential and the promise of rejuvenation for the aging brain. Ageing Res Rev 2017; 40:168-181. [PMID: 28903069 DOI: 10.1016/j.arr.2017.09.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Revised: 08/27/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023]
Abstract
Aging is associated with a progressive increase in the incidence of neurodegenerative diseases, with Alzheimer's (AD) and Parkinson's (PD) disease being the most conspicuous examples. Within this context, the absence of efficacious therapies for most age-related brain pathologies has increased the interest in regenerative medicine. In particular, cell reprogramming technologies have ushered in the era of personalized therapies that not only show a significant potential for the treatment of neurodegenerative diseases but also promise to make biological rejuvenation feasible. We will first review recent evidence supporting the emerging view that aging is a reversible epigenetic phenomenon. Next, we will describe novel reprogramming approaches that overcome some of the intrinsic limitations of conventional induced-pluripotent-stem-cell technology. One of the alternative approaches, lineage reprogramming, consists of the direct conversion of one adult cell type into another by transgenic expression of multiple lineage-specific transcription factors (TF). Another strategy, termed pluripotency factor-mediated direct reprogramming, uses universal TF to generate epigenetically unstable intermediates able to differentiate into somatic cell types in response to specific differentiation factors. In the third part we will review studies showing the potential relevance of the above approaches for the treatment of AD and PD.
Collapse
Affiliation(s)
- Micaela López-León
- Institute for Biochemical Research (INIBIOLP) - Histology B & Pathology B, School of Medicine, National University of La Plata, La Plata, Argentina
| | - Tiago F Outeiro
- Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany; Max Planck Institute for Experimental Medicine, Göttingen, Germany
| | - Rodolfo G Goya
- Institute for Biochemical Research (INIBIOLP) - Histology B & Pathology B, School of Medicine, National University of La Plata, La Plata, Argentina.
| |
Collapse
|
|
46
|
Tong G, Izquierdo P, Raashid RA. Human Induced Pluripotent Stem Cells and the Modelling of Alzheimer's Disease: The Human Brain Outside the Dish. Open Neurol J 2017; 11:27-38. [PMID: 29151989 PMCID: PMC5678240 DOI: 10.2174/1874205x01711010027] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Revised: 08/18/2017] [Accepted: 08/20/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Neurodegenerative diseases like Alzheimer's Disease (AD) are a global health issue primarily in the elderly. Although AD has been investigated using primary cultures, animal models and post-mortem human brain tissues, there are currently no effective treatments. SUMMARY With the advent of induced pluripotent stem cells (iPSCs) reprogrammed from fully differentiated adult cells such as skin fibroblasts, newer opportunities have arisen to study the pathophysiology of many diseases in more depth. It is envisioned that iPSCs could be used as a powerful tool for neurodegenerative disease modelling and eventually be an unlimited source for cell replacement therapy. This paper provides an overview of; the contribution of iPSCs towards modeling and understanding AD pathogenesis, the novel human/mouse chimeric models in elucidating current AD pathogenesis hypotheses, the possible use of iPSCs in drug screening, and perspectives on possible future directions. KEY MESSAGES Human/mouse chimeric models using iPSCs to study AD offer much promise in better replicating AD pathology and can be further exploited to elucidate disease pathogenesis with regards to the neuroinflammation hypothesis of AD.
Collapse
Affiliation(s)
- Godwin Tong
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
| | - Pablo Izquierdo
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
| | - Rana Arham Raashid
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
| |
Collapse
|
|
47
|
Stem Cell Technology for (Epi)genetic Brain Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 978:443-475. [PMID: 28523560 DOI: 10.1007/978-3-319-53889-1_23] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Despite the enormous efforts of the scientific community over the years, effective therapeutics for many (epi)genetic brain disorders remain unidentified. The common and persistent failures to translate preclinical findings into clinical success are partially attributed to the limited efficiency of current disease models. Although animal and cellular models have substantially improved our knowledge of the pathological processes involved in these disorders, human brain research has generally been hampered by a lack of satisfactory humanized model systems. This, together with our incomplete knowledge of the multifactorial causes in the majority of these disorders, as well as a thorough understanding of associated (epi)genetic alterations, has been impeding progress in gaining more mechanistic insights from translational studies. Over the last years, however, stem cell technology has been offering an alternative approach to study and treat human brain disorders. Owing to this technology, we are now able to obtain a theoretically inexhaustible source of human neural cells and precursors in vitro that offer a platform for disease modeling and the establishment of therapeutic interventions. In addition to the potential to increase our general understanding of how (epi)genetic alterations contribute to the pathology of brain disorders, stem cells and derivatives allow for high-throughput drugs and toxicity testing, and provide a cell source for transplant therapies in regenerative medicine. In the current chapter, we will demonstrate the validity of human stem cell-based models and address the utility of other stem cell-based applications for several human brain disorders with multifactorial and (epi)genetic bases, including Parkinson's disease (PD), Alzheimer's disease (AD), fragile X syndrome (FXS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Rett syndrome (RTT).
Collapse
|
|
48
|
Wulansari N, Kim EH, Sulistio YA, Rhee YH, Song JJ, Lee SH. Vitamin C-Induced Epigenetic Modifications in Donor NSCs Establish Midbrain Marker Expressions Critical for Cell-Based Therapy in Parkinson's Disease. Stem Cell Reports 2017; 9:1192-1206. [PMID: 28943252 PMCID: PMC5639382 DOI: 10.1016/j.stemcr.2017.08.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 08/24/2017] [Accepted: 08/24/2017] [Indexed: 11/20/2022] Open
Abstract
Cultured neural stem/precursor cells (NSCs) are regarded as a potential systematic cell source to treat Parkinson's disease (PD). However, the therapeutic potential of these cultured NSCs is lost during culturing. Here, we show that treatment of vitamin C (VC) enhances generation of authentic midbrain-type dopamine (mDA) neurons with improved survival and functions from ventral midbrain (VM)-derived NSCs. VC acted by upregulating a series of mDA neuron-specific developmental and phenotype genes via removal of DNA methylation and repressive histone code (H3K9m3, H3K27m3) at associated gene promoter regions. Notably, the epigenetic changes induced by transient VC treatment were sustained long after VC withdrawal. Accordingly, transplantation of VC-treated NSCs resulted in improved behavioral restoration, along with enriched DA neuron engraftment, which faithfully expressed midbrain-specific markers in PD model rats. These results indicate that VC treatment to donor NSCs could be a simple, efficient, and safe therapeutic strategy for PD in the future.
Vitamin C (VC) potentiates therapeutic capacity of donor NSCs to treat PD Long-lasting epigenetic activation of VM-specific genes underlies the VC effects The VC effects enhanced mDA neuron engraftment
Collapse
Affiliation(s)
- Noviana Wulansari
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Korea; Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Eun-Hee Kim
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Korea; Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Yanuar Alan Sulistio
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Korea; Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Yong-Hee Rhee
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Korea; Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Jae-Jin Song
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Korea; Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Sang-Hun Lee
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Korea; Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.
| |
Collapse
|
|
49
|
Martínez-Cerdeño V, Barrilleaux BL, McDonough A, Ariza J, Yuen BTK, Somanath P, Le CT, Steward C, Horton-Sparks K, Knoepfler PS. Behavior of Xeno-Transplanted Undifferentiated Human Induced Pluripotent Stem Cells Is Impacted by Microenvironment Without Evidence of Tumors. Stem Cells Dev 2017; 26:1409-1423. [PMID: 28693365 DOI: 10.1089/scd.2017.0059] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Human pluripotent stem cells (hPSC) have great clinical potential through the use of their differentiated progeny, a population in which there is some concern over risks of tumorigenicity or other unwanted cellular behavior due to residual hPSC. Preclinical studies using human stem cells are most often performed within a xenotransplant context. In this study, we sought to measure how undifferentiated hPSC behave following xenotransplant. We directly transplanted undifferentiated human induced pluripotent stem cells (hIPSC) and human embryonic stem cells (hESC) into the adult mouse brain ventricle and analyzed their fates. No tumors or precancerous lesions were present at more than one year after transplantation. This result differed with the tumorigenic capacity we observed after allotransplantation of mouse ESC into the mouse brain. A substantial population of cellular derivatives of undifferentiated hESC and hIPSC engrafted, survived, and migrated within the mouse brain parenchyma. Within brain structures, transplanted cell distribution followed a very specific pattern, suggesting the existence of distinct microenvironments that offer different degrees of permissibility for engraftment. Most of the transplanted hESC and hIPSC that developed into brain cells were NeuN+ neuronal cells, and no astrocytes were detected. Substantial cell and nuclear fusion occurred between host and transplanted cells, a phenomenon influenced by microenvironment. Overall, hIPSC appear to be largely functionally equivalent to hESC in vivo. Altogether, these data bring new insights into the behavior of stem cells without prior differentiation following xenotransplantation into the adult brain.
Collapse
Affiliation(s)
- Veronica Martínez-Cerdeño
- 1 Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine , Sacramento, California.,2 Institute for Regenerative Cures, University of California Davis School of Medicine , Sacramento, California.,3 Institute of Pediatric Regenerative Medicine , Shriners Hospital for Children, Northern California, Sacramento, California
| | - Bonnie L Barrilleaux
- 2 Institute for Regenerative Cures, University of California Davis School of Medicine , Sacramento, California.,3 Institute of Pediatric Regenerative Medicine , Shriners Hospital for Children, Northern California, Sacramento, California.,4 Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine , Sacramento, California
| | - Ashley McDonough
- 3 Institute of Pediatric Regenerative Medicine , Shriners Hospital for Children, Northern California, Sacramento, California
| | - Jeanelle Ariza
- 3 Institute of Pediatric Regenerative Medicine , Shriners Hospital for Children, Northern California, Sacramento, California
| | - Benjamin T K Yuen
- 2 Institute for Regenerative Cures, University of California Davis School of Medicine , Sacramento, California.,3 Institute of Pediatric Regenerative Medicine , Shriners Hospital for Children, Northern California, Sacramento, California.,4 Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine , Sacramento, California
| | - Priyanka Somanath
- 2 Institute for Regenerative Cures, University of California Davis School of Medicine , Sacramento, California.,3 Institute of Pediatric Regenerative Medicine , Shriners Hospital for Children, Northern California, Sacramento, California.,4 Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine , Sacramento, California
| | - Catherine T Le
- 2 Institute for Regenerative Cures, University of California Davis School of Medicine , Sacramento, California.,3 Institute of Pediatric Regenerative Medicine , Shriners Hospital for Children, Northern California, Sacramento, California.,4 Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine , Sacramento, California
| | - Craig Steward
- 3 Institute of Pediatric Regenerative Medicine , Shriners Hospital for Children, Northern California, Sacramento, California
| | - Kayla Horton-Sparks
- 3 Institute of Pediatric Regenerative Medicine , Shriners Hospital for Children, Northern California, Sacramento, California
| | - Paul S Knoepfler
- 2 Institute for Regenerative Cures, University of California Davis School of Medicine , Sacramento, California.,3 Institute of Pediatric Regenerative Medicine , Shriners Hospital for Children, Northern California, Sacramento, California.,4 Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine , Sacramento, California
| |
Collapse
|
|
50
|
Kim SM, Lim MS, Lee EH, Jung SJ, Chung HY, Kim CH, Park CH. Efficient Generation of Dopamine Neurons by Synthetic Transcription Factor mRNAs. Mol Ther 2017; 25:2028-2037. [PMID: 28705346 DOI: 10.1016/j.ymthe.2017.06.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 06/15/2017] [Accepted: 06/18/2017] [Indexed: 12/25/2022] Open
Abstract
Generation of functional dopamine (DA) neurons is an essential step for the development of effective cell therapy for Parkinson's disease (PD). The generation of DA neurons can be accomplished by overexpression of DA-inducible genes using virus- or DNA-based gene delivery methods. However, these gene delivery methods often cause chromosomal anomalies. In contrast, mRNA-based gene delivery avoids this problem and therefore is considered safe to use in the development of cell-based therapy. Thus, we used mRNA-based gene delivery method to generate safe DA neurons. In this study, we generated transformation-free DA neurons by transfection of mRNA encoding DA-inducible genes Nurr1 and FoxA2. The delivery of mRNA encoding dopaminergic fate inducing genes proved sufficient to induce naive rat forebrain precursor cells to differentiate into neurons exhibiting the biochemical, electrophysiological, and functional properties of DA neurons in vitro. Additionally, the generation efficiency of DA neurons was improved by the addition of small molecules, db-cAMP, and the adjustment of transfection timing. The successful generation of DA neurons using an mRNA-based method offers the possibility of developing clinical-grade cell sources for neuronal cell replacement treatment for PD.
Collapse
Affiliation(s)
- Sang-Mi Kim
- Department of Biomedical Science, Graduate School, Hanyang University, Seoul 04763, Korea; Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea
| | - Mi-Sun Lim
- R&D Center, Jeil Pharmaceutical Co., Ltd., Yongin 17172, Korea; Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul 06360, Korea
| | - Eun-Hye Lee
- Department of Biomedical Science, Graduate School, Hanyang University, Seoul 04763, Korea
| | - Sung Jun Jung
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea; Department of Physiology, College of Medicine, Hanyang University, Seoul 04763, Korea
| | - Hee Yong Chung
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea; Department of Microbiology, College of Medicine, Hanyang University, Seoul 04763, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea.
| | | | - Chang-Hwan Park
- Department of Biomedical Science, Graduate School, Hanyang University, Seoul 04763, Korea; Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea; Department of Microbiology, College of Medicine, Hanyang University, Seoul 04763, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea.
| |
Collapse
|