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Wei R, Yang M, Cao Y, Qiu S, Fan X, Fang M, Chen L, Cheng S, Li J, Zhang S. Efficacy and Potential Mechanisms of Umbilical Cord-Derived Mesenchymal Stem Cells in the Treatment of Ischemic Stroke in Animal Models: A Meta-Analysis. CNS Neurosci Ther 2025; 31:e70357. [PMID: 40202099 PMCID: PMC11979713 DOI: 10.1111/cns.70357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 03/11/2025] [Accepted: 03/14/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Umbilical cord-derived mesenchymal stem cells (UCMSCs) have emerged as a promising treatment for ischemic stroke. This study aimed to evaluate the therapeutic efficacy and potential mechanisms of UCMSCs in treating ischemic stroke. METHODS A systematic search of PubMed, Web of Science, and Embase was conducted up to April 25, 2024. Literature was screened based on the PICOS principle, with predefined inclusion and exclusion criteria. Relevant data were extracted and analyzed using Review Manager 5.4. RESULTS Out of 1390 retrieved articles, 30 were included in the meta-analysis. UCMSCs significantly reduced infarct size and volume, improved neurological deficit scores, and facilitated neurobehavioral recovery. UCMSCs treatment also modulated inflammatory cytokine levels in brain tissue and serum, promoted microglial polarization, inhibited apoptosis, and increased vessel density in the peri-infarct tissue. CONCLUSIONS UCMSCs administration significantly promoted the neurological function recovery after ischemic stroke. Their mechanisms of action may be related to immune response regulation, inhibition of apoptosis, and promotion of angiogenesis. These findings provide theoretical guidance for improving the quality of basic research and clinical translation.
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Affiliation(s)
- Renli Wei
- Fujian Key Laboratory of Aptamers TechnologyFuzhou General Teaching Hospital (The 900th Hospital), Fujian University of Traditional Chinese MedicineFuzhouFujianChina
- College of Rehabilitation MedicineFujian University of Traditional Chinese MedicineFuzhouFujianChina
| | - Minguang Yang
- The Institute of Rehabilitation IndustryFujian University of Traditional Chinese MedicineFuzhouFujianChina
| | - Yue Cao
- Department of Clinical Laboratory MedicineFuzhou General Clinical Medical School, Fujian Medical UniversityFuzhouFujianChina
| | - Shuqian Qiu
- Fujian Key Laboratory of Aptamers TechnologyFuzhou General Teaching Hospital (The 900th Hospital), Fujian University of Traditional Chinese MedicineFuzhouFujianChina
| | - Xu Fan
- Fujian Key Laboratory of Aptamers TechnologyFuzhou General Teaching Hospital (The 900th Hospital), Fujian University of Traditional Chinese MedicineFuzhouFujianChina
- College of Rehabilitation MedicineFujian University of Traditional Chinese MedicineFuzhouFujianChina
| | - Muxuan Fang
- Fujian Key Laboratory of Aptamers TechnologyFuzhou General Teaching Hospital (The 900th Hospital), Fujian University of Traditional Chinese MedicineFuzhouFujianChina
- College of Rehabilitation MedicineFujian University of Traditional Chinese MedicineFuzhouFujianChina
| | - Li Chen
- Fujian Key Laboratory of Aptamers Technology900th Hospital of Joint Logistics Support Force, People's Liberation Army (PLA)FuzhouFujianChina
| | - Shaojie Cheng
- Fujian Key Laboratory of Aptamers Technology900th Hospital of Joint Logistics Support Force, People's Liberation Army (PLA)FuzhouFujianChina
| | - Jianhong Li
- Fujian Key Laboratory of Aptamers TechnologyFuzhou General Teaching Hospital (The 900th Hospital), Fujian University of Traditional Chinese MedicineFuzhouFujianChina
- College of Rehabilitation MedicineFujian University of Traditional Chinese MedicineFuzhouFujianChina
- Fujian Key Laboratory of Aptamers Technology900th Hospital of Joint Logistics Support Force, People's Liberation Army (PLA)FuzhouFujianChina
| | - Shenghang Zhang
- Fujian Key Laboratory of Aptamers TechnologyFuzhou General Teaching Hospital (The 900th Hospital), Fujian University of Traditional Chinese MedicineFuzhouFujianChina
- Fujian Key Laboratory of Aptamers Technology900th Hospital of Joint Logistics Support Force, People's Liberation Army (PLA)FuzhouFujianChina
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Eivazi Zadeh Z, Nour S, Kianersi S, Jonidi Shariatzadeh F, Williams RJ, Nisbet DR, Bruggeman KF. Mining human clinical waste as a rich source of stem cells for neural regeneration. iScience 2024; 27:110307. [PMID: 39156636 PMCID: PMC11326931 DOI: 10.1016/j.isci.2024.110307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/20/2024] Open
Abstract
Neural diseases are challenging to treat and are regarded as one of the major causes of disability and morbidity in the world. Stem cells can provide a solution, by offering a mechanism to replace damaged circuitry. However, obtaining sufficient cell sources for neural regeneration remains a significant challenge. In recent years, waste-derived stem(-like) cells (WDS-lCs) extracted from both prenatal and adult clinical waste tissues/products, have gained increasing attention for application in neural tissue repair and remodeling. This often-overlooked pool of cells possesses favorable characteristics; including self-renewal, neural differentiation, secretion of neurogenic factors, cost-effectiveness, and low ethical concerns. Here, we offer a perspective regarding the biological properties, extraction protocols, and preclinical and clinical treatments where prenatal and adult WDS-lCs have been utilized for cell replacement therapy in neural applications, and the challenges involved in optimizing these approaches toward patient led therapies.
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Affiliation(s)
- Zahra Eivazi Zadeh
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
| | - Shirin Nour
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- Polymer Science Group, Department of Chemical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
| | - Sogol Kianersi
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences, University of Galway, Galway, Ireland
| | | | - Richard J. Williams
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- iMPACT, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
| | - David R. Nisbet
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, ANU College of Health & Medicine, Canberra, ACT, Australia
- Research School of Chemistry, ANU College of Science, Canberra, ACT, Australia
- Melbourne Medical School, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Melbourne, VIC, Australia
- Founder and Scientific Advisory of Nano Status, Building 137, Sullivans Creek Rd, ANU, Acton, Canberra, ACT, Australia
| | - Kiara F. Bruggeman
- Laboratory of Advanced Biomaterials Research, School of Engineering, Australian National University, Canberra, ACT, Australia
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Deng T, Ding R, Wang Y, Chen Y, Sun H, Zheng M. Mapping knowledge of the stem cell in traumatic brain injury: a bibliometric and visualized analysis. Front Neurol 2024; 15:1301277. [PMID: 38523616 PMCID: PMC10957745 DOI: 10.3389/fneur.2024.1301277] [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: 09/24/2023] [Accepted: 02/27/2024] [Indexed: 03/26/2024] Open
Abstract
Background Traumatic brain injury (TBI) is a brain function injury caused by external mechanical injury. Primary and secondary injuries cause neurological deficits that mature brain tissue cannot repair itself. Stem cells can self-renewal and differentiate, the research of stem cells in the pathogenesis and treatment of TBI has made significant progress in recent years. However, numerous articles must be summarized to analyze hot spots and predict trends. This study aims to provide a panorama of knowledge and research hotspots through bibliometrics. Method We searched in the Web of Science Core Collection (WoSCC) database to identify articles pertaining to TBI and stem cells published between 2000 and 2022. Visualization knowledge maps, including co-authorship, co-citation, and co-occurrence analysis were generated by VOSviewer, CiteSpace, and the R package "bibliometrix." Results We retrieved a total of 459 articles from 45 countries. The United States and China contributed the majority of publications. The number of publications related to TBI and stem cells is increasing yearly. Tianjin Medical University was the most prolific institution, and Professor Charles S. Cox, Jr. from the University of Texas Health Science Center at Houston was the most influential author. The Journal of Neurotrauma has published the most research articles on TBI and stem cells. Based on the burst references, "immunomodulation," "TBI," and "cellular therapy" have been regarded as research hotspots in the field. The keywords co-occurrence analysis revealed that "exosomes," "neuroinflammation," and "microglia" were essential research directions in the future. Conclusion Research on TBI and stem cells has shown a rapid growth trend in recent years. Existing studies mainly focus on the activation mechanism of endogenous neural stem cells and how to make exogenous stem cell therapy more effective. The combination with bioengineering technology is the trend in this field. Topics related to exosomes and immune regulation may be the future focus of TBI and stem cell research.
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Affiliation(s)
- Tingzhen Deng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ruiwen Ding
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yatao Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yueyang Chen
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Hongtao Sun
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Tianjin Key Laboratory of Neurotrauma Repair, Institute of Neurotrauma Repair, Characteristic Medical Center of Chinese People’s Armed Police Force, Tianjin, China
| | - Maohua Zheng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Neurosurgery, The First Hospital of Lanzhou University, Lanzhou, China
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Chen DH, Huang JR, Su SL, Chen Q, Wu BY. Therapeutic potential of mesenchymal stem cells for cerebral small vessel disease. Regen Ther 2024; 25:377-386. [PMID: 38414558 PMCID: PMC10899004 DOI: 10.1016/j.reth.2023.11.002] [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: 08/23/2023] [Revised: 10/12/2023] [Accepted: 11/05/2023] [Indexed: 02/29/2024] Open
Abstract
Cerebral small vessel disease (CSVD), as the most common, chronic and progressive vascular disease on the brain, is a serious neurological disease, whose pathogenesis remains unclear. The disease is a leading cause of stroke and vascular cognitive impairment and dementia, and contributes to about 20% of strokes, including 25% of ischemic strokes and 45% of dementias. Undoubtedly, the high incidence and poor prognosis of CSVD have brought a heavy economic and medical burden to society. The present treatment of CSVD focuses on the management of vascular risk factors. Although vascular risk factors may be important causes or accelerators of CSVD and should always be treated in accordance with best clinical practice, controlling risk factors alone could not curb the progression of CSVD brain injury. Therefore, developing safer and more effective treatment strategies for CSVD is urgently needed. Recently, mesenchymal stem cells (MSCs) therapy has become an emerging therapeutic modality for the treatment of central nervous system disease, given their paracrine properties and immunoregulatory. Herein, we discussed the therapeutic potential of MSCs for CSVD, aiming to enable clinicians and researchers to understand of recent progress and future directions in the field.
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Affiliation(s)
- Dong-Hua Chen
- Neurology Department, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515, China
| | - Jia-Rong Huang
- Neurology Department, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515, China
| | - Shuo-Lei Su
- Shaoguan University, No.288 University Road, Xinshaozhen Zhenjiang District, Shaoguan, 512005, China
| | - Qiong Chen
- Medical Research center of Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515, China
- Precision Medicine Center of Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515, China
| | - Bing-Yi Wu
- Medical Research center of Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515, China
- Precision Medicine Center of Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, 510515, China
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Chiu YS, Wu KJ, Yu SJ, Wu KL, Hsieh CY, Chou YS, Chen KY, Wang YS, Bae EK, Hung TW, Lin SH, Lin CH, Hsu SC, Wang Y, Chen YH. Transplantation of Exosomes Derived From Human Wharton's Jelly Mesenchymal Stromal Cells Enhances Functional Improvement in Stroke Rats. Cell Transplant 2024; 33:9636897241296366. [PMID: 39624898 PMCID: PMC11613244 DOI: 10.1177/09636897241296366] [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: 08/07/2024] [Revised: 09/28/2024] [Accepted: 10/15/2024] [Indexed: 12/06/2024] Open
Abstract
Cerebral ischemic stroke is a major cerebrovascular disease and the leading cause of adult disability. We and others previously demonstrated that transplantation of human Wharton's jelly mesenchymal stromal cells (WJ-MSCs) attenuated neuronal damage and promoted functional improvement in stroke animals. This study aimed to investigate the protective effects of human WJ-MSC exosome (Exo) transplant in cellular and rat models of cerebral stroke. Administration of Exo significantly antagonized glutamate-mediated neuronal loss and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-X nick end labeling (TUNEL) in rat primary cortical neuronal cultures. Adult male rats underwent a 60-min middle cerebral artery occlusion (MCAo); Exo or vehicle was injected through the tail vein 5-10 min after the MCAo. Two days later, the rats underwent a series of behavioral tests. Stroke rats receiving Exo developed a significant improvement in locomotor function and forelimb strength while reductions in body asymmetry and Bederson's neurological score. After the behavioral test, brain tissues were harvested for histological and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analyses. Animals receiving Exo had less infarction volume, measured by 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Transplantation of Exo increased the expression of protective neurotrophic factors (BMP7, GDNF) and anti-apoptotic factors (Bcl2, Bcl-xL) in the ischemic brain. These findings suggest that early post-treatment with WJ-MSC Exo, given non-invasively through the vein, improved functional recovery and reduced brain damage in the stroke brain.
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Affiliation(s)
- Yu-Sung Chiu
- YJ Biotechnology Co., Ltd., New Taipei City, Taiwan
| | - Kuo-Jen Wu
- School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan
| | - Seong-Jin Yu
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan
| | - Kun-Lieh Wu
- YJ Biotechnology Co., Ltd., New Taipei City, Taiwan
- Department of Electrical Engineering, I-Shou University, Kaohsiung, Taiwan
| | | | | | - Kuan-Yu Chen
- YJ Biotechnology Co., Ltd., New Taipei City, Taiwan
| | - Yu-Syuan Wang
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan
| | - Eun-Kyung Bae
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan
| | - Tsai-Wei Hung
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan
| | - Shih-Hsun Lin
- Department of Life Science, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Chih-Hsueh Lin
- Department of Life Science, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Shu-Ching Hsu
- Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- PhD Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung, Taiwan
- Immunology Research and Development Center, China Medical University, Taichung City, Taiwan
- Department of Life Sciences, Tzu Chi University, Hualien, Taiwan
| | - Yun Wang
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan
| | - Yun-Hsiang Chen
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan
- Department of Life Science, Fu-Jen Catholic University, New Taipei City, Taiwan
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Giovannelli L, Bari E, Jommi C, Tartara F, Armocida D, Garbossa D, Cofano F, Torre ML, Segale L. Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access. Bioact Mater 2023; 29:16-35. [PMID: 37456581 PMCID: PMC10338239 DOI: 10.1016/j.bioactmat.2023.06.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/01/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023] Open
Abstract
Neurodegenerative diseases represent a growing burden on healthcare systems worldwide. Mesenchymal stem cells (MSCs) have shown promise as a potential therapy due to their neuroregenerative, neuroprotective, and immunomodulatory properties, which are, however, linked to the bioactive substances they release, collectively known as secretome. This paper provides an overview of the most recent research on the safety and efficacy of MSC-derived secretome and extracellular vesicles (EVs) in clinical (if available) and preclinical models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, acute ischemic stroke, and spinal cord injury. The article explores the biologically active substances within MSC-secretome/EVs, the mechanisms responsible for the observed therapeutic effects, and the strategies that may be used to optimize MSC-secretome/EVs production based on specific therapeutic needs. The review concludes with a critical discussion of current clinical trials and a perspective on potential future directions in translating MSC-secretome and EVs into the clinic, specifically regarding how to address the challenges associated with their pharmaceutical manufacturing, including scalability, batch-to-batch consistency, adherence to Good Manufacturing Practices (GMP) guidelines, formulation, and storage, along with quality controls, access to the market and relative costs, value for money and impact on total expenditure.
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Affiliation(s)
- Lorella Giovannelli
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100, Novara, Italy
| | - Elia Bari
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100, Novara, Italy
| | - Claudio Jommi
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100, Novara, Italy
| | | | - Daniele Armocida
- A.U.O, Policlinico Umberto I, Neurosurgery Division, Human Neurosciences Department, Sapienza University, 00135, Roma, Italy
| | - Diego Garbossa
- Department of Neuroscience Rita Levi Montalcini, Neurosurgery Unit, University of Turin, 10126, Turin, Italy
| | - Fabio Cofano
- Department of Neuroscience Rita Levi Montalcini, Neurosurgery Unit, University of Turin, 10126, Turin, Italy
| | - Maria Luisa Torre
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100, Novara, Italy
- PharmaExceed S.r.l, 27100, Pavia, Italy
| | - Lorena Segale
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100, Novara, Italy
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Sun XC, Wang H, Ma X, Xia HF. Application of Human Umbilical Cord Mesenchymal Stem Cells in Rat Spinal Cord Injury Model. ASAIO J 2023; 69:e256-e264. [PMID: 37039820 DOI: 10.1097/mat.0000000000001938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2023] Open
Abstract
The treatment of spinal cord injury (SCI) is a hot topic in clinic. In this study, female rats were selected and randomly divided into four groups (normal, sham, SCI, and mesenchymal stem cells [MSCs] groups). Hemostatic forceps were used to clamp the spinal cord for 1 min to establish the SCI animal model in rats. The levels of proinflammatory factors in the blood of each group were compared 4 h after operation. The motor function of hind limb was estimated by Basso, Beattie & Bresnahan Locomotor rating scale (BBB scale) at 3 months after surgery, the spinal cord tissue from the experimental area was obtained and stained histologically and immunohistochemically. Basso, Beattie & Bresnahan Locomotor rating scale results indicated that human umbilical cord (HUC) MSCs transplantation could improve the walking ability in rats with the SCI. Human umbilical cord mesenchymal stem cells substantially upregulated the secretion of anti-inflammatory factors and downregulated the secretion of proinflammatory factors, and promoted the repair of the SCI and inhibited the increase of glial cells induced by the SCI. Human umbilical cord mesenchymal stem cells transplantation can partially recovered the motor ability of rats with the SCI through promoting the regeneration of nerve cell and the expression of neural related genes, and inhibiting inflammatory reaction.
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Affiliation(s)
- Xue-Cheng Sun
- From the Reproductive and Genetic Center, NHC Key Laboratory of Reproductive Health Engineering Technology Research (NRIFP), National Research Institute for Family Planning, Beijing, China
- Medical Genetics, Zibo Maternal and Child Health Hospital, Zibo, China
| | - Hu Wang
- From the Reproductive and Genetic Center, NHC Key Laboratory of Reproductive Health Engineering Technology Research (NRIFP), National Research Institute for Family Planning, Beijing, China
- Graduate Schools, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Xu Ma
- From the Reproductive and Genetic Center, NHC Key Laboratory of Reproductive Health Engineering Technology Research (NRIFP), National Research Institute for Family Planning, Beijing, China
- Graduate Schools, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Hong-Fei Xia
- From the Reproductive and Genetic Center, NHC Key Laboratory of Reproductive Health Engineering Technology Research (NRIFP), National Research Institute for Family Planning, Beijing, China
- Graduate Schools, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
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Honda Pazili T. Treatment of postherpetic neuralgia by bone marrow aspirate injection: A case report. World J Clin Cases 2023; 11:3619-3624. [PMID: 37383904 PMCID: PMC10294184 DOI: 10.12998/wjcc.v11.i15.3619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/27/2023] [Accepted: 04/17/2023] [Indexed: 05/25/2023] Open
Abstract
BACKGROUND Postherpetic neuralgia (PHN) is the most frequent and a difficult-to-treat complication of herpes zoster (HZ). Its symptoms include allodynia, hyperalgesia, burning, and an electric shock-like sensation stemming from the hyperexcitability of damaged neurons and varicella-zoster virus-mediated inflammatory tissue damage. HZ-related PHN has an incidence of 5%–30%, and in some patients, the pain is intolerable and can lead to insomnia or depression. In many cases, the pain is resistant to pain-relieving drugs, necessitating radical therapy.
CASE SUMMARY We present the case of a patient with PHN whose pain was not cured by conventional treatments, such as analgesics, block injections, or Chinese medicines, but by bone marrow aspirate concentrate (BMAC) injection containing bone marrow mesenchymal stem cells. BMAC has already been used for joint pains. However, this is the first report on its use for PHN treatment.
CONCLUSION This report reveals that bone marrow extract can be a radical therapy for PHN.
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Affiliation(s)
- Takahiro Honda Pazili
- Regenerative Medicine, Department of Cell Therapy, Japan Tokyo Stem Cell Transplant Research Institute, Tokyo 104-0061, Japan
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Soliman AH, Abdellatif M. COVID-19 disease treatment: pivotal challenges in the arena of umbilical cord-mesenchymal stem cells (UC-MSCs). Front Cell Dev Biol 2023; 11:1146835. [PMID: 37274737 PMCID: PMC10235792 DOI: 10.3389/fcell.2023.1146835] [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: 01/17/2023] [Accepted: 05/10/2023] [Indexed: 06/06/2023] Open
Abstract
This century's first major epidemic of a new coronavirus illness (2019-nCoV) was a tremendous shock to the healthcare system. The onset of the pandemic has caused severe economic and health shortages. At this time, there are no viable treatments for COVID-19. Several clinical studies using cell-based therapies, such as umbilical cord mesenchymal stem cells, have showed promising results (UC-MSCs). UC-MSCs have been the focus of much study because to their potential as a treatment option for COVID-19 patients. Cytokine release syndrome, often called cytokine storm, increases the risk of morbidity and mortality from COVID-19. It has been established that UC-MSCs may suppress and control both the adaptive and innate immune responses by modulating the release of immunostimulatory cytokines. The purpose of this study is to assess and clarify the use of UC-MSCs for the treatment of ARDS caused by COVID-19.
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Maassen J, Guenther R, Hondrich TJJ, Cepkenovic B, Brinkmann D, Maybeck V, Offenhäusser A, Dittrich B, Müller A, Skazik-Voogt C, Kosel M, Baum C, Gutermuth A. In Vitro Simulated Neuronal Environmental Conditions Qualify Umbilical Cord Derived Highly Potent Stem Cells for Neuronal Differentiation. Stem Cell Rev Rep 2023:10.1007/s12015-023-10538-w. [PMID: 37093520 PMCID: PMC10390376 DOI: 10.1007/s12015-023-10538-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 04/25/2023]
Abstract
The healing of neuronal injuries is still an unachieved goal. Medicine-based therapies can only extend the survival of patients, but not finally lead to a healing process. Currently, a variety of stem cell-based tissue engineering developments are the subject of many research projects to bridge this gap. As yet, neuronal differentiation of induced pluripotent stem cells (iPS), embryonic cell lines, or neuronal stem cells could be accomplished and produce functional neuronally differentiated cells. However, clinical application of cells from these sources is hampered by ethical considerations. To overcome these hurdles numerous studies investigated the potential of adult mesenchymal stem cells (MSCs) as a potential stem cell source. Adult MSCs have been approved as cellular therapeutical products due to their regenerative potential and immunomodulatory properties. Only a few of these studies could demonstrate the capacity to differentiate MSCs into active firing neuron like cells. With this study we investigated the potential of Wharton's Jelly (WJ) derived stem cells and focused on the intrinsic pluripotent stem cell pool and their potential to differentiate into active neurons. With a comprehensive neuronal differentiation protocol comprised of mechanical and biochemical inductive cues, we investigated the capacity of spontaneously forming stem cell spheroids (SCS) from cultured WJ stromal cells in regard to their neuronal differentiation potential and compared them to undifferentiated spheroids or adherent MSCs. Spontaneously formed SCSs show pluripotent and neuroectodermal lineage markers, meeting the pre-condition for neuronal differentiation and contain a higher amount of cells which can be differentiated into cells whose functional phenotypes in calcium and voltage responsive electrical activity are similar to neurons. In conclusion we show that up-concentration of stem cells from WJ with pluripotent characteristics is a tool to generate neuronal cell replacement.
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Affiliation(s)
- Jessika Maassen
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Rebecca Guenther
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Timm J J Hondrich
- Institute for Biological Information Processing, IBI-3, Forschungszentrum Jülich GmbH, Leo Brandtstrasse Station 71, 52425, Jülich, Germany
| | - Bogdana Cepkenovic
- Institute for Biological Information Processing, IBI-3, Forschungszentrum Jülich GmbH, Leo Brandtstrasse Station 71, 52425, Jülich, Germany
- Department of Biology, RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany
| | - Dominik Brinkmann
- Institute for Biological Information Processing, IBI-3, Forschungszentrum Jülich GmbH, Leo Brandtstrasse Station 71, 52425, Jülich, Germany
| | - Vanessa Maybeck
- Institute for Biological Information Processing, IBI-3, Forschungszentrum Jülich GmbH, Leo Brandtstrasse Station 71, 52425, Jülich, Germany
| | - Andreas Offenhäusser
- Institute for Biological Information Processing, IBI-3, Forschungszentrum Jülich GmbH, Leo Brandtstrasse Station 71, 52425, Jülich, Germany
| | - Barbara Dittrich
- DWI-Leibniz Institute for Interactive Materials, Forckenbeckstrasse 50, 52074, Aachen, Germany
| | - Anna Müller
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Claudia Skazik-Voogt
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Maximilian Kosel
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Christoph Baum
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Angela Gutermuth
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany.
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11
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Shen D, Wang H, Zhu H, Jiang C, Xie F, Zhang H, Lv Q, Liu Q, Wang Z, Qi N, Wang H. Pre-clinical efficacy evaluation of human umbilical cord mesenchymal stem cells for ischemic stroke. Front Immunol 2023; 13:1095469. [PMID: 36726973 PMCID: PMC9885855 DOI: 10.3389/fimmu.2022.1095469] [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: 11/11/2022] [Accepted: 12/29/2022] [Indexed: 01/15/2023] Open
Abstract
Objective This study explored the underlying therapeutic mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs) for ischemic stroke (IS), and determined the optimal administration time windows and dose-effect relationship. Methods The levels of SDF-1α, IL-10, IL-6, TNF-α, BDNF, IL-1β, and VEGF-A factors in serum and brain tissue lysate were measured by ELISA. The pathological status of brain tissues was evaluated by Hematoxylin-Eosin (HE) staining, and apoptosis of nerve cells was detected by tunel. The protein expression of CXCR-4, NeuN, and Nestin in the brain tissues was assessed through immunofluorescence. The balance beam, forelimb muscle strength, and limb placement were tested on MCAO rats at different time points and doses. The infarct area of the rat brain tissues was measured at the end of the experiment. Results The hUCMSC treatment during the acute phase of MCAO significantly reduced the secretion of IL-6, TNF-α, IL-1β but increased IL-10 in serum, and the levels of SDF-α and BDNF in serum and brain tissues lysate were also increased. The pathological results showed that there were more neurons in the treatment group compared to the model group. Immunofluorescence assays showed that the expression of CXCR4、Nestin、NeuN was relatively higher than that in the model group. The d4 and d7 treatment significantly improves the motor function, promotes the recovery of forelimb muscle strength, increases the forelimb placement rate and reduces the scope of cerebral infarction, but the d14 treatment group has less therapeutic effect compared to the d4 and d7 treatment. The 2×107/kg treatment showed the best therapeutic effect, followed by the 1×107/kg treatment, and the worst is 0.5×107/kg treatment from the test of balance beam, forelimb muscle strength, limb placement and the infarct area of the rat brain tissues. Conclusion The hUCMSCs can inhibit the infiltration of inflammatory cells in the brain tissue, and promote the repair of brain tissue structure and function. Early intervention by injecting high-dose of hUCMSCs can significantly improve the recovery of neurological/motor function and reduce the size of cerebral infarction in rats.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Nianmin Qi
- *Correspondence: Hao Wang, ; Nianming Qi,
| | - Hao Wang
- *Correspondence: Hao Wang, ; Nianming Qi,
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12
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Milczarek O, Swadźba J, Swadźba P, Starowicz-Filip A, Krzyżewski RM, Kwiatkowski S, Majka M. Comparative Analysis of the Results of Stroke Treatment With Multiple Administrations of Wharton's Jelly Mesenchymal Stem Cells-Derived HE-ATMP and Standard Conservative Treatment: Case Series Study. Cell Transplant 2023; 32:9636897231195145. [PMID: 37644776 PMCID: PMC10469225 DOI: 10.1177/09636897231195145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 07/25/2023] [Accepted: 08/01/2023] [Indexed: 08/31/2023] Open
Abstract
Stroke remains still the leading cause of long-term disability worldwide. Although interventions such as early reperfusion, intravenous thrombolysis, and endovascular revascularization have shown neurological benefit in stroke patients, there is still lack of effective treatment enabling regeneration of nervous tissue after cerebral ischemic episodes. Cell therapy is an evolving opportunity for stroke survivors with residual neurological deficits. The purpose of this study was to evaluate safety and potential efficacy of multiple administration of Hospital Exemption-Advanced Therapy Medicinal Product (HE-ATMP) comprising 3 × 107 Wharton's jelly mesenchymal stem cells (WJMSCs). A study group was composed of six patients-three women and three men. The patients were qualified to the treatment with diagnosis of chronic stroke (2-24 months after cerebral ischemic episode), during 2 years. All the patients undergone repeated rounds of HE-ATMP administration to the CSF (cerebrospinal fluid) via lumbar puncture. The control group consisted of six patients (two women and four men) who experienced stroke, treated at the same time (follow-up period: 24 months) using standard treatment methods, without endovascular treatment. To evaluate the results of the therapy, we used both impairment scales [National Institutes of Health Stroke Score (NIHSS)] and functional outcomes scales [Modified Rankin Scale (MRS) and Barthel Index (BI)]. In four patients, who received at least three repeated rounds of HE-ATMP, we reported neurological improvement and reduction of functional neurodeficiency. The biggest improvement concerned the reduction of speech disorders in two cases; significant improvement in the field of motor skills in three patients and reduction of apraxia and improvement of logical communication skills in two patients were also reported. All the patients became more independent. Significant improvement of the neurological condition using the same scales was registered only in two patients from the control group. We did not report any adverse events in the treated group during follow-up. At 1-year follow-up, we demonstrate safety and beneficial effect of WJMSC transplantation including neurological improvement and reduction of functional neurodeficiency. We are aware that the samples size of this study is relatively small. The treatment regimen needs to be further tested in larger group of patients.
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Affiliation(s)
- Olga Milczarek
- Department of Children’s Neurosurgery, Institute of Pediatrics, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Jakub Swadźba
- Department of Laboratory Medicine, Andrzej Frycz–Modrzewski Cracow University, Cracow, Poland
| | | | - Anna Starowicz-Filip
- Department of Psychology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Roger M. Krzyżewski
- Department of Neurosurgery and Neurotraumatology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Stanisław Kwiatkowski
- Department of Children’s Neurosurgery, Institute of Pediatrics, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Majka
- Department of Transplantation, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
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13
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Moayeri A, Alizadeh R, Ghasemi Hamidabadi H, Nazm Bojnordi M, Niapour A, Hedayatpour A, Darvishi M, Heidari F, Soleimani M, Elyasi L. Transdifferentiation of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Dopaminergic Neurons in a Three-Dimensional Culture. Basic Clin Neurosci 2022; 13:625-636. [PMID: 37313021 PMCID: PMC10258594 DOI: 10.32598/bcn.2021.973.3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 03/03/2021] [Accepted: 08/07/2021] [Indexed: 10/27/2023] Open
Abstract
Introduction The induction of human umbilical cord-derived mesenchymal stem cells (HUC-MSCs) toward dopaminergic neurons is a major challenge in tissue engineering and experimental and clinical treatments of various neurodegenerative diseases, including Parkinson disease. This study aims to differentiate HUC-MSCs into dopaminergic neuron-like cells. Methods Following the isolation and characterization of HUC-MSCs, they were transferred to Matrigel-coated plates and incubated with a cocktail of dopaminergic neuronal differentiation factors. The capacity of differentiation into dopaminergic neuron-like cells in 2-dimensional culture and on Matrigel was assessed by real-time polymerase chain reaction, immunocytochemistry, and high-performance liquid chromatography. Results Our results showed that dopaminergic neuronal markers' transcript and protein levels were significantly increased on the Matrigel differentiated cells compared to 2D culture plates. Conclusion Overall, the results of this study suggest that HUC-MSCs can successfully differentiate toward dopaminergic neuron-like cells on Matrigel, having great potential for the treatment of dopaminergic neuron-related diseases.
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Affiliation(s)
- Ardeshir Moayeri
- Department of Anatomy, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Rafieh Alizadeh
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hatef Ghasemi Hamidabadi
- Department of Anatomy & Cell Biology, Immunogenetic Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Maryam Nazm Bojnordi
- Department of Anatomy & Cell Biology, Immunogenetic Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ali Niapour
- Department of Anatomical Sciences, Research Laboratory for Embryology and Stem Cells, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Azim Hedayatpour
- Department of Anatomy, School of Medicine, University of Tehran, Tehran, Iran
| | - Marzieh Darvishi
- Department of Anatomy, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Fatemeh Heidari
- Department of Anatomy, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Maryam Soleimani
- Department of Basic Sciences, School of Rehabilitation Sciences, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Leila Elyasi
- Department of Anatomy, Neuroscience Research Center, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
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14
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Tang X, Li H, An B, Ma H, Huang N, Li X. Transplantation of human cord blood-derived multipotent stem cells (CB-SCs) enhances the recovery of Parkinson in rats. Transpl Immunol 2022; 75:101701. [PMID: 36038047 DOI: 10.1016/j.trim.2022.101701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/23/2022] [Accepted: 08/23/2022] [Indexed: 10/15/2022]
Abstract
Earlier published research showed that cord blood-derived multipotent stem cells (CB-SCs) exhibited the intrinsic expression of specific transcription factors (e.g., En1, Nurr1 and Wnt1) and seems to be induced to form dopamine neurons in vitro. In this research, we further investigated the therapeutic potential of CB-SCs in 6-hydroxydopamine lesioned Parkinson's disease (PD) rats. The results of PCR analysis showed that CB-SCs could express transcription factors associated with pluripotentiality and dopaminergic differentiation (e.g., Klf4, c-Myc, Nanog, Sox2, Ngn2, and Nurr1). After being transplanted into the striatum and substantia nigra of PD rats, most of CB-SCs (>90%) developed a fate commitment to dopaminergic differentiation, expressed as the expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT). The improvement effect of cell transplantation on dyskinesia in PD rats was better than that in sham control group. Moreover, higher levels of TH protein in brain homogenates further demonstrated that there were more surviving dopamine neurons in the brain of transplanted PD rats. Study concluds, CB SCS transplantation could promote the regeneration of dopamine neurons and behavioral recovery of PD rats.
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Affiliation(s)
- Xiaosan Tang
- Department of Neurology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250031, China
| | - Heng Li
- Department of Neurology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250031, China
| | - Baozeng An
- Department of Psychology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250031, China
| | - Haibo Ma
- Department of Neurology, Shandong Provincial Third Hospital, Shandong University, Jinan, Shandong 250031, China
| | - Nana Huang
- Department of Neurology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250031, China
| | - Xiaohong Li
- Department of Neurology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250031, China.
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15
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Gala D, Gurusamy V, Patel K, Damodar S, Swaminath G, Ullal G. Stem Cell Therapy for Post-Traumatic Stress Disorder: A Novel Therapeutic Approach. Diseases 2021; 9:diseases9040077. [PMID: 34842629 PMCID: PMC8628773 DOI: 10.3390/diseases9040077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/11/2021] [Accepted: 10/25/2021] [Indexed: 12/04/2022] Open
Abstract
Stem cell therapy is a rapidly evolving field of regenerative medicine being employed for the management of various central nervous system disorders. The ability to self-renew, differentiate into specialized cells, and integrate into neuronal networks has positioned stem cells as an ideal mechanism for the treatment of epilepsy. Epilepsy is characterized by repetitive seizures caused by imbalance in the GABA and glutamate neurotransmission following neuronal damage. Stem cells provide benefit by reducing the glutamate excitotoxicity and strengthening the GABAergic inter-neuron connections. Similar to the abnormal neuroanatomic location in epilepsy, post-traumatic stress disorder (PTSD) is caused by hyperarousal in the amygdala and decreased activity of the hippocampus and medial prefrontal cortex. Thus, stem cells could be used to modulate neuronal interconnectivity. In this review, we provide a rationale for the use of stem cell therapy in the treatment of PTSD.
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16
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Zhang Y, Warden AR, Ahmad KZ, Liu Y, He X, Zheng M, Huo X, Zhi X, Ke Y, Li H, Yan S, Su W, Cai D, Ding X. Single-Cell Microwell Platform Reveals Circulating Neural Cells as a Clinical Indicator for Patients with Blood-Brain Barrier Breakdown. RESEARCH 2021; 2021:9873545. [PMID: 34327332 PMCID: PMC8285994 DOI: 10.34133/2021/9873545] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 06/01/2021] [Indexed: 12/21/2022]
Abstract
Central nervous system diseases commonly occur with the destruction of the blood-brain barrier. As a primary cause of morbidity and mortality, stroke remains unpredictable and lacks cellular biomarkers that accurately quantify its occurrence and development. Here, we identify NeuN+/CD45−/DAPI+ phenotype nonblood cells in the peripheral blood of mice subjected to middle cerebral artery occlusion (MCAO) and stroke patients. Since NeuN is a specific marker of neural cells, we term these newly identified cells as circulating neural cells (CNCs). We find that the enumeration of CNCs in the blood is significantly associated with the severity of brain damage in MCAO mice (p < 0.05). Meanwhile, the number of CNCs is significantly higher in stroke patients than in negative subjects (p < 0.0001). These findings suggest that the amount of CNCs in circulation may serve as a clinical indicator for the real-time prognosis and progression monitor of the occurrence and development of ischemic stroke and other nervous system disease.
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Affiliation(s)
- Yu Zhang
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
| | - Antony R Warden
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
| | - Khan Zara Ahmad
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
| | - Yanlei Liu
- Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Xijun He
- Department of Neurosurgery, Wenling Hospital Affiliated to Wenzhou Medical University, Chuan'an Nan Road, Chengxi Subdistrict, Wenling, 317500 Zhejiang, China
| | - Minqiao Zheng
- Central Laboratory, Wenling Hospital Affiliated to Wenzhou Medical University, Chuan'an Nan Road, Chengxi Subdistrict, Wenling, 317500 Zhejiang, China
| | - Xinlong Huo
- Department of Neurology, Wenling Hospital Affiliated to Wenzhou Medical University, Chuan'an Nan Road, Chengxi Subdistrict, Wenling, 317500 Zhejiang, China
| | - Xiao Zhi
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
| | - Yuqing Ke
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
| | - Hongxia Li
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
| | - Sijia Yan
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
| | - Wenqiong Su
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
| | - Deng Cai
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China
| | - Xianting Ding
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
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17
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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.
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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
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18
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Zhang XL, Zhang XG, Huang YR, Zheng YY, Ying PJ, Zhang XJ, Lu X, Wang YJ, Zheng GQ. Stem Cell-Based Therapy for Experimental Ischemic Stroke: A Preclinical Systematic Review. Front Cell Neurosci 2021; 15:628908. [PMID: 33935650 PMCID: PMC8079818 DOI: 10.3389/fncel.2021.628908] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 02/24/2021] [Indexed: 12/21/2022] Open
Abstract
Stem cell transplantation offers promise in the treatment of ischemic stroke. Here we utilized systematic review, meta-analysis, and meta-regression to study the biological effect of stem cell treatments in animal models of ischemic stroke. A total of 98 eligible publications were included by searching PubMed, EMBASE, and Web of Science from inception to August 1, 2020. There are about 141 comparisons, involving 5,200 animals, that examined the effect of stem cell transplantation on neurological function and infarct volume as primary outcome measures in animal models for stroke. Stem cell-based therapy can improve both neurological function (effect size, −3.37; 95% confidence interval, −3.83 to −2.90) and infarct volume (effect size, −11.37; 95% confidence interval, −12.89 to −9.85) compared with controls. These results suggest that stem cell therapy could improve neurological function deficits and infarct volume, exerting potential neuroprotective effect for experimental ischemic stroke, but further clinical studies are still needed.
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Affiliation(s)
- Xi-Le Zhang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Guang Zhang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yan-Ran Huang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yan-Yan Zheng
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Peng-Jie Ying
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Jie Zhang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao Lu
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yi-Jing Wang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guo-Qing Zheng
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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Liao Z, Yang X, Wang W, Deng W, Zhang Y, Song A, Ni B, Zhao H, Zhang S, Li Z. hucMSCs transplantation promotes locomotor function recovery, reduces apoptosis and inhibits demyelination after SCI in rats. Neuropeptides 2021; 86:102125. [PMID: 33486279 DOI: 10.1016/j.npep.2021.102125] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/18/2020] [Accepted: 01/10/2021] [Indexed: 11/23/2022]
Abstract
AIMS Spinal cord injury (SCI) can cause a variety of cells apoptosis, neurodegeneration, and eventually permanent paralysis. This study aimed to examine whether transplanting human umbilical cord mesenchymal stem cells (hucMSCs) can promote locomotor function recovery, reduce apoptosis and inhibit demyelination in SCI models. MAIN METHODS Rats were allocated into Sham group (spinal cord exposure only), SCI + PBS group (spinal cord impact plus phosphate-buffered saline (PBS) injections), SCI + hucMSCs group (spinal cord impact plus hucMSCs injections) groups. Behavioral tests, Basso-Beattie-Bresnahan locomotion scores (BBB scores), were carried out at 0, 3, 7, 14, 21, 28 days after SCI surgery. Hematoxylin-eosin staining observed spinal cord morphology. Nissl staining detected the number of nissl bodies. Myelin basic protein (MBP) and oligodendrocyte (CNPase) were examed by immunohistochemical staining. The apoptosis of oligodendrocyte and neurons were detected by immunofluorescence. RESULTS The 28-day behavioral test showed that the BBB score of rats in the SCI + hucMSCs group increased significantly, comparing to the SCI + PBS group. The numbers of nissl bodies and myelin sheath in the damaged area of SCI + hucMSCs group were also significantly increased compared to the SCI + PBS group. HucMSCs transplanting decreased the expression of protein level of Caspase-3 and Bax and increased the Bcl-2, MBP and CNPase, rescued the apoptosis of neurons and the oligodendrocyte. CONCLUSION These results showed that hucMSCs can improve motor function, tissue repairing and reducing apoptosis in SCI rats.
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Affiliation(s)
- Ziling Liao
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Xiuzhen Yang
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Wei Wang
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Weiyue Deng
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Yuying Zhang
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Aishi Song
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Bin Ni
- NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China
| | - Huifang Zhao
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Shusheng Zhang
- Changsha Stomatological Hospital, Changsha, Hunan 410004, China
| | - Zhiyuan Li
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China; NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China; CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; GZMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangdong, China; Changsha Stomatological Hospital, Changsha, Hunan 410004, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China.
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20
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Shigematsu K, Takeda T, Komori N, Tahara K, Yamagishi H. Hypothesis: Intravenous administration of mesenchymal stem cells is effective in the treatment of Alzheimer's disease. Med Hypotheses 2021; 150:110572. [PMID: 33799163 DOI: 10.1016/j.mehy.2021.110572] [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] [Received: 12/28/2020] [Revised: 03/09/2021] [Accepted: 03/13/2021] [Indexed: 01/24/2023]
Abstract
We propose the intravenous administration of autologous adipose-derived stem cells as a new treatment for Alzheimer's disease. We hypothesize that the stem cells will secrete neprilysin in the brain to break down and remove amyloid deposits in the Alzheimer's brain. We have shown a case of skin amyloid deposition that disappeared after stem cell administration and confirmed that the stem cells administered had neprilysin activity. In addition to neprilysin secretion, other mechanisms of action of stem cells include nerve regeneration, nerve repair, growth factor secretion, anti-inflammatory effects, and angiogenesis. The harvesting of adipose-derived stem cells is minimally invasive, and intravenous administration can be safely repeated. We hope that the efficacy of this new treatment will be verified and that it will bring a ray of hope to patients suffering from this incurable disease.
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Affiliation(s)
- Kazuo Shigematsu
- Department of Neurology, Minami Kyoto Hospital, National Hospital Organization, Kyoto, Japan; Nagituji Hospital. Kyoto, Japan.
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21
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Asgharzade S, Talaei A, Farkhondeh T, Forouzanfar F. A Review on Stem Cell Therapy for Neuropathic Pain. Curr Stem Cell Res Ther 2021; 15:349-361. [PMID: 32056531 DOI: 10.2174/1574888x15666200214112908] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 09/16/2019] [Accepted: 11/25/2019] [Indexed: 12/13/2022]
Abstract
Neuropathic pain is a complex, chronic pain state that is heterogeneous in nature and caused by the consequence of a lesion or disease affecting the somatosensory system. Current medications give a long-lasting pain relief only in a limited percentage of patients also associated with numerous side effects. Stem cell transplantation is one of the attractive therapeutic platforms for the treatment of a variety of diseases, such as neuropathic pain. Here, the authors review the therapeutic effects of stem cell transplantation of different origin and species in different models of neuropathic pain disorders. Stem cell transplantation could alleviate the neuropathic pain; indeed, stem cells are the source of cells, which differentiate into a variety of cell types and lead trophic factors to migrate to the lesion site opposing the effects of damage. In conclusion, this review suggests that stem cell therapy can be a novel approach for the treatment of neuropathic pain.
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Affiliation(s)
- Samira Asgharzade
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Andisheh Talaei
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Tahereh Farkhondeh
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Fatemeh Forouzanfar
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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22
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Um S, Ha J, Choi SJ, Oh W, Jin HJ. Prospects for the therapeutic development of umbilical cord blood-derived mesenchymal stem cells. World J Stem Cells 2020; 12:1511-1528. [PMID: 33505598 PMCID: PMC7789129 DOI: 10.4252/wjsc.v12.i12.1511] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/23/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Umbilical cord blood (UCB) is a primitive and abundant source of mesenchymal stem cells (MSCs). UCB-derived MSCs have a broad and efficient therapeutic capacity to treat various diseases and disorders. Despite the high latent self-renewal and differentiation capacity of these cells, the safety, efficacy, and yield of MSCs expanded for ex vivo clinical applications remains a concern. However, immunomodulatory effects have emerged in various disease models, exhibiting specific mechanisms of action, such as cell migration and homing, angiogenesis, anti-apoptosis, proliferation, anti-cancer, anti-fibrosis, anti-inflammation and tissue regeneration. Herein, we review the current literature pertaining to the UCB-derived MSC application as potential treatment strategies, and discuss the concerns regarding the safety and mass production issues in future applications.
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Affiliation(s)
- Soyoun Um
- Research Team for Immune Cell Therapy, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Jueun Ha
- Research Team for Osteoarthritis, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
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23
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Dagnino APA, Chagastelles PC, Medeiros RP, Estrázulas M, Kist LW, Bogo MR, Weber JBB, Campos MM, Silva JB. Neural Regenerative Potential of Stem Cells Derived from the Tooth Apical Papilla. Stem Cells Dev 2020; 29:1479-1496. [PMID: 32988295 DOI: 10.1089/scd.2020.0121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The regenerative effects of stem cells derived from dental tissues have been previously investigated. This study assessed the potential of human tooth stem cells from apical papilla (SCAP) on nerve regeneration. The SCAP collected from nine individuals were characterized and polarized by exposure to interferon-γ (IFN-γ). IFN-γ increased kynurenine and interleukin-6 (IL-6) production by SCAP, without affecting the cell viability. IFN-γ-primed SCAP exhibited a decrease of brain-derived neurotrophic factor (BDNF) mRNA levels, followed by an upregulation of glial cell-derived neurotrophic factor mRNA. Ex vivo, the co-culture of SCAP with neurons isolated from the rat dorsal root ganglion induced neurite outgrowth, accompanied by increased BDNF secretion, irrespective of IFN-γ priming. In vivo, the local application of SCAP reduced the mechanical and thermal hypersensitivity in Wistar rats that had been submitted to sciatic chronic constriction injury. The SCAP also reduced the pain scores, according to the evaluation of the Grimace scale, partially restoring the myelin damage and BDNF immunopositivity secondary to nerve lesion. Altogether, our results provide novel evidence about the regenerative effects of human SCAP, indicating their potential to handle nerve injury-related complications.
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Affiliation(s)
- Ana Paula Aquistapase Dagnino
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Centro de Pesquisa em Toxicologia e Farmacologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Pedro Cesar Chagastelles
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Renata Priscila Medeiros
- Centro de Pesquisa em Toxicologia e Farmacologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Programa de Pós-Graduação em Odontologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Marina Estrázulas
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Centro de Pesquisa em Toxicologia e Farmacologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Luiza Wilges Kist
- Programa de Pós-Graduação em Biologia Celular e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Laboratório de Biologia Genômica e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Maurício Reis Bogo
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Programa de Pós-Graduação em Biologia Celular e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Laboratório de Biologia Genômica e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - João Batista Blessmann Weber
- Programa de Pós-Graduação em Odontologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Maria Martha Campos
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Centro de Pesquisa em Toxicologia e Farmacologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Programa de Pós-Graduação em Odontologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Programa de Pós-Graduação em Biologia Celular e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Jefferson Braga Silva
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
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24
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Ma S, Wang Y, Zhou X, Li Z, Zhang Z, Wang Y, Huang T, Zhang Y, Shi J, Guan F. MG53 Protects hUC-MSCs against Inflammatory Damage and Synergistically Enhances Their Efficacy in Neuroinflammation Injured Brain through Inhibiting NLRP3/Caspase-1/IL-1β Axis. ACS Chem Neurosci 2020; 11:2590-2601. [PMID: 32786312 DOI: 10.1021/acschemneuro.0c00268] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The inflammatory microenvironment in a lesion is not conducive to the survival of stem cells. Improving the inflammatory microenvironment may be an alternative strategy to enhance the efficacy of stem cells. We evaluated the therapeutic effect and molecular mechanism of mitsugumin53 (MG53) on lipopolysaccharide (LPS)-induced damage in human umbilical cord mesenchymal stem cells (hUC-MSCs) and in C57/BL6 mice. MG53 significantly promoted the proliferation and migration of hUC-MSCs, protected hUC-MSCs against LPS-induced apoptosis and mitochondrial dysfunction, and reversed LPS-induced inflammatory cytokine release. Furthermore, MG53 combined with hUC-MSCs transplantation improved LPS-induced memory impairment and activated neurogenesis by promoting the migration of hUC-MSCs and enhancing βIII-tubulin and doublecortin (DCX) expression. MG53 protein combined with hUC-MSCs improved the M1/M2 phenotype polarization of microglia accompanied by lower inducible nitric oxide synthase (iNOS) expression and higher arginase 1 (ARG1) expression. MG53 significantly suppressed the expression of tumor necrosis factor α (TNF-α), Toll-like receptor 4 (TLR4), nucleotide oligomerization domain-like receptor protein 3 (NLRP3), cleaved-caspase-1, and interleukin (IL)-1β to alleviate LPS-induced neuroinflammation on hUC-MSCs and C57/BL6 mice. In conclusion, our results indicated that MG53 could protect hUC-MSCs against LPS-induced inflammatory damage and facilitate their efficacy in LPS-treated C57/BL6 mice partly by inhibiting the NLRP3/caspase-1/IL-1β axis.
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Affiliation(s)
- Shanshan Ma
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan, China
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450052 Henan, China
| | - Yaping Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan, China
| | - Xinkui Zhou
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan, China
| | - Zhe Li
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan, China
| | - Zhenkun Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan, China
| | - Yingying Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan, China
| | - Tuanjie Huang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan, China
| | - Yanting Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan, China
| | - Jijing Shi
- Central Lab of the First People’s Hospital of Zhengzhou, Zhengzhou, 450001 Henan. China
| | - Fangxia Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan, China
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450052 Henan, China
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25
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Liu XYE, Park E, Barretto T, Liu E, Ferrier GA, Tavakkoli J, J Baker A. Effect of Human Umbilical Cord Perivascular Cell-Conditioned Media in an Adult Zebrafish Model of Traumatic Brain Injury. Zebrafish 2020; 17:177-186. [PMID: 32434437 DOI: 10.1089/zeb.2020.1859] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The pathophysiological events of secondary brain injury contribute to poor outcome after traumatic brain injury (TBI). The neuroprotective effects of mesenchymal cells have been extensively studied and evidence suggests that their effects are mostly mediated through paracrine effects. Human umbilical cord perivascular cells (HUCPVCs) are mesenchymal stem cells with potential therapeutic value in TBI. In this study, we assessed the effect of HUCPVC-conditioned media (CM) in an established adult zebrafish model of TBI induced by pulsed high-intensity focused ultrasound (pHIFU). This model demonstrates similarities to mammalian outcome after TBI. Administration of HUCPVC-CM 1 h postinjury (hpi) resulted in improved outcome after pHIFU-induced TBI. Western blot and immunohistochemistry results demonstrated that the HUCPVC-CM reduced (p < 0.05) reactive astrogliosis at 24 hpi. Moreover, at 24 hpi, the HUCPVC-CM treatment resulted in reduced apoptosis in HUCPVC-CM-treated zebrafish. Behavioral analysis demonstrated improvement in locomotor activity (p < 0.05) and anxiety (p < 0.05) at 6 and 24 hpi following HUCPVC-CM treatment. Overall, HUCPVC-CM treatment improved acute outcome measures in pHIFU-injured zebrafish. Collectively, the data demonstrate a cell-free treatment approach for traumatic brain injuries.
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Affiliation(s)
| | - Eugene Park
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada
| | - Tanya Barretto
- Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Elaine Liu
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada
| | | | - Jahan Tavakkoli
- Department of Physics, Ryerson University, Toronto, Canada
- Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
| | - Andrew J Baker
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada
- Department of Critical Care and Anesthesia, St. Michael's Hospital, Toronto, Canada
- Department of Anesthesia and Surgery, University of Toronto, Toronto, Canada
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26
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Tobin MK, Stephen TKL, Lopez KL, Pergande MR, Bartholomew AM, Cologna SM, Lazarov O. Activated Mesenchymal Stem Cells Induce Recovery Following Stroke Via Regulation of Inflammation and Oligodendrogenesis. J Am Heart Assoc 2020; 9:e013583. [PMID: 32204666 PMCID: PMC7428606 DOI: 10.1161/jaha.119.013583] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 02/17/2020] [Indexed: 02/07/2023]
Abstract
Background Brain repair mechanisms fail to promote recovery after stroke, and approaches to induce brain regeneration are scarce. Mesenchymal stem cells (MSC) are thought to be a promising therapeutic option. However, their efficacy is not fully elucidated, and the mechanism underlying their effect is not known. Methods and Results The middle cerebral artery occlusion model was utilized to determine the efficacy of interferon-γ-activated mesenchymal stem cells (aMSCγ) as an acute therapy for stroke. Here we show that treatment with aMSCγ is a more potent therapy for stroke than naive MSC. aMSCγ treatment results in significant functional recovery assessed by the modified neurological severity score and open-field analysis compared with vehicle-treated animals. aMSCγ-treated animals showed significant reductions in infarct size and inhibition of microglial activation. The aMSCγ treatment suppressed the hypoxia-induced microglial proinflammatory phenotype more effectively than treatment with naive MSC. Importantly, treatment with aMSCγ induced recruitment and differentiation of oligodendrocyte progenitor cells to myelin-producing oligodendrocytes in vivo. To elucidate the mechanism underlying high efficacy of aMSCγ therapy, we examined the secretome of aMSCγ and compared it to that of naive MSC. Intriguingly, we found that aMSCγ but not nMSC upregulated neuron-glia antigen 2, an important extracellular signal and a hallmark protein of oligodendrocyte progenitor cells. Conclusions These results suggest that activation of MSC with interferon-γ induces a potent proregenerative, promyelinating, and anti-inflammatory phenotype of these cells, which increases the potency of aMSCγ as an effective therapy for ischemic stroke.
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Affiliation(s)
- Matthew K. Tobin
- Department of Anatomy and Cell BiologyUniversity of Illinois at ChicagoIL
| | | | - Kyra L. Lopez
- Department of Anatomy and Cell BiologyUniversity of Illinois at ChicagoIL
| | | | | | | | - Orly Lazarov
- Department of Anatomy and Cell BiologyUniversity of Illinois at ChicagoIL
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27
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Cunningham CJ, Wong R, Barrington J, Tamburrano S, Pinteaux E, Allan SM. Systemic conditioned medium treatment from interleukin-1 primed mesenchymal stem cells promotes recovery after stroke. Stem Cell Res Ther 2020; 11:32. [PMID: 31964413 PMCID: PMC6975095 DOI: 10.1186/s13287-020-1560-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 12/18/2019] [Accepted: 01/09/2020] [Indexed: 12/15/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) hold great potential as a therapy for stroke and have previously been shown to promote recovery in preclinical models of cerebral ischaemia. MSCs secrete a wide range of growth factors, chemokines, cytokines and extracellular vesicles—collectively termed the secretome. In this study, we assessed for the first time the efficacy of the IL-1α-primed MSC-derived secretome on brain injury and functional recovery after cerebral ischaemia. Methods Stroke was induced in male C57BL/6 mice using the intraluminal filament model of middle cerebral artery occlusion. Conditioned medium from IL-1α-primed MSCs or vehicle was administered at the time of reperfusion or at 24 h post-stroke by subcutaneous injection. Results IL-1α-primed MSC-derived conditioned medium treatment at the time of stroke led to a ~ 30% reduction in lesion volume at 48 h and was associated with modest improvements in body mass gain, 28-point neurological score and nest building. Administration of MSC-derived conditioned medium at 24 h post-stroke led to improved nest building and neurological score despite no observed differences in lesion volume at day 2 post-stroke. Conclusions Our results show for the first time that the administration of conditioned medium from IL-1α-primed MSCs leads to improvements in behavioural outcomes independently of neuroprotection.
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Affiliation(s)
- Catriona J Cunningham
- Lydia Becker Institute of Immunology and Inflammation, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, AV Hill Building, Manchester, M13 9PT, UK
| | - Raymond Wong
- Lydia Becker Institute of Immunology and Inflammation, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, AV Hill Building, Manchester, M13 9PT, UK
| | - Jack Barrington
- Lydia Becker Institute of Immunology and Inflammation, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, AV Hill Building, Manchester, M13 9PT, UK
| | - Sabrina Tamburrano
- Lydia Becker Institute of Immunology and Inflammation, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, AV Hill Building, Manchester, M13 9PT, UK
| | - Emmanuel Pinteaux
- Lydia Becker Institute of Immunology and Inflammation, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, AV Hill Building, Manchester, M13 9PT, UK
| | - Stuart M Allan
- Lydia Becker Institute of Immunology and Inflammation, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, AV Hill Building, Manchester, M13 9PT, UK.
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28
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Zhao Y, Zhu T, Li H, Zhao J, Li X. Transplantation of Lymphocytes Co-Cultured with Human Cord Blood-Derived Multipotent Stem Cells Attenuates Inflammasome Activity in Ischemic Stroke. Clin Interv Aging 2019; 14:2261-2271. [PMID: 31908436 PMCID: PMC6927491 DOI: 10.2147/cia.s223595] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 12/11/2019] [Indexed: 01/25/2023] Open
Abstract
Background Manipulating the immune inflammatory response after cerebral ischemia has been a novel therapeutic strategy for ischemic stroke. This study attempted to investigate the effects of the transplantation of lymphocytes co-cultured with human cord blood-derived multipotent stem cells (HCB-SCs) on the inflammatory response in transient middle cerebral occlusion (tMCAO) rats. Methods The tMCAO rats were subjected to the transplantation of lymphocytes co-cultured with HCB-SCs through tail vein injection. Infarct size and neurological deficits were measured at 48 hrs after stroke. Neurological deficits were assessed using Bederson’s scoring system and tape removal test. Blood T cell flow cytometry was performed to measure the differentiation of regulatory T cells (Tregs). Western blot was used to detect the protein levels of inflammation-related molecules, apoptosis-related molecule, and signaling molecules in ischemic brain. TUNEL staining was performed to analyze cell apoptosis in ischemic cerebral cortex. Results The transplantation of lymphocytes co-cultured with HCB-SCs significantly improved the neurological defects, reduced ischemic brain damage, and increased the proportion of peripheral CD4+CD25+Foxp3+ Tregs. Meanwhile, the transplantation of co-cultured cells decreased the expression of NLRP3 inflammasome and associated factors, such as caspase-1 and IL-1β, and inhibited the activation of NF-κB, ERK and caspase-3 in ischemic brain. The co-cultured cells significantly decreased the number of tMCAO-induced cell apoptosis. Conclusion Lymphocytes co-cultured with HCB-SCs exhibit a neuroprotective effect after ischemic stroke by promoting Tregs differentiation and suppressing NLRP3 inflammasome activation and neuron apoptosis, and might be a promising therapeutic strategy for ischemic stroke.
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Affiliation(s)
- Yanxin Zhao
- Department of Neurology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, People's Republic of China
| | - Tianrui Zhu
- Department of Neurology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, People's Republic of China
| | - Heng Li
- Department of Neurology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, People's Republic of China
| | - Jing Zhao
- Department of Neurology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, People's Republic of China
| | - Xiaohong Li
- Department of Neurology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, People's Republic of China
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29
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Han YH, Kim KH, Abdi S, Kim TK. Stem cell therapy in pain medicine. Korean J Pain 2019; 32:245-255. [PMID: 31569916 PMCID: PMC6813895 DOI: 10.3344/kjp.2019.32.4.245] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 12/31/2022] Open
Abstract
Stem cells are attracting attention as a key element in future medicine, satisfying the desire to live a healthier life with the possibility that they can regenerate tissue damaged or degenerated by disease or aging. Stem cells are defined as undifferentiated cells that have the ability to replicate and differentiate themselves into various tissues cells. Stem cells, commonly encountered in clinical or preclinical stages, are largely classified into embryonic, adult, and induced pluripotent stem cells. Recently, stem cell transplantation has been frequently applied to the treatment of pain as an alternative or promising approach for the treatment of severe osteoarthritis, neuropathic pain, and intractable musculoskeletal pain which do not respond to conventional medicine. The main idea of applying stem cells to neuropathic pain is based on the ability of stem cells to release neurotrophic factors, along with providing a cellular source for replacing the injured neural cells, making them ideal candidates for modulating and possibly reversing intractable neuropathic pain. Even though various differentiation capacities of stem cells are reported, there is not enough knowledge and technique to control the differentiation into desired tissues in vivo. Even though the use of stem cells is still in the very early stages of clinical use and raises complicated ethical problems, the future of stem cells therapies is very bright with the help of accumulating evidence and technology.
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Affiliation(s)
- Yong Hee Han
- Department of Anesthesia and Pain Medicine, Pusan National University School of Medicine, Yangsan, Korea
| | - Kyung Hoon Kim
- Department of Anesthesia and Pain Medicine, Pusan National University School of Medicine, Yangsan, Korea
| | - Salahadin Abdi
- Division of Anesthesia and Critical Care, Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tae Kyun Kim
- Department of Anesthesia and Pain Medicine, Pusan National University School of Medicine, Yangsan, Korea
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30
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Choi C, Kim HM, Shon J, Park J, Kim HT, Kang SH, Oh SH, Kim NK, Kim OJ. The combination of mannitol and temozolomide increases the effectiveness of stem cell treatment in a chronic stroke model. Cytotherapy 2019; 20:820-829. [PMID: 29776835 DOI: 10.1016/j.jcyt.2018.04.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/19/2018] [Accepted: 04/25/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND The blood-brain barrier (BBB) presents a significant challenge to the therapeutic efficacy of stem cells in chronic stroke. Various methods have been developed to increase BBB permeability, but these are associated with adverse effects and are, therefore, not clinically applicable. We recently identified that combination drug treatment of mannitol and temozolomide improved BBB permeability in vitro. Here, we investigated whether this combination could increase the effectiveness of stem cell treatment in an animal model of chronic ischemic stroke. METHODS Chronic stroke was induced in rats by middle cerebral artery occlusion (MCAo). After then, rats were administered human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) by intravenous injection with or without combination drug treatment of mannitol and temozolomide. To evaluate the therapeutic efficacy, behavioral and immunohistochemical tests were performed, and the differences among control, stem cell only, combination drug only and stem cell with combination drug treatment were analyzed. RESULTS Although no hUC-MSCs were detected in any group, treatment with stem cells and combination drug of mannitol and temozolomide increased the intracerebral delivery of hCD63-positive microvesicles compared with stem cell only treatment. Furthermore, treatment with stem cells and drug combination ameliorated behavioral deficits and increased bromodeoxyuridine-, doublecortin- and Reca-1-positive cells in the perilesional area as compared with other groups. DISCUSSION The combination drug treatment of mannitol and temozolomide allowed for the efficient delivery of hUC-MSC-derived microvesicles into the brain in a chronic stroke rat model. This attenuated behavioral deficits, likely by improving neural regeneration and angiogenesis. Thus, combination drug treatment of mannitol and temozolomide could be a novel therapeutic option for patients with chronic ischemic stroke.
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Affiliation(s)
- Chunggab Choi
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Hye Min Kim
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Jeeheun Shon
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Jiae Park
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Hyeong-Taek Kim
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Suk Ho Kang
- Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Seung-Hun Oh
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Nam Keun Kim
- Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Ok Joon Kim
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
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31
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Vermeulen M, Giudice MG, Del Vento F, Wyns C. Role of stem cells in fertility preservation: current insights. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2019; 12:27-48. [PMID: 31496751 PMCID: PMC6689135 DOI: 10.2147/sccaa.s178490] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 05/24/2019] [Indexed: 12/11/2022]
Abstract
While improvements made in the field of cancer therapy allow high survival rates, gonadotoxicity of chemo- and radiotherapy can lead to infertility in male and female pre- and postpubertal patients. Clinical options to preserve fertility before starting gonadotoxic therapies by cryopreserving sperm or oocytes for future use with assisted reproductive technology (ART) are now applied worldwide. Cryopreservation of pre- and postpubertal ovarian tissue containing primordial follicles, though still considered experimental, has already led to the birth of healthy babies after autotransplantation and is performed in an increasing number of centers. For prepubertal boys who do not produce gametes ready for fertilization, cryopreservation of immature testicular tissue (ITT) containing spermatogonial stem cells may be proposed as an experimental strategy with the aim of restoring fertility. Based on achievements in nonhuman primates, autotransplantation of ITT or testicular cell suspensions appears promising to restore fertility of young cancer survivors. So far, whether in two- or three-dimensional culture systems, in vitro maturation of immature male and female gonadal cells or tissue has not demonstrated a capacity to produce safe gametes for ART. Recently, primordial germ cells have been generated from embryonic and induced pluripotent stem cells, but further investigations regarding efficiency and safety are needed. Transplantation of mesenchymal stem cells to improve the vascularization of gonadal tissue grafts, increase the colonization of transplanted cells, and restore the damaged somatic compartment could overcome the current limitations encountered with transplantation.
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Affiliation(s)
- Maxime Vermeulen
- Gynecology-Andrology Research Unit, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, 1200, Belgium
| | - Maria-Grazia Giudice
- Gynecology-Andrology Research Unit, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, 1200, Belgium.,Department of Gynecology-Andrology, Cliniques Universitaires Saint-Luc, Brussels 1200, Belgium
| | - Federico Del Vento
- Gynecology-Andrology Research Unit, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, 1200, Belgium
| | - Christine Wyns
- Gynecology-Andrology Research Unit, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, 1200, Belgium.,Department of Gynecology-Andrology, Cliniques Universitaires Saint-Luc, Brussels 1200, Belgium
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Safety and Efficacy of Intraventricular Delivery of Bone Marrow-Derived Mesenchymal Stem Cells in Hemorrhagic Stroke Model. Sci Rep 2019; 9:5674. [PMID: 30952961 PMCID: PMC6450980 DOI: 10.1038/s41598-019-42182-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 03/21/2019] [Indexed: 01/01/2023] Open
Abstract
External ventricular drain (EVD) is used clinically to relieve intracranial pressure and occasionally to deliver medications following intracerebral hemorrhage (ICH). Mesenchymal stem cell (MSC) therapy has been shown to be neuroprotective and can induce neuroregeneration in stroke models. We evaluated the safety and efficacy of delivering MSCs intraventricularly in a rat hemorrhagic stroke model. Using autologous blood, hemorrhagic stroke was induced at specific coordinates in the right basal ganglia. After 30 minutes, rats were treated with either bone marrow-derived MSCs or a phosphate-buffered saline placebo via direct intraventricular infusion. Three dosages (2 × 105/kg, 5 × 105/kg, and 1 × 106/kg) of MSCs were administered. Forelimb use asymmetry test was employed to evaluate functional improvement after cell therapy. At the end of the experiment, peripheral blood samples and organs were harvested; biochemistry, cytokine, and growth factor analysis and histology evaluations were performed to explore cell toxicity and cell fate, and the effects of MSC therapy on injury volume, anti-inflammation, and neurogenesis. Intraventricular administration of MSCs in ICH rat model showed improved behavior and alleviated brain damage. Additionally, treated ICH rats showed significantly reduced expression of IL-1α, IL-6, and IFN-γ. No obvious cell toxicity was noticed through blood chemistry and histology evaluation. None of the infused MSCs were detected at the end of the experiment. EVD is safe and effective to use as a method of delivering MSCs to treat ICH. Intraventricularly delivered MSCs have anti-inflammatory properties and a capacity to induce neurogenesis and improve function following ICH injury.
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33
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Cho KHT, Xu B, Blenkiron C, Fraser M. Emerging Roles of miRNAs in Brain Development and Perinatal Brain Injury. Front Physiol 2019; 10:227. [PMID: 30984006 PMCID: PMC6447777 DOI: 10.3389/fphys.2019.00227] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 02/21/2019] [Indexed: 12/14/2022] Open
Abstract
In human beings the immature brain is highly plastic and depending on the stage of gestation is particularly vulnerable to a range of insults that if sufficiently severe, can result in long-term motor, cognitive and behavioral impairment. With improved neonatal care, the incidence of major motor deficits such as cerebral palsy has declined with prematurity. Unfortunately, however, milder forms of injury characterized by diffuse non-cystic white matter lesions within the periventricular region and surrounding white matter, involving loss of oligodendrocyte progenitors and subsequent axonal hypomyelination as the brain matures have not. Existing therapeutic options for treatment of preterm infants have proved inadequate, partly owing to an incomplete understanding of underlying post-injury cellular and molecular changes that lead to poor neurodevelopmental outcomes. This has reinforced the need to improve our understanding of brain plasticity, explore novel solutions for the development of protective strategies, and identify biomarkers. Compelling evidence exists supporting the involvement of microRNAs (miRNAs), a class of small non-coding RNAs, as important post-transcriptional regulators of gene expression with functions including cell fate specification and plasticity of synaptic connections. Importantly, miRNAs are differentially expressed following brain injury, and can be packaged within exosomes/extracellular vesicles, which play a pivotal role in assuring their intercellular communication and passage across the blood-brain barrier. Indeed, an increasing number of investigations have examined the roles of specific miRNAs following injury and regeneration and it is apparent that this field of research could potentially identify protective therapeutic strategies to ameliorate perinatal brain injury. In this review, we discuss the most recent findings of some important miRNAs in relation to the development of the brain, their dysregulation, functions and regulatory roles following brain injury, and discuss how these can be targeted either as biomarkers of injury or neuroprotective agents.
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Affiliation(s)
- Kenta Hyeon Tae Cho
- Department of Physiology, Faculty of Medical Health and Sciences, University of Auckland, Auckland, New Zealand
| | - Bing Xu
- Department of Physiology, Faculty of Medical Health and Sciences, University of Auckland, Auckland, New Zealand
| | - Cherie Blenkiron
- Departments of Molecular Medicine and Pathology, Faculty of Medical Health and Sciences, University of Auckland, Auckland, New Zealand
| | - Mhoyra Fraser
- Department of Physiology, Faculty of Medical Health and Sciences, University of Auckland, Auckland, New Zealand
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Yuan O, Lin C, Wagner J, Archard JA, Deng P, Halmai J, Bauer G, Fink KD, Fury B, Perotti NH, Walker JE, Pollock K, Apperson M, Butters J, Belafsky P, Farwell DG, Kuhn M, Nolta J, Anderson JD. Exosomes Derived from Human Primed Mesenchymal Stem Cells Induce Mitosis and Potentiate Growth Factor Secretion. Stem Cells Dev 2019; 28:398-409. [PMID: 30638129 PMCID: PMC6441283 DOI: 10.1089/scd.2018.0200] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 01/11/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) facilitate functional recovery in numerous animal models of inflammatory and ischemic tissue-related diseases with a growing body of research suggesting that exosomes mediate many of these therapeutic effects. It remains unclear, however, which types of proteins are packaged into exosomes compared with the cells from which they are derived. In this study, using comprehensive proteomic analysis, we demonstrated that human primed MSCs secrete exosomes (pMEX) that are packaged with markedly higher fractions of specific protein subclasses compared with their cells of origin, indicating regulation of their contents. Notably, we found that pMEX are also packaged with substantially elevated levels of extracellular-associated proteins. Fibronectin was the most abundant protein detected, and data established that fibronectin mediates the mitogenic properties of pMEX. In addition, treatment of SHSY5Y cells with pMEX induced the secretion of growth factors known to possess mitogenic and neurotrophic properties. Taken together, our comprehensive analysis indicates that pMEX are packaged with specific protein subtypes, which may provide a molecular basis for their distinct functional properties.
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Affiliation(s)
- Oliver Yuan
- Department of Otolaryngology, University of California, Davis, Davis, California
| | - Clayton Lin
- Department of Otolaryngology, University of California, Davis, Davis, California
| | - Joseph Wagner
- Drug Discovery Consortium, University of California, San Francisco, San Francisco, California
| | - Joehleen A. Archard
- Department of Otolaryngology, University of California, Davis, Davis, California
| | - Peter Deng
- Department of Neurology, University of California, Davis, Davis, California
| | - Julian Halmai
- Department of Neurology, University of California, Davis, Davis, California
| | - Gerhard Bauer
- Good Manufacturing Practice Facility, University of California, Davis, Davis, California
| | - Kyle D. Fink
- Department of Neurology, University of California, Davis, Davis, California
| | - Brian Fury
- Good Manufacturing Practice Facility, University of California, Davis, Davis, California
| | - Nicholas H. Perotti
- Good Manufacturing Practice Facility, University of California, Davis, Davis, California
| | - Jon E. Walker
- Stem Cell Program, University of California, Davis, Davis, California
| | - Kari Pollock
- Stem Cell Program, University of California, Davis, Davis, California
| | - Michelle Apperson
- Department of Neurology, University of California, Davis, Davis, California
| | - Janelle Butters
- Department of Neurology, University of California, Davis, Davis, California
| | - Peter Belafsky
- Department of Otolaryngology, University of California, Davis, Davis, California
| | - D. Gregory Farwell
- Department of Otolaryngology, University of California, Davis, Davis, California
| | - Maggie Kuhn
- Department of Otolaryngology, University of California, Davis, Davis, California
| | - Jan Nolta
- Stem Cell Program, University of California, Davis, Davis, California
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Pischiutta F, Sammali E, Parolini O, Carswell HVO, Zanier ER. Placenta-Derived Cells for Acute Brain Injury. Cell Transplant 2019; 27:151-167. [PMID: 29562781 PMCID: PMC6434489 DOI: 10.1177/0963689717732992] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Acute brain injury resulting from ischemic/hemorrhagic or traumatic damage is one of the leading causes of mortality and disability worldwide and is a significant burden to society. Neuroprotective options to counteract brain damage are very limited in stroke and traumatic brain injury (TBI). Given the multifaceted nature of acute brain injury and damage progression, several therapeutic targets may need to be addressed simultaneously to interfere with the evolution of the injury and improve the patient’s outcome. Stem cells are ideal candidates since they act on various mechanisms of protection and repair, improving structural and functional outcomes after experimental stroke or TBI. Stem cells isolated from placenta offer advantages due to their early embryonic origin, ease of procurement, and ethical acceptance. We analyzed the evidence for the beneficial effects of placenta-derived stem cells in acute brain injury, with the focus on experimental studies of TBI and stroke, the engineering strategies pursued to foster cell potential, and characterization of the bioactive molecules secreted by placental cells, known as their secretome, as an alternative cell-free strategy. Results from the clinical application of placenta-derived stem cells for acute brain injury and ongoing clinical trials are summarily discussed.
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Affiliation(s)
- Francesca Pischiutta
- 1 Department of Neuroscience, Laboratory of Acute Brain Injury and Therapeutic Strategies, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Eliana Sammali
- 1 Department of Neuroscience, Laboratory of Acute Brain Injury and Therapeutic Strategies, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.,2 Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Ornella Parolini
- 3 Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy.,4 Institute of Anatomy and Cell Biology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Hilary V O Carswell
- 5 Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde, Glasgow, United Kingdom
| | - Elisa R Zanier
- 1 Department of Neuroscience, Laboratory of Acute Brain Injury and Therapeutic Strategies, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
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Pham VM, Matsumura S, Katano T, Funatsu N, Ito S. Diabetic neuropathy research: from mouse models to targets for treatment. Neural Regen Res 2019; 14:1870-1879. [PMID: 31290436 PMCID: PMC6676867 DOI: 10.4103/1673-5374.259603] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Diabetic neuropathy is one of the most serious complications of diabetes, and its increase shows no sign of stopping. Furthermore, current clinical treatments do not yet approach the best effectiveness. Thus, the development of better strategies for treating diabetic neuropathy is an urgent matter. In this review, we first discuss the advantages and disadvantages of some major mouse models of diabetic neuropathy and then address the targets for mechanism-based treatment that have been studied. We also introduce our studies on each part. Using stem cells as a source of neurotrophic factors to target extrinsic factors of diabetic neuropathy, we found that they present a promising treatment.
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Affiliation(s)
- Vuong M Pham
- Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan; Singapore Institute for Neurotechnology (SINAPSE), National University of Singapore, Singapore
| | - Shinji Matsumura
- Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan
| | - Tayo Katano
- Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan
| | - Nobuo Funatsu
- Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan
| | - Seiji Ito
- Department of Medical Chemistry, Kansai Medical University, Hirakata; Department of Anesthesiology, Osaka Medical College, Takatsuki, Osaka, Japan
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Shamsara A, Sheibani V, Asadi-Shekaari M, Nematollahi-Mahani SN. Neural like cells and acetyl-salicylic acid alter rat brain structure and function following transient middle cerebral artery occlusion. Biomol Concepts 2018; 9:155-168. [PMID: 30864349 DOI: 10.1515/bmc-2018-0014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 11/14/2018] [Indexed: 01/05/2023] Open
Abstract
Introduction Transient cerebral ischemia is a pandemic neurological disorder and the main aim of medical intervention is to reduce complications. Human umbilical cord mesenchymal cells (hUCMs) are capable of differentiating into neural-like cells (NLC) in vitro, therefore we investigated the neuroprotective potential of these cells in comparison to aspirin and in combination (NLC-Aspirin) on spatial memory and neural morphologic changes in male rats submitted to transient cerebral ischemia. Methods Ten days after the intervention, the improvement in learning and memory were assessed in the animals by Morris Water Maze. Thence, the animals were examined for the presence of PKH26 labeled cells in the ischemic area of the brain, the infarct volume and neural changes in the brain tissue. Results Significant spatial memory deficits in the ischemic animals were detected compared with the control animals. The learning and memory were significantly improved (p ≤ 0.05) in the aspirin and NLC groups compared with the ischemic animals. Co-treatment of aspirin and NLCs did not improve the outcome. Moreover, infarction volume and neural changes were significantly altered when aspirin or NLCs were administered. Conclusions Our data suggest the significant neuroprotective potential of aspirin and neural-like cells derived from hUCM cells in the treatment of brain ischemic stroke. Further studies are required to evaluate possible underlying mechanisms, and to evaluate the possible interactions between aspirin and stem cells in a joint treatment aimed at the recovery of cognitive impairments.
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Affiliation(s)
- Ali Shamsara
- Department of Anatomy, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Vahid Sheibani
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Majid Asadi-Shekaari
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
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Enhancement of the efficacy of mesenchymal stem cells in the treatment of ischemic diseases. Biomed Pharmacother 2018; 109:2022-2034. [PMID: 30551458 DOI: 10.1016/j.biopha.2018.11.068] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/17/2018] [Accepted: 11/19/2018] [Indexed: 02/05/2023] Open
Abstract
Ischemic diseases refer to a wide range of diseases caused by reduced blood flow and a subsequently deficient oxygen and nutrient supply. The pathogenesis of ischemia is multifaceted and primarily involves inflammation, oxidative stress and an apoptotic response. Over the last decade, mesenchymal stem cells (MSCs) have been widely studied as potential cell therapy agents for ischemic diseases due to their multiple favourable functions. However, the low homing and survival rates of transplanted cells have been concerns limiting for their clinical application. Recently, increasing studies have attempted to enhance the efficacy of MSCs by various strategies including genetic modification, pretreatment, combined application and biomaterial application. The purpose of this review is to summarize these creative strategies and the progress in basic and preclinical studies.
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Muhammad SA, Nordin N, Fakurazi S. Regenerative potential of secretome from dental stem cells: a systematic review of preclinical studies. Rev Neurosci 2018; 29:321-332. [PMID: 29220331 DOI: 10.1515/revneuro-2017-0069] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 08/22/2017] [Indexed: 12/21/2022]
Abstract
Injury to tissues is a major clinical challenge due to the limited regenerative capacity of endogenous cells. Stem cell therapy is evolving rapidly as an alternative for tissue regeneration. However, increasing evidence suggests that the regenerative ability of stem cells is mainly mediated by paracrine actions of secretome that are generally secreted by the cells. We aimed to systematically evaluate the efficacy of dental stem cell (DSC)-conditioned medium in in vivo animal models of various tissue defects. A total of 15 eligible studies was included by searching Pubmed, Scopus and Medline databases up to August 2017. The risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation risk of bias tool. Of 15 studies, seven reported the therapeutic benefit of the conditioned medium on neurological diseases and three reported on joint/bone-related defects. Two interventions were on liver diseases, whereas the remaining three addressed myocardial infarction and reperfusion, lung injury and diabetes. Nine studies were performed using mouse models and the remaining six studies used rat models. The methodological quality of the studies was low, as most of the key elements required in reports of preclinical studies were not reported. The findings of this review suggested that conditioned medium from DSCs improved tissue regeneration and functional recovery. This current review strengthens the therapeutic benefit of cell-free product for tissue repair in animal models. A well-planned study utilizing validated outcome measures and long-term safety studies are required for possible translation to clinical trials.
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Affiliation(s)
| | - Norshariza Nordin
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra, Serdang, Selangor, Malaysia
| | - Sharida Fakurazi
- Institute of Bioscience and Pharmacology Unit, Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
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40
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Influence of passage number on the impact of the secretome of adipose tissue stem cells on neural survival, neurodifferentiation and axonal growth. Biochimie 2018; 155:119-128. [PMID: 30342112 DOI: 10.1016/j.biochi.2018.09.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 09/13/2018] [Accepted: 09/20/2018] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cells (MSCs), and within them adipose tissue derived stem cells (ASCs), have been shown to have therapeutic effects on central nervous system (CNS) cell populations. Such effects have been mostly attributed to soluble factors, as well as vesicles, present in their secretome. Yet, little is known about the impact that MSC passaging might have in the secretion therapeutic profile. Our aim was to show how human ASCs (hASCs) passage number influences the effect of their secretome in neuronal survival, differentiation and axonal growth. For this purpose, post-natal rat hippocampal primary cultures, human neural progenitor cell (hNPCs) cultures and dorsal root ganglia (DRGs) explants were incubated with secretome, collected as conditioned media (CM), obtained from hASCs in P3, P6, P9 and P12. Results showed no differences when comparing percentages of MAP-2 positive cells (a mature neuronal marker) in neuronal cultures or hNPCs, after incubation with hASCs secretome from different passages. The same was observed regarding DRG neurite outgrowth. In order to characterize the secretomes obtained from different passages, a proteomic analysis was performed, revealing that its composition did not vary significantly with passage number P3 to P12. Results allowed us to identify several key proteins, such as pigment epithelium derived factor (PEDF), DJ-1, interleucin-6 (IL-6) and galectin, all of which have already proven to play neuroprotective and neurodifferentiating roles. Proteins that promote neurite outgrowth were also found present, such as semaphorin 7A and glypican-1. We conclude that cellular passaging does not influence significantly hASCs's secretome properties especially their ability to support post-natal neuronal survival, induce neurodifferentiation and promote axonal growth.
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Cunningham CJ, Redondo-Castro E, Allan SM. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J Cereb Blood Flow Metab 2018; 38:1276-1292. [PMID: 29768965 PMCID: PMC6077926 DOI: 10.1177/0271678x18776802] [Citation(s) in RCA: 167] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) hold great potential as a regenerative therapy for stroke, leading to increased repair and functional recovery in animal models of cerebral ischaemia. While it was initially hypothesised that cell replacement was an important mechanism of action of MSCs, focus has shifted to their paracrine actions or the so called "bystander" effect. MSCs secrete a wide array of growth factors, chemokines, cytokines and extracellular vesicles, commonly referred to as the MSC secretome. There is evidence suggesting the MSC secretome can promote repair through a number of mechanisms including preventing cell apoptosis, modulating the inflammatory response and promoting endogenous repair mechanisms such as angiogenesis and neurogenesis. In this review, we will discuss the in vitro approaches currently being employed to drive the MSC secretome towards a more anti-inflammatory and regenerative phenotype. We will then examine the role of the secretome in promoting repair and improving recovery in preclinical models of cerebral ischaemia.
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Affiliation(s)
- Catriona J Cunningham
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Elena Redondo-Castro
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Stuart M Allan
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Macrin D, Joseph JP, Pillai AA, Devi A. Eminent Sources of Adult Mesenchymal Stem Cells and Their Therapeutic Imminence. Stem Cell Rev Rep 2018; 13:741-756. [PMID: 28812219 DOI: 10.1007/s12015-017-9759-8] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In the recent times, stem cell biology has garnered the attention of the scientific fraternity and the general public alike due to the immense therapeutic potential that it holds in the field of regenerative medicine. A breakthrough in this direction came with the isolation of stem cells from human embryo and their differentiation into cell types of all three germ layers. However, the isolation of mesenchymal stem cells from adult tissues proved to be advantageous over embryonic stem cells due to the ethical and immunological naivety. Mesenchymal Stem Cells (MSCs) isolated from the bone marrow were found to differentiate into multiple cell lineages with the help of appropriate differentiation factors. Furthermore, other sources of stem cells including adipose tissue, dental pulp, and breast milk have been identified. Newer sources of stem cells have been emerging recently and their clinical applications are also being studied. In this review, we examine the eminent sources of Mesenchymal Stem Cells (MSCs), their immunophenotypes, and therapeutic imminence.
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Affiliation(s)
- Dannie Macrin
- Department of Genetic Engineering, SRM University, Kattankulathur, Tamil Nadu, India
| | - Joel P Joseph
- Department of Genetic Engineering, SRM University, Kattankulathur, Tamil Nadu, India
| | | | - Arikketh Devi
- Department of Genetic Engineering, SRM University, Kattankulathur, Tamil Nadu, India.
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Oh SH, Choi C, Noh JE, Lee N, Jeong YW, Jeon I, Shin JM, Kim JH, Kim HJ, Lee JM, Kim HS, Kim OJ, Song J. Interleukin-1 receptor antagonist-mediated neuroprotection by umbilical cord-derived mesenchymal stromal cells following transplantation into a rodent stroke model. Exp Mol Med 2018; 50:1-12. [PMID: 29650950 PMCID: PMC5938060 DOI: 10.1038/s12276-018-0041-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 12/21/2017] [Indexed: 01/01/2023] Open
Abstract
The human umbilical cord is a promising source of mesenchymal stromal cells (MSCs). Intravenous administration of human umbilical cord-derived MSCs (IV-hUMSCs) showed a favorable effect in a rodent stroke model by a paracrine mechanism. However, its underlying therapeutic mechanisms must be determined for clinical application. We investigated the therapeutic effects and mechanisms of our good manufacturing practice (GMP)-manufactured hUMSCs using various cell doses and delivery time points in a rodent model of stroke. IV-hUMSCs at a dose of 1 × 106 cells at 24 h after stroke improved functional deficits and reduced neuronal damage by attenuation of post-ischemic inflammation. Transcriptome and immunohistochemical analyses showed that interleukin-1 receptor antagonist (IL-1ra) was highly upregulated in ED-1-positive inflammatory cells in rats treated with IV-hUMSCs. Treatment with conditioned medium of hUMSCs increased the expression of IL-1ra in a macrophage cell line via activation of cAMP-response element-binding protein (CREB). These results strongly suggest that the attenuation of neuroinflammation mediated by endogenous IL-1ra is an important therapeutic mechanism of IV-hUMSCs for the treatment of stroke.
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Affiliation(s)
- Seung-Hun Oh
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Chunggab Choi
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Jeong-Eun Noh
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Nayeon Lee
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Yong-Woo Jeong
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Iksoo Jeon
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Jeong-Min Shin
- Development Division, CHA Biotech, Co. Ltd., Seongnam, Republic of Korea.,Department of Biotechnology, CHA University, Seongnam, Republic of Korea
| | - Ji-Hye Kim
- Development Division, CHA Biotech, Co. Ltd., Seongnam, Republic of Korea
| | - Ho-Jin Kim
- Development Division, CHA Biotech, Co. Ltd., Seongnam, Republic of Korea
| | - Ji-Min Lee
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Hyun-Sook Kim
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Ok-Joon Kim
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
| | - Jihwan Song
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea. .,CHA Stem Cell Institute, CHA University, Seongnam, Republic of Korea.
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44
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Kang JM, Yeon BK, Cho SJ, Suh YH. Stem Cell Therapy for Alzheimer's Disease: A Review of Recent Clinical Trials. J Alzheimers Dis 2018; 54:879-889. [PMID: 27567851 DOI: 10.3233/jad-160406] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Stem cell therapy has been noted to be a disease-modifying treatment for Alzheimer's disease (AD). After the failure to develop new drugs for AD, the number of studies on stem cells, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs), has increased from the early 2000 s. Issues pertaining to stem cells have been investigated in many animal studies in terms of stem cell origin, differentiation potency, method of culture, tumor formation, injection route, and mobility. Since 2010, mainly in East Asia, researchers began clinical trials investigating the use of stem cells for AD. Two phase I trials on moderate AD have been completed; though they revealed no severe acute or long-term side effects, no significant clinical efficacy was observed. Several studies, which involve more sophisticated study designs using different injection routes, well-established scales, and biomarkers such as amyloid positron emission tomography, are planned for mild to moderate AD patients. Here, we review the concept of stem cell therapy for AD and the progress of recent clinical trials.
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Affiliation(s)
- Jae Myeong Kang
- Department of Psychiatry, Gil Medical Center, Gachon University, College of Medicine, Incheon, Korea
| | - Byeong Kil Yeon
- Department of Psychiatry, Gil Medical Center, Gachon University, College of Medicine, Incheon, Korea.,Incheon Metropolitan Dementia Center, Incheon, Korea
| | - Seong-Jin Cho
- Department of Psychiatry, Gil Medical Center, Gachon University, College of Medicine, Incheon, Korea
| | - Yoo-Hun Suh
- Neuroscience Research Institute, Gachon University, College of Medicine, Incheon, Korea
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45
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Donders R, Bogie JF, Ravanidis S, Gervois P, Vanheusden M, Marée R, Schrynemackers M, Smeets HJ, Pinxteren J, Gijbels K, Walbers S, Mays RW, Deans R, Van Den Bosch L, Stinissen P, Lambrichts I, Gyselaers W, Hellings N. Human Wharton's Jelly-Derived Stem Cells Display a Distinct Immunomodulatory and Proregenerative Transcriptional Signature Compared to Bone Marrow-Derived Stem Cells. Stem Cells Dev 2018; 27:65-84. [DOI: 10.1089/scd.2017.0029] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Raf Donders
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Jeroen F.J. Bogie
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | | | - Pascal Gervois
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Marjan Vanheusden
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Raphaël Marée
- University of Liège, GIGA Bioinformatics Core Facility, Liège, Belgium
| | | | - Hubert J.M. Smeets
- Maastricht UMC+, Department of Genetics and Cell Biology, Research School GROW and CARIM, Maastricht, the Netherlands
| | - Jef Pinxteren
- ReGenesys BVBA, Bio-Incubator Leuven, Heverlee, Belgium
| | | | - Sara Walbers
- ReGenesys BVBA, Bio-Incubator Leuven, Heverlee, Belgium
| | - Robert W. Mays
- Department of Regenerative Medicine, Athersys, Inc., Cleveland, Ohio
| | - Robert Deans
- Department of Regenerative Medicine, Athersys, Inc., Cleveland, Ohio
| | - Ludo Van Den Bosch
- KU Leuven, Laboratory of Neurobiology, Experimental Neurology and VIB, Center for Brain & Disease, Leuven, Belgium
| | - Piet Stinissen
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Ivo Lambrichts
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Wilfried Gyselaers
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- Ziekenhuis Oost-Limburg, Campus St. Jan, Genk, Belgium
| | - Niels Hellings
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
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46
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Xu L, Xing Q, Huang T, Zhou J, Liu T, Cui Y, Cheng T, Wang Y, Zhou X, Yang B, Yang GL, Zhang J, Zang X, Ma S, Guan F. HDAC1 Silence Promotes Neuroprotective Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Mouse Model of Traumatic Brain Injury via PI3K/AKT Pathway. Front Cell Neurosci 2018; 12:498. [PMID: 30662396 PMCID: PMC6328439 DOI: 10.3389/fncel.2018.00498] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 12/03/2018] [Indexed: 01/09/2023] Open
Abstract
Stem cell transplantation is a promising therapy for traumatic brain injury (TBI), but low efficiency of survival and differentiation of transplanted stem cells limits its clinical application. Histone deacetylase 1 (HDAC1) plays important roles in self-renewal of stem cells as well as the recovery of brain disorders. However, little is known about the effects of HDAC1 on the survival and efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in vivo. In this study, our results showed that HDAC1 silence promoted hUC-MSCs engraftment in the hippocampus and increased the neuroprotective effects of hUC-MSCs in TBI mouse model, which was accompanied by improved neurological function, enhanced neurogenesis, decreased neural apoptosis, and reduced oxidative stress in the hippocampus. Further mechanistic studies revealed that the expressions of phosphorylated PTEN (p-PTEN), phosphorylated Akt (p-Akt), and phosphorylated GSK-3β (p-GSK-3β) were upregulated. Intriguingly, the neuroprotective effects of hUC-MSCs with HDAC1 silence on behavioral performance of TBI mice was markedly attenuated by LY294002, an inhibitor of the PI3K/AKT pathway. Taken together, our findings suggest that hUC-MSCs transplantation with HDAC1 silence may provide a potential strategy for treating TBI in the future.
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Affiliation(s)
- Ling Xu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial People’s Hospital, Zhengzhou, China
| | - Qu Xing
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Tuanjie Huang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Jiankang Zhou
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Tengfei Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Yuanbo Cui
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
- Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Tian Cheng
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yaping Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Xinkui Zhou
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Bo Yang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | | | - Jiewen Zhang
- Henan Provincial People’s Hospital, Zhengzhou, China
| | - Xingxing Zang
- Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, United States
| | - Shanshan Ma
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
- *Correspondence: Shanshan Ma Fangxia Guan
| | - Fangxia Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial People’s Hospital, Zhengzhou, China
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Shanshan Ma Fangxia Guan
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47
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Teixeira FG, Serra SC, Salgado AJ. Tips on How to Collect and Administer the Mesenchymal Stem Cell Secretome for Central Nervous System Applications. Methods Mol Biol 2017; 1416:457-65. [PMID: 27236689 DOI: 10.1007/978-1-4939-3584-0_27] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Human mesenchymal stem cells (hMSCs) have been proposed as possible therapeutic agents for central nervous system (CNS) disorders. Recently, it has been suggested that their effects are mostly mediated through their secretome, which contains a number of neuroregulatory molecules capable of increasing cell proliferation, differentiation, and survival in different physiological conditions. Here, we present an overview of the hMSC secretome as a possible candidate in the creation of new cell-free therapies, demonstrating the process of its collection and route of administration, focusing our attention on their effects in CNS regenerative medicine.
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Affiliation(s)
- F G Teixeira
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, Braga, 4710-057, Portugal
- ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - S C Serra
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, Braga, 4710-057, Portugal
- ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - A J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, Braga, 4710-057, Portugal.
- ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal.
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48
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Li Z, Zhang Z, Ming WK, Chen X, Xiao XM. Tracing GFP-labeled WJMSCs in vivo using a chronic salpingitis model: an animal experiment. Stem Cell Res Ther 2017; 8:272. [PMID: 29191249 PMCID: PMC5709981 DOI: 10.1186/s13287-017-0714-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 09/22/2017] [Accepted: 10/26/2017] [Indexed: 12/22/2022] Open
Abstract
Background The present study was conducted to evaluate the distribution of Wharton’s jelly-derived mesenchymal stem cells (WJMSCs) and their repairing function on the oviduct. Methods WJMSCs were transfected with the LV3-GFP-PURO lentivirus. Female New Zealand rabbits (n = 24) were divided randomly into control A and B groups and experimental C and D groups to establish inflammation models. Sterile saline solution or WJMSCs were injected into rabbits via ear veins and/or genital tract perfusion once weekly for 3 weeks. All rabbits were humanely sacrificed 1 week after the last perfusion to collect the oviduct, uterus, liver, and bladder for examination. Green fluorescent protein (GFP) and cytokeratin 7 (CK7) were imaged using a Leica Qwin Plus V3 fluorescence confocal microscope and analyzed as mean optical densities in an Image-Pro Plus analysis system. Results We found that lentivirus expressing the GFP gene produced an efficient transfection. The mean optical density values of GFP and CK7 in the oviducts were higher in the experimental D group than those in the control A and experimental C groups. No GFP fluorescence deposits occurred in the bladder of the control A group or experimental C group. Colocalization of CK7 and WJMSCs was observed in the oviducts in all groups. Conclusions WJMSCs exhibited homing characteristics and migrated to the injured oviduct to promote epithelial cell growth. Additionally, local treatment resulted in higher efficiency.
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Affiliation(s)
- Zhe Li
- The Department of Obstetrics and Gynecology, 1st Affiliated Hospital of Jinan University, Guangzhou, 510000, China
| | - Zhao Zhang
- The Department of Obstetrics and Gynecology, 1st Affiliated Hospital of Jinan University, Guangzhou, 510000, China.,The Department of Reproduction, Southern Medical University Affiliate Dongguan People's Hospital, Dongguan, China
| | - Wai-Kit Ming
- The Department of Obstetrics and Gynecology, 1st Affiliated Hospital of Jinan University, Guangzhou, 510000, China.,Harvard Medical School, Harvard University, Boston, MA, USA
| | - Xin Chen
- The Department of Obstetrics and Gynecology, 1st Affiliated Hospital of Jinan University, Guangzhou, 510000, China
| | - Xiao-Min Xiao
- The Department of Obstetrics and Gynecology, 1st Affiliated Hospital of Jinan University, Guangzhou, 510000, China.
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49
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Sironi F, Vallarola A, Violatto MB, Talamini L, Freschi M, De Gioia R, Capelli C, Agostini A, Moscatelli D, Tortarolo M, Bigini P, Introna M, Bendotti C. Multiple intracerebroventricular injections of human umbilical cord mesenchymal stem cells delay motor neurons loss but not disease progression of SOD1G93A mice. Stem Cell Res 2017; 25:166-178. [PMID: 29154076 DOI: 10.1016/j.scr.2017.11.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 11/02/2017] [Accepted: 11/04/2017] [Indexed: 12/13/2022] Open
Abstract
Stem cell therapy is considered a promising approach in the treatment of amyotrophic lateral sclerosis (ALS) and mesenchymal stem cells (MSCs) seem to be the most effective in ALS animal models. The umbilical cord (UC) is a source of highly proliferating fetal MSCs, more easily collectable than other MSCs. Recently we demonstrated that human (h) UC-MSCs, double labeled with fluorescent nanoparticles and Hoechst-33258 and transplanted intracerebroventricularly (ICV) into SOD1G93A transgenic mice, partially migrated into the spinal cord after a single injection. This prompted us to assess the effect of repeated ICV injections of hUC-MSCs on disease progression in SOD1G93A mice. Although no transplanted cells migrated to the spinal cord, a partial but significant protection of motor neurons (MNs) was found in the lumbar spinal cord of hUC-MSCs-treated SOD1G93A mice, accompanied by a shift from a pro-inflammatory (IL-6, IL-1β) to anti-inflammatory (IL-4, IL-10) and neuroprotective (IGF-1) environment in the lumbar spinal cord, probably linked to the activation of p-Akt survival pathway in both motor neurons and reactive astrocytes. However, this treatment neither prevented the muscle denervation nor delayed the disease progression of mice, emphasizing the growing evidence that protecting the motor neuron perikarya is not sufficient to delay the ALS progression.
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Affiliation(s)
- Francesca Sironi
- Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Antonio Vallarola
- Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Martina Bruna Violatto
- Department of Biochemistry and Molecular Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Laura Talamini
- Department of Biochemistry and Molecular Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Mattia Freschi
- Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Roberta De Gioia
- Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Chiara Capelli
- USS Center of Cellular Therapy"G. Lanzani", ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Azzurra Agostini
- Department of Chemistry, Material and Chemical Engineering "G. Natta", Politecnico di Milano, Milano, Italy
| | - Davide Moscatelli
- Department of Chemistry, Material and Chemical Engineering "G. Natta", Politecnico di Milano, Milano, Italy
| | - Massimo Tortarolo
- Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Paolo Bigini
- Department of Biochemistry and Molecular Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Martino Introna
- USS Center of Cellular Therapy"G. Lanzani", ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Caterina Bendotti
- Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
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50
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Li Z, Zhang Z, Chen X, Zhou J, Xiao XM. Treatment evaluation of Wharton's jelly-derived mesenchymal stem cells using a chronic salpingitis model: an animal experiment. Stem Cell Res Ther 2017; 8:232. [PMID: 29041961 PMCID: PMC5645885 DOI: 10.1186/s13287-017-0685-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 09/27/2017] [Accepted: 09/28/2017] [Indexed: 12/13/2022] Open
Abstract
Background The present study was conducted to evaluate new methods to repair the reproductive function of the oviduct, thereby allowing gametes to combine and grow in vivo under natural circumstances. Methods Sixty pathogen-free female New Zealand rabbits were divided into three groups: a wild-type group, an untreated control group, and a treatment group. Disposable sterile newborn sputum suction tubes were inserted into the urogenital tract to instill an Escherichia coli suspension into the uterine cavity to establish the chronic salpingitis model. Wharton’s jelly-derived mesenchymal stem cells (WJMSCs) or normal saline were used to treat this infection via different methods. The therapeutic effect was assessed by evaluating morphology, inflammatory factors, proteinology, and pregnancy outcomes. Results Oviducts of New Zealand rabbits in the untreated control group showed structural failure and abnormal supermicrostructure of epithelial cells. WJMSCs could partially repair the structure and supermicrostructure of the tubal epithelium. The concentration of tumor necrosis factor (TNF)-α in the untreated control group was significantly higher than that in the wild-type group (P = 0.015). The concentration of TNF-α in the local treatment group was significantly lower than that in the untreated control group (P = 0.011). The expression of oviductal glycoprotein (OVGP) and OVGP mRNA in the wild-type group was significantly higher than those in the untreated control group (P = 0.024 and P = 0.013, respectively). The litter size of the treatment group was 2 ± 2.39 kits, which was higher than that of the untreated control group (P = 0.035). Conclusion Chronic inflammation can destroy the structure of the oviduct and the supermicrostructure of epithelial cells as well as leading to infertility. WJMSC transplantation therapy in rabbits with chronic salpingitis partially restored fertility. WJMSCs also repaired the structure of the tubal epithelium subjected to chronic inflammation, decreased the level of inflammatory factors, and partially restored the secretion level of OVGP.
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Affiliation(s)
- Zhe Li
- The Department of Obstetrics and Gynecology at the 1st Affiliated Hospital of Jinan University, Guangzhou, 510000, China
| | - Zhao Zhang
- The Department of Obstetrics and Gynecology at the 1st Affiliated Hospital of Jinan University, Guangzhou, 510000, China.,The Department of Reproduction at the Southern Medical University Affiliate Dongguan People's Hospital, Dongguan, China
| | - Xin Chen
- The Department of Obstetrics and Gynecology at the 1st Affiliated Hospital of Jinan University, Guangzhou, 510000, China
| | - Juan Zhou
- The Department of Obstetrics and Gynecology at the 1st Affiliated Hospital of Jinan University, Guangzhou, 510000, China
| | - Xiao-Min Xiao
- The Department of Obstetrics and Gynecology at the 1st Affiliated Hospital of Jinan University, Guangzhou, 510000, China.
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