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Paton MCB, Griffin AR, Blatch-Williams R, Webb A, Verter F, Couto PS, Bersenev A, Dale RC, Popat H, Novak I, Finch-Edmondson M. Clinical Evidence of Mesenchymal Stromal Cells for Cerebral Palsy: Scoping Review with Meta-Analysis of Efficacy in Gross Motor Outcomes. Cells 2025; 14:700. [PMID: 40422203 DOI: 10.3390/cells14100700] [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: 03/28/2025] [Revised: 04/24/2025] [Accepted: 05/08/2025] [Indexed: 05/28/2025] Open
Abstract
Mesenchymal stromal cells (MSCs) have been under clinical investigation for the treatment of cerebral palsy (CP) for over a decade. However, the field has been limited by study heterogeneity and variable reports of efficacy. We conducted a scoping review of published and registered reports of MSC treatment for CP, with meta-analysis of Gross Motor Function Measure (GMFM) outcomes to summarize research and provide future recommendations. Thirty published reports and 10 registered trials were identified, including 1292 people with CP receiving MSCs. Most received ≥2 doses (72%) of umbilical cord tissue MSCs (75%), intrathecally (40%) or intravenously (38%), and 31% were treated via compassionate/Expanded access. MSC treatment was safe and meta-analyses demonstrated that MSCs conferred significant improvements in GMFM at 3 - (1.05 (0.19-1.92), p = 0.02), 6 - (0.97 (0.30-1.64), p = 0.005) and 12 months (0.99 (0.30-1.67), p = 0.005) post-treatment. Whilst MSCs are safe and improve GMFM outcomes in CP with large effect sizes, study and participant variability continues to confound data interpretation and limits subgroup analyses. With no published Phase 3 trials and high rates of compassionate access, the field would benefit from well-designed trials with unified outcomes. Additionally, data sharing to enable Individual Participant Data Meta-Analysis would support the determination of optimal source, route and dose to progress towards regulatory approval.
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Affiliation(s)
- Madison C B Paton
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC 3800, Australia
| | - Alexandra R Griffin
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | - Remy Blatch-Williams
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | - Annabel Webb
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | - Frances Verter
- Parent's Guide to Cord Blood Foundation, Brookeville, MD 20833, USA
| | - Pedro S Couto
- Parent's Guide to Cord Blood Foundation, Brookeville, MD 20833, USA
- Department of Biochemical Engineering, University College London, London WC1N 3QS, UK
| | - Alexey Bersenev
- Cell Therapy Laboratories at Yale, New Haven Hospital, Yale University, New Haven, CT 06520, USA
| | - Russell C Dale
- Department of Neurology and Neurosurgery, Children's Hospital, Westmead, NSW 2145, Australia
- Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | - Himanshu Popat
- Grace Centre for Newborn Care, The Children's Hospital at Westmead, Sydney, NSW 2006, Australia
- The Children's Hospital at Westmead Clinical School, The University of Sydney, Sydney, NSW 2006, Australia
| | - Iona Novak
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | - Megan Finch-Edmondson
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
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Akat A, Karaöz E. A systematic review of cell therapy modalities and outcomes in cerebral palsy. Mol Cell Biochem 2025; 480:891-922. [PMID: 39033213 DOI: 10.1007/s11010-024-05072-3] [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: 03/27/2024] [Accepted: 07/11/2024] [Indexed: 07/23/2024]
Abstract
Cerebral palsy is widely recognized as a condition that results in significant physical and cognitive disabilities. Interventions aim to improve the quality of life and reduce disability. Despite numerous treatments and significant advancements, cerebral palsy remains incurable due to its diverse origins. This review evaluated clinical trials, studies, and case reports on various cell therapy approaches for cerebral palsy. It assessed the clinical outcomes of applying different cell types, including mesenchymal stem cells, olfactory ensheathing cells, neural stem/progenitor cells, macrophages, and mononuclear cells derived from peripheral blood, cord blood, and bone marrow. In 60 studies involving 1474 CP patients, six major adverse events (0.41%) and 485 mild adverse events (32.9%) were reported. Favorable therapeutic effects were observed in 54 out of 60 cell therapy trials, indicating a promising potential for cell treatments in cerebral palsy. Intrathecal MSC and BM-MNC applications revealed therapeutic benefits, with MSC studies being generally safer than other cell therapies. However, MSC and BM-MNC trials have shown inconsistent results, with some demonstrating superior efficacy for certain outcomes. Cell dosage, transplantation route, and frequency of administration can affect the efficacy of these therapies. Our findings highlight the promise of cell therapies for improving cerebral palsy treatment and stress the need for ongoing research to refine treatment protocols and enhance safety. To establish conclusive evidence on the comparative effectiveness of various cell types in treating cerebral palsy, randomized, double-blind clinical trials are essential.
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Affiliation(s)
- Ayberk Akat
- Yıldız Technical University, Davutpaşa Caddesi No.127, Esenler, 34210, Istanbul, Turkey.
| | - Erdal Karaöz
- Liv Hospital Ulus, Regenerative Medicine and Stem Cell Center, Istanbul, Turkey
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Jiang Y, Song Y, Zeng Q, Jiang B. Mesenchymal Stem Cells and Their Extracellular Vesicles Are a Promising Alternative to Antibiotics for Treating Sepsis. Bioengineering (Basel) 2024; 11:1160. [PMID: 39593820 PMCID: PMC11591657 DOI: 10.3390/bioengineering11111160] [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: 10/09/2024] [Revised: 11/08/2024] [Accepted: 11/10/2024] [Indexed: 11/28/2024] Open
Abstract
Sepsis is a life-threatening disease caused by the overwhelming response to pathogen infections. Currently, treatment options for sepsis are limited to broad-spectrum antibiotics and supportive care. However, the growing resistance of pathogens to common antibiotics complicates treatment efforts. Excessive immune response (i.e., cytokine storm) can persist even after the infection is cleared. This overactive inflammatory response can severely damage multiple organ systems. Given these challenges, managing the excessive immune response is critical in controlling sepsis progression. Therefore, Mesenchymal stem cells (MSCs), with their immunomodulatory and antibacterial properties, have emerged as a promising option for adjunctive therapy in treating sepsis. Moreover, MSCs exhibit a favorable safety profile, as they are eventually eliminated by the host's immune system within several months post-administration, resulting in minimal side effects and have not been linked to common antibiotic therapy drawbacks (i.e., antibiotic resistance). This review explores the potential of MSCs as a personalized therapy for sepsis treatment, clarifying their mechanisms of action and providing up-to-date technological advancements to enhance their protective efficacy for patients suffering from sepsis and its consequences.
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Affiliation(s)
- Yu Jiang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Chengdu 610041, China
| | - Yunjuan Song
- R&D Division, Eureka Biotech Inc., Philadelphia, PA 19104, USA
| | - Qin Zeng
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610065, China
| | - Bin Jiang
- R&D Division, Eureka Biotech Inc., Philadelphia, PA 19104, USA
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Yoshimaru K, Matsuura T, Uchida Y, Sonoda S, Maeda S, Kajihara K, Kawano Y, Shirai T, Toriigahara Y, Kalim AS, Zhang XY, Takahashi Y, Kawakubo N, Nagata K, Yamaza H, Yamaza T, Taguchi T, Tajiri T. Cutting-edge regenerative therapy for Hirschsprung disease and its allied disorders. Surg Today 2024; 54:977-994. [PMID: 37668735 DOI: 10.1007/s00595-023-02741-6] [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: 05/12/2023] [Accepted: 08/06/2023] [Indexed: 09/06/2023]
Abstract
Hirschsprung disease (HSCR) and its associated disorders (AD-HSCR) often result in severe hypoperistalsis caused by enteric neuropathy, mesenchymopathy, and myopathy. Notably, HSCR involving the small intestine, isolated hypoganglionosis, chronic idiopathic intestinal pseudo-obstruction, and megacystis-microcolon-intestinal hypoperistalsis syndrome carry a poor prognosis. Ultimately, small-bowel transplantation (SBTx) is necessary for refractory cases, but it is highly invasive and outcomes are less than optimal, despite advances in surgical techniques and management. Thus, regenerative therapy has come to light as a potential form of treatment involving regeneration of the enteric nervous system, mesenchyme, and smooth muscle in affected areas. We review the cutting-edge regenerative therapeutic approaches for managing HSCR and AD-HSCR, including the use of enteric nervous system progenitor cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells as cell sources, the recipient intestine's microenvironment, and transplantation methods. Perspectives on the future of these treatments are also discussed.
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Affiliation(s)
- Koichiro Yoshimaru
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Toshiharu Matsuura
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Yasuyuki Uchida
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Soichiro Sonoda
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Shohei Maeda
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Keisuke Kajihara
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yuki Kawano
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takeshi Shirai
- Department of Pediatric Surgery, Miyazaki Prefectural Miyazaki Hospital, 5-30 Kitatakamatsu-cho, Miyazaki, Miyazaki, 880-8510, Japan
| | - Yukihiro Toriigahara
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Alvin Santoso Kalim
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Xiu-Ying Zhang
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yoshiaki Takahashi
- Department of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata, Japan
| | - Naonori Kawakubo
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kouji Nagata
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Haruyoshi Yamaza
- Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takayoshi Yamaza
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Tomoaki Taguchi
- Fukuoka College of Health Sciences, 2-15-1 Tamura, Sawara-ku, Fukuoka, 814-0193, Japan
| | - Tatsuro Tajiri
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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Chen W, Ren Q, Zhou J, Liu W. Mesenchymal Stem Cell-Induced Neuroprotection in Pediatric Neurological Diseases: Recent Update of Underlying Mechanisms and Clinical Utility. Appl Biochem Biotechnol 2024; 196:5843-5858. [PMID: 38261236 DOI: 10.1007/s12010-023-04752-y] [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] [Accepted: 10/17/2023] [Indexed: 01/24/2024]
Abstract
Pediatric neurological diseases refer to a group of disorders that affect the nervous system in children. These conditions can have a significant impact on a child's development, cognitive function, motor skills, and overall quality of life. Stem cell therapy is a new and innovative approach to treat various neurological conditions by repairing damaged neurons and replacing those that have been lost. Mesenchymal stem cells (MSCs) have gained significant recognition in this regard due to their ability to differentiate into different cell types. MSCs are multipotent self-replicating stem cells known to render promising results in the treatment of stroke and spinal cord injury in adults. When delivered to the foci of damage in the central nervous system, stem cells begin to differentiate into neural cells under the stimulation of paracrine factors and secrete various neurotrophic factors (NTFs) like nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) that expedite the repair process in injured neurons. In the present review, we will focus on the therapeutic benefits of the MSC-based therapies in salient pediatric neurological disorders including cerebral palsy, stroke, and autism.
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Affiliation(s)
- Wei Chen
- Department of Neurology, People's Liberation Army, Southern Theater, Naval First Hospital, Zhanjiang, 524002, China
| | - Qiaoling Ren
- Department of Neurology, People's Liberation Army, Southern Theater, Naval First Hospital, Zhanjiang, 524002, China
| | - Junchen Zhou
- Department of Acupuncture and Moxibustion, Rehabilitation Medical Center, Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, China
| | - Wenchun Liu
- Department of Neurology, People's Liberation Army, Southern Theater, Naval First Hospital, Zhanjiang, 524002, China.
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Zhidu S, Ying T, Rui J, Chao Z. Translational potential of mesenchymal stem cells in regenerative therapies for human diseases: challenges and opportunities. Stem Cell Res Ther 2024; 15:266. [PMID: 39183341 PMCID: PMC11346273 DOI: 10.1186/s13287-024-03885-z] [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: 05/17/2024] [Accepted: 08/14/2024] [Indexed: 08/27/2024] Open
Abstract
Advances in stem cell technology offer new possibilities for patients with untreated diseases and disorders. Stem cell-based therapy, which includes multipotent mesenchymal stem cells (MSCs), has recently become important in regenerative therapies. MSCs are multipotent progenitor cells that possess the ability to undergo in vitro self-renewal and differentiate into various mesenchymal lineages. MSCs have demonstrated promise in several areas, such as tissue regeneration, immunological modulation, anti-inflammatory qualities, and wound healing. Additionally, the development of specific guidelines and quality control methods that ultimately result in the therapeutic application of MSCs has been made easier by recent advancements in the study of MSC biology. This review discusses the latest clinical uses of MSCs obtained from the umbilical cord (UC), bone marrow (BM), or adipose tissue (AT) in treating various human diseases such as pulmonary dysfunctions, neurological disorders, endocrine/metabolic diseases, skin burns, cardiovascular conditions, and reproductive disorders. Additionally, this review offers comprehensive information regarding the clinical application of targeted therapies utilizing MSCs. It also presents and examines the concept of MSC tissue origin and its potential impact on the function of MSCs in downstream applications. The ultimate aim of this research is to facilitate translational research into clinical applications in regenerative therapies.
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Affiliation(s)
- Song Zhidu
- Department of Ophthalmology, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun City, Jilin Province, China
| | - Tao Ying
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jiang Rui
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhang Chao
- Department of Ophthalmology, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun City, Jilin Province, China.
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Nahar A, Jain S, Paul S. Advances in Cerebral Palsy Treatment. RECENT PATENTS ON ENGINEERING 2024; 18. [DOI: 10.2174/1872212118666230822124440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 07/06/2023] [Accepted: 07/11/2023] [Indexed: 01/05/2025]
Abstract
Background:Cerebral palsy is a complex neurodevelopmental disorder with various etiological factors and treatment options. This narrative review aimed to summarize the causes of cerebral palsy, identify areas needing additional research in treatment approaches, and highlight areas requiring further investigation. In order to provide a thorough overview of management techniques to lessen the effects of the illness and its consequences, this review has drawn data from a number of studies.Introduction:Prematurity increases the risk of brain damage during the developing stage and accounts for a sizable fraction of cerebral palsy cases. In a sizable portion of cases, maternal diabetes and hypertension are listed as the main causes. Damage to the brain tissue results from hypoxic-ischemic injuries sustained during pregnancy that upset the equilibrium of oxidants and antioxidants. To alter the oxidative stress pathway and ease related issues, pharmacological treatments, such as therapeutic hypothermia, free radical inhibition therapy, and mitochondrial therapy, have been proposed. Therapeutic strategies, such as physiotherapy, occupational therapy, speech therapy, and surgical interventions, have added quality to the lives of the children. Some of the most recent developments in this area include the development of biomarkers for muscle activity detection, machine learning to predict the types of cerebral palsy and abnormal movements, disease prediction with eye images, wireless inertia measuring unit for spasticity detection, computerbased video analysis of typical and atypical infants, identification of intellectual disabilities with algorithms, and deep learning methods for predicting cerebral palsy.Methods:This narrative review is based on a careful analysis of numerous researches conducted on cerebral palsy, which have served as the basis for statistical distribution. It reviews the causes of cerebral palsy, available treatments, and ongoing research with the goal of providing physicians and researchers in the field with useful information. The objectives, study questions, inclusion criteria, and search approach have all been outlined in a thorough protocol. To find pertinent research published up to September 2021, a literature search was carried out using electronic databases, including Google Scholar, PubMed, Cochrane Library, Scopus, and Web of Science. A combination of pertinent keywords, such as "cerebral palsy," "management," "technology," "wearable technology," "prematurity," and "artificial intelligence," has been used in the search approach.Results:Recent advances in the field include the discovery of biomarkers for the detection of muscle activity, machine learning algorithms to predict the types of cerebral palsy and abnormal movements, disease prediction using eye images, wireless inertia measuring units for the detection of spasticity, computer-based video analysis for the detection of atypical infants, and algorithms to identify intellectual disabilities. Additionally, employing technologies, like virtual reality systems, electrical stimulators, activity trackers, machine learning, and deep learning approaches, has shown promise in evaluating, diagnosing, and predicting treatment outcomes linked to gait, upper limb, and lower limb function.Conclusion:Future research should examine the clinical application of nanomedicine, stem cell therapy, and cutting-edge therapeutic strategies to prevent hypoxic-ischemic damage in the developing brain. Additionally, research is required to effectively assist children with severe speech difficulties using alternate communication modalities and cutting-edge computational tools. The outcomes for people with cerebral palsy can be improved by combining interdisciplinary efforts with cutting-edge technological interventions.
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Affiliation(s)
- Anjuman Nahar
- Department of Biomedical Engineering, North-Eastern Hill University, Shillong, India
| | - Shruti Jain
- Department of ECE, Jaypee University of Information Technology, Solan, Himachal Pradesh, India
| | - Sudip Paul
- Department of Biomedical Engineering, North-Eastern Hill University, Shillong, India
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Chrościńska-Kawczyk M, Zdolińska-Malinowska I, Boruczkowski D. The Impact of Umbilical Cord Mesenchymal Stem Cells on Motor Function in Children with Cerebral Palsy: Results of a Real-world, Compassionate use Study. Stem Cell Rev Rep 2024; 20:1636-1649. [PMID: 38877284 DOI: 10.1007/s12015-024-10742-2] [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] [Accepted: 05/27/2024] [Indexed: 06/16/2024]
Abstract
The aim of this study was to analyze the impact of human umbilical cord-derived MSCs (hUC-MSCs) on motor function in children with cerebral palsy (CP). The study enrolled 152 children with CP who received up to two courses of five hUC-MSCs injections. Children's motor functions were assessed with the Gross Motor Function Measure (GMFM), 6-Minute Walk Test (6-MWT), Timed Up and Go test (Up&Go test), and Lovett's test, and mental abilities were assessed with the Clinical Global Impression (CGI) scale. Data collected at visit 1 (baseline) and visit 5 (after four injections) were analyzed retrospectively. After four hUC-MSCs administrations, all evaluated parameters improved. The change in GMFM score, by a median of 1.9 points (IQR: 0.0-8.0), correlated with age. This change was observed in all GFMCS groups and was noticed in all assessed GMFM areas. A median increase of 75 m (IQR: 20.0-115.0) was noted on the 6-MWT, and this correlated with GMFM score change. Time on the Up&Go test was reduced by a median of 2 s (IQR: -3 to - 1) and the change correlated with age, GMFM score at baseline, and the difference observed on the 6-MWT. Results of Lovett's test indicated slight changes in muscle strength. According to the CGI, 75.5% (96/151) of children were seriously (level VI) or significantly ill (level V) at the 1st visit, with any improvement observed in 63.6% (96/151) of patients at the 5th visit, 23.8% (36/151) with improvement (level II) or great improvement (level I). In conclusion, the application of hUC-MSCs generally enhanced functional performance, but individual responses varied. The therapy also benefited children with high level of disability but not to the same extent as the initially less disabled children. Although younger patients responded better to the treatment, older children can also benefit. Trial Registration 152/2018/KB/VII and 119/2021/KB/VIII. Retrospective registration in ClinicalTrials: ongoing.
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Xiao QX, Geng MJ, Sun YF, Pi Y, Xiong LL. Stem Cell Therapy in Neonatal Hypoxic-Ischemic Encephalopathy and Cerebral Palsy: a Bibliometric Analysis and New Strategy. Mol Neurobiol 2024; 61:4538-4564. [PMID: 38102517 DOI: 10.1007/s12035-023-03848-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 11/15/2023] [Indexed: 12/17/2023]
Abstract
The aim of this study was to identify related scientific outputs and emerging topics of stem cells in neonatal hypoxic-ischemic encephalopathy (NHIE) and cerebral palsy (CP) through bibliometrics and literature review. All relevant publications on stem cell therapy for NHIE and CP were screened from websites and analyzed research trends. VOSviewer and CiteSpace were applied to visualize and quantitatively analyze the published literature to provide objective presentation and prediction. In addition, the clinical trials, published articles, and projects of the National Natural Science Foundation of China associated with stem cell therapy for NHIE and CP were summarized. A total of 294 publications were associated with stem cell therapy for NHIE and CP. Most publications and citations came from the USA and China. Monash University and University Medical Center Utrecht produced the most publications. Pediatric research published the most studies on stem cell therapy for NHIE and CP. Heijnen C and Kavelaars A published the most articles. Cluster analyses show that current research trend is more inclined toward the repair mechanism and clinical translation of stem cell therapy for NHIE and CP. By summarizing various studies of stem cells in NHIE and CP, it is indicated that this research direction is a hot topic at present. Furthermore, organoid transplantation, as an emerging and new therapeutic approach, brings new hope for the treatment of NHIE and CP. This study comprehensively summarized and analyzed the research trend of global stem cell therapy for NHIE and CP. It has shown a marked increase in stem cell therapy for NHIE and CP research. In the future, more efforts will be made on exploring stem cell or organoid therapy for NHIE and CP and more valuable related mechanisms of action to achieve clinical translation as soon as possible.
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Affiliation(s)
- Qiu-Xia Xiao
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Min-Jian Geng
- Department of Anesthesiology, Nanchong Central Hospital, Nanchong, 637000, Sichuan, China
| | - Yi-Fei Sun
- Institute of Neurological Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yu Pi
- Department of Anesthesiology, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Liu-Lin Xiong
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China.
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Boyalı O, Kabatas S, Civelek E, Ozdemir O, Bahar-Ozdemir Y, Kaplan N, Savrunlu EC, Karaöz E. Allogeneic mesenchymal stem cells may be a viable treatment modality in cerebral palsy. World J Clin Cases 2024; 12:1585-1596. [PMID: 38576742 PMCID: PMC10989435 DOI: 10.12998/wjcc.v12.i9.1585] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/11/2024] [Accepted: 02/28/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Cerebral palsy (CP) describes a group of disorders affecting movement, balance, and posture. Disturbances in motor functions constitute the main body of CP symptoms. These symptoms surface in early childhood and patients are affected for the rest of their lives. Currently, treatment involves various pharmacotherapies for different types of CP, including antiepileptics for epilepsy and Botox A for focal spasticity. However, none of these methods can provide full symptom relief. This has prompted researchers to look for new treatment modalities, one of which is mesenchymal stem cell therapy (MSCT). Despite being a promising tool and offering a wide array of possibilities, mesenchymal stem cells (MSCs) still need to be investigated for their efficacy and safety. AIM To analyze the efficacy and safety of MSCT in CP patients. METHODS Our sample consists of four CP patients who cannot stand or walk without external support. All of these cases received allogeneic MSCT six times as 1 × 106/kg intrathecally, intravenously, and intramuscularly using umbilical cord-derived MSCs (UC-MSC). We monitored and assessed the patients pre- and post-treatment using the Wee Functional Independence Measure (WeeFIM), Gross Motor Function Classification System (GMFCS), and Manual Ability Classification Scale (MACS) instruments. We utilized the Modified Ashworth Scale (MAS) to measure spasticity. RESULTS We found significant improvements in MAS scores after the intervention on both sides. Two months: Right χ2 = 4000, P = 0.046, left χ2 = 4000, P = 0.046; four months: Right χ2 = 4000, P = 0.046, left χ2 = 4000, P = 0.046; 12 months: Right χ2 = 4000, P = 0.046, left χ2 = 4000, P = 0.046. However, there was no significant difference in motor functions based on WeeFIM results (P > 0.05). GMFCS and MACS scores differed significantly at 12 months after the intervention (P = 0.046, P = 0.046). Finally, there was no significant change in cognitive functions (P > 0.05). CONCLUSION In light of our findings, we believe that UC-MSC therapy has a positive effect on spasticity, and it partially improves motor functions.
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Affiliation(s)
- Osman Boyalı
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Turkey
| | - Serdar Kabatas
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Turkey
- Center for Stem Cell & Gene Therapy Research and Practice, University of Health Sciences Turkey, Istanbul 34360, Turkey
| | - Erdinç Civelek
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Turkey
| | - Omer Ozdemir
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Istanbul 34360, Turkey
| | - Yeliz Bahar-Ozdemir
- Department of Physical Medicine and Rehabilitation, Health Sciences University Sultan Abdulhamid Han Training and Research Hospital, Istanbul 34668, Turkey
| | - Necati Kaplan
- Department of Neurosurgery, Istanbul Rumeli University, Çorlu Reyap Hospital, Tekirdağ 59860, Turkey
| | - Eyüp Can Savrunlu
- Department of Neurosurgery, Nevşehir State Hospital, Nevşehir 50300, Turkey
| | - Erdal Karaöz
- Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell), Liv Hospital, Istanbul 34340, Turkey
- Department of Histology and Embryology, Istinye University, Faculty of Medicine, İstanbul 34010, Turkey
- Center for Stem Cell and Tissue Engineering Research and Practice, Istinye University, Istanbul 34340, Turkey
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Huang L, Zou J, Zhang Y, Gu J, Wu J, Zhang C. Human umbilical cord mesenchymal stem cell therapy for renal dysfunction in Alport syndrome: protocol for an open-label, single-arm trial in China. BMJ Open 2024; 14:e075138. [PMID: 38490657 PMCID: PMC10946359 DOI: 10.1136/bmjopen-2023-075138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 02/01/2024] [Indexed: 03/17/2024] Open
Abstract
INTRODUCTION Alport syndrome (AS) is one of the most common fatal hereditary renal diseases in human, with a high risk of progressing to end-stage renal disease without effective treatments. Mesenchymal stem cells (MSCs) have recently emerged as a promising therapeutic strategy for chronic kidney disease. However, the safety and therapeutic potential of MSC transfusion for patients with AS are still need to be confirmed. Therefore, we have designed a clinical trial to evaluate the hypothesis that intravenous infusion of human umbilical cord-derived MSC (hUC-MSC) is safe, feasible, and well-tolerated in children with AS. METHODS AND ANALYSIS We report the protocol of the first prospective, open-label, single-arm clinical trial to evaluate the safety and preliminary efficacy of hUC-MSC transfusion in children with early-stage AS. Paediatric patients diagnosed with AS who have persistent albuminuria will be candidates for screening. Twelve eligible patients are planned to recruit and will receive hUC-MSC infusions under close safety monitoring, and complete the efficacy assessments at scheduled follow-up visits. The primary endpoints include the occurrence of adverse events to assess safety and the albuminuria level for efficacy evaluation. Secondary endpoint assessments are based on haematuria and glomerular filtration measurements. Each patient's efficacy endpoints will be evaluated against their baseline levels. Additionally, the underlying mechanism of hUC-MSC therapy will be explored through transcriptomic and proteomic analysis of blood and urine samples. ETHICS AND DISSEMINATION The protocol (V.1.0, date 17 January 2015) was approved by the institutional review board of the Affiliated Taihe Hospital of Hubei University of Medicine (ethical approval 03 March 2015). Written informed consent will be obtained from the patient and/or guardians before study specific process. In addition to publication in a peer-reviewed scientific journal, a lay summary of study will be available for participants and the public on the Chinese Organization for Rare Disorders website (http://www.cord.org.cn/). TRIAL REGISTRATION NUMBER ISRCTN62094626.
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Affiliation(s)
- Li Huang
- Department of Pharmacy, Shenzhen Second People's Hospital, Shenzhen, Guangdong, China
| | - Jun Zou
- Hainan Women and Children's Medical Center, Haikou, Hainan, China
| | | | | | - Jianlong Wu
- Department of Pharmacy, Shenzhen Second People's Hospital, Shenzhen, Guangdong, China
| | - Che Zhang
- Department of Pharmacy, South China Hospital, Medical School, Shenzhen University, Shenzhen, Guangdong, China
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Li X, Li M, Qin X, Li Y, Wang Y, Han C, Ni S, Sun X, Dong P, Liu J. Providing holistic care to children with cerebral palsy treated with transnasal neural stem cell transplantation. Front Pediatr 2024; 11:1297563. [PMID: 38250587 PMCID: PMC10796742 DOI: 10.3389/fped.2023.1297563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/14/2023] [Indexed: 01/23/2024] Open
Abstract
Objective Holistic care is a key element in nursing care. Aiming at the heterogeneous disease of cerebral palsy, researchers focused on children with cerebral palsy who received transnasal transplantation of neural stem cells as a specific group. Based on establishing a multidisciplinary team, comprehensive care is carried out for this type of patient during the perioperative period to improve the effectiveness and safety of clinical research and increase the comfort of children. Methods Between January 2018 and June 2023, 22 children with cerebral palsy underwent three transnasal transplants of neural stem cells. Results No adverse reactions related to immune rejection were observed in the 22 children during hospitalization and follow-up. All children tolerated the treatment well, and the treatment was superior. One child developed nausea and vomiting after sedation; three had a small amount of bleeding of nasal mucosa after transplantation. Two children had a low fever (≤38.5°C), and one had a change in the type and frequency of complex partial seizures. Moreover, 3 children experienced patch shedding within 4 h of patch implantation into the nasal cavity. Conclusion The project team adopted nasal stem cell transplantation technology. Based on the characteristics of transnasal transplantation of neural stem cells in the treatment of neurological diseases in children, a comprehensive and novel holistic care plan is proposed. It is of great significance to guide caregivers of children to complete proper care, further improve the safety and effectiveness of treatment, and reduce the occurrence of complications.
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Affiliation(s)
- Xiaoyan Li
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
- Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning Province, China
| | - Mengyao Li
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Xixian Qin
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Ying Li
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
- Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning Province, China
| | - Yachen Wang
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
- Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning Province, China
| | - Chao Han
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
- Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning Province, China
| | - Shiwei Ni
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
- Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning Province, China
| | - Xuna Sun
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Peipei Dong
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Jing Liu
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
- Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning Province, China
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Laue J, Ambühl J, Surbek D. Hybrid umbilical cord blood banking: literature review. Arch Gynecol Obstet 2024; 309:93-104. [PMID: 37093267 PMCID: PMC10124678 DOI: 10.1007/s00404-023-07003-x] [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: 01/24/2023] [Accepted: 03/03/2023] [Indexed: 04/25/2023]
Abstract
PURPOSE Interest gaps between public and private umbilical cord blood banks have led to the introduction of hybrid banking options. Hybrid models combine features of private and public banks as well as interests of parents, children and of patients, in order to find an optimized solution. While several different models of hybrid banks exist, there is a lack of literature about this novel model of cord blood stem cell banking. Therefore, the aim of this literature review is to assess different options of umbilical cord blood banking and whether hybrid banking could be a valuable alternative to the existing public and private cord blood banking models. METHODS We performed a systematic literature search, using five main databases. Five hybrid models regarding their advantages as well as their challenges are discussed in this review. RESULTS We found that a wealth of literature exists about public cord blood banking, while private and hybrid banking are understudied. Different modalities of hybrid cord blood banking are being described in several publications, providing the basis to assess different advantages and disadvantages as well as practicability. CONCLUSION Hybrid banks, especially the sequential model, seem to have potential as an alternative to the existing banking models worldwide. A previously conducted survey among pregnant women showed a preference for hybrid banking, if such an option was available. Nevertheless, opinions among stakeholders differ and more research is needed to evaluate, if hybrid banking provides the expected benefits.
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Affiliation(s)
- Jessica Laue
- Department of Obstetrics and Gynecology, University Hospital of Bern, University of Bern, Friedbühlstrasse 19, 3010, Bern, Switzerland.
| | - Johanna Ambühl
- Department of Obstetrics and Gynecology, University Hospital of Bern, University of Bern, Friedbühlstrasse 19, 3010, Bern, Switzerland
| | - Daniel Surbek
- Department of Obstetrics and Gynecology, University Hospital of Bern, University of Bern, Friedbühlstrasse 19, 3010, Bern, Switzerland
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Suh MR, Min K, Cho KH, Kim J, Lim I, Park M, Noh EM, Kim MY. Maintenance of the synergistic effects of cord blood cells and erythropoietin combination therapy after additional cord blood infusion in children with cerebral palsy: 1-year open-label extension study of randomized placebo-controlled trial. Stem Cell Res Ther 2023; 14:362. [PMID: 38087394 PMCID: PMC10717973 DOI: 10.1186/s13287-023-03600-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 12/05/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND This 1-year open-label extension study aimed to identify the persistent synergistic effects of allogeneic umbilical cord blood (UCB) cells and erythropoietin (EPO) in children with cerebral palsy (CP) for up to 2 years. METHODS This open-label extension study followed children with CP who were enrolled in the previous randomized, double blind, placebo-controlled trial. The following groups from the first trial were maintained: (A) UCB + EPO, (B) UCB, (C) EPO, and (D) only placebo, and all the participants had continued active rehabilitation. This extended study started 3 months after termination of the first trial, which had a 1-year follow-up duration. All subjects received single additional UCB intravenous infusion at the extension baseline regardless of their initial allocation. Outcome measures were the gross motor performance measure (GMPM), gross motor function measure-66 (GMFM-66), and Bayley scales of infant development-II (BSID-II), which were followed at 3, 6, and 12 months after the extension baseline. Changes in the outcome scores from the baseline values of the previous trial and this study were analysed. RESULTS Sixty-nine children (4.29 ± 1.28 years, M:F = 34:35) were included in this study. Each group showed improvements in the outcome measures at 12 months after additional UCB infusion compared to the baseline scores, except for GMFM and GMPM in Group C which were elevated at 3 and 6 months post-therapy. Total subject analyses did not show significant differences in the outcome measures between the four different groups at 3, 6 and 12 months after additional UCB therapy. However, patients with severe dysfunction, whose GMFCS levels were IV and V, revealed a larger improvement of the GMPM score in Group A than in Group D (Ps < 0.05) from the baseline value of the previous trial. The changes in BSID-II mental scale scores were positively correlated with the number of administered total nucleated cells per unit body weight during this one-year extension study period (r = 0.536, P = 0.001). CONCLUSIONS These results suggest that when administering UCB to treat patients with CP, combination therapy with EPO is more effective, and the effect might last as long as 2 years, especially in patients with severe impairments. TRIAL REGISTRATION CHA Bundang Medical Center IRB, No. 2015-06-093, approved on July 29, 2015, ( https://www.e-irb.com:3443/devlpg/nlpgS200.jsp ), ClinicalTrials.gov, NCT03130816, retrospectively registered on April 27, 2017 ( https://clinicaltrials.gov/ct2/show/NCT03130816?term=NCT03130816&draw=2&rank=1 ).
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Affiliation(s)
- Mi Ri Suh
- Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-Ro, Bundang-Gu, Seongnam, Gyeonggi-Do, Republic of Korea
- Rehabilitation and Regeneration Research Center, CHA University, Pocheon, Republic of Korea
| | - Kyunghoon Min
- Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-Ro, Bundang-Gu, Seongnam, Gyeonggi-Do, Republic of Korea
- Rehabilitation and Regeneration Research Center, CHA University, Pocheon, Republic of Korea
| | - Kye Hee Cho
- Rehabilitation and Regeneration Research Center, CHA University, Pocheon, Republic of Korea
- Department of Rehabilitation Medicine, CHA Ilsan Medical Center, CHA University School of Medicine, Goyang, Republic of Korea
| | - Jongwook Kim
- Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-Ro, Bundang-Gu, Seongnam, Gyeonggi-Do, Republic of Korea
- Rehabilitation and Regeneration Research Center, CHA University, Pocheon, Republic of Korea
| | - Ikhyun Lim
- Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-Ro, Bundang-Gu, Seongnam, Gyeonggi-Do, Republic of Korea
- Rehabilitation and Regeneration Research Center, CHA University, Pocheon, Republic of Korea
| | - Mijin Park
- Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-Ro, Bundang-Gu, Seongnam, Gyeonggi-Do, Republic of Korea
| | - Eun-Min Noh
- Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-Ro, Bundang-Gu, Seongnam, Gyeonggi-Do, Republic of Korea
| | - Min Young Kim
- Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-Ro, Bundang-Gu, Seongnam, Gyeonggi-Do, Republic of Korea.
- Rehabilitation and Regeneration Research Center, CHA University, Pocheon, Republic of Korea.
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Huang S, Liu L, Huang Y, Fu C, Peng T, Yang X, Zhou H, Zhao Y, Xu Y, Zeng X, Zeng P, Tang H, He L, Xu K. Potential optimized route for mesenchymal stem cell transplantation in a rat model of cerebral palsy. Exp Cell Res 2023; 430:113734. [PMID: 37532123 DOI: 10.1016/j.yexcr.2023.113734] [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: 03/14/2023] [Revised: 07/04/2023] [Accepted: 07/26/2023] [Indexed: 08/04/2023]
Abstract
Cerebral palsy (CP) is a movement and posture disorder that affects over 50 million people worldwide. Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation has emerged as an attractive therapeutic strategy for CP. The administration route appears to be crucial for hUC-MSC to provide adequate neuroprotection. Wistar rats were given hypoxia-ischemia to make the CP model on postnatal day 5. On postnatal day 21, DiR-labeled hUC-MSC were transplanted into the CP rats by intravenous, intrathecal, and lateral ventricle for cell tracking. Uninfused CP rats served as the negative control. The motor behavioral and pathological alteration was analyzed 11, 25, and 39 days after transplantation to assess motor function, immune inflammation, neurotrophy, and endogenous repair. In vivo imaging tracking techniques revealed that intravenous infusion resulted in fewer transplanted cells in the target brain than intrathecal and lateral ventricle infusion (p＜0.05). Three different routes of hUC-MSC infusion improved the motor function of CP rats (p＜0.05). At 11 days post-infusion, intrathecal infusion outperformed intravenous with a significant neurotrophic and oligodendrocyte maturation effect (p＜0.05). Intrathecal infusion equaled lateral ventricle infusion after 25 days. At 39 days post-infusion, lateral ventricle infusion exceeded intravenous and intrathecal infusion with a significant immunosuppressive effect (p＜0.05). Considering the improved effect and less trauma shown early in the intrathecal infusion, repeated intrathecal administration may ultimately lead to the greatest benefit.
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Affiliation(s)
- Shiya Huang
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China; School of Exercise and Health, Shanghai University of Sport, Shanghai, 200438, China
| | - Liru Liu
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China
| | - Yuan Huang
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China; School of Medicine, South China University of Technology, Guangzhou, 510655, China
| | - Chaoqiong Fu
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China; School of Exercise and Health, Shanghai University of Sport, Shanghai, 200438, China
| | - Tingting Peng
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China
| | - Xubo Yang
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China
| | - Hongyu Zhou
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China
| | - Yiting Zhao
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China
| | - Yi Xu
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China
| | - Xiaoli Zeng
- Guangdong Xiangxue Stem Cell Regenerative Medicine Technology Co., Ltd, Guangzhou, 510120, China
| | - Peishan Zeng
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China
| | - Hongmei Tang
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China
| | - Lu He
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China.
| | - Kaishou Xu
- Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China; Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510120, China.
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Chen D, Huang H, Saberi H, Sharma HS. Positive and negative cell therapy in randomized control trials for central nervous system diseases. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 171:241-254. [PMID: 37783557 DOI: 10.1016/bs.irn.2023.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
Abstract
Neurorestorative cell therapies have been tested to treat patients with nervous system diseases for over 20 years. Now it is still hard to answer which kinds of cells can really play a role on improving these patients' quality of life. Non-randomized clinical trials or studies could not provide strong evidences in answering this critical question. In this review, we summarized randomized clinical trials of cell therapies for central nervous diseases, such as stroke, spinal cord injury, cerebral palsy (CP), Parkinson's disease (PD), multiple sclerosis (MS), brain trauma, amyotrophic lateral sclerosis (ALS), etc. Most kinds of cell therapies demonstrated negative results for stoke, brain trauma and amyotrophic lateral sclerosis. A few kinds of cell therapies showed neurorestorative effects in this level of evidence-based medicine, such as olfactory ensheating cells for chronic ischemic stroke. Some kinds of cells showed positive or negative effects from different teams in the same or different diseases. We analyzed the possible failed reasons of negative results and the cellular bio-propriety basis of positive results. Based on therapeutic results of randomized control trials and reasonable analysis, we recommend: (1) to further conduct trials for successful cell therapies with positive results to increase neurorestorative effects; (2) to avoid in repeating failed cell therapies with negative results in same diseases because it is nonsense for them to be done with similar treatment methods, such as cell dosage, transplanting way, time of window, etc. Furthermore, we strongly suggest not to do non-randomized clinical trials for cells that had shown negative results in randomized clinical trials.
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Affiliation(s)
- Di Chen
- Beijing Hongtianji Neuroscience Academy, Beijing, P.R. China
| | - Hongyun Huang
- Beijing Hongtianji Neuroscience Academy, Beijing, P.R. China.
| | - Hooshang Saberi
- Department of Neurosurgery, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Dept. of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
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Yang S, Chen S, Zhang C, Han J, Lin C, Zhao X, Guo H, Tan Y. Enhanced therapeutic effects of mesenchymal stem cell-derived extracellular vesicles within chitosan hydrogel in the treatment of diabetic foot ulcers. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2023; 34:43. [PMID: 37639051 PMCID: PMC10462522 DOI: 10.1007/s10856-023-06746-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/09/2023] [Indexed: 08/29/2023]
Abstract
Extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) have emerged as promising candidates for cell-free therapy in various diseases, including chronic cutaneous wounds. However, the lack of standardized protocols for EVs' preparation and identification poses a significant challenge to their clinical application. Thus, the objective was to develop a safe and efficient method for the large-scale production of hUCMSC-derived EVs while establishing a comprehensive identification protocol encompassing morphology, particle size distribution, protein expression, and purity. This study observed that most of the EVs acquired through the protocol exhibited either a cup-shaped or round-shaped structure, with a median diameter of ~73.25 nm. The proportions of EVs positive for CD9, CD63, and CD81 were 37.5%, 38.6%, and 19.8%, respectively. To enhance their therapeutic potential in wound treatment, EVs were incorporated into chitosan hydrogel, forming chitosan hydrogel-EVs (CS-EVs). Furthermore, it was demonstrated that CS-EVs exhibited continuous release of EVs into the surrounding environment and, importantly, that the released EVs were internalized by human umbilical vein endothelial cells (HUVECs), resulting in significant enhancement of cell migration and angiogenesis. Additionally, in a rat model of diabetic foot ulcers, CS-EVs demonstrated a robust therapeutic effect in promoting wound healing. Following a 15-day treatment period, the group treated with CS-EVs demonstrated an impressive 93.3% wound closure ability, accompanied by a high degree of re-epithelialization. In contrast, the control group exhibited only a 71.5% reduction in wound size. In summary, this study offers solutions for the purification, characterization, and application of EVs in clinical wound treatment. These results not only offer fresh perspectives on the involvement of hUCMSC-derived EVs in wound healing but also introduce a non-invasive approach for applying EVs that holds practical significance in skin repair.
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Affiliation(s)
- Shuangshuang Yang
- Qilu Cell Therapy Technology Co., Ltd, No.1758 Gangyuan Six Road, Ji'nan, Shandong, China
| | - Siyu Chen
- Qilu Cell Therapy Technology Co., Ltd, No.1758 Gangyuan Six Road, Ji'nan, Shandong, China
| | - Chengpeng Zhang
- Qilu Cell Therapy Technology Co., Ltd, No.1758 Gangyuan Six Road, Ji'nan, Shandong, China
| | - Jing Han
- Qilu Cell Therapy Technology Co., Ltd, No.1758 Gangyuan Six Road, Ji'nan, Shandong, China
| | - Chunyuan Lin
- Qilu Cell Therapy Technology Co., Ltd, No.1758 Gangyuan Six Road, Ji'nan, Shandong, China
| | - Xiaohui Zhao
- Qilu Cell Therapy Technology Co., Ltd, No.1758 Gangyuan Six Road, Ji'nan, Shandong, China
| | - Huizhen Guo
- Qilu Cell Therapy Technology Co., Ltd, No.1758 Gangyuan Six Road, Ji'nan, Shandong, China
| | - Yi Tan
- Qilu Cell Therapy Technology Co., Ltd, No.1758 Gangyuan Six Road, Ji'nan, Shandong, China.
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Lian XF, Lu DH, Liu HL, Liu YJ, Yang Y, Lin Y, Xie F, Huang CH, Wu HM, Long AM, Hui CJ, Shi Y, Chen Y, Gao YF, Zhang F. Safety evaluation of human umbilical cord-mesenchymal stem cells in type 2 diabetes mellitus treatment: A phase 2 clinical trial. World J Clin Cases 2023; 11:5083-5096. [PMID: 37583846 PMCID: PMC10424020 DOI: 10.12998/wjcc.v11.i21.5083] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/23/2023] [Accepted: 06/16/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Progressive pancreatic β cell dysfunction is a fundamental aspect of the pathology underlying type 2 diabetes mellitus (T2DM). Recently, mesenchymal stem cell (MSC) transplantation has emerged as a new therapeutic method due to its ability to promote the regeneration of pancreatic β cells. However, current studies have focused on its efficacy, and there are few clinical studies on its safety. AIM To evaluate the safety of human umbilical cord (hUC)-MSC infusion in T2DM treatment. METHODS An open-label and randomized phase 2 clinical trial was designed to evaluate the safety of hUC-MSC transplantation in T2DM in a Class A hospital. Ten patients in the placebo group received acellular saline intravenously once per week for 3 wk. Twenty-four patients in the hUC-MSC group received hUC-MSCs (1 × 106 cells/kg) intravenously once per week for 3 wk. Diabetic clinical symptoms and signs, laboratory findings, and imaging findings were evaluated weekly for the 1st mo and then at weeks 12 and 24 post-treatment. RESULTS No serious adverse events were observed during the 24-wk follow-up. Four patients (16.7%) in the hUC-MSC group experienced transient fever, which occurred within 24 h after the second or third infusion; this did not occur in any patients in the placebo group. One patient from the hUC-MSC group experienced hypoglycemic attacks within 1 mo after transplantation. Significantly lower lymphocyte levels (weeks 2 and 3) and thrombin coagulation time (week 2) were observed in the hUC-MSC group compared to those in the placebo group (all P < 0.05). Significantly higher platelet levels (week 3), immunoglobulin levels (weeks 1, 2, 3, and 4), fibrinogen levels (weeks 2 and 3), D-dimer levels (weeks 1, 2, 3, 4, 12, and 24), and neutrophil-to-lymphocyte ratios (weeks 2 and 3) were observed in the hUC-MSC group compared to those in the placebo group (all P < 0.05). There were no significant differences between the two groups for tumor markers (alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 199) or blood fat. No liver damage or other side effects were observed on chest X-ray. CONCLUSION Our study suggested that hUC-MSC transplantation has good tolerance and high safety in the treatment of T2DM. It can improve human immunity and inhibit lymphocytes. Coagulation function should be monitored vigilantly for abnormalities.
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Affiliation(s)
- Xiao-Fen Lian
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Dong-Hui Lu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Hong-Li Liu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yan-Jing Liu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yang Yang
- Department of Endocrinology, Huizhou Central People’s Hospital, Huizhou 516000, Guangdong Province, China
| | - Yuan Lin
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Feng Xie
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Cai-Hao Huang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Hong-Mei Wu
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Ai-Mei Long
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Chen-Jun Hui
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yu Shi
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yun Chen
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yun-Feng Gao
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Fan Zhang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
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Zhangdi H, Jiang Y, Gao Y, Li S, Xu R, Shao J, Liu J, Hu Y, Zhang X, Zhang X, Zhao L, Qi J, Geng X, Jin S. From Phenomenon to Essence: A Newly Involved lncRNA Kcnq1ot1 Protective Mechanism of Bone Marrow Mesenchymal Stromal Cells in Liver Cirrhosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2206758. [PMID: 37282819 PMCID: PMC10375186 DOI: 10.1002/advs.202206758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 05/18/2023] [Indexed: 06/08/2023]
Abstract
Bone marrow mesenchymal stromal cells (BMSCs) have a protective effect against liver cirrhosis. Long noncoding RNAs (lncRNAs) play crucial roles in the progression of liver cirrhosis. Therefore, it is aimed to clarify the lncRNA Kcnq1ot1 involved protective mechanism of BMSCs in liver cirrhosis. This study found that BMSCs treatment attenuates CCl4 -induced liver cirrhosis in mice. Additionally, the expression of lncRNA Kcnq1ot1 is upregulated in human and mouse liver cirrhosis tissues, in addition to TGF-β1-treated LX2 cells and JS1 cells. The expression of Kcnq1ot1 in liver cirrhosis is reversed with BMSCs treatment. The knockdown of Kcnq1ot1 alleviated liver cirrhosis both in vivo and in vitro. Fluorescence in situ hybridization (FISH) confirms that Kcnq1ot1 is mainly distributed in the cytoplasm of JS1 cells. It is predicted that miR-374-3p can directly bind with lncRNA Kcnq1ot1 and Fstl1, which is verified via luciferase activity assay. The inhibition of miR-374-3p or the overexpression of Fstl1 can attenuate the effect of Kcnq1ot1 knockdown. In addition, the transcription factor Creb3l1 is upregulated during JS1 cells activation. Moreover, Creb3l1 can directly bind to the Kcnq1ot1 promoter and positively regulate its transcription. In conclusion, BMSCs alleviate liver cirrhosis by modulating the Creb3l1/lncRNA Kcnq1ot1/miR-374-3p/Fstl1 signaling pathway.
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Affiliation(s)
- Hanjing Zhangdi
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Yanan Jiang
- Department of Pharmacology (State‐Province Key Laboratories of Biomedicine‐Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education)College of PharmacyHarbin Medical UniversityHarbin150081China
- Translational Medicine Research and Cooperation Center of Northern ChinaHeilongjiang Academy of Medical SciencesHarbin150081China
| | - Yang Gao
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Shuang Li
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Ruiling Xu
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Jing Shao
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Jingyang Liu
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Ying Hu
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Xu Zhang
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Xiaoyu Zhang
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Lei Zhao
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Jihan Qi
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Xinyu Geng
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Shizhu Jin
- Department of Gastroenterology and HepatologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150001China
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20
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Shao J, Xia L, Ye Z, Yang Q, Zhang C, Shi Y, Zhang L, Gu L, Xu C, Chen Y, Chen Y, Pan X, Wu F, Pan R, Liang J, Zhang L. A repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in NOG mice by intravenous injection. Expert Opin Drug Metab Toxicol 2023; 19:857-866. [PMID: 37921457 DOI: 10.1080/17425255.2023.2279243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 10/28/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND Stem cell-based therapies have demonstrated great potential in several clinical trials. However, safety data on stem cell application remain inadequate. This study evaluated the toxicity of human umbilical cord mesenchymal stem cells (hUC-MSCs) in NOD/Shi-scid/IL-2 Rγnull (NOG) mice. RESEARCH DESIGN AND METHODS Mice were administered hUC-MSCs intravenously at doses of 3.5 × 106 cells/kg and 3.5 × 107 cells/kg. Toxicity was assessed by clinical observation, behavioral evaluation, pathology, organ weight, and histopathology. We determined the distribution of hUC-MSCs using a validated qPCR method and colonization using immunohistochemistry. RESULTS No significant abnormal effects on clinical responses, body weight, or food intake were observed in the mice, except for two in the high-dose group that died during the last administration. Mouse activity in the high-dose group decreased 6 h after the first administration. Terminal examination revealed dose-dependent changes in hematology. The mice in the high-dose group displayed pulmonary artery wall plaques and mild alveolar wall microthrombi. hUC-MSCs colonized primarily the lung tissues and were largely distributed there 24 h after the final administration. CONCLUSIONS The no observed adverse effect level for intravenous administration of hUC-MSCs in NOG mice over a period of 3 w was 3.5 × 106 cells/kg.
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Affiliation(s)
- Jinjin Shao
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
| | - Lijuan Xia
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
| | - Zhichao Ye
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
| | - Qian Yang
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
| | - Chengda Zhang
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
| | - Yuhua Shi
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
| | - Lili Zhang
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
| | - Liqiang Gu
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
| | - Cong Xu
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
| | - Ying Chen
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
| | - Yunxiang Chen
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
| | - Xin Pan
- Zhejiang Key Laboratory of Cell-Based Drug and Applied Technology Development, S-Evans Biosciences Co., Ltd, Hangzhou, China
| | - Feifei Wu
- Zhejiang Key Laboratory of Cell-Based Drug and Applied Technology Development, S-Evans Biosciences Co., Ltd, Hangzhou, China
| | - Ruolang Pan
- Zhejiang Key Laboratory of Cell-Based Drug and Applied Technology Development, S-Evans Biosciences Co., Ltd, Hangzhou, China
| | - Jinfeng Liang
- Zhejiang Center for Drugs and Cosmetics Evaluation, Zhejiang Province Food and Drug Administration, Hangzhou, China
| | - Lijiang Zhang
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College (Zhejiang Academy of Medical Sciences), Hangzhou, China
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El Sayed R, Shankar KM, Mankame AR, Cox CS. Innovations in cell therapy in pediatric diseases: a narrative review. Transl Pediatr 2023; 12:1239-1257. [PMID: 37427072 PMCID: PMC10326759 DOI: 10.21037/tp-23-92] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 05/25/2023] [Indexed: 07/11/2023] Open
Abstract
Background and Objective Stem cell therapy is a regenerative medicine modality that has the potential to decrease morbidity and mortality by promoting tissue regeneration or modulating the inflammatory response. An increase in the number of clinical trials investigating the efficacy and safety of stem cell therapy in pediatric diseases has led to advancements in this field. Currently, multiple sources and types of stem cells have been utilized in the treatment of pediatric diseases. This review aims to inform researchers and clinicians about preclinical and clinical stem cell therapy trials in pediatric patients. We discuss the different types of stem cells and the wide spectrum of stem cell therapy trials for pediatric diseases, with an emphasis on the outcomes and advancements in the field. Methods PubMed and clinicaltrials.gov databases were searched on October 28, 2022 using the following Medical Subject Headings (MeSH) terms "stem cell" or "stem cell therapy" with an age filter <18 years. Our search was limited to publications published between 2000 and 2022. Key Content and Findings Diverse sources of stem cells have different properties and mechanisms of action, which allow tailored application of stem cells according to the pathophysiology of the disease. Advancements in stem cell therapies for pediatric diseases have led to improvements in clinical outcomes in some pediatric diseases or in quality of life, such therapies represent a potential alternative to the current treatment modalities. Conclusions Stem cell therapy in pediatric diseases has shown promising results and outcomes. However, further studies focusing on the implementation and optimal treatment timeframe are needed. An increase in preclinical and clinical trials of stem cell therapy targeting pediatric patients is required to advance our therapeutic applications.
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Affiliation(s)
- Razan El Sayed
- Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Center for Translational Injury Research, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Karan Michael Shankar
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Atharwa Rajan Mankame
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Charles S. Cox
- Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Center for Translational Injury Research, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
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22
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Huang H, Ramon-Cueto A, El Masri W, Moviglia GA, Saberi H, Sharma HS, Otom A, Chen L, Siniscalco D, Sarnowska A. Advances in Neurorestoratology-Current status and future developments. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 171:207-239. [PMID: 37783556 DOI: 10.1016/bs.irn.2023.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
Abstract
Neurorestoratology constitutes a novel discipline aimed at the restoration of damaged neural structures and impaired neurological functions. This area of knowledge integrates and compiles all concepts and strategies dealing with the neurorestoration. Although currently, this discipline has already been well recognized by physicians and scientists throughout the world, this article aimed at broadening its knowledge to the academic circle and the public society. Here we shortly introduced why and how Neurorestoratology was born since the fact that the central nervous system (CNS) can be repaired and the subsequent scientific evidence of the neurorestorative mechanisms behind, such as neurostimulation or neuromodulation, neuroprotection, neuroplasticity, neurogenesis, neuroregeneration or axonal regeneration or sprouting, neuroreplacement, loop reconstruction, remyelination, immunoregulation, angiogenesis or revascularization, and others. The scope of this discipline is the improvement of therapeutic approaches for neurological diseases and the development of neurorestorative strategies through the comprehensive efforts of experts in the different areas and all articulated by the associations of Neurorestoratology and its journals. Strikingly, this article additionally explores the "state of art" of the Neurorestoratology field. This includes the development process of the discipline, the achievements and advances of novel neurorestorative treatments, the most efficient procedures exploring and evaluating outcome after the application of pioneer therapies, all the joining of a multidisciplinary expert associations and the specialized journals being more and more impact. We believe that in a near future, this discipline will evolve fast, leading to a general application of cell-based comprehensive neurorestorative treatments to fulfill functional recovery demands for patients with neurological deficits or dysfunctions.
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Affiliation(s)
- Hongyun Huang
- Beijing Hongtianji Neuroscience Academy, Beijing, P.R. China.
| | - Almudena Ramon-Cueto
- Health Center Colmenar Norte, Plaza de Los Ríos 1, Colmenar Viejo, Madrid, Spain
| | - Wagih El Masri
- Robert Jones & Agnes Hunt Orthopaedic Hospital, Spinal Injuries Keele University, Oswestry, United Kingdom
| | - Gustavo A Moviglia
- Wake Forest Institute for Regenerative Medicine. Winston Salem, NC, United States
| | - Hooshang Saberi
- Department of Neurosurgery, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Dept. of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Ali Otom
- Royal Specialty Center for Spine & M-Skeletal Disorders, Amman, Jordan
| | - Lin Chen
- Department of Neurosurgery, Dongzhimen Hospital of Beijing University of Traditional Chinese Medicine, Beijing, P.R. China
| | - Dario Siniscalco
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Anna Sarnowska
- Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland
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23
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Huang H, Sanberg PR, Moviglia GA, Sharma A, Chen L, Chen D. Clinical results of neurorestorative cell therapies and therapeutic indications according to cellular bio-proprieties. Regen Ther 2023; 23:52-59. [PMID: 37122360 PMCID: PMC10130496 DOI: 10.1016/j.reth.2023.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/09/2023] [Accepted: 03/21/2023] [Indexed: 05/02/2023] Open
Abstract
Cell therapies have been explored to treat patients with nervous diseases for over 20 years. Even though most kinds of cell therapies demonstrated neurorestorative effects in non-randomized clinical trials; the effects of the majority type cells could not be confirmed by randomized controlled trials. In this review, clinical therapeutic results of neurorestorative cell therapies according to cellular bio-proprieties or cellular functions were introduced. Currently it was demonstrated from analysis of this review that some indications of cell therapies were not appropriate, they might be reasons why their neurorestorative effects could not be proved by multicenter, randomized, double blind, placebo-controlled clinical trials. Theoretically if one kind of cell therapy has neurorestorative effects according to its cellular bio-proprieties, it should have appropriate indications. The cell therapies with special bio-properties is promising if the indication selections are appropriate, such as olfactory ensheathing cells for chronic ischemic stroke, and their neurorestorative effects can be confirmed by higher level clinical trials of evidence-based medicine.
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Affiliation(s)
- Hongyun Huang
- Beijing Hongtianji Neuroscience Academy, Beijing 100143, China
- Corresponding author.
| | - Paul R. Sanberg
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa 33612, Florida, USA
| | | | - Alok Sharma
- Department of Neurosurgery, LTM Medical College, LTMG Hospital, Mumbai, India
| | - Lin Chen
- Department of Neurosurgery, Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine, Beijing 100700, China
| | - Di Chen
- Beijing Hongtianji Neuroscience Academy, Beijing 100143, China
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Wang L, Zhang N, Fang L, Cui Z, Niu H, Lv F, Hu D, Wu D. Effect of hip CPM on gross motor function and development of the hip joint: a single-center randomized controlled study on spastic cerebral palsy children with hip dysplasia. Front Pediatr 2023; 11:1090919. [PMID: 37228431 PMCID: PMC10203473 DOI: 10.3389/fped.2023.1090919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 04/17/2023] [Indexed: 05/27/2023] Open
Abstract
Objective To investigate the effectiveness of hip continuous passive motion (hCPM) on hip development at skeletal maturity and gross motor function for spastic cerebral palsy children with hip dysplasia. Methods Prospective case-control research of hCPM with goal-directed training versus merely goal-directed training. On the basis of goal-directed training, the hCPM group used the hip joint CPM instrument (the external fixator was connected to the power device to make the hip joint carry out continuous passive movement) for 40-60 min, twice a day, and five times a week, and received continuous training for 8 weeks simultaneously. The control group received only goal-directed training for 8 weeks. Functional outcomes pertaining to the affected hip joints were assessed via gross motor function measure (GMFM), migration percentage (MP), acetabular index (AI), and Harris hip functional score (HHS) at the time of enrollment and the end of the intervention. Results The case-control research included 65 participants (mean age = 46.20 months, SD = 17.09 months; Gross Motor Function Grading System level: III = 41, IV = 24) who were randomly selected to either the hCPM (n = 45) or the control group (n = 20). No differences were found in baseline (acquisition phase) GMFM, MP, AI, or HHS (t = -1.720, P = 0.090; t* = 1.836, P* = 0.071; t# = -1.517, P# = 0.139; t* = -1.310, P* = 0.195; t# = -1.084, P# = 0.097; t = -1.041, P = 0.301). At the 8-week follow-up, GMFM, MP, AI, and HHS significantly improved over baseline in the hCPM group (hCPM group: t = 18.59, 20.172*, 40.291#, 16.820*, 32.900#, 28.081; P < 0.001). Between-group differences at 8-week follow-up times points favored the hCPM group for GMFM (t = -2.637, P = 0.011), MP (t* = 2.615, P* = 0.014; t# = 3.000, P# = 0.006), AI (t* = 2.055, P* = 0.044; t# = 2.223, P# = 0.030), HHS (t = -4.685, P < 0.001) (*: left side; #: right side). Conclusion Spastic cerebral palsy children with hip dysplasia achieved meaningful functional improvement after 8 weeks of goal-directed training with hCPM therapy.
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Affiliation(s)
- Lulu Wang
- Pediatric Neurological Rehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Nuochen Zhang
- Pediatric Neurological Rehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Liwei Fang
- Pediatric Neurological Rehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhenzhen Cui
- Pediatric Neurological Rehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Huihui Niu
- Pediatric Neurological Rehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fuli Lv
- Pediatric Neurological Rehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Dayong Hu
- Department of Pediatrics, Anhui Hefei Southeast Surgical Hospital
| | - De Wu
- Pediatric Neurological Rehabilitation Center, Pediatric Department, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Pediatrics, Anhui Hefei Southeast Surgical Hospital
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25
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Liu Q, Ma F, Zhong Y, Wang G, Hu L, Zhang Y, Xie J. Efficacy and safety of human umbilical cord-derived mesenchymal stem cells for COVID-19 pneumonia: a meta-analysis of randomized controlled trials. Stem Cell Res Ther 2023; 14:118. [PMID: 37143167 PMCID: PMC10159228 DOI: 10.1186/s13287-023-03286-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 03/16/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Elevated levels of inflammatory factors are associated with poor prognosis in coronavirus disease-19 (COVID-19). However, mesenchymal stem cells (MSCs) have immunomodulatory functions. Accordingly, this meta-analysis aimed to determine the efficacy and safety of MSC-based therapy in patients with COVID-19 pneumonia. METHODS Online global databases were used to find relevant studies. Two independent researchers then selected and evaluated the studies for suitability while the Cochrane risk of bias tool determined the quality of all articles and Cochran's Q test and I2 index assessed the degree of heterogeneity in the principal studies. Statistical analysis was performed using Review Manager software, and the effect of each study on the overall estimate was evaluated by sensitivity analysis. RESULTS Seven studies were included in the meta-analysis, and all MSCs used in the trials were acquired from the umbilical cord. The results of these studies (n = 328) indicated that patients with COVID-19 pneumonia who received MSCs had a 0.58 risk of death compared with controls (95% CI = 0.38, 0.87; P = 0.53; I2 = 0%). In terms of inflammatory biomarkers, MSCs reduced the levels of C-reactive protein (n = 88; MD = - 32.49; 95% CI = - 48.43, - 16.56; P = 0.46; I2 = 0%) and interferon-gamma (n = 44; SMD = - 1.23; 95% CI = - 1.89, - 0.57; P = 0.37; I2 = 0%) in severe COVID-19 patients but had no significant effect on interleukin-6 (n = 185; MD = - 0.75; 95% CI = - 7.76, 6.27; P = 0.57; I2 = 0%). A summary of the data revealed no significant differences in adverse events (n = 287) or serious adverse events (n = 229) between the MSC and control groups. CONCLUSIONS Infusion of umbilical cord-derived MSCs is an effective strategy for treating patients with COVID-19 pneumonia, with no noticeable adverse effects.
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Affiliation(s)
- Qinxue Liu
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Fengjie Ma
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Yizhi Zhong
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Gaojian Wang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Li Hu
- Department of Anesthesiology, Second Affiliated Hospital of Jiaxing University, No.1518 North Huancheng Road, Nanhu District, Jiaxing, 314000, China
| | - Yaping Zhang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Junran Xie
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China.
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26
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Phan TN, Fan CH, Yeh CK. Application of Ultrasound to Enhancing Stem Cells Associated Therapies. Stem Cell Rev Rep 2023:10.1007/s12015-023-10546-w. [PMID: 37119453 DOI: 10.1007/s12015-023-10546-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2023] [Indexed: 05/01/2023]
Abstract
Pluripotent stem cell therapy exhibits self-renewal capacity and multi-directional differentiation potential and is considered an important regenerative approach for the treatment of several diseases. However, insufficient cell transplantation efficiency, uncontrollable differentiation, low cell viability, and difficult tracing limit its clinical applications and treatment outcome. Ultrasound (US) has mechanical, cavitation, and thermal effects that can produce different biological effects on organs, tissues, and cells. US can be combined with different US-responsive particles for enhanced physical-chemical stimulation and drug delivery. In the meantime, US also can provide a noninvasive and harmless imaging modality for deep tissue in vivo. An in-depth evaluation of the role and mechanism of action of US in stem cell therapy would enhance understanding of US and encourage research in this field. In this article, we comprehensively review progress in the application of US alone and combined with US-responsive particles for the promotion of proliferation, differentiation, migration, and in vivo detection of stem cells and the potential clinical applications.
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Affiliation(s)
- Thi-Nhan Phan
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
| | - Ching-Hsiang Fan
- Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
- Medical Device Innovation Center, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Kuang Yeh
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
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Tesiye MR, Gol M, Fadardi MR, Kani SNM, Costa AM, Ghasemi-Kasman M, Biagini G. Therapeutic Potential of Mesenchymal Stem Cells in the Treatment of Epilepsy and Their Interaction with Antiseizure Medications. Cells 2022; 11:cells11244129. [PMID: 36552892 PMCID: PMC9777461 DOI: 10.3390/cells11244129] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 12/11/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
Epilepsy is a life-threatening neurological disease that affects approximately 70 million people worldwide. Although the vast majority of patients may be successfully managed with currently used antiseizure medication (ASM), the search for alternative therapies is still necessary due to pharmacoresistance in about 30% of patients with epilepsy. Here, we review the effects of ASMs on stem cell treatment when they could be, as expected, co-administered. Indeed, it has been reported that ASMs produce significant effects on the differentiation and determination of stem cell fate. In addition, we discuss more recent findings on mesenchymal stem cells (MSCs) in pre-clinical and clinical investigations. In this regard, their ability to differentiate into various cell types, reach damaged tissues and produce and release biologically active molecules with immunomodulatory/anti-inflammatory and regenerative properties make them a high-potential therapeutic tool to address neuroinflammation in different neurological disorders, including epilepsy. Overall, the characteristics of MSCs to be genetically engineered, in order to replace dysfunctional elements with the aim of restoring normal tissue functioning, suggested that these cells could be good candidates for the treatment of epilepsy refractory to ASMs. Further research is required to understand the potential of stem cell treatment in epileptic patients and its interaction with ASMs.
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Affiliation(s)
- Maryam Rahimi Tesiye
- Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran 19839-69411, Iran
| | - Mohammad Gol
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
- PhD School of Clinical and Experimental Medicine (CEM), University of Modena and Reggio Emilia, 41125 Modena, Italy
| | | | | | - Anna-Maria Costa
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Maryam Ghasemi-Kasman
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol 47176-47745, Iran
- Department of Physiology, School of Medical Sciences, Babol University of Medical Sciences, Babol 47176-47745, Iran
- Correspondence: (M.G.-K.); (G.B.)
| | - Giuseppe Biagini
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
- Correspondence: (M.G.-K.); (G.B.)
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Qu J, Zhou L, Zhang H, Han D, Luo Y, Chen J, Li L, Zou Z, He Z, Zhang M, Ye J. Efficacy and safety of stem cell therapy in cerebral palsy: A systematic review and meta-analysis. Front Bioeng Biotechnol 2022; 10:1006845. [PMID: 36588957 PMCID: PMC9794999 DOI: 10.3389/fbioe.2022.1006845] [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: 07/29/2022] [Accepted: 11/30/2022] [Indexed: 12/15/2022] Open
Abstract
Aim: Although the efficacy and safety of stem cell therapy for cerebral palsy has been demonstrated in previous studies, the number of studies is limited and the treatment protocols of these studies lack consistency. Therefore, we included all relevant studies to date to explore factors that might influence the effectiveness of treatment based on the determination of safety and efficacy. Methods: The data source includes PubMed/Medline, Web of Science, EMBASE, Cochrane Library, from inception to 2 January 2022. Literature was screened according to the PICOS principle, followed by literature quality evaluation to assess the risk of bias. Finally, the outcome indicators of each study were extracted for combined analysis. Results: 9 studies were included in the current analysis. The results of the pooled analysis showed that the improvements in both primary and secondary indicators except for Bayley Scales of Infant and Toddler Development were more skewed towards stem cell therapy than the control group. In the subgroup analysis, the results showed that stem cell therapy significantly increased Gross Motor Function Measure (GMFM) scores of 3, 6, and 12 months. Besides, improvements in GMFM scores were more skewed toward umbilical cord mesenchymal stem cells, low dose, and intrathecal injection. Importantly, there was no significant difference in the adverse events (RR = 1.13; 95% CI = [0.90, 1.42]) between the stem cell group and the control group. Conclusion: The results suggested that stem cell therapy for cerebral palsy was safe and effective. Although the subgroup analysis results presented guiding significance in the selection of clinical protocols for stem cell therapy, high-quality RCTs validations are still needed.
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Affiliation(s)
- Jiayang Qu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,School of Rehabilitation Medicine Gannan Medical University, GanZhou City, Jiangxi, China,The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Lin Zhou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Hao Zhang
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Dongmiao Han
- School of Rehabilitation Medicine Gannan Medical University, GanZhou City, Jiangxi, China
| | - Yaolin Luo
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,Clinical Medicine Research Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junming Chen
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,School of Rehabilitation Medicine Gannan Medical University, GanZhou City, Jiangxi, China
| | - Lincai Li
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Zhengwei Zou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Zhengyi He
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,Clinical Medicine Research Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Minhong Zhang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,Clinical Medicine Research Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China,Key Laboratory of Biomaterials and Biofabrication in Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, Jiangxi, China,Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,*Correspondence: Junsong Ye,
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Finch-Edmondson M, Paton MCB, Honan I, Karlsson P, Stephenson C, Chiu D, Reedman S, Griffin AR, Morgan C, Novak I. Are We Getting It Right? A Scoping Review of Outcomes Reported in Cell Therapy Clinical Studies for Cerebral Palsy. J Clin Med 2022; 11:7319. [PMID: 36555936 PMCID: PMC9786692 DOI: 10.3390/jcm11247319] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/01/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Cell therapies are an emergent treatment for cerebral palsy (CP) with promising evidence demonstrating efficacy for improving gross motor function. However, families value improvements in a range of domains following intervention and the non-motor symptoms, comorbidities and complications of CP can potentially be targeted by cell therapies. We conducted a scoping review to describe all outcomes that have been reported in cell therapy studies for CP to date, and to examine what instruments were used to capture these. Through a systematic search we identified 54 studies comprising 2066 participants that were treated with a range of cell therapy interventions. We categorized the reported 53 unique outcome instruments and additional descriptive measures into 10 categories and 12 sub-categories. Movement and Posture was the most frequently reported outcome category, followed by Safety, however Quality of Life, and various prevalent comorbidities and complications of CP were infrequently reported. Notably, many outcome instruments used do not have evaluative properties and thus are not suitable for measuring change following intervention. We provide a number of recommendations to ensure that future trials generate high-quality outcome data that is aligned with the priorities of the CP community.
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Affiliation(s)
- Megan Finch-Edmondson
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Madison C. B. Paton
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Ingrid Honan
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Petra Karlsson
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Candice Stephenson
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Darryl Chiu
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Sarah Reedman
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Alexandra R. Griffin
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Catherine Morgan
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Iona Novak
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
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Optimal Intravenous Administration Procedure for Efficient Delivery of Canine Adipose-Derived Mesenchymal Stem Cells. Int J Mol Sci 2022; 23:ijms232314681. [PMID: 36499004 PMCID: PMC9740176 DOI: 10.3390/ijms232314681] [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: 11/02/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 11/27/2022] Open
Abstract
Mesenchymal stem cells (MSC) are currently being investigated for their therapeutic applications in a wide range of diseases. Although many studies examined peripheral venous administration of MSC, few have investigated the detailed intravenous administration procedures of MSC from their preparation until they enter the body. The current study therefore aimed to explore the most efficient infusion procedure for MSC delivery by preparing and infusing them under various conditions. Canine adipose-derived mesenchymal stem cells (cADSC) were infused using different infusion apparatuses, suspension solutions, allogenic serum supplementation, infusion time and rates, and cell densities, respectively. Live and dead cell counts were then assessed by manual measurements and flow cytometry. Efficiency of live- and dead-cell infusion and cell viability were calculated from the measured cell counts and compared under each condition. Efficiency of live-cell infusion differed significantly according to the infusion apparatus, infusion rate, and combination of cell density and serum supplementation. Cell viability after infusion differed significantly between the infusion apparatuses. The optimal infusion procedure resulting in the highest cell delivery and viability involved suspending cADSC in normal saline supplemented with 5% allogenic serum at a density of 5 × 105 cells/mL, and infusing them using an automatic infusion device for 15 min. This procedure is therefore recommended as the standard procedure for the intravenous administration of ADSC in terms of cell-delivery efficiency.
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31
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Cell-Based and Gene-Based Therapy Approaches in Neuro-orthopedic Disorders: a Literature Review. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2022. [DOI: 10.1007/s40883-022-00284-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Lian XF, Lu DH, Liu HL, Liu YJ, Han XQ, Yang Y, Lin Y, Zeng QX, Huang ZJ, Xie F, Huang CH, Wu HM, Long AM, Deng LP, Zhang F. Effectiveness and safety of human umbilical cord-mesenchymal stem cells for treating type 2 diabetes mellitus. World J Diabetes 2022; 13:877-887. [PMID: 36312002 PMCID: PMC9606793 DOI: 10.4239/wjd.v13.i10.877] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/19/2022] [Accepted: 09/07/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Progressive pancreatic β-cell dysfunction is a fundamental part of the pathology of type 2 diabetes mellitus (T2DM). Cellular therapies offer novel opportunities for the treatment of T2DM to improve the function of islet β-cells.
AIM To evaluate the effectiveness and safety of human umbilical cord-mesenchymal stem cell (hUC-MSC) infusion in T2DM treatment.
METHODS Sixteen patients were enrolled and received 1 × 106 cells/kg per week for 3 wk as intravenous hUC-MSC infusion. The effectiveness was evaluated by assessing fasting blood glucose, C-peptide, normal glycosylated hemoglobin A1c (HbA1c), insulin resistance index (homeostatic model assessment for insulin resistance), and islet β-cell function (homeostasis model assessment of β-cell function). The dosage of hypoglycemic agents and safety were evaluated by monitoring the occurrence of any adverse events (AEs).
RESULTS During the entire intervention period, the fasting plasma glucose level was significantly reduced [baseline: 9.3400 (8.3575, 11.7725), day 14 ± 3: 6.5200 (5.2200, 8.6900); P < 0.01]. The HbA1c level was significantly reduced on day 84 ± 3 [baseline: 7.8000 (7.5250, 8.6750), day 84 ± 3: 7.150 (6.600, 7.925); P < 0.01]. The patients’ islet β-cell function was significantly improved on day 28 ± 3 of intervention [baseline: 29.90 (16.43, 37.40), day 28 ± 3: 40.97 (19.27, 56.36); P < 0.01]. The dosage of hypoglycemic agents was reduced in all patients, of whom 6 (50%) had a decrement of more than 50% and 1 (6.25%) discontinued the hypoglycemic agents. Four patients had transient fever, which occurred within 24 h after the second or third infusion. One patient (2.08%) had asymptomatic nocturnal hypoglycemia after infusion on day 28 ± 3. No liver damage or other side effects were reported.
CONCLUSION The results of this study suggest that hUC-MSC infusion can improve glycemia, restore islet β-cell function, and reduce the dosage of hypoglycemic agents without serious AEs. Thus, hUC-MSC infusion may be a novel option for the treatment of T2DM.
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Affiliation(s)
- Xiao-Fen Lian
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Dong-Hui Lu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Hong-Li Liu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yan-Jing Liu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Xiu-Qun Han
- Department of Research & Development, Zhejiang MaiDa Gene Tech Co. Ltd, Zhoushan 316000, Zhejiang Province, China
| | - Yang Yang
- Department of Endocrinology, Huizhou Central People's Hospital, Huizhou 516000, Guangdong Province, China
| | - Yuan Lin
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Qing-Xiang Zeng
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Zheng-Jie Huang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Feng Xie
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Cai-Hao Huang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Hong-Mei Wu
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Ai-Mei Long
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Ling-Ping Deng
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Fan Zhang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
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Wu R, Gao Y, Zhang H, Chen Y, Tan F, Zeng D, Wan H, Yang Y, Gu J, Pei Z. Metabolic assessment of cerebral palsy with normal clinical MRI using 18F-FDG PET imaging: A preliminary report. Front Neurol 2022; 13:844911. [PMID: 36188357 PMCID: PMC9520285 DOI: 10.3389/fneur.2022.844911] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 08/17/2022] [Indexed: 11/13/2022] Open
Abstract
To explore the cerebral metabolic patterns of cerebral palsy (CP) patients without structural abnormalities by brain magnetic resonance imaging (MRI) scans, we evaluated 18F-fluoro-deoxyglucose positron emission tomography (18F-FDG PET) imaging features in patients. Thirty-one children with CP [Gross Motor Function Classification System (GMFCS) levels II-V] showing no structural abnormalities by MRI were enrolled in this study. Regional glucose metabolic activity values were calculated using Scenium software and compared between the right and left cerebral hemispheres. These comparisons revealed asymmetric metabolic reductions in the central region, cerebellum, frontal lobe, and parietal lobe (p < 0.01). We next determined whether averaged brain metabolic activity values in different brain regions correlated with GMFCS levels. The metabolic activity values of basal ganglia, left temporal lobe, and cerebellum correlated negatively with GMFCS scores (all p < 0.05). This method was applied to the left cerebellum, which showed higher metabolic activity values than those in the right cerebellum in most patients (83.8%), and these values also correlated negatively with GMFCS scores (Spearman's r = −0.36, p = 0.01). Differential cortical glucose metabolism by 18F-FDG PET, may help to distinguish between different CP diagnoses that are not detected by MRI.
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Affiliation(s)
- Ruimin Wu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yan Gao
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Huaqiong Zhang
- Department of Nursing, Hubei University of Medicine, Shiyan, China
| | - Yijia Chen
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Fan Tan
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Daobing Zeng
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Huabing Wan
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yi Yang
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Jiaowei Gu
- Department of Pediatrics, Hubei University of Medicine, Shiyan, China
- Jiaowei Gu
| | - Zhijun Pei
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, China
- *Correspondence: Zhijun Pei
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Zhang C, Huang L, Wang X, Zhou X, Zhang X, Li L, Wu J, Kou M, Cai C, Lian Q, Zhou X. Topical and intravenous administration of human umbilical cord mesenchymal stem cells in patients with diabetic foot ulcer and peripheral arterial disease: a phase I pilot study with a 3-year follow-up. Stem Cell Res Ther 2022; 13:451. [PMID: 36064461 PMCID: PMC9446755 DOI: 10.1186/s13287-022-03143-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 08/16/2022] [Indexed: 12/26/2022] Open
Abstract
Background Diabetic foot ulcer (DFU) is a serious chronic complication of diabetes mellitus that contributes to 85% of nontraumatic lower extremity amputations in diabetic patients. Preliminary clinical benefits have been shown in treatments based on mesenchymal stem cells for patients with DFU or peripheral arterial disease (PAD). However, the long-term safety and benefits are unclear for patients with both DFU and PAD who are not amenable to surgical revascularization. Methods In this phase I pilot study, 14 patients with PAD and incurable DFU were enrolled to assess the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) administration based on conservative treatments. All patients received topical and intravenous administrations of hUC-MSCs at a dosage of 2 × 105 cells/kg with an upper limit of 1 × 107 cells for each dose. The adverse events during treatment and follow-up were documented for safety assessments. The therapeutic efficacy was assessed by ulcer healing status, recurrence rate, and 3-year amputation-free rate in the follow-up phase. Results The safety profiles were favorable. Only 2 cases of transient fever were observed within 3 days after transfusion and considered possibly related to hUC-MSC administration intravenously. Ulcer disclosure was achieved for more than 95% of the lesion area for all patients within 1.5 months after treatment. The symptoms of chronic limb ischaemia were alleviated along with a decrease in Wagner scores, Rutherford grades, and visual analogue scale scores. No direct evidence was observed to indicate the alleviation of the obstruction in the main vessels of target limbs based on computed tomography angiography. The duration of rehospitalization for DFU was 2.0 ± 0.6 years. All of the patients survived without amputation due to the recurrence of DFU within 3 years after treatments. Conclusions Based on the current pilot study, the preliminary clinical benefits of hUC-MSCs on DFU healing were shown, including good tolerance, a shortened healing time to 1.5 months and a favorable 3-year amputation-free survival rate. The clinical evidence in the current study suggested a further phase I/II study with a larger patient population and a more rigorous design to explore the efficacy and mechanism of hUC-MSCs on DFU healing. Trial registration: The current study was registered retrospectively on 22 Jan 2022 with the Chinese Clinical Trial Registry (ChiCTR2200055885), http://www.chictr.org.cn/showproj.aspx?proj=135888 Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03143-0.
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Affiliation(s)
- Che Zhang
- Department of Pediatrics, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, Shaanxi, China.,Clinical Research Centre, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China
| | - Li Huang
- Clinical Research Centre, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China.,Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Xiaofen Wang
- Department of Endocrinology, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China
| | - Xiaoya Zhou
- Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Xiaoxian Zhang
- Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Ling Li
- Clinical Data Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jieying Wu
- Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Meng Kou
- Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Cheguo Cai
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Qizhou Lian
- Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. .,Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Xihui Zhou
- Department of Pediatrics, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, Shaanxi, China.
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Hoang DM, Pham PT, Bach TQ, Ngo ATL, Nguyen QT, Phan TTK, Nguyen GH, Le PTT, Hoang VT, Forsyth NR, Heke M, Nguyen LT. Stem cell-based therapy for human diseases. Signal Transduct Target Ther 2022; 7:272. [PMID: 35933430 PMCID: PMC9357075 DOI: 10.1038/s41392-022-01134-4] [Citation(s) in RCA: 451] [Impact Index Per Article: 150.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/07/2023] Open
Abstract
Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated. Stem cell-based therapy, including human pluripotent stem cells (hPSCs) and multipotent mesenchymal stem cells (MSCs), has recently emerged as a key player in regenerative medicine. hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. MSCs are multipotent progenitor cells possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages, according to the International Society for Cell and Gene Therapy (ISCT). This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow (BM), adipose tissue (AT), or the umbilical cord (UC) for the treatment of human diseases, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions. Moreover, we discuss our own clinical trial experiences on targeted therapies using MSCs in a clinical setting, and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications, with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications. The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment, AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration, and UC-MSCs are potentially good candidates for pulmonary disease and acute respiratory distress syndrome treatment.
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Affiliation(s)
- Duc M Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam.
| | - Phuong T Pham
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trung Q Bach
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Anh T L Ngo
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Quyen T Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trang T K Phan
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Giang H Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Phuong T T Le
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Van T Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Nicholas R Forsyth
- Institute for Science & Technology in Medicine, Keele University, Keele, UK
| | - Michael Heke
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Liem Thanh Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
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Li X, Huang Q, Zhang X, Xie C, Liu M, Yuan Y, Feng J, Xing H, Ru L, Yuan Z, Xu Z, Yang Y, Long Y, Xing C, Song J, Hu X, Xu Q. Reproductive and Developmental Toxicity Assessment of Human Umbilical Cord Mesenchymal Stem Cells in Rats. Front Cell Dev Biol 2022; 10:883996. [PMID: 35663387 PMCID: PMC9160830 DOI: 10.3389/fcell.2022.883996] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: Human umbilical cord mesenchymal stem cells (hUC-MSCs) have shown very attractive potential in clinical applications for the treatment of various diseases. However, the data about the reproductive and developmental toxicity of hUC-MSCs remains insufficient. Thus, we assessed the potential effects of intravenous injection of hUC-MSCs on reproduction and development in Sprague-Dawley rats. Methods: In the fertility and early embryonic development study, hUC-MSCs were administered at dose levels of 0, 6.0 × 106, 8.5 × 106, and 1.2 × 107/kg to male and female rats during the pre-mating, mating and gestation period. In the embryo-fetal development study, the pregnant female rats received 0, 6.0 × 106, 1.2 × 107, and 2.4 × 107/kg of hUC-MSCs from gestation days (GD) 6-15. Assessments made included mortality, clinical observations, body weight, food consumption, fertility parameters of male and female, litter, and fetus parameters, etc. Results: No hUC-MSCs-related toxicity was observed on the fertility of male and female rats, and no teratogenic effect on fetuses. hUC-MSCs at 1.2 × 107/kg caused a mildly decrease in body weight gain of male rats, transient listlessness, tachypnea, and hematuria symptoms in pregnant female rats. Death was observed in part of the pregnant females at a dose of 2.4 × 107/kg, which could be due to pulmonary embolism. Conclusion: Based on the results of the studies, the no-observed-adverse-effect levels (NOAELs) are 8.5 × 106/kg for fertility and early embryonic development, 1.2 × 107/kg for maternal toxicity and 2.4 × 107/kg for embryo-fetal development in rats intravenous injected with hUC-MSCs, which are equivalent to 8.5-fold, 12-fold, and 24-fold respectively of its clinical dosage in humans. These findings may provide a rational basis for human health risk assessment of hUC-MSCs.
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Affiliation(s)
- Xiaobo Li
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qijing Huang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiangxiang Zhang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Changfeng Xie
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Muyun Liu
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Yueming Yuan
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jianjia Feng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haoyu Xing
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li Ru
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zheng Yuan
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhiyong Xu
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - YaoXiang Yang
- Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yan Long
- Guangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou, China
| | - Chengfeng Xing
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jianping Song
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiang Hu
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Qin Xu
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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Zarrabi M, Akbari MG, Amanat M, Majmaa A, Moaiedi AR, Montazerlotfelahi H, Nouri M, Hamidieh AA, Badv RS, Karimi H, Rabbani A, Mohebbi A, Rahimi-Dehgolan S, Rahimi R, Dehghan E, Vosough M, Abroun S, Shamsabadi FM, Tavasoli AR, Alizadeh H, Pak N, Zamani GR, Mohammadi M, Javadzadeh M, Ghofrani M, Hassanpour SH, Heidari M, Taghdiri MM, Mohseni MJ, Noparast Z, Masoomi S, Goudarzi M, Mohamadpour M, Shodjaee R, Samimi S, Mohammad M, Gholami M, Vafaei N, Koochakzadeh L, Valizadeh A, Malamiri RA, Ashrafi MR. The safety and efficacy of umbilical cord blood mononuclear cells in individuals with spastic cerebral palsy: a randomized double-blind sham-controlled clinical trial. BMC Neurol 2022; 22:123. [PMID: 35351020 PMCID: PMC8966246 DOI: 10.1186/s12883-022-02636-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 03/15/2022] [Indexed: 11/21/2022] Open
Abstract
INTRODUCTION The current multi-center, randomized, double-blind study was conducted among children with cerebral palsy (CP) to assess the safety and efficacy of umbilical cord blood mononuclear cell (UCB-MNC). We performed the diffusion tensor imaging to assess the changes in the white matter structure. METHODS Males and females aged 4 to 14 years old with spastic CP were included. Eligible participants were allocated in 4:1 ratio to be in the experimental or control groups; respectively. Individuals who were assigned in UCB-MNC group were tested for human leukocyte antigen (HLA) and fully-matched individuals were treated with UCB-MNCs. A single dose (5 × 106 /kg) UCB-MNCs were administered via intrathecal route in experimental group. The changes in gross motor function measure (GMFM)-66 from baseline to one year after treatment were the primary endpoints. The mean changes in modified Ashworth scale (MAS), pediatric evaluation of disability inventory (PEDI), and CP quality of life (CP-QoL) were also evaluated and compared between groups. The mean changes in fractional anisotropy (FA) and mean diffusivity (MD) of corticospinal tract (CST) and posterior thalamic radiation (PTR) were the secondary endpoints. Adverse events were safety endpoint. RESULTS There were 72 included individuals (36 cases in each group). The mean GMFM-66 scores increased in experimental group; compared to baseline (+ 9.62; 95%CI: 6.75, 12.49) and control arm (β: 7.10; 95%CI: 2.08, 12.76; Cohen's d: 0.62) and mean MAS reduced in individuals treated with UCB-MNCs compared to the baseline (-0.87; 95%CI: -1.2, -0.54) and control group (β: -0.58; 95%CI: -1.18, -0.11; Cohen's d: 0.36). The mean PEDI scores and mean CP-QoL scores in two domains were higher in the experimental group compared to the control. The imaging data indicated that mean FA increased and MD decreased in participants of UCB-MNC group indicating improvements in white matter structure. Lower back pain, headaches, and irritability were the most common adverse events within 24 h of treatment that were related to lumbar puncture. No side effects were observed during follow-up. CONCLUSIONS This trial showed that intrathecal injection of UCB-MNCs were safe and effective in children with CP. TRIAL REGISTRATION The study was registered with ClinicalTrials.gov ( NCT03795974 ).
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Affiliation(s)
- Morteza Zarrabi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Masood Ghahvechi Akbari
- Physical Medicine and Rehabilitation Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Man Amanat
- Division of Neurogenetics and Neuroscience, The Moser Center for Leukodystrophies, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Anahita Majmaa
- Pediatrics Center of Excellence, Pediatric Intensive Unit, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Reza Moaiedi
- Department of Pediatric Neurology, Clinical Research Development Center of Children Hospital, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Hadi Montazerlotfelahi
- Department of Pediatrics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Masoumeh Nouri
- R & D Department, Royan Stem Cell Technology Co, Tehran, Iran
| | - Amir Ali Hamidieh
- Pediatrics Center of Excellence Pediatric Hematology, Oncology and Stem Cell Transplantation Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Shervin Badv
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Karimi
- Neurorehabilitation Research Center University of Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Ali Rabbani
- Pediatrics Center of Excellence Pediatric Endocrinology Department, Growth and Development Research Center, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Mohebbi
- Pediatrics Center of Excellence, Growth and Development Research Center, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahram Rahimi-Dehgolan
- Physical Medicine and Rehabilitation Department, Tehran University of Medical Sciences, Tehran, Iran
| | - Rosa Rahimi
- Physical Medicine and Rehabilitation Department, Khatamolanbia Hospital, Tehran, Iran
| | - Ensieh Dehghan
- Transplantation Department, Royan Stem Cell Technology Co, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Saeed Abroun
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Ali Reza Tavasoli
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Houman Alizadeh
- Pediatrics Center of Excellence, Department of Radiology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Pak
- Pediatrics Center of Excellence, Department of Radiology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholam Reza Zamani
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Mohammadi
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Javadzadeh
- Department of Pediatric Neurology, Mofid Children's Hospital, Pediatric Neurology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Ghofrani
- Department of Pediatric Neurology, Mofid Children's Hospital, Pediatric Neurology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Hossein Hassanpour
- Department of Pediatric Neurology, Aliasghar Children's Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Morteza Heidari
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mehdi Taghdiri
- Department of Pediatric Neurology, Mofid Children's Hospital, Pediatric Neurology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohamad Javad Mohseni
- Pediatric Urology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Noparast
- Department of Pediatric Nephrology, Bahrami Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Safdar Masoomi
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Goudarzi
- Department of Pediatric Anesthesiology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Masood Mohamadpour
- Pediatrics Center of Excellence, Pediatric Intensive Unit, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Razieh Shodjaee
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Solaleh Samimi
- Physical Medicine and Rehabilitation Department, Khatamolanbia Hospital, Tehran, Iran
| | | | - Mona Gholami
- Physical Medicine and Rehabilitation Department, Khatamolanbia Hospital, Tehran, Iran
| | - Nahid Vafaei
- Faculty of Medicine, Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Leyli Koochakzadeh
- Pediatrics Center of Excellence Pediatric Hematology, Department of Hematology & Oncology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Valizadeh
- Faculty of Medicine, Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Azizi Malamiri
- Department of Paediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahmoud Reza Ashrafi
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Ding Y, Botchway BOA, Zhang Y, Jin T, Liu X. The combination of autologous mesenchymal stem cell-derived exosomes and neurotrophic factors as an intervention for amyotrophic lateral sclerosis. Ann Anat 2022; 242:151921. [PMID: 35278658 DOI: 10.1016/j.aanat.2022.151921] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/19/2022] [Accepted: 02/24/2022] [Indexed: 10/18/2022]
Abstract
Amyotrophic lateral sclerosis is a chronic progressive degeneration of motor neurons and has a high mortality. Riluzole and edaravone are the only approved medications currently being used for amyotrophic lateral sclerosis in clinical settings. However, they can lead to serious complications, such as injuries to the liver and kidney. To date, there is no effective treatment for amyotrophic lateral sclerosis. In this regard, investigations concerning the employment of exosomes, mesenchymal stem cells, and neurotrophic factors to ameliorate amyotrophic lateral sclerosis are attracting considerable attention in the scientific community. Herein, we systematically analyze the relationship relevant to autologous mesenchymal stem cell derived-exosomes, neurotrophic factors and amyotrophic lateral sclerosis. Mesenchymal stem cells modulate immune response, mitigate oxidative stress, promote neuronal regeneration, and differentiate into neuronal and glial cells. Furthermore, exosomes from mesenchymal stem cells exert beneficial effects on their mother cells by preventing abnormal differentiation of mesenchymal stem cells. Similarly, neurotrophic factors regulate inflammatory response, stimulate the neuron repair, and the recovery of neuronal functioning. Therefore, autologous mesenchymal stem cells-derived exosomes combined with neurotrophic factors could potentially be an effective interventional medium for amyotrophic lateral sclerosis.
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Affiliation(s)
- Yingying Ding
- Department of Histology and Embryology, Medical College, Shaoxing University, Zhejiang, China; School of Basic Medical Sciences, Hangzhou Normal University, Zhejiang, China
| | - Benson O A Botchway
- Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China
| | - Yong Zhang
- Department of Histology and Embryology, Medical College, Shaoxing University, Zhejiang, China
| | - Tian Jin
- Department of Histology and Embryology, Medical College, Shaoxing University, Zhejiang, China
| | - Xuehong Liu
- Department of Histology and Embryology, Medical College, Shaoxing University, Zhejiang, China.
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Brégère C, Schwendele B, Radanovic B, Guzman R. Microglia and Stem-Cell Mediated Neuroprotection after Neonatal Hypoxia-Ischemia. Stem Cell Rev Rep 2022; 18:474-522. [PMID: 34382141 PMCID: PMC8930888 DOI: 10.1007/s12015-021-10213-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2021] [Indexed: 12/14/2022]
Abstract
Neonatal hypoxia-ischemia encephalopathy (HIE) refers to a brain injury in term infants that can lead to death or lifelong neurological deficits such as cerebral palsy (CP). The pathogenesis of this disease involves multiple cellular and molecular events, notably a neuroinflammatory response driven partly by microglia, the brain resident macrophages. Treatment options are currently very limited, but stem cell (SC) therapy holds promise, as beneficial outcomes are reported in animal studies and to a lesser degree in human trials. Among putative mechanisms of action, immunomodulation is considered a major contributor to SC associated benefits. The goal of this review is to examine whether microglia is a cellular target of SC-mediated immunomodulation and whether the recruitment of microglia is linked to brain repair. We will first provide an overview on microglial activation in the rodent model of neonatal HI, and highlight its sensitivity to developmental age. Two complementary questions are then addressed: (i) do immune-related treatments impact microglia and provide neuroprotection, (ii) does stem cell treatment modulates microglia? Finally, the immune-related findings in patients enrolled in SC based clinical trials are discussed. Our review points to an impact of SCs on the microglial phenotype, but heterogeneity in experimental designs and methodological limitations hamper our understanding of a potential contribution of microglia to SC associated benefits. Thorough analyses of the microglial phenotype are warranted to better address the relevance of the neuroimmune crosstalk in brain repair and improve or advance the development of SC protocols in humans.
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Affiliation(s)
- Catherine Brégère
- Department of Biomedicine and Department of Neurosurgery, Faculty of Medicine, University Hospital Basel, Basel, Switzerland
| | - Bernd Schwendele
- Department of Biomedicine and Department of Neurosurgery, Faculty of Medicine, University Hospital Basel, Basel, Switzerland
| | - Boris Radanovic
- Department of Biomedicine and Department of Neurosurgery, Faculty of Medicine, University Hospital Basel, Basel, Switzerland
| | - Raphael Guzman
- Department of Biomedicine and Department of Neurosurgery, Faculty of Medicine, University Hospital Basel, Basel, Switzerland.
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Huang J, U KP, Yang F, Ji Z, Lin J, Weng Z, Tsang LL, Merson TD, Ruan YC, Wan C, Li G, Jiang X. Human pluripotent stem cell-derived ectomesenchymal stromal cells promote more robust functional recovery than umbilical cord-derived mesenchymal stromal cells after hypoxic-ischaemic brain damage. Am J Cancer Res 2022; 12:143-166. [PMID: 34987639 PMCID: PMC8690936 DOI: 10.7150/thno.57234] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 08/06/2021] [Indexed: 02/07/2023] Open
Abstract
Aims: Hypoxic-ischaemic encephalopathy (HIE) is one of the most serious complications in neonates and infants. Mesenchymal stromal cell (MSC)-based therapy is emerging as a promising treatment avenue for HIE. However, despite its enormous potential, the clinical application of MSCs is limited by cell heterogeneity, low isolation efficiency and unpredictable effectiveness. In this study, we examined the therapeutic effects and underlying mechanisms of human pluripotent stem cell-derived ectomesenchymal stromal cells (hPSC-EMSCs) in a rat model of HIE. Methods: hPSC-EMSCs were induced from either human embryonic stem cells or induced pluripotent stem cells. Stem cells or the conditioned medium (CM) derived from stem cells were delivered intracranially or intranasally to neonatal rats with HIE. Human umbilical cord-derived MSCs (hUC-MSCs) were used as the therapeutic comparison control and phosphate-buffered saline (PBS) was used as a negative control. Lesion size, apoptosis, neurogenesis, astrogliosis and microgliosis were evaluated. The rotarod test and Morris water maze were used to determine brain functional recovery. The PC-12 cell line, rat primary cortical neurons and neural progenitor cells were used to evaluate neurite outgrowth and the neuroprotective and neurogenesis effects of hPSC-EMSCs/hUC-MSCs. RNA-seq and enzyme-linked immunosorbent assays were used to determine the secretory factors that were differentially expressed between hPSC-EMSCs and hUC-MSCs. The activation and suppression of extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) were characterised using western blotting and immunofluorescent staining. Results: hPSC-EMSCs showed a higher neuroprotective potential than hUC-MSCs, as demonstrated by a more significant reduction in lesion size and apoptosis in the rat brain following hypoxia-ischaemia (HI). Compared with PBS treatment, hPSC-EMSCs promoted endogenous neurogenesis and alleviated astrogliosis and microgliosis. hPSC-EMSCs were more effective than hUC-MSCs. hPSC-EMSCs achieved a greater recovery of brain function than hUC-MSCs and PBS in rats with HIE. CM derived from hPSC-EMSCs had neuroprotective and neurorestorative effects in vitro through anti-apoptotic and neurite outgrowth- and neurogenesis-promoting effects. Direct comparisons between hPSC-EMSCs and hUC-MSCs revealed the significant enrichment of a group of secretory factors in hPSC-EMSCs, including nerve growth factor (NGF), platelet-derived growth factor-AA and transforming growth factor-β2, which are involved in neurogenesis, synaptic transmission and neurotransmitter transport, respectively. Mechanistically, the CM derived from hPSC-EMSCs was found to potentiate NGF-induced neurite outgrowth and the neuronal differentiation of NPCs via the ERK/CREB pathway. Suppression of ERK or CREB abolished CM-potentiated neuritogenesis and neuronal differentiation. Finally, intranasal delivery of the CM derived from hPSC-EMSCs significantly reduced brain lesion size, promoted endogenous neurogenesis, mitigated inflammatory responses and improved functional recovery in rats with HIE. Conclusion: hPSC-EMSCs promote functional recovery after HI through multifaceted neuromodulatory activities via paracrine/trophic mechanisms. We propose the use of hPSC-EMSCs for the treatment of HIE, as they offer an excellent unlimited cellular source of MSCs.
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Paprocka J, Kaminiów K, Kozak S, Sztuba K, Emich-Widera E. Stem Cell Therapies for Cerebral Palsy and Autism Spectrum Disorder-A Systematic Review. Brain Sci 2021; 11:1606. [PMID: 34942908 PMCID: PMC8699362 DOI: 10.3390/brainsci11121606] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/27/2021] [Accepted: 12/01/2021] [Indexed: 12/05/2022] Open
Abstract
Autism spectrum disorder (ASD) and cerebral palsy (CP) are some of the most common neurodevelopmental diseases. They have multifactorial origin, which means that each case may manifest differently from the others. In patients with ASD, symptoms associated with deficits in social communication and characteristic, repetitive types of behaviors or interests are predominant, while in patients with CP, motor disability is diagnosed with accompanying cognitive impairment of various degrees. In order to minimize their adverse effects, it is necessary to promptly diagnose and incorporate appropriate management, which can significantly improve patient quality of life. One of the therapeutic possibilities is stem cell therapy, already known from other branches of medicine, with high hopes for safe and effective treatment of these diseases. Undoubtedly, in the future we will have to face the challenges that will arise due to the still existing gaps in knowledge and the heterogeneity of this group of patients. The purpose of this systematic review is to summarize briefly the latest achievements and advances in stem cell therapy for ASD and CP.
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Affiliation(s)
- Justyna Paprocka
- Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland;
| | - Konrad Kaminiów
- Students’ Scientific Society, Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; (K.K.); (S.K.); (K.S.)
| | - Sylwia Kozak
- Students’ Scientific Society, Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; (K.K.); (S.K.); (K.S.)
| | - Karolina Sztuba
- Students’ Scientific Society, Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; (K.K.); (S.K.); (K.S.)
| | - Ewa Emich-Widera
- Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland;
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Kulus M, Sibiak R, Stefańska K, Zdun M, Wieczorkiewicz M, Piotrowska-Kempisty H, Jaśkowski JM, Bukowska D, Ratajczak K, Zabel M, Mozdziak P, Kempisty B. Mesenchymal Stem/Stromal Cells Derived from Human and Animal Perinatal Tissues-Origins, Characteristics, Signaling Pathways, and Clinical Trials. Cells 2021; 10:cells10123278. [PMID: 34943786 PMCID: PMC8699543 DOI: 10.3390/cells10123278] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/13/2021] [Accepted: 11/19/2021] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are currently one of the most extensively researched fields due to their promising opportunity for use in regenerative medicine. There are many sources of MSCs, of which cells of perinatal origin appear to be an invaluable pool. Compared to embryonic stem cells, they are devoid of ethical conflicts because they are derived from tissues surrounding the fetus and can be safely recovered from medical waste after delivery. Additionally, perinatal MSCs exhibit better self-renewal and differentiation properties than those derived from adult tissues. It is important to consider the anatomy of perinatal tissues and the general description of MSCs, including their isolation, differentiation, and characterization of different types of perinatal MSCs from both animals and humans (placenta, umbilical cord, amniotic fluid). Ultimately, signaling pathways are essential to consider regarding the clinical applications of MSCs. It is important to consider the origin of these cells, referring to the anatomical structure of the organs of origin, when describing the general and specific characteristics of the different types of MSCs as well as the pathways involved in differentiation.
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Affiliation(s)
- Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.K.); (K.R.)
| | - Rafał Sibiak
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (R.S.); (K.S.)
- Division of Reproduction, Department of Obstetrics, Gynecology, and Gynecologic Oncology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Katarzyna Stefańska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (R.S.); (K.S.)
| | - Maciej Zdun
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.Z.); (M.W.); (H.P.-K.)
| | - Maria Wieczorkiewicz
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.Z.); (M.W.); (H.P.-K.)
| | - Hanna Piotrowska-Kempisty
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.Z.); (M.W.); (H.P.-K.)
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
| | - Jędrzej M. Jaśkowski
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (J.M.J.); (D.B.)
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (J.M.J.); (D.B.)
| | - Kornel Ratajczak
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.K.); (K.R.)
| | - Maciej Zabel
- Division of Anatomy and Histology, University of Zielona Gora, 65-046 Zielona Gora, Poland;
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.K.); (K.R.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (R.S.); (K.S.)
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland
- Correspondence:
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Liu D, Bobrovskaya L, Zhou XF. Cell Therapy for Neurological Disorders: The Perspective of Promising Cells. BIOLOGY 2021; 10:1142. [PMID: 34827135 PMCID: PMC8614777 DOI: 10.3390/biology10111142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/05/2021] [Accepted: 11/05/2021] [Indexed: 12/13/2022]
Abstract
Neurological disorders are big public health challenges that are afflicting hundreds of millions of people around the world. Although many conventional pharmacological therapies have been tested in patients, their therapeutic efficacies to alleviate their symptoms and slow down the course of the diseases are usually limited. Cell therapy has attracted the interest of many researchers in the last several decades and has brought new hope for treating neurological disorders. Moreover, numerous studies have shown promising results. However, none of the studies has led to a promising therapy for patients with neurological disorders, despite the ongoing and completed clinical trials. There are many factors that may affect the outcome of cell therapy for neurological disorders due to the complexity of the nervous system, especially cell types for transplantation and the specific disease for treatment. This paper provides a review of the various cell types from humans that may be clinically used for neurological disorders, based on their characteristics and current progress in related studies.
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Affiliation(s)
| | | | - Xin-Fu Zhou
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5000, Australia; (D.L.); (L.B.)
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Amanat M, Majmaa A, Zarrabi M, Nouri M, Akbari MG, Moaiedi AR, Ghaemi O, Zamani F, Najafi S, Badv RS, Vosough M, Hamidieh AA, Salehi M, Montazerlotfelahi H, Tavasoli AR, Heidari M, Mohebi H, Fatemi A, Garakani A, Ashrafi MR. Clinical and imaging outcomes after intrathecal injection of umbilical cord tissue mesenchymal stem cells in cerebral palsy: a randomized double-blind sham-controlled clinical trial. Stem Cell Res Ther 2021; 12:439. [PMID: 34362453 PMCID: PMC8343813 DOI: 10.1186/s13287-021-02513-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 06/08/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND This study assessed the safety and efficacy of intrathecal injection of umbilical cord tissue mesenchymal stem cells (UCT-MSC) in individuals with cerebral palsy (CP). The diffusion tensor imaging (DTI) was performed to evaluate the alterations in white-matter integrity. METHODS Participants (4-14 years old) with spastic CP were assigned in 1:1 ratio to receive either UCT-MSC or sham procedure. Single-dose (2 × 107) cells were administered in the experimental group. Small needle pricks to the lower back were performed in the sham-control arm. All individuals were sedated to prevent awareness. The primary endpoints were the mean changes in gross motor function measure (GMFM)-66 from baseline to 12 months after procedures. The mean changes in the modified Ashworth scale (MAS), pediatric evaluation of disability inventory (PEDI), and CP quality of life (CP-QoL) were also assessed. Secondary endpoints were the mean changes in fractional anisotropy (FA) and mean diffusivity (MD) of corticospinal tract (CST) and posterior thalamic radiation (PTR). RESULTS There were 36 participants in each group. The mean GMFM-66 scores after 12 months of intervention were significantly higher in the UCT-MSC group compared to baseline (10.65; 95%CI 5.39, 15.91) and control (β 8.07; 95%CI 1.62, 14.52; Cohen's d 0.92). The increase was also seen in total PEDI scores (vs baseline 8.53; 95%CI 4.98, 12.08; vs control: β 6.87; 95%CI 1.52, 12.21; Cohen's d 0.70). The mean change in MAS scores after 12 months of cell injection reduced compared to baseline (-1.0; 95%CI -1.31, -0.69) and control (β -0.72; 95%CI -1.18, -0.26; Cohen's d 0.76). Regarding CP-QoL, mean changes in domains including friends and family, participation in activities, and communication were higher than the control group with a large effect size. The DTI analysis in the experimental group showed that mean FA increased (CST 0.032; 95%CI 0.02, 0.03. PTR 0.024; 95%CI 0.020, 0.028) and MD decreased (CST -0.035 × 10-3; 95%CI -0.04 × 10-3, -0.02 × 10-3. PTR -0.045 × 10-3; 95%CI -0.05 × 10-3, -0.03 × 10-3); compared to baseline. The mean changes were significantly higher than the control group. CONCLUSIONS The UCT-MSC transplantation was safe and may improve the clinical and imaging outcomes. TRIAL REGISTRATION The study was registered with ClinicalTrials.gov ( NCT03795974 ).
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Affiliation(s)
- Man Amanat
- Department of Science and Research Branch, AJA University of Medical Sciences, Tehran, Iran
| | - Anahita Majmaa
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Zarrabi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Masoumeh Nouri
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Masood Ghahvechi Akbari
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Reza Moaiedi
- Department of Pediatric Neurology, Clinical Research Development Center of Children Hospital, Hormozgan University of Medical Sciences, Bandar Abass, Iran
| | - Omid Ghaemi
- Pediatrics Center of Excellence, Department of Radiology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Zamani
- Pediatrics Center of Excellence, Department of Radiology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sharif Najafi
- Clinical Biomechanics and Ergonomics Research Center, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Reza Shervin Badv
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Amir Ali Hamidieh
- Pediatrics Center of Excellence Pediatric Hematology, Oncology and Stem Cell Transplantation Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mona Salehi
- Psychiatry and Psychology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hadi Montazerlotfelahi
- Department of Pediatrics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ali Reza Tavasoli
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Heidari
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Mohebi
- Department of Pediatric Neurology, AJA University of Medical Sciences, Tehran, Iran
| | - Ali Fatemi
- Moser Center for Leukodystrophies, Kennedy Krieger Institute, Baltimore, MD, 21205, USA
- Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Amir Garakani
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mahmoud Reza Ashrafi
- Pediatrics Center of Excellence, Department of Pediatric Neurology, Children's Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Mukai T, Sei K, Nagamura-Inoue T. Mesenchymal Stromal Cells Perspective: New Potential Therapeutic for the Treatment of Neurological Diseases. Pharmaceutics 2021; 13:pharmaceutics13081159. [PMID: 34452120 PMCID: PMC8401282 DOI: 10.3390/pharmaceutics13081159] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/23/2021] [Accepted: 07/24/2021] [Indexed: 12/13/2022] Open
Abstract
Several studies have shown that mesenchymal stromal/stem cells (MSCs) exert their neuroprotective and neurorestorative efficacy via the secretion of neurotrophic factors. Based on these studies, many clinical trials using MSCs for the treatment of neurological disorders have been conducted, and results regarding their feasibility and efficacy have been reported. The present review aims to highlight the characteristics and basic research regarding the role of MSCs in neurological disease and to discuss the recent progress in clinical trials using MSCs to treat various neurological disorders.
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Affiliation(s)
- Takeo Mukai
- Department of Pediatrics, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; (K.S.); (T.N.-I.)
- Correspondence: ; Tel.: +81-3-3815-5411; Fax: 81-3-5449-5452
| | - Kenshi Sei
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; (K.S.); (T.N.-I.)
| | - Tokiko Nagamura-Inoue
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; (K.S.); (T.N.-I.)
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Li S, Liu J, Liu S, Jiao W, Wang X. Mesenchymal stem cell-derived extracellular vesicles prevent the development of osteoarthritis via the circHIPK3/miR-124-3p/MYH9 axis. J Nanobiotechnology 2021; 19:194. [PMID: 34193158 PMCID: PMC8244143 DOI: 10.1186/s12951-021-00940-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 06/20/2021] [Indexed: 12/16/2022] Open
Abstract
Background Extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSCs) may play a vital role in a variety of biological processes, including cartilage regeneration. However, few studies reported their potential in the development of osteoarthritis (OA) previously. In this study, we explored the biological roles and underlying mechanism of MSCs-EVs in OA. Results Co-culture experiments revealed that MSCs-EVs could promote the expression of collagen type II alpha 1 chain (COL2A1), SRY-box transcription factor 9 (SOX9) and Aggrecan while negatively regulate the expression of chondrocyte hypertrophy markers matrix metallopeptidase 13 (MMP-13) and RUNX family transcription factor 2 (Runx2) in mouse chondrocytes in the OA model. Besides, the results of cell experiments indicated that MSCs-EVs could notably weaken the suppression of chondrocyte proliferation, migration and the promotion of chondrocyte apoptosis via interleukin1β (IL-1β) induction. In addition, MSCs-circHIPK3-EVs (EVs derived from MSCs overexpressing circHIPK3) considerably improved IL-1β-induced chondrocyte injury. Mechanistically, we elucidated that circHIPK3 could directly bind to miR-124-3p and subsequently elevate the expression of the target gene MYH9. Conclusion The findings in our study demonstrated that EVs-circHIPK3 participated in MSCs-EVs-mediated chondrocyte proliferation and migration induction and in chondrocyte apoptosis inhibition via the miR-124-3p/MYH9 axis. This offers a promising novel cell-free therapy for treating OA. Graphic abstract ![]()
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Affiliation(s)
- Shenglong Li
- Department of Tissue Engineering, Center of 3D Printing & Organ Manufacturing, School of Fundamental Sciences, China Medical University (CMU), No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China.,Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, Liaoning Province, China
| | - Jie Liu
- Department of Prosthodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, 110002, China
| | - Siyu Liu
- Department of Tissue Engineering, Center of 3D Printing & Organ Manufacturing, School of Fundamental Sciences, China Medical University (CMU), No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China
| | - Weijie Jiao
- Department of Tissue Engineering, Center of 3D Printing & Organ Manufacturing, School of Fundamental Sciences, China Medical University (CMU), No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China
| | - Xiaohong Wang
- Department of Tissue Engineering, Center of 3D Printing & Organ Manufacturing, School of Fundamental Sciences, China Medical University (CMU), No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China. .,Center of Organ Manufacturing, Department of Mechanical Engineering, Tsinghua University, Beijing, 100084, China.
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Sun JM, Kurtzberg J. Stem cell therapies in cerebral palsy and autism spectrum disorder. Dev Med Child Neurol 2021; 63:503-510. [PMID: 33398874 DOI: 10.1111/dmcn.14789] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/12/2020] [Indexed: 02/06/2023]
Abstract
Across disciplines, there is great anticipation that evolving cell therapies may finally provide a therapeutic option for conditions in dire need. These conditions are typically complex and their pathophysiology incompletely understood, hindering the development of robust preclinical models and the precise assessment of therapeutic effects in human studies. This article provides an overview of the status of cell therapy investigations in two common neurodevelopmental disorders, cerebral palsy and autism spectrum disorder. Challenges facing this line of study, including inherent heterogeneity, knowledge gaps, and unrealistic expectations, are discussed. Much progress has been made in the past decade, but to definitively determine if cell therapies have a role in the treatment of neurodevelopmental disorders, both fields will need to evolve together. WHAT THIS PAPER ADDS: The safety profile of reported cell therapies in children with neurodevelopmental disorders is encouraging. Efficacy trials in cerebral palsy and autism spectrum disorder are ongoing in the United States and Asia. Unresolved issues pertain to the properties of the cells being studied and the characteristics of the neurodevelopmental conditions themselves.
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Affiliation(s)
- Jessica M Sun
- The Marcus Center for Cellular Cures, Duke University, Durham, NC, USA
| | - Joanne Kurtzberg
- The Marcus Center for Cellular Cures, Duke University, Durham, NC, USA
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Nabetani M, Mukai T, Shintaku H. Preventing Brain Damage from Hypoxic-Ischemic Encephalopathy in Neonates: Update on Mesenchymal Stromal Cells and Umbilical Cord Blood Cells. Am J Perinatol 2021; 39:1754-1763. [PMID: 33853147 PMCID: PMC9674406 DOI: 10.1055/s-0041-1726451] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) causes permanent motor deficit "cerebral palsy (CP)," and may result in significant disability and death. Therapeutic hypothermia (TH) had been established as the first effective therapy for neonates with HIE; however, TH must be initiated within the first 6 hours after birth, and the number needed to treat is from 9 to 11 to prevent brain damage from HIE. Therefore, additional therapies for HIE are highly needed. In this review, we provide an introduction on the mechanisms of HIE cascade and how TH and cell therapies such as umbilical cord blood cells and mesenchymal stromal cells (MSCs), especially umbilical cord-derived MSCs (UC-MSCs), may protect the brain in newborns, and discuss recent progress in regenerative therapies using UC-MSCs for neurological disorders.The brain damage process "HIE cascade" was divided into six stages: (1) energy depletion, (2) impairment of microglia, (3) inflammation, (4) excitotoxity, (5) oxidative stress, and (6) apoptosis in capillary, glia, synapse and/or neuron. The authors showed recent 13 clinical trials using UC-MSCs for neurological disorders.The authors suggest that the next step will include reaching a consensus on cell therapies for HIE and establishment of effective protocols for cell therapy for HIE. KEY POINTS: · This study includes new insights about cell therapy for neonatal HIE and CP in schema.. · This study shows precise mechanism of neonatal HIE cascade.. · The mechanism of cell therapy by comparing umbilical cord blood stem cell with MSC is shown.. · The review of recent clinical trials of UC-MSC is shown..
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Affiliation(s)
- Makoto Nabetani
- Department of Pediatrics, Yodogawa Christian Hospital, Osaka, Japan,Address for correspondence Makoto Nabetani, MD, PhD Department of Pediatrics, Yodogawa Christian HospitalOsaka, Japan, 1-7-50 Kunijima, Higashi-yodogawa-ku, Osaka 5330024Japan
| | - Takeo Mukai
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Haruo Shintaku
- Department of Pediatrics, Faculty of Medicine, Osaka City University, Osaka, Japan
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An T, Chen Y, Tu Y, Lin P. Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Treatment of Diabetic Foot Ulcers: Application and Challenges. Stem Cell Rev Rep 2021; 17:369-378. [PMID: 32772239 DOI: 10.1007/s12015-020-10014-9] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Diabetic foot ischemia and ulcer (DFU) persists as a serious diabetes mellitus complication in spite of increased understanding of the pathophysiology and the cellular and molecular responses. Contributing to this pessimistic situation is the lack of effective treatments that are slow to heal the deep chronic wounds and microvascular obstruction. Mesenchymal stromal cells (MSCs) have been tested as a promising cell-based therapy for diabetes in vitro and in vivo, which is able to accelerate wound closure with increased epithelialization, granulation tissue formation and angiogenesis by differentiation into skin cells and paracrine pathways to repair injured cells. The secretomes of MSCs, including cytokines, growth factors, chemokines, and extracellular vesicles containing mRNA, proteins and microRNAs, have immunomodulatory and regenerative effects. This review will shed new light on the therapeutic potential of MSC-derived extracellular vesicles (MSC-EVs) for the treatment of diabetes-induced lower limb ischemia and ulcers. The identification of underlying mechanisms for MSC-EVs regulation on impaired diabetic wound healing might provide a new direction for MSC-centered treatment for diabetic lower limb ischemia and ulcers. Immunomodulatory and angiogenic effects of MSC-derived extracellular vesicles on diabetic foot ulcer.
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Affiliation(s)
- Tao An
- Department of hand and foot surgery, Jinhua Hospital of Zhejiang University, Jinhua, People's Republic of China
- Department of hand and foot surgery, Jinhua Central Hospital, 365 Renmin East Road, Jinhua, Zhejiang Province, People's Republic of China
| | - Yi Chen
- Department of hand and foot surgery, Jinhua Hospital of Zhejiang University, Jinhua, People's Republic of China
- Department of hand and foot surgery, Jinhua Central Hospital, 365 Renmin East Road, Jinhua, Zhejiang Province, People's Republic of China
| | - Yingchun Tu
- Department of hand and foot surgery, Jinhua Hospital of Zhejiang University, Jinhua, People's Republic of China
- Department of hand and foot surgery, Jinhua Central Hospital, 365 Renmin East Road, Jinhua, Zhejiang Province, People's Republic of China
| | - Ping Lin
- Department of hand and foot surgery, Jinhua Hospital of Zhejiang University, Jinhua, People's Republic of China.
- Department of hand and foot surgery, Jinhua Central Hospital, 365 Renmin East Road, Jinhua, Zhejiang Province, People's Republic of China.
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Abstract
Cerebral palsy is the most common disease in children associated with lifelong disability in many countries. Clinical research has demonstrated that traditional physiotherapy and rehabilitation therapies cannot alone cure cerebral palsy. Stem cell transplantation is an emerging therapy that has been applied in clinical trials for a variety of neurological diseases because of the regenerative and unlimited proliferative capacity of stem cells. In this review, we summarize the design schemes and results of these clinical trials. Our findings reveal great differences in population characteristics, stem cell types and doses, administration methods, and evaluation methods among the included clinical trials. Furthermore, we also assess the safety and efficacy of these clinical trials. We anticipate that our findings will advance the rational development of clinical trials of stem cell therapy for cerebral palsy and contribute to the clinical application of stem cells.
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Affiliation(s)
- Zhong-Yue Lv
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University; Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning Province, China
| | - Ying Li
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University; Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning Province, China
| | - Jing Liu
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University; Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning Province, China
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