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1
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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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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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Motavaf M, Dehghan S, Ghajarzadeh M, Ebrahimi N, Zali A, Safari S, Mirmosayyeb O. Stem Cell Treatment and Cerebral Palsy: A Systematic Review and Meta-Analysis. Curr Stem Cell Res Ther 2024; 19:210-219. [PMID: 36464870 DOI: 10.2174/1574888x18666221201114756] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/03/2022] [Accepted: 10/14/2022] [Indexed: 12/12/2022]
Abstract
OBJECTIVE We designed this systematic review and meta-analysis to estimate the pooled efficacy and safety profile of different types of stem cells in treating patients with cerebral palsy (CP). METHODS We systematically searched PubMed, Scopus, EMBASE, Web of Science, Google Scholar, and also gray literature, including references of the included studies which were published before November 2021. We extracted data regarding the total number of participants, first author, publication year, country of origin, mean age, cell type, cell dose, cell source, method of transplantation, duration of follow-up, Gross motor function, Ashworth scale, and adverse events. RESULTS We found 2073 articles by literature search; after deleting duplicates, 1194 remained. Nine articles remained for meta-analysis. The SMD of GMF-66 score (after-before) treatment was 1.5 (95% CI:0.7-2.3) (I2 = 89.9%, P < 0.001). The pooled incidence of Gastrointestinal (GI) complications after transplantation was 21% (95% CI:9-33%) (I2 = 56%, P = 0.08). The pooled incidence of fever after transplantation was 18 % (95% CI:6-30%) (I2 = 87.9%, P = 0.08 < 0.001) Conclusion: The result of this systematic review and meta-analysis show that stem cell therapy in cerebral palsy has neuroprotective properties from anti-inflammatory and anti-apoptotic activities. Stem cell therapy seems to be a promising adjunct to traditional therapies for cerebral palsy patients.
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Affiliation(s)
- Mahsa Motavaf
- Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Comprehensive Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Dehghan
- Stem cell and Regeneration Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Eye Research Center, The Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Ghajarzadeh
- Universal Council of Epidemiology (UCE), Universal Scientific Education and Research Network (USERN), Tehran University of Medical Sciences, Tehran, Iran
| | - Narges Ebrahimi
- School of medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Zali
- Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Comprehensive Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeid Safari
- Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Comprehensive Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Omid Mirmosayyeb
- Isfahan Neurosciences Research Center, Isfahan University of medical sciences, Isfahan, Iran
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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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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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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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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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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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10
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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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11
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Huang H, Al Zoubi ZM, Moviglia G, Sharma HS, Sarnowska A, Sanberg PR, Chen L, Xue Q, Siniscalco D, Feng S, Saberi H, Guo X, Xue M, Dimitrijevic MR, Andrews RJ, Mao G, Zhao RC, Han F. Clinical cell therapy guidelines for neurorestoration (IANR/CANR 2022). JOURNAL OF NEURORESTORATOLOGY 2022. [DOI: 10.1016/j.jnrt.2022.100015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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12
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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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13
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Goncharov AG, Yurova KA, Shupletsova VV, Gazatova ND, Melashchenko OB, Litvinova LS. Characteristics of Umbilical-Cord Blood and Its Use in Clinical Practice. CELL AND TISSUE BIOLOGY 2022; 16:15-31. [DOI: 10.1134/s1990519x22010047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 05/31/2021] [Accepted: 06/05/2021] [Indexed: 01/04/2025]
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14
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Eastman G, Sharlow ER, Lazo JS, Bloom GS, Sotelo-Silveira JR. Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer's Disease Model Mice. J Alzheimers Dis 2022; 86:365-386. [PMID: 35034904 DOI: 10.3233/jad-215357] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Defining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD. OBJECTIVE To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2 -/- ) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling). METHODS Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools. RESULTS Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection. CONCLUSION This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.
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Affiliation(s)
- Guillermo Eastman
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Ministerio de Educación y Cultura, Montevideo, Uruguay.,Department of Biology, University of Virginia, Charlottesville, VA, USA
| | - Elizabeth R Sharlow
- Department of Pharmacology, University of Virginia, Charlottesville, VA, USA
| | - John S Lazo
- Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.,Department of Chemistry, University of Virginia, Charlottesville, VA, USA
| | - George S Bloom
- Department of Biology, University of Virginia, Charlottesville, VA, USA.,Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.,Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - José R Sotelo-Silveira
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Ministerio de Educación y Cultura, Montevideo, Uruguay.,Sección Biología Celular, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
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15
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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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16
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Chitu V, Biundo F, Stanley ER. Colony stimulating factors in the nervous system. Semin Immunol 2021; 54:101511. [PMID: 34743926 DOI: 10.1016/j.smim.2021.101511] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/23/2021] [Indexed: 01/02/2023]
Abstract
Although traditionally seen as regulators of hematopoiesis, colony-stimulating factors (CSFs) have emerged as important players in the nervous system, both in health and disease. This review summarizes the cellular sources, patterns of expression and physiological roles of the macrophage (CSF-1, IL-34), granulocyte-macrophage (GM-CSF) and granulocyte (G-CSF) colony stimulating factors within the nervous system, with a particular focus on their actions on microglia. CSF-1 and IL-34, via the CSF-1R, are required for the development, proliferation and maintenance of essentially all CNS microglia in a temporal and regional specific manner. In contrast, in steady state, GM-CSF and G-CSF are mainly involved in regulation of microglial function. The alterations in expression of these growth factors and their receptors, that have been reported in several neurological diseases, are described and the outcomes of their therapeutic targeting in mouse models and humans are discussed.
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Affiliation(s)
- Violeta Chitu
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
| | - Fabrizio Biundo
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
| | - E Richard Stanley
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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17
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Shariati M, Esfahani RJ, Bidkhori HR, Sabouri E, Mehrzad S, Sadr-Nabavi A. Cell-based treatment of cerebral palsy: still a long way ahead. Curr Stem Cell Res Ther 2021; 17:741-749. [PMID: 34727864 DOI: 10.2174/1574888x16666211102090230] [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: 04/21/2021] [Revised: 07/28/2021] [Accepted: 08/19/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cerebral palsy (CP) is a permanent neurodevelopmental disorder with considerable global disability. Various rehabilitation strategies are currently available. However, none represents a convincing curative result. Cellular therapy recently holds much promise as an alternative strategy to repair neurologic defects. METHOD In this narrative review, a comprehensive search of the MEDLINE and ClinicalTrials.gov was made, using the terms: "cell therapy" and "cerebral palsy", including published and registered clinical studies, respectively. RESULTS The early effects of these studies demonstrated that using cell therapy in CP patients is safe and improves the deficits for a variable duration. Despite such hopeful early bird results, the long-term outcomes are not conclusive. CONCLUSIONS Due to the heterogeneous nature of CP, personal factors seem essential to consider. Cell dosage, routes of administration, and repeated dosing are pivotal to establish optimal personalized treatments. Future clinical trials should consider employing other cell types, specific cell modifications before administration, and cell-free platforms.
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Affiliation(s)
- Mohammad Shariati
- Stem Cells and Regenerative Medicine Research Department, Academic Center for Education, Culture, and Research (ACECR)-Khorasan Razavi, Mashhad. Iran
| | - Reza Jafarzadeh Esfahani
- Blood Borne Infections Research Center, Academic Center for Education, Culture and Research (ACECR)- Khorasan Razavi, Mashhad. Iran
| | - Hamid Reza Bidkhori
- Stem Cells and Regenerative Medicine Research Department, Academic Center for Education, Culture, and Research (ACECR)-Khorasan Razavi, Mashhad. Iran
| | - Ehsan Sabouri
- Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Shadi Mehrzad
- Stem Cells and Regenerative Medicine Research Department, Academic Center for Education, Culture, and Research (ACECR)-Khorasan Razavi, Mashhad. Iran
| | - Ariane Sadr-Nabavi
- Department of Neurology, School of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
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18
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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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19
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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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20
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Min K, Suh MR, Cho KH, Park W, Kang MS, Jang SJ, Kim SH, Rhie S, Choi JI, Kim HJ, Cha KY, Kim M. Potentiation of cord blood cell therapy with erythropoietin for children with CP: a 2 × 2 factorial randomized placebo-controlled trial. Stem Cell Res Ther 2020; 11:509. [PMID: 33246489 PMCID: PMC7694426 DOI: 10.1186/s13287-020-02020-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023] Open
Abstract
Background Concomitant administration of allogeneic umbilical cord blood (UCB) infusion and erythropoietin (EPO) showed therapeutic efficacy in children with cerebral palsy (CP). However, no clinical studies have investigated the effects of UCB and EPO combination therapy using a 2 × 2 four-arm factorial blinded design with four arms. This randomized placebo-controlled trial aimed to identify the synergistic and individual efficacies of UCB cell and EPO for the treatment of CP. Methods Children diagnosed with CP were randomly segregated into four groups: (A) UCB+EPO, (B) UCB+placebo EPO, (C) placebo UCB+EPO, and (D) placebo UCB+placebo EPO. Based on the UCB unit selection criteria of matching for ≥ 4/6 of human leukocyte antigen (HLA)-A, -B, and DRB1 and total nucleated cell (TNC) number of ≥ 3 × 107/kg, allogeneic UCB was intravenously infused and 500 IU/kg human recombinant EPO was administered six times. Functional measurements, brain imaging studies, and electroencephalography were performed from baseline until 12 months post-treatment. Furthermore, adverse events were closely monitored. Results Eighty-eight of 92 children enrolled (3.05 ± 1.22 years) completed the study. Change in gross motor performance measure (GMPM) was greater in group A than in group D at 1 month (△2.30 vs. △0.71, P = 0.025) and 12 months (△6.85 vs. △2.34, P = 0.018) post-treatment. GMPM change ratios were calculated to adjust motor function at the baseline. Group A showed a larger improvement in the GMPM change ratio at 1 month and 12 months post-treatment than group D. At 12 months post-treatment, the GMPM change ratios were in the order of groups A, B, C, and D. These results indicate synergistic effect of UCB and EPO combination better than each single therapy. In diffusion tensor imaging, the change ratio of fractional anisotropy at spinothalamic radiation was higher in group A than group D in subgroup of age ≥ 3 years. Additionally, higher TNC and more HLA-matched UCB units led to better gross motor outcomes in group A. Adverse events remained unchanged upon UCB or EPO administration. Conclusions These results indicate that the efficacy of allogeneic UCB cell could be potentiated by EPO for neurological recovery in children with CP without harmful effects. Trial registration ClinicalTrials.gov, NCT01991145, registered 25 November 2013.
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Affiliation(s)
- 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, Seongnam, Republic of Korea
| | - 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
| | - Kye Hee Cho
- Rehabilitation and Regeneration Research Center, CHA University, Seongnam, Republic of Korea.,Department of Rehabilitation Medicine, CHA Ilsan Medical Center, CHA University School of Medicine, Ilsan, Republic of Korea
| | - Wookyung 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.,Rehabilitation and Regeneration Research Center, CHA University, Seongnam, Republic of Korea
| | - Myung Seo Kang
- Department of Laboratory Medicine, CHA Bundang Medical Center, CHA University School of Medicine and CHA Cord Blood Bank, Seongnam, Republic of Korea
| | - Su Jin Jang
- Department of Nuclear Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Sang Heum Kim
- Department of Radiology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Seonkyeong Rhie
- Department of Pediatrics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Jee In Choi
- Rehabilitation and Regeneration Research Center, CHA University, Seongnam, Republic of Korea
| | - Hyun-Jin Kim
- Rehabilitation and Regeneration Research Center, CHA University, Seongnam, Republic of Korea
| | - Kwang Yul Cha
- CHA Hollywood Presbyterian Medical Center, Los Angeles, CA, USA
| | - MinYoung 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, Seongnam, Republic of Korea.
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21
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Qiu H, Qian T, Wu T, Wang X, Zhu C, Chen C, Wang L. Umbilical cord blood cells for the treatment of preterm white matter injury: Potential effects and treatment options. J Neurosci Res 2020; 99:778-792. [PMID: 33207392 DOI: 10.1002/jnr.24751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/31/2022]
Abstract
Preterm birth is a global public health problem. A large number of preterm infants survive with preterm white matter injury (PWMI), which leads to neurological deficits, and has multifaceted etiology, clinical course, monitoring, and outcomes. The principal upstream insults leading to PWMI initiation are hypoxia-ischemia and infection and/or inflammation and the key target cells are late oligodendrocyte precursor cells. Current PWMI treatments are mainly supportive, and thus have little effect in terms of protecting the immature brain or repairing injury to improve long-term outcomes. Umbilical cord blood (UCB) cells comprise abundant immunomodulatory and stem cells, which have the potential to reduce brain injury, mainly due to anti-inflammatory and immunomodulatory mechanisms, and also through their release of neurotrophic or growth factors to promote endogenous neurogenesis. In this review, we briefly summarize PWMI pathogenesis and pathophysiology, and the specific properties of different cell types in UCB. We further explore the potential mechanism by which UCB can be used to treat PWMI, and discuss the advantages of and potential issues related to UCB cell therapy. Finally, we suggest potential future studies of UCB cell therapy in preterm infants.
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Affiliation(s)
- Han Qiu
- Key Laboratory of Neonatal Diseases of Health Commission of the People's Republic of China, Shanghai, China.,Department of Neonatology, National Children's Medical Center/Children's Hospital of Fudan University, Shanghai, China
| | - Tianyang Qian
- Key Laboratory of Neonatal Diseases of Health Commission of the People's Republic of China, Shanghai, China.,Department of Neonatology, National Children's Medical Center/Children's Hospital of Fudan University, Shanghai, China
| | - Tong Wu
- Key Laboratory of Neonatal Diseases of Health Commission of the People's Republic of China, Shanghai, China.,Department of Neonatology, National Children's Medical Center/Children's Hospital of Fudan University, Shanghai, China
| | - Xiaoyang Wang
- Center of Perinatal Medicine and Health, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Changlian Zhu
- Center of Perinatal Medicine and Health, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Chao Chen
- Key Laboratory of Neonatal Diseases of Health Commission of the People's Republic of China, Shanghai, China.,Department of Neonatology, National Children's Medical Center/Children's Hospital of Fudan University, Shanghai, China
| | - Laishuan Wang
- Key Laboratory of Neonatal Diseases of Health Commission of the People's Republic of China, Shanghai, China.,Department of Neonatology, National Children's Medical Center/Children's Hospital of Fudan University, Shanghai, China
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22
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Bartlett RD, Burley S, Ip M, Phillips JB, Choi D. Cell Therapies for Spinal Cord Injury: Trends and Challenges of Current Clinical Trials. Neurosurgery 2020; 87:E456-E472. [DOI: 10.1093/neuros/nyaa149] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 03/11/2020] [Indexed: 12/22/2022] Open
Abstract
Abstract
Cell therapies have the potential to revolutionize the treatment of spinal cord injury. Basic research has progressed significantly in recent years, with a plethora of cell types now reaching early-phase human clinical trials, offering new strategies to repair the spinal cord. However, despite initial enthusiasm for preclinical and early-phase clinical trials, there has been a notable hiatus in the translation of cell therapies to routine clinical practice. Here, we review cell therapies that have reached clinical trials for spinal cord injury, providing a snapshot of all registered human trials and a summary of all published studies. Of registered trials, the majority have used autologous cells and approximately a third have been government funded, a third industry sponsored, and a third funded by university or healthcare systems. A total of 37 cell therapy trials have been published, primarily using stem cells, although a smaller number have used Schwann cells or olfactory ensheathing cells. Significant challenges remain for cell therapy trials in this area, including achieving stringent regulatory standards, ensuring appropriately powered efficacy trials, and establishing sustainable long-term funding. However, cell therapies hold great promise for human spinal cord repair and future trials must continue to capitalize on the exciting developments emerging from preclinical studies.
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Affiliation(s)
- Richard D Bartlett
- Centre for Nerve Engineering, University College London, London, United Kingdom
- Department of Pharmacology, UCL School of Pharmacy, University College London, London, United Kingdom
- Brain Repair and Rehabilitation, Institute of Neurology, University College London, London, United Kingdom
| | - Sarah Burley
- Centre for Nerve Engineering, University College London, London, United Kingdom
| | - Mina Ip
- Centre for Nerve Engineering, University College London, London, United Kingdom
| | - James B Phillips
- Centre for Nerve Engineering, University College London, London, United Kingdom
- Department of Pharmacology, UCL School of Pharmacy, University College London, London, United Kingdom
| | - David Choi
- Centre for Nerve Engineering, University College London, London, United Kingdom
- Brain Repair and Rehabilitation, Institute of Neurology, University College London, London, United Kingdom
- Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, United Kingdom
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23
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Novak I, Morgan C, Fahey M, Finch-Edmondson M, Galea C, Hines A, Langdon K, Namara MM, Paton MC, Popat H, Shore B, Khamis A, Stanton E, Finemore OP, Tricks A, Te Velde A, Dark L, Morton N, Badawi N. State of the Evidence Traffic Lights 2019: Systematic Review of Interventions for Preventing and Treating Children with Cerebral Palsy. Curr Neurol Neurosci Rep 2020; 20:3. [PMID: 32086598 PMCID: PMC7035308 DOI: 10.1007/s11910-020-1022-z] [Citation(s) in RCA: 532] [Impact Index Per Article: 106.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Cerebral palsy is the most common physical disability of childhood, but the rate is falling, and severity is lessening. We conducted a systematic overview of best available evidence (2012-2019), appraising evidence using GRADE and the Evidence Alert Traffic Light System and then aggregated the new findings with our previous 2013 findings. This article summarizes the best available evidence interventions for preventing and managing cerebral palsy in 2019. RECENT FINDINGS Effective prevention strategies include antenatal corticosteroids, magnesium sulfate, caffeine, and neonatal hypothermia. Effective allied health interventions include acceptance and commitment therapy, action observations, bimanual training, casting, constraint-induced movement therapy, environmental enrichment, fitness training, goal-directed training, hippotherapy, home programs, literacy interventions, mobility training, oral sensorimotor, oral sensorimotor plus electrical stimulation, pressure care, stepping stones triple P, strength training, task-specific training, treadmill training, partial body weight support treadmill training, and weight-bearing. Effective medical and surgical interventions include anti-convulsants, bisphosphonates, botulinum toxin, botulinum toxin plus occupational therapy, botulinum toxin plus casting, diazepam, dentistry, hip surveillance, intrathecal baclofen, scoliosis correction, selective dorsal rhizotomy, and umbilical cord blood cell therapy. We have provided guidance about what works and what does not to inform decision-making, and highlighted areas for more research.
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Affiliation(s)
- Iona Novak
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia.
| | - Catherine Morgan
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
| | - Michael Fahey
- Department of Paediatric Neurology, Monash Health, Clayton, Victoria, Australia
- Department of Paediatrics, Monash University, Clayton, Victoria, Australia
| | - Megan Finch-Edmondson
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
| | - Claire Galea
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
- Grace Centre for Newborn Care, Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - Ashleigh Hines
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
| | - Katherine Langdon
- Department of Paediatric Rehabilitation, Kids Rehab WA, Perth Children's Hospital, Perth, Australia
| | - Maria Mc Namara
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
| | - Madison Cb Paton
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
| | - Himanshu Popat
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
- Grace Centre for Newborn Care, Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - Benjamin Shore
- Department of Orthopedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Amanda Khamis
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
| | - Emma Stanton
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
| | - Olivia P Finemore
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
| | - Alice Tricks
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
| | - Anna Te Velde
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
| | - Leigha Dark
- Allied and Public Helath, Faculty of Health Sciences, Western Sydney University, Sydney, New South Wales, Australia
| | - Natalie Morton
- Allied and Public Helath, Faculty of Health Sciences, Western Sydney University, Sydney, New South Wales, Australia
- School of Allied Health, Australian Catholic University, North Sydney, New South Wales, Australia
| | - Nadia Badawi
- Cerebral Palsy Alliance Research Institute, Discipline of Child & Adolescent Health, Faculty of Medicine & Health, The University of Sydney, PO Box 6427, Frenchs Forest, Sydney, NSW, 2086, Australia
- Grace Centre for Newborn Care, Children's Hospital at Westmead, Westmead, New South Wales, Australia
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Huang H, Chen L, Mao G, Sharma HS. Clinical neurorestorative cell therapies: Developmental process, current state and future prospective. JOURNAL OF NEURORESTORATOLOGY 2020. [DOI: 10.26599/jnr.2020.9040009] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Clinical cell therapies (CTs) for neurological diseases and cellular damage have been explored for more than 2 decades. According to the United States Food and Drug Administration, there are 2 types of cell categories for therapy, namely stem cell-derived CT products and mature/functionally differentiated cell-derived CT products. However, regardless of the type of CT used, the majority of reports of clinical CTs from either small sample sizes based on single-center phase 1 or 2 unblinded trials or retrospective clinical studies showed effects on neurological improvement and the ability to either partially or temporarily thwart the deteriorating cellular processes of the neurodegenerative diseases. There have been only a few prospective, multicenter, randomized, double- blind placebo-control clinical trials of CTs so far in this developing novel area that have shown negative results, and more clinical trials are needed. This will expand our knowledge in exploring the type of cells that yield promising results and restore damaged neurological structure and functions of the central nervous system based on higher level evidence-based medical data. In this review, we briefly introduce the developmental process, current state, and future prospective for clinical neurorestorative CT.
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Wang Y, Guo X, Liu J, Zheng Z, Liu Y, Gao W, Xiao J, Liu Y, Li Y, Tang M, Wang L, Chen L, Chen D, Guo D, Liu F, Chen W, Chan B, Zhou B, Liu A, Mao G, Huang H. Olfactory ensheathing cells in chronic ischemic stroke: A phase 2, double-blind, randomized, controlled trial. JOURNAL OF NEURORESTORATOLOGY 2020. [DOI: 10.26599/jnr.2020.9040019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Olfactory ensheathing cells (OECs) have shown promising results for patients with neurologic diseases in non-double-blind, placebo control studies. Thirty patients with a unilateral ischemic stroke of more than a year were enrolled in a phase 2, multicenter, randomized, double-blind, and placebo-controlled cell therapy trial with a subsequent 12-month follow-up. The primary therapeutic objective has shown that after 12 months, there were significant differences in National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) assessment scores among the OEC group, Schwann cell group and placebo medium group at one-year follow-up. The second therapeutic objective found that there were significant differences in NIHSS, mRS, and BI assessment scores when comparing the endpoint data with the baseline data in the OEC group. There was neither hypersensitivity reaction nor adverse event. The results of this multicenter, randomized, double-blind, and placebo-controlled study indicate that injecting OECs into the olfactory sub-mucosa have neurorestorative effects, which can improve the quality of life for patients with chronic ischemic strokes without serious side effects.
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Eggenberger S, Boucard C, Schoeberlein A, Guzman R, Limacher A, Surbek D, Mueller M. Stem cell treatment and cerebral palsy: Systemic review and meta-analysis. World J Stem Cells 2019; 11:891-903. [PMID: 31692977 PMCID: PMC6828595 DOI: 10.4252/wjsc.v11.i10.891] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 07/31/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Perinatal complications may result in life-long morbidities, among which cerebral palsy (CP) is the most severe motor disability. Once developed, CP is a non-progressive disease with a prevalence of 1-2 per 1000 live births in developed countries. It demands an extensive and multidisciplinary care. Therefore, it is a challenge for our health system and a burden for patients and their families. Recently, stem cell therapy emerged as a promising treatment option and raised hope in patients and their families.
AIM The aim is to evaluate the efficacy and safety of stem cell treatment in children with CP using a systematic review and meta-analysis
METHODS We performed a systematic literature search on PubMed and EMBASE to find randomized controlled clinical trials (RCT) investigating the effect of stem cell transplantation in children with CP. After the review, we performed a random-effects meta-analysis focusing on the change in gross motor function, which was quantified using the gross motor function measure. We calculated the pooled standardized mean differences of the 6- and/or 12-mo-outcome by the method of Cohen. We quantified the heterogeneity using the I-squared measure.
RESULTS We identified a total of 8 RCT for a qualitative review. From the initially selected trials, 5 met the criteria and were included in the meta-analysis. Patients’ population ranged from 0.5 up to 35 years (n = 282). We detected a significant improvement in the gross motor function with a pooled standard mean difference of 0.95 (95% confidence interval: 0.13-1.76) favoring the stem cell group and a high heterogeneity (I2 = 90.1%). Serious adverse events were rare and equally distributed among both intervention and control groups.
CONCLUSION Stem cell therapy for CP compared with symptomatic standard care only, shows a significant positive effect on the gross motor function, although the magnitude of the improvement is limited. Short-term safety is present and further high-quality RCTs are needed.
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Affiliation(s)
- Simone Eggenberger
- Department of Obstetrics and Gynaecology, Inselspital, University Hospital Bern, Bern 3010, Switzerland
| | - Céline Boucard
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
| | | | - Raphael Guzman
- Department of Neurosurgery, University Hospital of Basel, Basel 4056, Switzerland
| | | | - Daniel Surbek
- Department of Obstetrics and Gynaecology, Inselspital, University Hospital Bern, Bern 3010, Switzerland
| | - Martin Mueller
- Department of Obstetrics and Gynaecology, Inselspital, University Hospital Bern, Bern 3010, Switzerland
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Boruczkowski D, Pujal JM, Zdolińska-Malinowska I. Autologous cord blood in children with cerebral palsy: a review. Int J Mol Sci 2019; 20:2433. [PMID: 31100943 PMCID: PMC6566649 DOI: 10.3390/ijms20102433] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 05/11/2019] [Accepted: 05/12/2019] [Indexed: 02/07/2023] Open
Abstract
The aim of this narrative review is to report on the current knowledge regarding the clinical use of umbilical cord blood (CB) based on articles from PubMed and clinical trials registered on ClinicalTrials.gov. An increasing amount of evidence suggests that CB may be used for both early diagnostics and treatment of cerebral palsy. The acidity of CB and its biochemical parameters, including dozens of cytokines, growth factors, and other metabolites (such as amino acids, acylcarnitines, phosphatidylcholines, succinate, glycerol, 3-hydroxybutyrate, and O-phosphocholine) are predictors of future neurodevelopment. In addition, several clinical studies confirmed the safety and efficacy of CB administration in both autologous and allogeneic models, including a meta-analysis of five clinical trials involving a total of 328 participants. Currently, nine clinical trials assessing the use of autologous umbilical CB in children diagnosed with hypoxic-ischemic encephalopathy or cerebral palsy are in progress. The total population assessed in these trials exceeds 2500 patients.
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Affiliation(s)
- Dariusz Boruczkowski
- Polski Bank Komórek Macierzystych S.A. (FamiCord Group), Jana Pawła II 29, 00-867 Warsaw, Poland.
| | - Josep-Maria Pujal
- Sevibe Cells, Parc Científic i Tecnològic de la UdG, C/Pic de Peguera No. 11, 17003 Girona, Spain.
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Ma Y, Shi Q, Xiao K, Wang J, Chen C, Gao LP, Gao C, Dong XP. Stimulations of the Culture Medium of Activated Microglia and TNF-Alpha on a Scrapie-Infected Cell Line Decrease the Cell Viability and Induce Marked Necroptosis That Also Occurs in the Brains from the Patients of Human Prion Diseases. ACS Chem Neurosci 2019; 10:1273-1283. [PMID: 30399321 DOI: 10.1021/acschemneuro.8b00354] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Activation of microglia and increased expression of TNF-α are frequently observed in the brains of human and animal prion diseases. As an important cytokine, TNF-α participates in not only pro-inflammatory responses but also in cellular communication, cell differentiation, and cell death. However, the role of TNF-α in the pathogenesis of prion disease remains ambiguous. In this study, the activities of a scrapie-infected cell line SMB-S15 and its normal partner SMB-PS exposed to the supernatant of a LPS-activated microglia cell line BV2 were evaluated. After it was exposed to the LPS-stimulated supernatant of BV2 cells, the cell viability of SMB-S15 cells was markedly decreased, whereas that of the SMB-PS cells remained unchanged. The level of TNF-α was significantly increased in the LPS-stimulated supernatant of BV2 cells. Further, we found that the recombinant TNF-α alone induced the decreased cell viability of SMB-S15 and the neutralizing antibody for TNF-α completely antagonized the decreased cell viability caused by the LPS-stimulated supernatant of BV2 cells. Stimulation with TNF-α induced the remarkable increases of apoptosis-associated proteins in SMB-PS cells, such as cleaved caspase-3 and RIP1, whereas an obvious increase of necroptosis-associated protein in SMB-S15 cells, such as p-MLKL. Meanwhile, the upregulation of caspase-8 activity in SMB-PS cells was more significant than that of SMB-S15 cells. The decreased cell viability of SMB-S15 and the increased expression of p-MLKL induced by TNF-α were completely rescued by Necrostatin-1. Moreover, we verified that removal of PrPSc propagation in SMB-S15 cells by resveratrol partially rescues the cell tolerance to the stimulation of TNF-α. These data indicate that the prion-infected cell line SMB-S15 is more vulnerable to the stimulations of activated microglia and TNF-α, which is likely due to the outcome of necroptosis rather than apoptosis. Furthermore, significant upregulation of p-MLKL, MLKL, and RIP3 was detected in the post-mortem cortical brains of the patients of various types of human prion diseases, including sporadic Creutzfeldt-Jakob disease (sCJD), G114 V-genetic CJD (gCJD), and fatal familial insomnia (FFI).
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Affiliation(s)
- Yue Ma
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing 102206, China
| | - Qi Shi
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing 102206, China
| | - Kang Xiao
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing 102206, China
| | - Jing Wang
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing 102206, China
| | - Cao Chen
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing 102206, China
| | - Li-Ping Gao
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing 102206, China
| | - Chen Gao
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing 102206, China
| | - Xiao-Ping Dong
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing 102206, China
- Center of Global Public Health, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing 102206, China
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Finch-Edmondson M, Morgan C, Hunt RW, Novak I. Emergent Prophylactic, Reparative and Restorative Brain Interventions for Infants Born Preterm With Cerebral Palsy. Front Physiol 2019; 10:15. [PMID: 30745876 PMCID: PMC6360173 DOI: 10.3389/fphys.2019.00015] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 01/08/2019] [Indexed: 12/13/2022] Open
Abstract
Worldwide, an estimated 15 million babies are born preterm (<37 weeks' gestation) every year. Despite significant improvements in survival rates, preterm infants often face a lifetime of neurodevelopmental disability including cognitive, behavioral, and motor impairments. Indeed, prematurity remains the largest risk factor for the development of cerebral palsy. The developing brain of the preterm infant is particularly fragile; preterm babies exhibit varying severities of cerebral palsy arising from reductions in both cerebral white and gray matter volumes, as well as altered brain microstructure and connectivity. Current intensive care therapies aim to optimize cardiovascular and respiratory function to protect the brain from injury by preserving oxygenation and blood flow. If a brain injury does occur, definitive diagnosis of cerebral palsy in the first few hours and weeks of life is difficult, especially when the lesions are subtle and not apparent on cranial ultrasound. However, early diagnosis of mildly affected infants is critical, because these are the patients most likely to respond to emergent treatments inducing neuroplasticity via high-intensity motor training programs and regenerative therapies involving stem cells. A current controversy is whether to test universal treatment in all infants at risk of brain injury, accepting that some patients never required treatment, because the perceived potential benefits outweigh the risk of harm. Versus, waiting for a diagnosis before commencing targeted treatment for infants with a brain injury, and potentially missing the therapeutic window. In this review, we discuss the emerging prophylactic, reparative, and restorative brain interventions for infants born preterm, who are at high risk of developing cerebral palsy. We examine the current evidence, considering the timing of the intervention with relation to the proposed mechanism/s of action. Finally, we consider the development of novel markers of preterm brain injury, which will undoubtedly lead to improved diagnostic and prognostic capability, and more accurate instruments to assess the efficacy of emerging interventions for this most vulnerable group of infants.
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Affiliation(s)
- Megan Finch-Edmondson
- The Discipline of Child and Adolescent Health, The Children's Hospital at Westmead Clinical School, The University of Sydney Medical School, Sydney, NSW, Australia
- Cerebral Palsy Alliance Research Institute, The University of Sydney, Sydney, NSW, Australia
| | - Catherine Morgan
- The Discipline of Child and Adolescent Health, The Children's Hospital at Westmead Clinical School, The University of Sydney Medical School, Sydney, NSW, Australia
- Cerebral Palsy Alliance Research Institute, The University of Sydney, Sydney, NSW, Australia
| | - Rod W. Hunt
- Department of Neonatal Medicine, The Royal Children's Hospital, Melbourne, VIC, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
- Neonatal Research, Murdoch Children's Research Institute, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Iona Novak
- The Discipline of Child and Adolescent Health, The Children's Hospital at Westmead Clinical School, The University of Sydney Medical School, Sydney, NSW, Australia
- Cerebral Palsy Alliance Research Institute, The University of Sydney, Sydney, NSW, Australia
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30
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Jiao Y, Li XY, Liu J. A New Approach to Cerebral Palsy Treatment: Discussion of the Effective Components of Umbilical Cord Blood and its Mechanisms of Action. Cell Transplant 2018; 28:497-509. [PMID: 30384766 PMCID: PMC7103597 DOI: 10.1177/0963689718809658] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cerebral palsy (CP) includes a group of persistent non-progressive disorders
affecting movement, muscle tone, and/or posture. The total economic loss during
the life-span of an individual with CP places a heavy financial burden on such
patients and their families worldwide; however, a complete cure is still
lacking. Umbilical cord blood (UCB)-based interventions are emerging as a
scientifically plausible treatment and possible cure for CP. Stem cells have
been used in many experimental CP animal models and achieved good results.
Compared with other types of stem cells, those from UCB have advantages in terms
of treatment safety and efficacy, ethics, non-neoplastic proliferation,
accessibility, ease of preservation, and regulation of immune responses, based
on findings in animal models and clinical trials. Currently, the use of
UCB-based interventions for CP is limited as the components of UCB are complex
and possess different therapeutic mechanisms. These can be categorized by three
aspects: homing and neuroregeneration, trophic factor secretion, and
neuroprotective effects. Our review summarizes the features of active components
of UCB and their therapeutic mechanism of action. This review highlights current
research findings and clinical evidence regarding UCB that contribute to
treatment suggestions, inform decision-making for therapeutic interventions, and
help to direct future research.
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Affiliation(s)
- Yang Jiao
- 1 Stem Cell Clinical Research Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Xiao-Yan Li
- 1 Stem Cell Clinical Research Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Jing Liu
- 1 Stem Cell Clinical Research Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
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31
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Lee TE, Kim A, Jang M, Jeon B. Underregistration and Underreporting of Stem Cell Clinical Trials in Neurological Disorders. J Clin Neurol 2018; 14:215-224. [PMID: 29629526 PMCID: PMC5897206 DOI: 10.3988/jcn.2018.14.2.215] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 11/30/2017] [Accepted: 11/30/2017] [Indexed: 12/13/2022] Open
Abstract
Background and Purpose Research on stem cells (SC) is growing rapidly in neurology, but clinical applications of SC for neurological disorders remain to be proven effective and safe. Human clinical trials need to be registered in registries in order to reduce publication bias and selective reporting. Methods We searched three databases—clinicaltrials.gov, the Clinical Research Information System (CRIS), and PubMed—for neurologically relevant SC-based human trials and articles in Korea. The registration of trials, posting and publication of results, and registration of published SC articles were examined. Results There were 17 completed trials registered at clinicaltrials.gov and the CRIS website, with results articles having been published for 5 of them. Our study found 16 publications, of which 1 was a review article, 1 was a protocol article, and 8 contained registered trial information. Conclusions Many registered SC trials related to neurological disorders are not reported, while many SC-related publications are not registered in a public registry. These results support the presence of biased reporting and publication bias in SC trials related to neurological disorders in Korea.
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Affiliation(s)
- Timothy E Lee
- University of South Florida, Morsani College of Medicine, Tampa, FL, USA
| | - Aryun Kim
- Department of Neurology, Seoul National University College of Medicine, Seoul, Korea
| | - Mihee Jang
- Department of Neurology, Seoul National University College of Medicine, Seoul, Korea
| | - Beomseok Jeon
- Departments of Neurology and Movement Disorder Center, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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Russ JB, Nallappan AM, Robichaux-Viehoever A. Management of Pediatric Movement Disorders: Present and Future. Semin Pediatr Neurol 2018; 25:136-151. [PMID: 29735111 DOI: 10.1016/j.spen.2018.02.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Management of movement disorders in children is an evolving field. This article outlines the major categories of treatment options for pediatric movement disorders and general guidelines for their use. We review the evidence for existing therapies, which continue to lack large-scale controlled trials to guide treatment decisions. The field continues to rely on extrapolations from adult studies and lower quality evidence such as case reports and case series to guide treatment guidelines and consensus statements. Developments in new pharmaceuticals for rare diseases have begun to provide hope for those cases in which a genetic diagnosis can be made. Advances in surgical therapies such as deep brain stimulation as well as new modes of treatment such as gene therapy, epigenetic modulation, and stem cell therapy hold promise for improving outcomes in both primary and secondary causes of movement disorders. There is a critical need for larger, multicenter, controlled clinical trials to fully evaluate treatments for pediatric movement disorders.
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Affiliation(s)
- Jeffrey B Russ
- Department of Pediatrics, University of California San Francisco, San Francisco, CA
| | - Akila M Nallappan
- Undergraduate Program, Case Western Reserve University, Cleveland, OH
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33
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Lee YH. Storage and use of cord blood. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2018. [DOI: 10.5124/jkma.2018.61.9.557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Young-Ho Lee
- Department of Pediatrics, Hanyang University College of Medicine, Seoul, Korea
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34
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Jantzie LL, Scafidi J, Robinson S. Stem cells and cell-based therapies for cerebral palsy: a call for rigor. Pediatr Res 2018; 83:345-355. [PMID: 28922350 DOI: 10.1038/pr.2017.233] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 07/22/2017] [Indexed: 02/07/2023]
Abstract
Cell-based therapies hold significant promise for infants at risk for cerebral palsy (CP) from perinatal brain injury (PBI). PBI leading to CP results from multifaceted damage to neural cells. Complex developing neural networks are injured by neural cell damage plus unique perturbations in cell signaling. Given that cell-based therapies can simultaneously repair multiple injured neural components during critical neurodevelopmental windows, these interventions potentially offer efficacy for patients with CP. Currently, the use of cell-based interventions in infants at risk for CP is limited by critical gaps in knowledge. In this review, we will highlight key questions facing the field, including: Who are optimal candidates for treatment? What are the goals of therapeutic interventions? What are the best strategies for agent delivery, including timing, dosage, location, and type? And, how are short- and long-term efficacy reliably tracked? Challenges unique to treating PBI with cell-based therapies, and lessons learned from cell-based therapies in closely related neurological disorders in the mature central nervous system, will be reviewed. Our goal is to update pediatric specialists who may be counseling families about the current state of the field. Finally, we will evaluate how rigor can be increased in the field to ensure the safety and best interests of this vulnerable patient population.
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Affiliation(s)
- Lauren L Jantzie
- Departments of Pediatrics and Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - Joseph Scafidi
- Department of Neurology, Children's National Health System, Washington, DC
| | - Shenandoah Robinson
- Division of Pediatric Neurosurgery, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland
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Ballen K. Umbilical Cord Blood Transplantation: Challenges and Future Directions. Stem Cells Transl Med 2017; 6:1312-1315. [PMID: 28456009 PMCID: PMC5442719 DOI: 10.1002/sctm.17-0069] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 03/30/2017] [Indexed: 01/05/2023] Open
Abstract
Since the first successful allogeneic transplants performed in Seattle 50 years ago, the field of transplantation has evolved considerably, with improvements in human leukocyte antigen typing, patient selection, reduced intensity regimens, and graft-versus-host disease prophylaxis. A major breakthrough has been the availability of more donor options, first via the National Marrow Donor Program-Be the Match [Biol Blood Marrow Transplant 2008;14:2-7]. Then, in the 1990s, unrelated umbilical cord blood transplantation became available, first for children and then for adults [New Engl J Med 1996;35:157-166]. More recently mismatched unrelated transplants and haploidentical donor options became available [Blood 2011;118:282-288]. In 2017, there is a donor for almost every patient who needs a transplant. In this review, we will discuss the state of the science (and art) of cord blood transplant, focusing on successes, challenges, and future directions. Stem Cells Translational Medicine 2017;6:1312-1315.
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