|
1
|
Akhlaghpasand M, Tavanaei R, Hosseinpoor M, Golmohammadi M, Mohammadi I, Jolfayi AG, Hosseinpour M, Hajikarimloo B, Yazdani KO, Zali A, Oraee-Yazdani S. Neurological, functional, and quality of life outcomes following combined mesenchymal stem cell and Schwann cell therapy in spinal cord injury: a 9-year experience. Stem Cell Res Ther 2025; 16:226. [PMID: 40325467 PMCID: PMC12054327 DOI: 10.1186/s13287-025-04312-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 04/04/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Spinal cord injury (SCI) often results in severe disabilities and significant socioeconomic burdens. OBJECTIVE This study aimed to evaluate the effects and safety of co-transplantation of autologous bone marrow-derived mesenchymal stem cells (MSCs) and Schwann cells (SCs) via the intrathecal route in patients with complete spinal cord injury (SCI). The analysis focused on the therapy's impact across various SCI subgroups (cervical vs. thoracolumbar, subacute vs. chronic) and the factors influencing its efficacy. METHODS This case series evaluated 106 patients with complete SCI treated with combined cell therapy between August 2013 and September 2022, with a one-year follow-up. Safety profiles were assessed, and neurological and functional outcomes were measured using the American Spinal Injury Association (ASIA) scores, Spinal Cord Independence Measure (SCIM-III), and the World Health Organization Quality of Life Brief Version (WHOQOL-BREF) at 6- and 12-month intervals post-injection. Multiple regression analysis was conducted to evaluate factors associated with outcomes. RESULTS Significant improvements were observed in ASIA scores (motor, light touch, and pinprick), SCIM-III scores (total and subscales), and WHOQOL-BREF scores after 12 months. These improvements were consistent across subgroups, regardless of injury level or duration. Multiple regression analysis indicated that improvements in ASIA motor scores were associated with injury level, while improvements in SCIM-III total and mobility scores were associated with time since injury and patient age. CONCLUSIONS This study demonstrates significant neurological, functional, and quality of life improvements following combined cell therapy with autologous MSCs and SCs in patients with complete SCI. Future research should investigate potential synergies with other therapies and conduct comparative efficacy analyses.
Collapse
Affiliation(s)
- Mohammadhosein Akhlaghpasand
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Roozbeh Tavanaei
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Maede Hosseinpoor
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
- Stem Cell Technology Research Center (STRC), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Maryam Golmohammadi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Ida Mohammadi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Amir Ghaffari Jolfayi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Melika Hosseinpour
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Bardia Hajikarimloo
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Kaveh Oraii Yazdani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Alireza Zali
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Saeed Oraee-Yazdani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran.
| |
Collapse
|
|
2
|
Abolghasemi R, Davoudi-Monfared E. Guide for Cell Therapy in Human Chronic Spinal Cord Injury. Tissue Eng Part C Methods 2025; 31:174-180. [PMID: 40279279 DOI: 10.1089/ten.tec.2025.0032] [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] [Indexed: 04/27/2025] Open
Abstract
Based on various research, different cells are effective for improving the symptoms and paraclinical indicators of patients with chronic spinal cord injury (SCI). A big gap in front of researchers and doctors is to know the source, the number of cells required for injection, the delivery method, and the required complementary treatments. We extracted the desired data (number of cells, autologous or allogeneic source of cell extraction, delivery method, and complementary treatments) from 40 clinical trials, which checked and recorded 17 scores of symptoms and paraclinical indicators in at least two studies. The most common cells for improving 11 scores were bone marrow hematopoietic stem cell and bone marrow mesenchymal stem cell. The mean effect was more in bone marrow mesenchymal stem cell with plasma as the complementary treatment. Then the highest mean effect was in bone marrow hematopoietic stem cell therapy, with the complementary treatment being methylprednisolone. The cell number (106/kg), the source (autologous), and the delivery method (intrathecal) were similar in both cell types. No life-threatening consequences or death were recorded. This guideline helps researchers and doctors choose the appropriate cell therapy method for chronic SCI.
Collapse
Affiliation(s)
- Reyhaneh Abolghasemi
- Community Medicine Specialist, New Hearing Technologies Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Esmat Davoudi-Monfared
- Health Management Research Center & Department of Community Medicine, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
3
|
Wang R, Wang Y, Yan F, Sun J, Zhang T. Assessment of mesenchymal stem cells for the treatment of spinal cord injury: a systematic review and network meta-analysis. Front Cell Neurosci 2025; 19:1532219. [PMID: 40308723 PMCID: PMC12040839 DOI: 10.3389/fncel.2025.1532219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 03/27/2025] [Indexed: 05/02/2025] Open
Abstract
Objective This study aims to explore the clinical efficacy of mesenchymal stem cell (MSC) transplantation in the treatment of patients with spinal cord injury (SCI) through a network meta-analysis and to discuss the optimal transplantation strategy for treatment. Methods We conducted a computer search of clinical randomized controlled studies on MSC treatment for SCI in databases including PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journal Database (VIP), Wanfang Database, and Chinese Biomedical Literature Service System (SinoMed) up to March 2024. Two researchers independently completed literature screening and data extraction according to the inclusion and exclusion criteria and used RevMan 5.4 software to assess the quality of the included studies. Network meta-analysis was performed using Stata 16.0 software. Results A total of 18 studies were included in the analysis. The results showed that MSCs significantly improved motor, sensory, and activities of daily living activities after SCI. Network meta-analysis indicated that umbilical cord mesenchymal stem cells (UCMSCs) were the most effective cell source, and intrathecal injection (IT) was the optimal transplantation method. Conclusion The study suggests that the current use of UCMSCs for IT transplantation may be the best transplantation strategy for improving functional impairment after SCI. Further high-quality studies are still needed to validate the results of this study and to ensure the reliability of the results. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier [CRD42023466102].
Collapse
Affiliation(s)
- Runfang Wang
- Department of Medicine, Shandong Xiandai University, Jinan, China
| | - Yiding Wang
- Department of Medicine, Shandong Xiandai University, Jinan, China
| | - Fangning Yan
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jinqing Sun
- Department of Medicine, Shandong Xiandai University, Jinan, China
| | - Tianyu Zhang
- Department of Medicine, Shandong Xiandai University, Jinan, China
| |
Collapse
|
|
4
|
Montoto-Marqués A, Benito-Penalva J, Ferreiro-Velasco ME, Andrew Wright M, Salvador-De la Barrera S, Kumru H, Gaitán-Pérez N, Hernández-Navarro A, Rodríguez-Sotillo A, Martins Braga F, Palencia-Vidal A, Vidal-Samsó J. Advances and New Therapies in Traumatic Spinal Cord Injury. J Clin Med 2025; 14:2203. [PMID: 40217653 PMCID: PMC11989486 DOI: 10.3390/jcm14072203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/06/2025] [Accepted: 03/18/2025] [Indexed: 04/14/2025] Open
Abstract
Recovery from traumatic spinal cord injury (tSCI) is challenging due to the limited regenerative capacity of the central nervous system to restore cells, myelin, and neural connections. At the clinical level, the fundamental pillars of treatment are the reduction in secondary damage (neuroprotection) and rehabilitation; these are the tools we have to mitigate the disability caused by spinal cord injury (SCI). To date, the treatments on which neuroprotection has been based are the prevention of acute respiratory failure to avoid hypoxia, early hemodynamic control, neuroprotective drugs and surgical management. Optimizing early hemodynamic control to ensure adequate spinal cord perfusion may be key to the management of SCI. While neuroprotective agents like methylprednisolone have fallen into disuse, several promising therapies are currently being tested in clinical trials. In terms of surgical treatment, although their impact on neurological recovery remains debated, appropriate early bone decompression followed by duroplasty in selected cases is increasingly recommended. Advances in cell therapies hold significant potential for enhancing both clinical and functional outcomes in SCI patients. Moreover, emerging neuromodulation techniques, such as transcutaneous and epidural stimulation, along with innovations in rehabilitation technologies-such as robotic systems and exoskeletons-are becoming indispensable tools for improving locomotion and overall mobility in individuals with SCI. This article provides an update on the advances in neuroprotection against secondary damage caused by tSCI, in cellular therapies, and in new rehabilitation therapies.
Collapse
Affiliation(s)
- Antonio Montoto-Marqués
- Unidad de Lesionados Medulares, Complejo Hospitalario Universitario de A Coruña, Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Instituto de Investigación Biomédica de A Coruña (INIBIC), 15006 A Coruña, Spain
| | - Jesús Benito-Penalva
- Fundación Institut Guttmann, Institut Universitari de Neurorehabilitació Adscrit a la UAB, 08916 Barcelona, Spain; (J.B.-P.); (M.A.W.); (H.K.); (A.H.-N.); (F.M.B.)
- Institut Universitari de Neurorehabilitació adscrit a la Universitat Autónoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
- Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, 08916 Badalona, Spain
| | - María Elena Ferreiro-Velasco
- Unidad de Lesionados Medulares, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, 15006 A Coruña, Spain; (M.E.F.-V.); (S.S.-D.l.B.); (N.G.-P.); (A.R.-S.); (A.P.-V.)
| | - Mark Andrew Wright
- Fundación Institut Guttmann, Institut Universitari de Neurorehabilitació Adscrit a la UAB, 08916 Barcelona, Spain; (J.B.-P.); (M.A.W.); (H.K.); (A.H.-N.); (F.M.B.)
- Institut Universitari de Neurorehabilitació adscrit a la Universitat Autónoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
- Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, 08916 Badalona, Spain
| | - Sebastian Salvador-De la Barrera
- Unidad de Lesionados Medulares, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, 15006 A Coruña, Spain; (M.E.F.-V.); (S.S.-D.l.B.); (N.G.-P.); (A.R.-S.); (A.P.-V.)
| | - Hatice Kumru
- Fundación Institut Guttmann, Institut Universitari de Neurorehabilitació Adscrit a la UAB, 08916 Barcelona, Spain; (J.B.-P.); (M.A.W.); (H.K.); (A.H.-N.); (F.M.B.)
- Institut Universitari de Neurorehabilitació adscrit a la Universitat Autónoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
- Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, 08916 Badalona, Spain
| | - Nelson Gaitán-Pérez
- Unidad de Lesionados Medulares, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, 15006 A Coruña, Spain; (M.E.F.-V.); (S.S.-D.l.B.); (N.G.-P.); (A.R.-S.); (A.P.-V.)
| | - Agustin Hernández-Navarro
- Fundación Institut Guttmann, Institut Universitari de Neurorehabilitació Adscrit a la UAB, 08916 Barcelona, Spain; (J.B.-P.); (M.A.W.); (H.K.); (A.H.-N.); (F.M.B.)
- Institut Universitari de Neurorehabilitació adscrit a la Universitat Autónoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
- Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, 08916 Badalona, Spain
| | - Antonio Rodríguez-Sotillo
- Unidad de Lesionados Medulares, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, 15006 A Coruña, Spain; (M.E.F.-V.); (S.S.-D.l.B.); (N.G.-P.); (A.R.-S.); (A.P.-V.)
| | - Fernando Martins Braga
- Fundación Institut Guttmann, Institut Universitari de Neurorehabilitació Adscrit a la UAB, 08916 Barcelona, Spain; (J.B.-P.); (M.A.W.); (H.K.); (A.H.-N.); (F.M.B.)
- Institut Universitari de Neurorehabilitació adscrit a la Universitat Autónoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
- Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, 08916 Badalona, Spain
| | - Angela Palencia-Vidal
- Unidad de Lesionados Medulares, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, 15006 A Coruña, Spain; (M.E.F.-V.); (S.S.-D.l.B.); (N.G.-P.); (A.R.-S.); (A.P.-V.)
| | - Joan Vidal-Samsó
- Fundación Institut Guttmann, Institut Universitari de Neurorehabilitació Adscrit a la UAB, 08916 Barcelona, Spain; (J.B.-P.); (M.A.W.); (H.K.); (A.H.-N.); (F.M.B.)
- Institut Universitari de Neurorehabilitació adscrit a la Universitat Autónoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
- Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, 08916 Badalona, Spain
| |
Collapse
|
|
5
|
Davoudi-Monfared E, Abolghasemi R, Allahyari F, Farzanegan G. Adverse events of cell therapy clinical trials in human chronic spinal cord injury, a systematic review and meta-analysis. Regen Ther 2024; 27:381-397. [PMID: 38694447 PMCID: PMC11061649 DOI: 10.1016/j.reth.2024.03.012] [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: 02/03/2024] [Revised: 03/10/2024] [Accepted: 03/15/2024] [Indexed: 05/04/2024] Open
Abstract
Spinal cord injury is a lesion with high mortality and significant morbidities. After the primary injury, during six months, a cascade of secondary cellular and molecular events makes the lesion chronic. Recently, cell-based clinical trials as a new procedure have been gradually tested to improve the symptoms of patients. Each treatment method is associated with different adverse events. Based on the PRISMA flow diagram of the identified records, and after multistep screening, finally in 76 reviewed studies with 1633 cases and 189 controls, 64 types of adverse events in 12 categories were recorded in 45 studies. The most common adverse events were transient backache and meningism (90%) and cord malacia (80%). The cell therapy method in which the treatment was associated with more adverse events was Olfactory ensheathing cell and bone marrow mesenchymal stem cell combination therapy in 55%, and the adverse events were less with the embryonic stem cell in 2.33% of patients. In a meta-analysis, the total prevalence of adverse events in cell therapy was 19% and the highest pulled effect size belonged to urinary tract and localized adverse events. Also, the total prevalence of adverse events in 14 cell therapy methods was 18% and four cell types (neural stem cell, bone marrow hematopoietic stem cell, embryonic stem cell, and umbilical cord mesenchymal stem cell) had the most effect. None of the adverse events were reported on the 4 (life-threatening consequences) and 5 (death) grading scales. We concluded that the frequency of life-threatening adverse events following cell therapy clinical trials in chronic spinal cord injury patients is very scarce and can be ignored.
Collapse
Affiliation(s)
- Esmat Davoudi-Monfared
- Health Management Research Center & Department of Community Medicine, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Reyhaneh Abolghasemi
- New Hearing Technologies Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Fakhri Allahyari
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Gholamreza Farzanegan
- Trauma Research Center & Department of Neurosurgery, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
6
|
Xu J, Zhang J, Liu Q, Wang B. Bone marrow mesenchymal stem cells-derived exosomes promote spinal cord injury repair through the miR-497-5p/TXNIP/NLRP3 axis. J Mol Histol 2024; 56:16. [PMID: 39611985 DOI: 10.1007/s10735-024-10289-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/30/2024] [Indexed: 11/30/2024]
Abstract
Bone marrow mesenchymal stem cells (BMSCs) indicate a repairing prospect to treat spinal cord injury, a major traumatic disease. This study investigated the repair effect of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) on spinal cord injury. BMSCs were collected to extract BMSC-Exos which were identified by different means. The SCI model of rats was established, the motor behavior was scored by BBB field test, and the spinal cord tissues were separated and stained by HE, Nissl, and Tunel, respectively, as well as analyzed to measure inflammatory and oxidative stress responses. PC12 cells were co-cultured with Exos and analyzed by CCK-8 and flow cytometry to measure cell proliferation and apoptosis. BMSC-Exos improved SCI in rats with the recovery of motor function, alleviation of pathological conditions, and reduction of apoptosis, inflammatory responses, and oxidative stress. BMSC-Exos increased miR-497-5p expression, and miR-497-5p overexpression strengthened the protective effect of BMSC-Exos on SCI. miR-497-5p targeted inactivation of TXNIP/NLRP3 pathway. TXNIP saved the repair effect of miR-497-5p-carrying BMSC-Exos on SCI rats. miR-497-5p-carrying BMSC-Exos alleviated apoptosis and induced proliferation of H2O2-treated PC12 cells. BMSC-Exos promote SCI repair via the miR-497-5p/TXNIP/NLRP3 axis, which may be a target for alleviating SCI-associated nerve damage.
Collapse
Affiliation(s)
- JiXu Xu
- Department of Rehabilitation Medicine, Wuxi No.8 People's Hospital, Jiangsu Province, Wuxi City, 214000, China
| | - Jun Zhang
- Department of Rehabilitation Medicine, Ezhou Central Hospital, Hubei Province, Ezhou City, 436000, China
| | - QiaoYun Liu
- Department of Rehabilitation Medicine, Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong UniversityChongchuan DistrictJiangsu Province, No. 60 Qingnian Middle Road, Nantong City, 226000, China
| | - Bin Wang
- Department of Rehabilitation Medicine, Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong UniversityChongchuan DistrictJiangsu Province, No. 60 Qingnian Middle Road, Nantong City, 226000, China.
| |
Collapse
|
|
7
|
Wang X, Wang Q, Xia Z, Yang Y, Dai X, Zhang C, Wang J, Xu Y. Mesenchymal stromal cell therapies for traumatic neurological injuries. J Transl Med 2024; 22:1055. [PMID: 39578845 PMCID: PMC11583761 DOI: 10.1186/s12967-024-05725-3] [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: 07/09/2024] [Accepted: 10/01/2024] [Indexed: 11/24/2024] Open
Abstract
Improved treatment options are urgently needed for neurological injuries resulting from trauma or iatrogenic events causing long-term disabilities that severely impact patients' quality of life. In vitro and animal studies have provided promising proof-of-concept examples of regenerative therapies using mesenchymal stromal cells (MSC) for a wide range of pathological conditions. Over the previous decade, various MSC-based therapies have been investigated in clinical trials to treat traumatic neurological injuries. However, while the safety and feasibility of MSC treatments has been established, the patient outcomes in these studies have not demonstrated significant success in the translation of MSC regenerative therapy for the treatment of human brain and spinal cord injuries. Herein, we have reviewed the literature and ongoing registered trials on the application of MSC for the treatment of traumatic brain injury, traumatic spinal cord injury, and peripheral nerve injury. We have focused on the shortcomings and technological hurdles that must be overcome to further advance clinical research to phase 3 trials, and we discuss recent advancements that represent potential solutions to these obstacles to progress.
Collapse
Affiliation(s)
- Xiujuan Wang
- Technology Department, Tianjin Everunion Biotechnology Co., Ltd, SOHO Nexus Center, No. 19A East 3rd Ring North Road, Chaoyang District, Beijing, 100020, China
| | - Qian Wang
- HELP Therapeutics Co., Ltd, No. 568 Longmian Avenue, Jiangning District, Nanjing, 211166, Jiangsu Province, China
- Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, E12 Avenida da Universidade, Macau, 519000, SAR, China
| | - Ziyao Xia
- Department of Ophthalmology, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China
| | - Ying Yang
- Technology Department, Tianjin Everunion Biotechnology Co., Ltd, SOHO Nexus Center, No. 19A East 3rd Ring North Road, Chaoyang District, Beijing, 100020, China
| | - Xunan Dai
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China
| | - Chun Zhang
- Department of Ophthalmology, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China.
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China.
| | - Jiaxian Wang
- HELP Therapeutics Co., Ltd, No. 568 Longmian Avenue, Jiangning District, Nanjing, 211166, Jiangsu Province, China.
- Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, E12 Avenida da Universidade, Macau, 519000, SAR, China.
| | - Yongsheng Xu
- Technology Department, Tianjin Everunion Biotechnology Co., Ltd, SOHO Nexus Center, No. 19A East 3rd Ring North Road, Chaoyang District, Beijing, 100020, China.
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, China.
| |
Collapse
|
|
8
|
Abraham M, Shalom M, Gold J, Seaton M, Maleski Smith A, Gendreau J, Brandel MG, Ciacci J. Stem Cells in the Treatment of Spinal Cord Injury: A Review of Currently Registered Clinical Trials. World Neurosurg 2024; 191:e116-e125. [PMID: 39159672 DOI: 10.1016/j.wneu.2024.08.074] [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: 08/04/2024] [Accepted: 08/12/2024] [Indexed: 08/21/2024]
Abstract
BACKGROUND Spinal cord injury (SCI) affects around 18,000 individuals annually, representing nearly one-third of all paralysis cases. Stem cell therapy, a focal point in contemporary neuroregeneration research for SCI treatment, holds potential in leveraging undifferentiated stem cells to regenerate damaged tissues. This study seeks to comprehensively analyze current clinical trials exploring the potential use of stem cells in treating spinal cord injuries. METHODS A data retrieval approach examined the ClinicalTrials.gov database using the terms "spinal cord injury" and "stem cells." Exclusion criteria eliminated studies not recruiting, terminated prematurely, suspended, withdrawn, or of unknown status. Data for each trial, including ClinicalTrial.gov NCT identifier, title, intervention details, initiation/completion dates, and sample size, were systematically collected. Literature searches on PubMed.gov were conducted for completed trials with results. RESULTS Thirty clinical trials were analyzed, with 20 completed and six with published results on PubMed.gov. Interventions included 20 biological (66.7%), 6 procedural (20%), and 4 drug interventions (13.3%). Stem cell sources varied, including bone marrow (46.7%), umbilical cells (20%), adipose tissue (20%), embryonic cells (6.7%), and neural cells (6.7%). Trials spanned 2005 to 2022, with 11 (36.7%) commencing in or after 2017. Among six trials with results, 50% used bone marrow-derived stem cells. CONCLUSIONS The promising potential of stem cells in neuroregenerative SCI treatment necessitates further exploration through large-scale, multicenter clinical trials to enhance understanding and guide wider adoption of this emerging treatment paradigm.
Collapse
Affiliation(s)
- Mickey Abraham
- Department of Neurosurgery, University of California San Diego, La Jolla, California, USA.
| | - Moshe Shalom
- Tel Aviv University Sackler School of Medicine, Tel Aviv, Israel
| | - Justin Gold
- Cooper Medical School of Rowan University, Camden, New Jersey, USA
| | - Margaret Seaton
- University of California San Diego School of Medicine, San Diego, California, USA
| | | | - Julian Gendreau
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA
| | - Michael G Brandel
- Department of Neurosurgery, University of California San Diego, La Jolla, California, USA
| | - Joseph Ciacci
- Department of Neurosurgery, University of California San Diego, La Jolla, California, USA
| |
Collapse
|
|
9
|
Ralph PC, Choi SW, Baek MJ, Lee SJ. Regenerative medicine approaches for the treatment of spinal cord injuries: Progress and challenges. Acta Biomater 2024; 189:57-72. [PMID: 39424019 DOI: 10.1016/j.actbio.2024.10.021] [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: 07/01/2024] [Revised: 10/03/2024] [Accepted: 10/15/2024] [Indexed: 10/21/2024]
Abstract
Spinal cord injury (SCI) is a profound medical condition that significantly hampers motor function, imposing substantial limitations on daily activities and exerting a considerable financial burden on patients and their families. The constrained regenerative capacity of endogenous spinal cord tissue, exacerbated by the inflammatory response following the initial trauma, poses a formidable obstacle to effective therapy. Recent advancements in the field, stem cells, biomaterials, and molecular therapy, show promising outcomes. This review provides a comprehensive analysis of tissue engineering and regenerative medicine approaches for SCI treatment, including cell transplantation, tissue-engineered construct implantation, and other potential therapeutic strategies. Additionally, it sheds light on preclinical animal studies and recent clinical trials incorporating these modalities, providing a glimpse into the evolving landscape of SCI management. STATEMENT OF SIGNIFICANCE: The investigation into spinal cord injury (SCI) treatments focuses on reducing long-term impacts by targeting scar inhibition and enhancing regeneration through stem cells, with or without growth factors. Induced pluripotent stem cells (iPSCs) show promise for autologous use, with clinical trials confirming their safety. Challenges include low cell viability and difficulty in targeted differentiation. Biomaterial scaffolds hold potential for improving cell viability and integration, and extracellular vesicles (EVs) are emerging as a novel therapy. While EV research is in its early stages, stem cell trials demonstrate safety and potential recovery. Advancing tissue engineering approaches with biomaterial scaffolds is crucial for human trials.
Collapse
Affiliation(s)
- Patrick C Ralph
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States
| | - Sung-Woo Choi
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States; Department of Orthopedic Surgery, Soonchunhyang University Hospital Seoul, Seoul 04401, Republic of Korea
| | - Min Jung Baek
- Department of Obstetrics and Gynecology, CHA University Bundang Medical Center, Seongnam, Gyeonggi-do 13496, Republic of Korea
| | - Sang Jin Lee
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States.
| |
Collapse
|
|
10
|
Macêdo CT, de Freitas Souza BS, Villarreal CF, Silva DN, da Silva KN, de Souza CLEM, da Silva Paixão D, da Rocha Bezerra M, da Silva Moura Costa AO, Brazão ES, Marins Filho JP, Matos AC, dos Santos RR, Soares MBP. Transplantation of autologous mesenchymal stromal cells in complete cervical spinal cord injury: a pilot study. Front Med (Lausanne) 2024; 11:1451297. [PMID: 39328312 PMCID: PMC11424397 DOI: 10.3389/fmed.2024.1451297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 07/29/2024] [Indexed: 09/28/2024] Open
Abstract
Objective Spinal cord injury (SCI) is a serious condition that can lead to partial or complete paraplegia or tetraplegia. Currently, there are few therapeutic options for these conditions, which are mainly directed toward the acute phase, such as surgical intervention and high-dose steroid administration. Mesenchymal stromal cells (MSC) have been shown to improve neurological function following spinal cord injury. The aim of the study was to evaluate the safety, feasibility, and potential efficacy of MSC transplantation in patients with cervical traumatic SCI. Methods We included seven subjects with chronic traumatic SCI (> 1 year) at the cervical level, classified as American Spinal Cord Injury Association impairment scale (AIS) grade A. Subjects received two doses of autologous bone marrow derived MSC, the first by direct injection into the lesion site after hemilaminectomy and the second three months later by intrathecal injection. Neurologic evaluation, spinal magnetic resonance imaging (MRI), urodynamics, and life quality questionnaires were assessed before and after treatment. Results Cell transplantation was safe without severe or moderate adverse effects, and the procedures were well tolerated. Neurological evaluation revealed discrete improvements in sensitivity below the lesion level, following treatment. Five subjects showed some degree of bilateral sensory improvement for both superficial and deep mechanical stimuli compared to the pretreatment profile. No significant alterations in bladder function were observed during this study. Conclusion Transplantation of autologous MSC in patients with chronic cervical SCI is a safe and feasible procedure. Further studies are required to confirm the efficacy of this therapeutic approach. Clinical trial registration https://clinicaltrials.gov/study/NCT02574572, identifier NCT02574572.
Collapse
Affiliation(s)
- Carolina Thé Macêdo
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil
- Hospital São Rafael, Salvador, Bahia, Brazil
- SENAI Institute for Innovation in Advanced Health Systems, SENAI CIMATEC, Salvador, Bahia, Brazil
| | - Bruno Solano de Freitas Souza
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil
- Hospital São Rafael, Salvador, Bahia, Brazil
- Center for Biotechnology and Cell Therapy, Hospital São Rafael, Salvador, Bahia, Brazil
| | - Cristiane Flora Villarreal
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil
- Faculty of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil
| | - Daniela Nascimento Silva
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil
- SENAI Institute for Innovation in Advanced Health Systems, SENAI CIMATEC, Salvador, Bahia, Brazil
| | - Kátia Nunes da Silva
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil
- Center for Biotechnology and Cell Therapy, Hospital São Rafael, Salvador, Bahia, Brazil
| | - Clarissa Lima e Moura de Souza
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil
- Hospital São Rafael, Salvador, Bahia, Brazil
| | | | | | | | | | | | | | - Ricardo Ribeiro dos Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil
- SENAI Institute for Innovation in Advanced Health Systems, SENAI CIMATEC, Salvador, Bahia, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Milena Botelho Pereira Soares
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil
- SENAI Institute for Innovation in Advanced Health Systems, SENAI CIMATEC, Salvador, Bahia, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Rio de Janeiro, Brazil
| |
Collapse
|
|
11
|
Akhlaghpasand M, Tavanaei R, Hosseinpoor M, Yazdani KO, Soleimani A, Zoshk MY, Soleimani M, Chamanara M, Ghorbani M, Deylami M, Zali A, Heidari R, Oraee-Yazdani S. Safety and potential effects of intrathecal injection of allogeneic human umbilical cord mesenchymal stem cell-derived exosomes in complete subacute spinal cord injury: a first-in-human, single-arm, open-label, phase I clinical trial. Stem Cell Res Ther 2024; 15:264. [PMID: 39183334 PMCID: PMC11346059 DOI: 10.1186/s13287-024-03868-0] [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: 02/01/2024] [Accepted: 07/30/2024] [Indexed: 08/27/2024] Open
Abstract
OBJECTIVE Neurological and functional impairments are commonly observed in individuals with spinal cord injury (SCI) due to insufficient regeneration of damaged axons. Exosomes play a crucial role in the paracrine effects of mesenchymal stem cells (MSCs) and have emerged as a promising therapeutic approach for SCI. Thus, this study aimed to evaluate the safety and potential effects of intrathecal administration of allogeneic exosomes derived from human umbilical cord MSCs (HUC-MSCs) in patients with complete subacute SCI. METHODS This study was a single-arm, open-label, phase I clinical trial with a 12-month follow-up period. HUC-MSCs were extracted from human umbilical cord tissue, and exosomes were isolated via ultracentrifugation. After intrathecal injection, each participant a underwent complete evaluation, including neurological assessment using the American Spinal Injury Association (ASIA) scale, functional assessment using the Spinal Cord Independence Measure (SCIM-III), neurogenic bowel dysfunction (NBD) assessment using the NBD score, modified Ashworth scale (MAS), and lower urinary tract function questionnaire. RESULTS Nine patients with complete subacute SCI were recruited. The intrathecal injection of allogeneic HUC-MSCs-exosomes was safe and well tolerated. No early or late adverse event (AE) attributable to the study intervention was observed. Significant improvements in ASIA pinprick (P-value = 0.039) and light touch (P-value = 0.038) scores, SCIM III total score (P-value = 0.027), and NBD score (P-value = 0.042) were also observed at 12-month after the injection compared with baseline. CONCLUSIONS This study demonstrated that intrathecal administration of allogeneic HUC-MSCs-exosomes is safe in patients with subacute SCI. Moreover, it seems that this therapy might be associated with potential clinical and functional improvements in these patients. In this regard, future larger phase II/III clinical trials with adequate power are highly required. TRIAL REGISTRATION Iranian Registry of Clinical Trials, IRCT20200502047277N1. Registered 2 October 2020, https://en.irct.ir/trial/48765 .
Collapse
Affiliation(s)
- Mohammadhosein Akhlaghpasand
- Medical Biotechnology Research Center, AJA University of Medical Sciences, PO box: 1411718541, Tehran, Iran
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Roozbeh Tavanaei
- Medical Biotechnology Research Center, AJA University of Medical Sciences, PO box: 1411718541, Tehran, Iran
| | - Maede Hosseinpoor
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
- Stem Cell Technology Research Center (STRC), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Kaveh Oraii Yazdani
- Department of cardiovascular diseases, Zahedan university of medical science, Zahedan, Iran
| | - Afsane Soleimani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Mojtaba Yousefi Zoshk
- Department of Pediatrics, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohsen Chamanara
- Department of Pharmacology, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Mahdi Ghorbani
- Medical Biotechnology Research Center, AJA University of Medical Sciences, PO box: 1411718541, Tehran, Iran
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, AJA University of Medical Sciences, Tehran, Iran
| | - Mohammad Deylami
- Department of ICU &Critical care, Faculty of Medicine, Loghman-e Hakim Hospital, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Alireza Zali
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran
| | - Reza Heidari
- Medical Biotechnology Research Center, AJA University of Medical Sciences, PO box: 1411718541, Tehran, Iran.
- Cancer Epidemiology Research Center, AJA University of Medical Sciences, Tehran, Iran.
| | - Saeed Oraee-Yazdani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, PO box: 1988873554, Tehran, Iran.
| |
Collapse
|
|
12
|
Awidi A, Al Shudifat A, El Adwan N, Alqudah M, Jamali F, Nazer F, Sroji H, Ahmad H, Al-Quzaa N, Jafar H. Safety and potential efficacy of expanded mesenchymal stromal cells of bone marrow and umbilical cord origins in patients with chronic spinal cord injuries: a phase I/II study. Cytotherapy 2024; 26:825-831. [PMID: 38703153 DOI: 10.1016/j.jcyt.2024.03.480] [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: 09/03/2023] [Revised: 03/11/2024] [Accepted: 03/19/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND AIMS Spinal cord injury (SCI) affects patients' physical, psychological, and social well-being. Presently, treatment modalities for chronic SCI have restricted clinical effectiveness. Mesenchymal stromal cells (MSCs) demonstrate promise in addressing nervous tissue damage. This single-center, open-label, parallel-group randomized clinical trial aimed to assess the safety and efficacy of intraoperative perilesional administration of expanded autologous bone marrow-derived MSCs (BMMSCs), followed by monthly intrathecal injections, in comparison to monthly intrathecal administration of expanded allogeneic umbilical cord-derived MSCs (UCMSCs) for individuals with chronic SCI. METHODS Twenty participants, who had a minimum of 1 year of SCI duration, were enrolled. Each participant in Group A received perilesional BMMSCs, followed by monthly intrathecal BMMSCs for three injections, while Group B received monthly intrathecal UCMSCs for three injections. Safety and efficacy were evaluated using the American Spinal Cord Injury Association (ASIA) score for at least 1 year post the final injection. Statistical analysis was conducted using the Wilcoxon signed-rank test. RESULTS Group A comprised 11 participants, while Group B included 9. The mean follow-up duration was 22.65 months. Mild short-term adverse events encompassed headaches and back pain, with no instances of long-term adverse events. Both groups demonstrated significant improvements in total ASIA scores, with Group A displaying more pronounced motor improvements. CONCLUSIONS Our findings indicate that perilesional administration of expanded autologous BMMSCs, followed by monthly intrathecal BMMSCs for three injections, or monthly intrathecal UCMSCs for three injections appear to be safe and hold promise for individuals with chronic SCI. Nonetheless, larger-scale clinical trials are imperative to validate these observations.
Collapse
Affiliation(s)
- Abdalla Awidi
- School of Medicine, University of Jordan, Amman, Jordan
| | | | | | | | - Fatima Jamali
- The University of Jordan Cell Therapy Centre, Amman, Jordan
| | - Fathy Nazer
- The University of Jordan School of Medicine, Amman, Jordan
| | - Halla Sroji
- The University of Jordan Cell Therapy Centre, Amman, Jordan
| | - Hady Ahmad
- The University of Jordan Cell Therapy Centre, Amman, Jordan
| | - Nahla Al-Quzaa
- The University of Jordan Cell Therapy Centre, Amman, Jordan
| | - Hanan Jafar
- The University of Jordan Cell Therapy Centre, Amman, Jordan
| |
Collapse
|
|
13
|
Mesa Bedoya LE, Camacho Barbosa JC, López Quiceno L, Barrios Arroyave F, Halpert K, España Peña JA, Salazar Uribe JC. The safety profile of mesenchymal stem cell therapy administered through intrathecal injections for treating neurological disorders: a systematic review and meta-analysis of randomised controlled trials. Stem Cell Res Ther 2024; 15:146. [PMID: 38764070 PMCID: PMC11103979 DOI: 10.1186/s13287-024-03748-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 04/29/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND Based on previous in vivo studies and human trials, intrathecal cell delivery is a safe and relevant therapeutic tool for improving patient's quality of life with neurological conditions. We aimed to characterise the safety profile of intrathecally delivered Mesenchymal stem cells (MSCs). METHODS Ovid MEDLINE, Embase, Scopus, Cochrane Library, KCI-Korean Journal Database, and Web of Science. Databases were searched from their inception until April 13, 2023. Randomised Controlled Trials (RCTs) that compared intrathecal delivery of MSCs to controls in adult populations were included. Adverse events (AEs) were pooled and meta-analysed using DerSimonian-Laird random effects models with a correction factor 0.5 added to studies with zero count cells. Pooled AEs were described using Risk ratio (RR) and 95% confidence intervals (95% CI). Then, a random-effects meta-regress model on study-level summary data was performed to explore the relationship between the occurrence of AEs and covariates thought to modify the overall effect estimate. Finally, publication bias was assessed. RESULTS 303 records were reviewed, and nine RCTs met the inclusion criteria and were included in the quantitative synthesis (n = 540 patients). MSCs delivered intrathecally, as compared to controls, were associated with an increased probability of AEs of musculoskeletal and connective tissue disorders (categorised by Common Terminology Criteria for Adverse Events-CTCAE version 5.0) (RR: 1.61, 95% CI 1.19-2.19, I2 = 0%). The random-effects meta-regress model suggested that fresh MSCs increased the probability of occurrence of AEs compared to cryopreserved MSCs (RR: 1.554; p-value = 0.048; 95% CI 1.004-2.404), and the multiple-dose, decreased the probability of AEs by 36% compared to single doses (RR: 0.644; p-value = 0.048; 95% CI 0.416-0.996); however, univariate random effects meta-regression models revealed a not significant association between the occurrence of AEs from MSCs intrathecal delivery and each covariate. CONCLUSIONS Intrathecal delivery of MSCs was associated with a slight increase in AEs associated with musculoskeletal and connective tissue disorders, albeit without serious AEs. We conclude that intrathecal MSCs delivery is safe for patients with neurological conditions. However, further high-quality, large-scale RCTs are needed to confirm these findings.
Collapse
Affiliation(s)
- Luz Estella Mesa Bedoya
- BioXcellerator/ BioXscience Advanced Therapies and Translational Medicine, Medellín, Antioquia, Colombia
| | | | - Lucas López Quiceno
- BioXcellerator/ BioXscience Advanced Therapies and Translational Medicine, Medellín, Antioquia, Colombia
| | - Freddy Barrios Arroyave
- BioXcellerator/ BioXscience Advanced Therapies and Translational Medicine, Medellín, Antioquia, Colombia
| | - Karolynn Halpert
- BioXcellerator/ BioXscience Advanced Therapies and Translational Medicine, Medellín, Antioquia, Colombia
| | - Julián Andrés España Peña
- BioXcellerator/ BioXscience Advanced Therapies and Translational Medicine, Medellín, Antioquia, Colombia
| | | |
Collapse
|
|
14
|
Wang S, Jia Z, Dai M, Feng X, Tang C, Liu L, Cao L. Advances in natural and synthetic macromolecules with stem cells and extracellular vesicles for orthopedic disease treatment. Int J Biol Macromol 2024; 268:131874. [PMID: 38692547 DOI: 10.1016/j.ijbiomac.2024.131874] [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: 10/15/2023] [Revised: 04/16/2024] [Accepted: 04/24/2024] [Indexed: 05/03/2024]
Abstract
Serious orthopedic disorders resulting from myriad diseases and impairments continue to pose a considerable challenge to contemporary clinical care. Owing to its limited regenerative capacity, achieving complete bone tissue regeneration and complete functional restoration has proven challenging with existing treatments. By virtue of cellular regenerative and paracrine pathways, stem cells are extensively utilized in the restoration and regeneration of bone tissue; however, low survival and retention after transplantation severely limit their therapeutic effect. Meanwhile, biomolecule materials provide a delivery platform that improves stem cell survival, increases retention, and enhances therapeutic efficacy. In this review, we present the basic concepts of stem cells and extracellular vesicles from different sources, emphasizing the importance of using appropriate expansion methods and modification strategies. We then review different types of biomolecule materials, focusing on their design strategies. Moreover, we summarize several forms of biomaterial preparation and application strategies as well as current research on biomacromolecule materials loaded with stem cells and extracellular vesicles. Finally, we present the challenges currently impeding their clinical application for the treatment of orthopedic diseases. The article aims to provide researchers with new insights for subsequent investigations.
Collapse
Affiliation(s)
- Supeng Wang
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China; Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang 332000, China; Ningxia Medical University, Ningxia 750004, China
| | - Zhiqiang Jia
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
| | - Minghai Dai
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
| | - Xujun Feng
- Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang 332000, China
| | - Chengxuan Tang
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
| | - Liangle Liu
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China.
| | - Lingling Cao
- Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang 332000, China.
| |
Collapse
|
|
15
|
Abolghasemi R, Davoudi-Monfared E, Allahyari F, Farzanegan G. Systematic Review of Cell Therapy Efficacy in Human Chronic Spinal Cord Injury. TISSUE ENGINEERING. PART B, REVIEWS 2024; 30:254-269. [PMID: 37917104 DOI: 10.1089/ten.teb.2023.0130] [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: 11/03/2023]
Abstract
Spinal cord injury (SCI) is one of the most debilitating problems for humans. About 6 months after the initial injury, a cascade of secondary cellular and molecular events occurs and the primary damage enters the chronic phase. Current treatments are not curative. One of the new treatment methods is the use of cell therapy, which is gradually being tested in clinical trials to improve the symptoms of SCI patients. In this review article, we investigated the effect of different cell therapy trials in improving patients' symptoms and their paraclinical indicators. In the 72 final reviewed studies with 1144 cases and 186 controls, 20 scores were recorded as outcomes. We categorized the scores into seven groups. In upper extremity motor score, daily living function, trunk stability, postural hypotension, somatosensory evoked potential, and motor evoked potential scores, the bone marrow hematopoietic stem cell therapy had a more healing effect. In the International Association of Neurorestoratology SCI Functional Rating Scale, light touch score, bowel function, decreased spasticity, Visual Analog Scale, and electromyography scores, the bone marrow mesenchymal stem cell had more impact. The olfactory ensheathing cell had a greater effect on lower extremity motor score and pinprick scores than other cells. The embryonic stem cell had the greatest effect in improving the important score of the American Spinal Injury Association scale. Based on the obtained results, it seems that a special cell should be used to improve each symptom of patients with chronic SCI, and if the improvement of several harms is involved, the combination of cells may be effective. Impact statement Compared to similar review articles published so far, we reviewed the largest number of published articles, and so the largest number of cases and controls, and the variety of cells we examined was more than other published articles. We concluded that different cells are effective for improving the symptoms and paraclinical indicators of patients with chronic spinal cord injury. Bone marrow hematopoietic stem cell and bone marrow mesenchymal stem cell have had the higher overall mean effect in more scores (each in six scores). If the improvement of several harms is involved, the combination of cells may be effective.
Collapse
Affiliation(s)
- Reyhaneh Abolghasemi
- New Hearing Technologies Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Esmat Davoudi-Monfared
- Health Management Research Center and Department of Community Medicine, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Fakhri Allahyari
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Gholamreza Farzanegan
- Trauma Research Center and Department of Neurosurgery, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
16
|
Patel GD, Liu L, Li A, Yang YH, Shen CC, Brand-Saberi B, Yang X. Mesenchymal stem cell-based therapies for treating well-studied neurological disorders: a systematic review. Front Med (Lausanne) 2024; 11:1361723. [PMID: 38601118 PMCID: PMC11004389 DOI: 10.3389/fmed.2024.1361723] [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: 12/26/2023] [Accepted: 03/13/2024] [Indexed: 04/12/2024] Open
Abstract
Background Millions of people across the globe are affected by conditions like Amyotrophic Lateral Sclerosis (ALS), Parkinson's Disease (PD), Multiple Sclerosis (MS), Spinal Cord Injury (SCI), and Traumatic Brain Injury (TBI), although most occurrences are common in the elderly population. This systematic review aims to highlight the safety of the procedures, their tolerability, and efficacy of the available therapies conducted over the years using mesenchymal stem cells (MSCs) in treating the neurological conditions mentioned above. Methods PubMed was used to search for published data from clinical trials performed using mesenchymal stem cells. Studies that provided the necessary information that mentioned the efficacy and adverse effects of the treatment in patients were considered for this review. Results In total, 43 manuscripts were selected after a strategic search, and these studies have been included in this systematic review. Most included studies reported the safety of the procedures used and the treatment's good tolerability, with mild adverse events such as fever, headache, mild pain at the injection site, or nausea being common. A few studies also reported death of some patients, attributed to the progression of the disease to severe stages before the treatment. Other severe events, such as respiratory or urinary infections reported in some studies, were not related to the treatment. Different parameters were used to evaluate the efficacy of the treatment based on the clinical condition of the patient. Conclusion Mesenchymal stem cells transplantation has so far proven to be safe and tolerable in select studies and patient types. This systematic review includes the results from the 43 selected studies in terms of safety and tolerability of the procedures, and several adverse events and therapeutic benefits during the follow-up period after administration of MSCs.
Collapse
Affiliation(s)
- Gaurav Deepak Patel
- Department of Anatomy and Molecular Embryology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
| | - Lichao Liu
- Division of Histology and Embryology, International Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China
| | - Ailian Li
- School of Stomatology, Southwest Medical University, Guangzhou, China
| | - Yun-Hsuan Yang
- School of Stomatology, Jinan University, Guangzhou, China
| | - Chia-Chi Shen
- School of Stomatology, Jinan University, Guangzhou, China
| | - Beate Brand-Saberi
- Department of Anatomy and Molecular Embryology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
| | - Xuesong Yang
- Division of Histology and Embryology, International Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China
- Clinical Research Center, Clifford Hospital, Guangzhou, China
| |
Collapse
|
|
17
|
Agosti E, Zeppieri M, Pagnoni A, Fontanella MM, Fiorindi A, Ius T, Panciani PP. Current status and future perspectives on stem cell transplantation for spinal cord injury. World J Transplant 2024; 14:89674. [PMID: 38576751 PMCID: PMC10989472 DOI: 10.5500/wjt.v14.i1.89674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/04/2023] [Accepted: 12/29/2023] [Indexed: 03/15/2024] Open
Abstract
BACKGROUND Previous assessments of stem cell therapy for spinal cord injuries (SCI) have encountered challenges and constraints. Current research primarily emphasizes safety in early-phase clinical trials, while systematic reviews prioritize effectiveness, often overlooking safety and translational feasibility. This situation prompts inquiries regarding the readiness for clinical adoption. AIM To offer an up-to-date systematic literature review of clinical trial results con cerning stem cell therapy for SCI. METHODS A systematic search was conducted across major medical databases [PubMed, Embase, Reference Citation Analysis (RCA), and Cochrane Library] up to October 14, 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "spinal cord", "injury", "clinical trials", "stem cells", "functional outcomes", and "adverse events". Studies included in this review consisted of randomized controlled trials and non-randomized controlled trials reporting on the use of stem cell therapies for the treatment of SCI. RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI, 496 papers were initially identified, with 237 chosen for full-text analysis. Among them, 236 were deemed eligible after excluding 170 for various reasons. These studies encompassed 1086 patients with varying SCI levels, with cervical injuries being the most common (42.2%). Bone marrow stem cells were the predominant stem cell type used (71.1%), with various administration methods. Follow-up durations averaged around 84.4 months. The 32.7% of patients showed functional impro vement from American spinal injury association Impairment Scale (AIS) A to B, 40.8% from AIS A to C, 5.3% from AIS A to D, and 2.1% from AIS B to C. Sensory improvements were observed in 30.9% of patients. A relatively small number of adverse events were recorded, including fever (15.1%), headaches (4.3%), muscle tension (3.1%), and dizziness (2.6%), highlighting the potential for SCI recovery with stem cell therapy. CONCLUSION In the realm of SCI treatment, stem cell-based therapies show promise, but clinical trials reveal potential adverse events and limitations, underscoring the need for meticulous optimization of transplantation conditions and parameters, caution against swift clinical implementation, a deeper understanding of SCI pathophysiology, and addressing ethical, tumorigenicity, immunogenicity, and immunotoxicity concerns before gradual and careful adoption in clinical practice.
Collapse
Affiliation(s)
- Edoardo Agosti
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Andrea Pagnoni
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Marco Maria Fontanella
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia 25123, BS, Italy
| | - Alessandro Fiorindi
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Tamara Ius
- Neurosurgery Unit, Head-Neck and NeuroScience Department, University Hospital of Udine, Udine 33100, Italy
| | - Pier Paolo Panciani
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| |
Collapse
|
|
18
|
Maličev E, Jazbec K. An Overview of Mesenchymal Stem Cell Heterogeneity and Concentration. Pharmaceuticals (Basel) 2024; 17:350. [PMID: 38543135 PMCID: PMC10975472 DOI: 10.3390/ph17030350] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/22/2024] [Accepted: 03/05/2024] [Indexed: 01/06/2025] Open
Abstract
Mesenchymal stem cells (MSCs) are of great interest in cell therapies due to the immunomodulatory and other effects they have after autologous or allogeneic transplantation. In most clinical applications, a high number of MSCs is required; therefore, the isolated MSC population must be expanded in the cell culture until the desired number is reached. Analysing freshly isolated MSCs is challenging due to their rareness and heterogeneity, which is noticeable among donors, tissues, and cell subpopulations. Although the phenotype of MSCs in tissue can differ from those of cultured cells, phenotyping and counting are usually performed only after MSC proliferation. As MSC applicability is a developing and growing field, there is a need to implement phenotyping and counting methods for freshly isolated MSCs, especially in new one-step procedures where isolated cells are implanted immediately without cell culturing. Only by analysing harvested cells can we correctly evaluate such studies. This review describes multilevel heterogeneity and concentrations of MSCs and different strategies for phenotype determination and enumeration of freshly isolated MSCs.
Collapse
Affiliation(s)
- Elvira Maličev
- Blood Transfusion Centre of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia;
- Biotechnical Faculty, University of Ljubljana, Jamnikarjeva ulica 101, 1000 Ljubljana, Slovenia
| | - Katerina Jazbec
- Blood Transfusion Centre of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia;
| |
Collapse
|
|
19
|
Naaldijk Y, Sherman LS, Turrini N, Kenfack Y, Ratajczak MZ, Souayah N, Rameshwar P, Ulrich H. Mesenchymal Stem Cell-Macrophage Crosstalk Provides Specific Exosomal Cargo to Direct Immune Response Licensing of Macrophages during Inflammatory Responses. Stem Cell Rev Rep 2024; 20:218-236. [PMID: 37851277 DOI: 10.1007/s12015-023-10612-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2023] [Indexed: 10/19/2023]
Abstract
Neurodegenerative diseases (NDDs) continue to be a significant healthcare problem. The economic and social implications of NDDs increase with longevity. NDDs are linked to neuroinflammation and activated microglia and astrocytes play a central role. There is a growing interest for stem cell-based therapy to deliver genes, and for tissue regeneration. The promise of mesenchymal stem cells (MSC) is based on their availability as off-the-shelf source, and ease of expanding from discarded tissues. We tested the hypothesis that MSC have a major role of resetting activated microglial cells. We modeled microglial cell lines by using U937 cell-derived M1 and M2 macrophages. We studied macrophage types, alone, or in a non-contact culture with MSCs. MSCs induced significant release of exosomes from both types of macrophages, but significantly more of the M1 type. RNA sequencing showed enhanced gene expression within the exosomes with the major changes linked to the inflammatory response, including cytokines and the purinergic receptors. Computational analyses of the transcripts supported the expected effect of MSCs in suppressing the inflammatory response of M1 macrophages. The inflammatory cargo of M1 macrophage-derived exosomes revealed involvement of cytokines and purinergic receptors. At the same time, the exosomes from MSC-M2 macrophages were able to reset the classical M2 macrophages to more balanced inflammation. Interestingly, we excluded transfer of purinergic receptor transcripts from the co-cultured MSCs by analyzing these cells for the identified purinergic receptors. Since exosomes are intercellular communicators, these findings provide insights into how MSCs may modulate tissue regeneration and neuroinflammation.
Collapse
Affiliation(s)
- Yahaira Naaldijk
- Department of Medicine, Rutgers New Jersey Medical School (NJMS), Newark, NJ, USA
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, 05508-000, Brazil
| | - Lauren S Sherman
- Department of Medicine, Rutgers New Jersey Medical School (NJMS), Newark, NJ, USA
- Rutgers School of Graduate Studies at NHMS, Newark, NJ, USA
| | - Natalia Turrini
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, 05508-000, Brazil
| | | | - Mariusz Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
- Laboratory of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland
| | - Nizar Souayah
- Department of Neurology, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Pranela Rameshwar
- Department of Medicine, Rutgers New Jersey Medical School (NJMS), Newark, NJ, USA.
| | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
- Department of Neuroscience and Physiology, Rutgers New Jersey Medical School, Newark, NJ, USA.
| |
Collapse
|
|
20
|
Zipser CM, Curt A. Disease-specific interventions using cell therapies for spinal cord disease/injury. HANDBOOK OF CLINICAL NEUROLOGY 2024; 205:263-282. [PMID: 39341658 DOI: 10.1016/b978-0-323-90120-8.00007-1] [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: 10/01/2024]
Abstract
Traumatic spinal cord injury (SCI) may occur across the lifespan and is of global relevance. Damage of the spinal cord results in para- or tetraplegia and is associated with neuropathic pain, spasticity, respiratory, and autonomic dysfunction (i.e., control of bladder-bowel function). While the acute surgical treatment aims at stabilizing the spine and decompressing the damaged spinal cord, SCI patients require neurorehabilitation to restore neural function and to compensate for any impairments including motor disability, pain treatment, and bladder/bowel management. However, the spinal cord has a limited capacity to regenerate and much of the disability may persist, depending on the initial lesion severity and level of injury. For this reason, and the lack of effective drug treatments, there is an emerging interest and urgent need in promoting axonal regeneration and remyelination after SCI through cell- and stem-cell based therapies. This review briefly summarizes the state-of the art management of acute SCI and its neurorehabilitation to critically appraise phase I/II trials from the last two decades that have investigated cell-based therapies (i.e., Schwann cells, macrophages, and olfactory ensheathing cells) and stem cell-based therapies (i.e., neural stem cells, mesenchymal, and hematopoietic stem cells). Recently, two large multicenter trials provided evidence for the safety and feasibility of neural stem cell transplantation into the injured cord, whilst two monocenter trials also showed this to be the case for the transplantation of Schwann cells into the posttraumatic cord cavity. These are milestone studies that will facilitate further interventional trials. However, the clinical adoption of such approaches remains unproven, as there is only limited encouraging data, often in single patients, and no proven trial evidence to support regulatory approval.
Collapse
Affiliation(s)
- Carl Moritz Zipser
- Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland
| | - Armin Curt
- Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland.
| |
Collapse
|
|
21
|
Giovannelli L, Bari E, Jommi C, Tartara F, Armocida D, Garbossa D, Cofano F, Torre ML, Segale L. Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access. Bioact Mater 2023; 29:16-35. [PMID: 37456581 PMCID: PMC10338239 DOI: 10.1016/j.bioactmat.2023.06.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/01/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023] Open
Abstract
Neurodegenerative diseases represent a growing burden on healthcare systems worldwide. Mesenchymal stem cells (MSCs) have shown promise as a potential therapy due to their neuroregenerative, neuroprotective, and immunomodulatory properties, which are, however, linked to the bioactive substances they release, collectively known as secretome. This paper provides an overview of the most recent research on the safety and efficacy of MSC-derived secretome and extracellular vesicles (EVs) in clinical (if available) and preclinical models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, acute ischemic stroke, and spinal cord injury. The article explores the biologically active substances within MSC-secretome/EVs, the mechanisms responsible for the observed therapeutic effects, and the strategies that may be used to optimize MSC-secretome/EVs production based on specific therapeutic needs. The review concludes with a critical discussion of current clinical trials and a perspective on potential future directions in translating MSC-secretome and EVs into the clinic, specifically regarding how to address the challenges associated with their pharmaceutical manufacturing, including scalability, batch-to-batch consistency, adherence to Good Manufacturing Practices (GMP) guidelines, formulation, and storage, along with quality controls, access to the market and relative costs, value for money and impact on total expenditure.
Collapse
Affiliation(s)
- Lorella Giovannelli
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100, Novara, Italy
| | - Elia Bari
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100, Novara, Italy
| | - Claudio Jommi
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100, Novara, Italy
| | | | - Daniele Armocida
- A.U.O, Policlinico Umberto I, Neurosurgery Division, Human Neurosciences Department, Sapienza University, 00135, Roma, Italy
| | - Diego Garbossa
- Department of Neuroscience Rita Levi Montalcini, Neurosurgery Unit, University of Turin, 10126, Turin, Italy
| | - Fabio Cofano
- Department of Neuroscience Rita Levi Montalcini, Neurosurgery Unit, University of Turin, 10126, Turin, Italy
| | - Maria Luisa Torre
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100, Novara, Italy
- PharmaExceed S.r.l, 27100, Pavia, Italy
| | - Lorena Segale
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100, Novara, Italy
| |
Collapse
|
|
22
|
Lambrechts MJ, Issa TZ, Hilibrand AS. Updates in the Early Management of Acute Spinal Cord Injury. J Am Acad Orthop Surg 2023; 31:e619-e632. [PMID: 37432977 DOI: 10.5435/jaaos-d-23-00281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/31/2023] [Indexed: 07/13/2023] Open
Abstract
Spinal cord injury (SCI) is a leading cause of disability worldwide, and effective management is necessary to improve clinical outcomes. Many long-standing therapies including early reduction and spinal cord decompression, methylprednisolone administration, and optimization of spinal cord perfusion have been around for decades; however, their efficacy has remained controversial because of limited high-quality data. This review article highlights studies surrounding the role of early surgical decompression and its role in relieving mechanical pressure on the microvascular circulation thereby reducing intraspinal pressure. Furthermore, the article touches on the current role of methylprednisolone and identifies promising studies evaluating neuroprotective and neuroregenerative agents. Finally, this article outlines the expanding body of literature evaluating mean arterial pressure goals, cerebrospinal fluid drainage, and expansive duroplasty to further optimize vascularization to the spinal cord. Overall, this review aims to highlight evidence for SCI treatments and ongoing trials that may markedly affect SCI care in the near future.
Collapse
Affiliation(s)
- Mark J Lambrechts
- From the Rothman Orthopaedic Institute, Thomas Jefferson University, Philadelphia, PA
| | | | | |
Collapse
|
|
23
|
Montoto-Meijide R, Meijide-Faílde R, Díaz-Prado SM, Montoto-Marqués A. Mesenchymal Stem Cell Therapy in Traumatic Spinal Cord Injury: A Systematic Review. Int J Mol Sci 2023; 24:11719. [PMID: 37511478 PMCID: PMC10380897 DOI: 10.3390/ijms241411719] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Recovery from a traumatic spinal cord injury (TSCI) is challenging due to the limited regenerative capacity of the central nervous system to restore cells, myelin, and neural connections. Cell therapy, particularly with mesenchymal stem cells (MSCs), holds significant promise for TSCI treatment. This systematic review aims to analyze the efficacy, safety, and therapeutic potential of MSC-based cell therapies in TSCI. A comprehensive search of PUBMED and COCHRANE databases until February 2023 was conducted, combining terms such as "spinal cord injury," "stem cells," "stem cell therapy," "mesenchymal stem cells," and "traumatic spinal cord injury". Among the 53 studies initially identified, 22 (21 clinical trials and 1 case series) were included. Findings from these studies consistently demonstrate improvements in AIS (ASIA Impairment Scale) grades, sensory scores, and, to a lesser extent, motor scores. Meta-analyses further support these positive outcomes. MSC-based therapies have shown short- and medium-term safety, as indicated by the absence of significant adverse events within the studied timeframe. However, caution is required when drawing generalized recommendations due to the limited scientific evidence available. Further research is needed to elucidate the long-term safety and clinical implications of these advancements. Although significant progress has been made, particularly with MSC-based therapies, additional studies exploring other potential future therapies such as gene therapies, neurostimulation techniques, and tissue engineering approaches are essential for a comprehensive understanding of the evolving TSCI treatment landscape.
Collapse
Affiliation(s)
- Rodrigo Montoto-Meijide
- Complejo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Rosa Meijide-Faílde
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Instituto de Investigación Biomédica de A Coruña (INIBIC), Centro Interdisciplinar de Química y Biología (CICA), Universidade da Coruña, 15071 A Coruña, Spain
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Universidade da Coruña, 15071 A Coruña, Spain
| | - Silvia María Díaz-Prado
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Instituto de Investigación Biomédica de A Coruña (INIBIC), Centro Interdisciplinar de Química y Biología (CICA), Universidade da Coruña, 15071 A Coruña, Spain
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Universidade da Coruña, 15071 A Coruña, Spain
| | - Antonio Montoto-Marqués
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Universidade da Coruña, 15071 A Coruña, Spain
- Unidad de Lesionados Medulares, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, 15006 A Coruña, Spain
| |
Collapse
|
|
24
|
Gouveia D, Correia J, Cardoso A, Carvalho C, Oliveira AC, Almeida A, Gamboa Ó, Ribeiro L, Branquinho M, Sousa A, Lopes B, Sousa P, Moreira A, Coelho A, Rêma A, Alvites R, Ferreira A, Maurício AC, Martins Â. Intensive neurorehabilitation and allogeneic stem cells transplantation in canine degenerative myelopathy. Front Vet Sci 2023; 10:1192744. [PMID: 37520009 PMCID: PMC10374290 DOI: 10.3389/fvets.2023.1192744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/12/2023] [Indexed: 08/01/2023] Open
Abstract
Introduction Degenerative myelopathy (DM) is a neurodegenerative spinal cord disease with upper motor neurons, with progressive and chronic clinical signs, similar to amyotrophic lateral sclerosis (ALS). DM has a complex etiology mainly associated with SOD1 gene mutation and its toxic role, with no specific treatment. Daily intensive rehabilitation showed survival time near 8 months but most animals are euthanized 6-12 months after clinical signs onset. Methods This prospective controlled blinded cohort clinical study aims to evaluate the neural regeneration response ability of DM dogs subjected to an intensive neurorehabilitation protocol with mesenchymal stem cells (MSCs) transplantation. In total, 13 non-ambulatory (OFS 6 or 8) dogs with homozygous genotype DM/DM and diagnosed by exclusion were included. All were allocated to the intensive neurorehabilitation with MSCs protocol (INSCP) group (n = 8) or to the ambulatory rehabilitation protocol (ARP) group (n = 5), which differ in regard to training intensity, modalities frequency, and MSCs transplantation. The INSCP group was hospitalized for 1 month (T0 to T1), followed by MSCs transplantation (T1) and a second month (T2), whereas the ARP group was under ambulatory treatment for the same 2 months. Results Survival mean time of total population was 375 days, with 438 days for the INSCP group and 274 for the ARP group, with a marked difference on the Kaplan-Meier survival analysis. When comparing the literature's results, there was also a clear difference in the one-sample t-test (p = 0.013) with an increase in time of approximately 70%. OFS classifications between groups at each time point were significantly different (p = 0.008) by the one-way ANOVA and the independent sample t-test. Discussion This INSCP showed to be safe, feasible, and a possibility for a long progression of DM dogs with quality of life and functional improvement. This study should be continued.
Collapse
Affiliation(s)
- Débora Gouveia
- Arrábida Veterinary Hospital, Arrábida Animal Rehabilitation Center, Setubal, Portugal
- Superior School of Health, Protection and Animal Welfare, Polytechnic Institute of Lusophony, Lisboa, Portugal
- Faculty of Veterinary Medicine, Lusófona University, Lisboa, Portugal
| | - Jéssica Correia
- Arrábida Veterinary Hospital, Arrábida Animal Rehabilitation Center, Setubal, Portugal
- Faculty of Veterinary Medicine, Lusófona University, Lisboa, Portugal
| | - Ana Cardoso
- Arrábida Veterinary Hospital, Arrábida Animal Rehabilitation Center, Setubal, Portugal
- Superior School of Health, Protection and Animal Welfare, Polytechnic Institute of Lusophony, Lisboa, Portugal
| | - Carla Carvalho
- Arrábida Veterinary Hospital, Arrábida Animal Rehabilitation Center, Setubal, Portugal
| | - Ana Catarina Oliveira
- Arrábida Veterinary Hospital, Arrábida Animal Rehabilitation Center, Setubal, Portugal
- Superior School of Health, Protection and Animal Welfare, Polytechnic Institute of Lusophony, Lisboa, Portugal
| | - António Almeida
- Faculty of Veterinary Medicine, University of Lisbon, Lisboa, Portugal
| | - Óscar Gamboa
- Faculty of Veterinary Medicine, University of Lisbon, Lisboa, Portugal
| | - Lénio Ribeiro
- Faculty of Veterinary Medicine, Lusófona University, Lisboa, Portugal
| | - Mariana Branquinho
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salaza, Universidade do Porto, Porto, Portugal
- Centro de Estudos de Ciência Animal, Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), Lisboa, Portugal
| | - Ana Sousa
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salaza, Universidade do Porto, Porto, Portugal
- Centro de Estudos de Ciência Animal, Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), Lisboa, Portugal
| | - Bruna Lopes
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salaza, Universidade do Porto, Porto, Portugal
- Centro de Estudos de Ciência Animal, Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), Lisboa, Portugal
| | - Patrícia Sousa
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salaza, Universidade do Porto, Porto, Portugal
- Centro de Estudos de Ciência Animal, Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), Lisboa, Portugal
| | - Alícia Moreira
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salaza, Universidade do Porto, Porto, Portugal
- Centro de Estudos de Ciência Animal, Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), Lisboa, Portugal
| | - André Coelho
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salaza, Universidade do Porto, Porto, Portugal
- Centro de Estudos de Ciência Animal, Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), Lisboa, Portugal
| | - Alexandra Rêma
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salaza, Universidade do Porto, Porto, Portugal
- Centro de Estudos de Ciência Animal, Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), Lisboa, Portugal
| | - Rui Alvites
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salaza, Universidade do Porto, Porto, Portugal
- Centro de Estudos de Ciência Animal, Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), Lisboa, Portugal
- Instituto Universitário de Ciências da Saúde (IUCS), Cooperativa de Ensino Superior Politécnico e Universitário (CESPU), Gandra, Portugal
| | - António Ferreira
- Faculty of Veterinary Medicine, University of Lisbon, Lisboa, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), Lisboa, Portugal
- CIISA - Centro Interdisciplinar-Investigáo em Saúde Animal, Faculdade de Medicina Veterinária, Av. Universi dade Técnica de Lisboa, Lisboa, Portugal
| | - Ana Colette Maurício
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salaza, Universidade do Porto, Porto, Portugal
- Centro de Estudos de Ciência Animal, Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), Lisboa, Portugal
| | - Ângela Martins
- Arrábida Veterinary Hospital, Arrábida Animal Rehabilitation Center, Setubal, Portugal
- Superior School of Health, Protection and Animal Welfare, Polytechnic Institute of Lusophony, Lisboa, Portugal
- Faculty of Veterinary Medicine, Lusófona University, Lisboa, Portugal
| |
Collapse
|
|
25
|
Ribeiro BF, da Cruz BC, de Sousa BM, Correia PD, David N, Rocha C, Almeida RD, Ribeiro da Cunha M, Marques Baptista AA, Vieira SI. Cell therapies for spinal cord injury: a review of the clinical trials and cell-type therapeutic potential. Brain 2023; 146:2672-2693. [PMID: 36848323 DOI: 10.1093/brain/awad047] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 12/23/2022] [Accepted: 01/29/2023] [Indexed: 03/01/2023] Open
Abstract
Spinal cord injury (SCI) is an as yet untreatable neuropathology that causes severe dysfunction and disability. Cell-based therapies hold neuroregenerative and neuroprotective potential, but, although being studied in SCI patients for more than two decades, long-term efficacy and safety remain unproven, and which cell types result in higher neurological and functional recovery remains under debate. In a comprehensive scoping review of 142 reports and registries of SCI cell-based clinical trials, we addressed the current therapeutical trends and critically analysed the strengths and limitations of the studies. Schwann cells, olfactory ensheathing cells (OECs), macrophages and various types of stem cells have been tested, as well as combinations of these and other cells. A comparative analysis between the reported outcomes of each cell type was performed, according to gold-standard efficacy outcome measures like the ASIA impairment scale, motor and sensory scores. Most of the trials were in the early phases of clinical development (phase I/II), involved patients with complete chronic injuries of traumatic aetiology and did not display a randomized comparative control arm. Bone marrow stem cells and OECs were the most commonly tested cells, while open surgery and injection were the main methods of delivering cells into the spinal cord or submeningeal spaces. Transplantation of support cells, such as OECs and Schwann cells, resulted in the highest ASIA Impairment Scale (AIS) grade conversion rates (improvements in ∼40% of transplanted patients), which surpassed the spontaneous improvement rate expected for complete chronic SCI patients within 1 year post-injury (5-20%). Some stem cells, such as peripheral blood-isolated and neural stem cells, offer potential for improving patient recovery. Complementary treatments, particularly post-transplantation rehabilitation regimes, may contribute highly to neurological and functional recovery. However, unbiased comparisons between the tested therapies are difficult to draw, given the great heterogeneity of the design and outcome measures used in the SCI cell-based clinical trials and how these are reported. It is therefore crucial to standardize these trials when aiming for higher value clinical evidence-based conclusions.
Collapse
Affiliation(s)
- Beatriz F Ribeiro
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bruna C da Cruz
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bárbara M de Sousa
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Patrícia D Correia
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Nuno David
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Camila Rocha
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Ramiro D Almeida
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Maria Ribeiro da Cunha
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
- Spinal Cord Injury Rehabilitation Unit, Centro de Reabilitação do Norte (CRN), Centro Hospitalar de Vila Nova de Gaia e Espinho (CHVNG/E), 4400-129 Vila Nova de Gaia, Portugal
| | - António A Marques Baptista
- Department of Neurosurgery, Centro Hospitalar de Vila Nova de Gaia e Espinho (CHVNG/E), 4400-129 Vila Nova de Gaia, Portugal
| | - Sandra I Vieira
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| |
Collapse
|
|
26
|
Hu X, Xu W, Ren Y, Wang Z, He X, Huang R, Ma B, Zhao J, Zhu R, Cheng L. Spinal cord injury: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther 2023; 8:245. [PMID: 37357239 DOI: 10.1038/s41392-023-01477-6] [Citation(s) in RCA: 231] [Impact Index Per Article: 115.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 03/22/2023] [Accepted: 05/07/2023] [Indexed: 06/27/2023] Open
Abstract
Spinal cord injury (SCI) remains a severe condition with an extremely high disability rate. The challenges of SCI repair include its complex pathological mechanisms and the difficulties of neural regeneration in the central nervous system. In the past few decades, researchers have attempted to completely elucidate the pathological mechanism of SCI and identify effective strategies to promote axon regeneration and neural circuit remodeling, but the results have not been ideal. Recently, new pathological mechanisms of SCI, especially the interactions between immune and neural cell responses, have been revealed by single-cell sequencing and spatial transcriptome analysis. With the development of bioactive materials and stem cells, more attention has been focused on forming intermediate neural networks to promote neural regeneration and neural circuit reconstruction than on promoting axonal regeneration in the corticospinal tract. Furthermore, technologies to control physical parameters such as electricity, magnetism and ultrasound have been constantly innovated and applied in neural cell fate regulation. Among these advanced novel strategies and technologies, stem cell therapy, biomaterial transplantation, and electromagnetic stimulation have entered into the stage of clinical trials, and some of them have already been applied in clinical treatment. In this review, we outline the overall epidemiology and pathophysiology of SCI, expound on the latest research progress related to neural regeneration and circuit reconstruction in detail, and propose future directions for SCI repair and clinical applications.
Collapse
Affiliation(s)
- Xiao Hu
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Wei Xu
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Yilong Ren
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Zhaojie Wang
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Xiaolie He
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Runzhi Huang
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Bei Ma
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Jingwei Zhao
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Rongrong Zhu
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China.
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China.
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China.
| | - Liming Cheng
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China.
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China.
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China.
| |
Collapse
|
|
27
|
Slovinska L, Harvanova D. The Role of Mesenchymal Stromal Cells and Their Products in the Treatment of Injured Spinal Cords. Curr Issues Mol Biol 2023; 45:5180-5197. [PMID: 37367078 DOI: 10.3390/cimb45060329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/28/2023] Open
Abstract
Spinal cord injury (SCI) is a destructive condition that results in lasting neurological damage resulting in disruption of the connection between the central nervous system and the rest of the body. Currently, there are several approaches in the treatment of a damaged spinal cord; however, none of the methods allow the patient to return to the original full-featured state of life before the injury. Cell transplantation therapies show great potential in the treatment of damaged spinal cords. The most examined type of cells used in SCI research are mesenchymal stromal cells (MSCs). These cells are at the center of interest of scientists because of their unique properties. MSCs regenerate the injured tissue in two ways: (i) they are able to differentiate into some types of cells and so can replace the cells of injured tissue and (ii) they regenerate tissue through their powerful known paracrine effect. This review presents information about SCI and the treatments usually used, aiming at cell therapy using MSCs and their products, among which active biomolecules and extracellular vesicles predominate.
Collapse
Affiliation(s)
- Lucia Slovinska
- Associated Tissue Bank, P.J. Šafárik University and L. Pasteur University Hospital, 040 01 Košice, Slovakia
- Department of Regenerative Medicine and Cell Therapy, Institute of Neurobiology Biomedical Research Center, Slovak Academy of Sciences, 040 01 Košice, Slovakia
| | - Denisa Harvanova
- Associated Tissue Bank, P.J. Šafárik University and L. Pasteur University Hospital, 040 01 Košice, Slovakia
| |
Collapse
|
|
28
|
Current Advancements in Spinal Cord Injury Research—Glial Scar Formation and Neural Regeneration. Cells 2023; 12:cells12060853. [PMID: 36980193 PMCID: PMC10046908 DOI: 10.3390/cells12060853] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/01/2023] [Accepted: 03/06/2023] [Indexed: 03/12/2023] Open
Abstract
Spinal cord injury (SCI) is a complex tissue injury resulting in permanent and degenerating damage to the central nervous system (CNS). Detrimental cellular processes occur after SCI, including axonal degeneration, neuronal loss, neuroinflammation, reactive gliosis, and scar formation. The glial scar border forms to segregate the neural lesion and isolate spreading inflammation, reactive oxygen species, and excitotoxicity at the injury epicenter to preserve surrounding healthy tissue. The scar border is a physicochemical barrier composed of elongated astrocytes, fibroblasts, and microglia secreting chondroitin sulfate proteoglycans, collogen, and the dense extra-cellular matrix. While this physiological response preserves viable neural tissue, it is also detrimental to regeneration. To overcome negative outcomes associated with scar formation, therapeutic strategies have been developed: the prevention of scar formation, the resolution of the developed scar, cell transplantation into the lesion, and endogenous cell reprogramming. This review focuses on cellular/molecular aspects of glial scar formation, and discusses advantages and disadvantages of strategies to promote regeneration after SCI.
Collapse
|
|
29
|
Xia Y, Zhu J, Yang R, Wang H, Li Y, Fu C. Mesenchymal stem cells in the treatment of spinal cord injury: Mechanisms, current advances and future challenges. Front Immunol 2023; 14:1141601. [PMID: 36911700 PMCID: PMC9999104 DOI: 10.3389/fimmu.2023.1141601] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 02/13/2023] [Indexed: 03/14/2023] Open
Abstract
Spinal cord injury (SCI) has considerable impact on patient physical, mental, and financial health. Secondary SCI is associated with inflammation, vascular destruction, and subsequent permanent damage to the nervous system. Mesenchymal stem cells (MSCs) have anti-inflammatory properties, promoting vascular regeneration and the release neuro-nutrients, and are a promising strategy for the treatment of SCI. Preclinical studies have shown that MSCs promote sensory and motor function recovery in rats. In clinical trials, MSCs have been reported to improve the American Spinal Injury Association (ASIA) sensory and motor scores. However, the effectiveness of MSCs in treating patients with SCI remains controversial. MSCs promote tumorigenesis and ensuring the survival of MSCs in the hostile environment of SCI is challenging. In this article we examine the evidence on the pathophysiological changes occurring after SCI. We then review the underlying mechanisms of MSCs in the treatment of SCI and summarize the potential application of MSCs in clinical practice. Finally, we highlight the challenges surrounding the use of MSCs in the treatment of SCI and discuss future applications.
Collapse
Affiliation(s)
- Yuanliang Xia
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun,
China
| | - Jianshu Zhu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun,
China
| | - Ruohan Yang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Hengyi Wang
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun,
China
| | - Yuehong Li
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun,
China
| | - Changfeng Fu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun,
China
| |
Collapse
|
|
30
|
Mou C, Wang X, Li W, Li Z, Liu N, Xu Y. Efficacy of mesenchymal stromal cells intraspinal transplantation for patients with different degrees of spinal cord injury: A systematic review and meta-analysis. Cytotherapy 2023; 25:530-536. [PMID: 36805381 DOI: 10.1016/j.jcyt.2023.01.012] [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: 09/23/2022] [Revised: 01/06/2023] [Accepted: 01/24/2023] [Indexed: 02/22/2023]
Abstract
BACKGROUND AIMS Several studies have reported that mesenchymal stromal cells (MSCs) may improve neurological functions in patients with spinal cord injury (SCI). In this study, we conducted a systematic review and meta-analysis to summarize the effects of MSC treatment on different degrees of severity of SCI. METHODS Systematic searching of studies reporting outcomes of MSCs on specific injury severities of patients with SCI was performed in The National Library of Medicine (MEDLINE), Embase and Cochrane for published articles up to the 6 July 2022. Two investigators independently reviewed the included studies and extracted the relevant data. The standardized mean differences of American Spinal Injury Association (ASIA) motor score, ASIA light touch scores, ASIA pinprick scores and the Barthel index between baseline and follow-ups were pooled. RESULTS A total of eight studies were included. A large majority focused on patients with ASIA grade A classification. The pooled mean differences of ASIA motor scores, ASIA light touch scores, ASIA pinprick scores and the Barthel index were -2.78 (95% confidence interval [CI] -5.12 to -0.43, P = 0.02), -18.26 (95% CI -26.09 to -10.43, P < 0.01), -17.08 (95% CI -24.10 to -10.07, P < 0.01) and -4.37 (95% CI -10.96 to 2.22, P = 0.19), respectively. CONCLUSIONS MSC transplantation was a significantly effective therapy for patients with SCI with ASIA grade A. In the future, further studies are warranted to confirm the potential beneficial effects of MSC therapy.
Collapse
Affiliation(s)
- Chunlin Mou
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China
| | - Xiujuan Wang
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China
| | - Wei Li
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China
| | - Zhengnan Li
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China
| | - Nian Liu
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China
| | - Yongsheng Xu
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China.
| |
Collapse
|
|
31
|
Sterner RC, Sterner RM. Immune response following traumatic spinal cord injury: Pathophysiology and therapies. Front Immunol 2023; 13:1084101. [PMID: 36685598 PMCID: PMC9853461 DOI: 10.3389/fimmu.2022.1084101] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/19/2022] [Indexed: 01/09/2023] Open
Abstract
Traumatic spinal cord injury (SCI) is a devastating condition that is often associated with significant loss of function and/or permanent disability. The pathophysiology of SCI is complex and occurs in two phases. First, the mechanical damage from the trauma causes immediate acute cell dysfunction and cell death. Then, secondary mechanisms of injury further propagate the cell dysfunction and cell death over the course of days, weeks, or even months. Among the secondary injury mechanisms, inflammation has been shown to be a key determinant of the secondary injury severity and significantly worsens cell death and functional outcomes. Thus, in addition to surgical management of SCI, selectively targeting the immune response following SCI could substantially decrease the progression of secondary injury and improve patient outcomes. In order to develop such therapies, a detailed molecular understanding of the timing of the immune response following SCI is necessary. Recently, several studies have mapped the cytokine/chemokine and cell proliferation patterns following SCI. In this review, we examine the immune response underlying the pathophysiology of SCI and assess both current and future therapies including pharmaceutical therapies, stem cell therapy, and the exciting potential of extracellular vesicle therapy.
Collapse
Affiliation(s)
- Robert C. Sterner
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Rosalie M. Sterner
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States,*Correspondence: Rosalie M. Sterner,
| |
Collapse
|
|
32
|
Li M, Chen H, Zhu M. Mesenchymal stem cells for regenerative medicine in central nervous system. Front Neurosci 2022; 16:1068114. [PMID: 36583105 PMCID: PMC9793714 DOI: 10.3389/fnins.2022.1068114] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/28/2022] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells, whose paracrine and immunomodulatory potential has made them a promising candidate for central nervous system (CNS) regeneration. Numerous studies have demonstrated that MSCs can promote immunomodulation, anti-apoptosis, and axon re-extension, which restore functional neural circuits. The therapeutic effects of MSCs have consequently been evaluated for application in various CNS diseases including spinal cord injury, cerebral ischemia, and neurodegenerative disease. In this review, we will focus on the research works published in the field of mechanisms and therapeutic effects of MSCs in CNS regeneration.
Collapse
Affiliation(s)
- Man Li
- Department of Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Chen
- Department of Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mingxin Zhu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,*Correspondence: Mingxin Zhu,
| |
Collapse
|
|
33
|
Hall A, Fortino T, Spruance V, Niceforo A, Harrop JS, Phelps PE, Priest CA, Zholudeva LV, Lane MA. Cell transplantation to repair the injured spinal cord. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 166:79-158. [PMID: 36424097 PMCID: PMC10008620 DOI: 10.1016/bs.irn.2022.09.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Adam Hall
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - Tara Fortino
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - Victoria Spruance
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States; Division of Kidney, Urologic, & Hematologic Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Alessia Niceforo
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - James S Harrop
- Department of Neurological and Orthopedic Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Patricia E Phelps
- Department of Integrative Biology & Physiology, UCLA, Los Angeles, CA, United States
| | | | - Lyandysha V Zholudeva
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States; Gladstone Institutes, San Francisco, CA, United States
| | - Michael A Lane
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States.
| |
Collapse
|
|
34
|
Shang Z, Wang M, Zhang B, Wang X, Wanyan P. Clinical translation of stem cell therapy for spinal cord injury still premature: results from a single-arm meta-analysis based on 62 clinical trials. BMC Med 2022; 20:284. [PMID: 36058903 PMCID: PMC9442938 DOI: 10.1186/s12916-022-02482-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND How much scientific evidence is there to show that stem cell therapy is sufficient in preclinical and clinical studies of spinal cord injury before it is translated into clinical practice? This is a complicated problem. A single, small-sample clinical trial is difficult to answer, and accurate insights into this question can only be given by systematically evaluating all the existing evidence. METHODS The PubMed, Ovid-Embase, Web of Science, and Cochrane databases were searched from inception to February 10, 2022. Two independent reviewers performed the literature search, identified and screened the studies, and performed a quality assessment and data extraction. RESULTS In total, 62 studies involving 2439 patients were included in the analysis. Of these, 42 were single-arm studies, and 20 were controlled studies. The meta-analysis showed that stem cells improved the ASIA impairment scale score by at least one grade in 48.9% [40.8%, 56.9%] of patients with spinal cord injury. Moreover, the rate of improvement in urinary and gastrointestinal system function was 42.1% [27.6%, 57.2%] and 52.0% [23.6%, 79.8%], respectively. However, 28 types of adverse effects were observed to occur due to stem cells and transplantation procedures. Of these, neuropathic pain, abnormal feeling, muscle spasms, vomiting, and urinary tract infection were the most common, with an incidence of > 20%. While no serious adverse effects such as tumorigenesis were reported, this could be due to the insufficient follow-up period. CONCLUSIONS Overall, the results demonstrated that although the efficacy of stem cell therapy is encouraging, the subsequent adverse effects remain concerning. In addition, the clinical trials had problems such as small sample sizes, poor design, and lack of prospective registration, control, and blinding. Therefore, the current evidence is not sufficiently strong to support the clinical translation of stem cell therapy for spinal cord injury, and several problems remain. Additional well-designed animal experiments and high-quality clinical studies are warranted to address these issues.
Collapse
Affiliation(s)
- Zhizhong Shang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Mingchuan Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Baolin Zhang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Xin Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China.
- Chengren Institute of Traditional Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
- Department of Spine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
| | - Pingping Wanyan
- Gansu University of Chinese Medicine, Lanzhou, 730000, China
- The Second Hospital of Lanzhou University, Lanzhou, 730000, China
| |
Collapse
|
|
35
|
Hoang DM, Pham PT, Bach TQ, Ngo ATL, Nguyen QT, Phan TTK, Nguyen GH, Le PTT, Hoang VT, Forsyth NR, Heke M, Nguyen LT. Stem cell-based therapy for human diseases. Signal Transduct Target Ther 2022; 7:272. [PMID: 35933430 PMCID: PMC9357075 DOI: 10.1038/s41392-022-01134-4] [Citation(s) in RCA: 451] [Impact Index Per Article: 150.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/07/2023] Open
Abstract
Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated. Stem cell-based therapy, including human pluripotent stem cells (hPSCs) and multipotent mesenchymal stem cells (MSCs), has recently emerged as a key player in regenerative medicine. hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. MSCs are multipotent progenitor cells possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages, according to the International Society for Cell and Gene Therapy (ISCT). This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow (BM), adipose tissue (AT), or the umbilical cord (UC) for the treatment of human diseases, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions. Moreover, we discuss our own clinical trial experiences on targeted therapies using MSCs in a clinical setting, and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications, with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications. The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment, AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration, and UC-MSCs are potentially good candidates for pulmonary disease and acute respiratory distress syndrome treatment.
Collapse
Affiliation(s)
- Duc M Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam.
| | - Phuong T Pham
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trung Q Bach
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Anh T L Ngo
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Quyen T Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trang T K Phan
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Giang H Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Phuong T T Le
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Van T Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Nicholas R Forsyth
- Institute for Science & Technology in Medicine, Keele University, Keele, UK
| | - Michael Heke
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Liem Thanh Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| |
Collapse
|
|
36
|
Effects of mesenchymal stem cell transplantation on spinal cord injury patients. Cell Tissue Res 2022; 389:373-384. [PMID: 35697943 DOI: 10.1007/s00441-022-03648-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 06/02/2022] [Indexed: 11/02/2022]
Abstract
Spinal cord injury (SCI) is a traumatic injury with sensory and motor deficits that more than 1 million patients worldwide suffer from disability due to it. Many pharmacological therapies help reduce SCI-related injury and protect CNS from more damage but no current therapy could improve the axonal repair. In this regard, stem cell therapy is considered a regenerative method for SCI patient treatment. The neurotrophic and immunomodulatory factor secretion, differentiation, neuroprotecting, and remyelinating properties have made mesenchymal stem cells (MSCs) principally useful in this field. There are studies on the role of MSCs in patients suffering from SCI. However, low number of SCI patients and the lack of control groups in these studies, the cell transplantation appropriate methods, including cell source, dose, route of delivery, and transplantation timing, are various in trials. This study reviews the beneficial effects of MSC transplantation in SCI clinical studies with a special focus on the MSC properties and limitations of MSC transplantation.
Collapse
|
|
37
|
Liu M, Shafiq M, Sun B, Wu J, Wang W, El-Newehy M, El-Hamshary H, Morsi Y, Ali O, Khan AUR, Mo X. Composite Superelastic Aerogel Scaffolds Containing Flexible SiO 2 Nanofibers Promote Bone Regeneration. Adv Healthc Mater 2022; 11:e2200499. [PMID: 35670086 DOI: 10.1002/adhm.202200499] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/25/2022] [Indexed: 11/08/2022]
Abstract
Repairing irregular-shaped bone defects poses enormous challenges. Scaffolds that can fully fit the defect site and simultaneously induce osteogenesis and angiogenesis hold great promise for bone defect healing. This study aimed to produce superelastic organic/inorganic composite aerogel scaffolds by blending silica nanofibers (SiO2 ) and poly (lactic acid)/gelatin (PLA/gel) nanofibers; the content of SiO2 nanofibers were varied from 0-60 wt% (e.g., PLA/gel, PLA/gel/SiO2 -L, PLA/gel/SiO2 -M, and PLA/gel/SiO2 -H for 0%, 20%, 40%, and 60% of SiO2 nanofibers, respectively) to produce a range of scaffolds. The PLA/gel/SiO2 -M scaffold had excellent elasticity and good mechanical properties. In vitro experiments demonstrated that the silicon ions released from PLA/gel/SiO2 -M scaffolds could promote the differentiation of rat bone marrow-derived mesenchymal stem cells (rBMSCs) into osteoblasts, thereby enhancing alkaline phosphatase activity and bone-related genes expressions. Meanwhile, the released silicon ions also promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and the expression of vascular endothelial growth factors, thereby promoting angiogenesis. The assessment of these scaffolds in a calvarial defect model in rats showed good potential of PLA/gel/SiO2 -M to induce bone regeneration as well as promote osteogenesis and angiogenesis. Overall, these superelastic scaffolds containing flexible SiO2 nanofibers can simultaneously induce osteogenesis and angiogenesis, which may have broad applications for tissue engineering applications. This article is protected by copyright. All rights reserved.
Collapse
Affiliation(s)
- Mingyue Liu
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, P. R. China
| | - Muhammad Shafiq
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, P. R. China
| | - Binbin Sun
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, P. R. China
| | - Jinglei Wu
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, P. R. China
| | - Wei Wang
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, P. R. China
| | - Mohamed El-Newehy
- Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Hany El-Hamshary
- Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Yosry Morsi
- Faculty of Engineering and Industrial Sciences, Swinburne University of Technology, Boroondara, VIC, 3122, Australia
| | - Onaza Ali
- School of Chemistry and Chemical Engineering, Tiangong University, Tianjin, 300387, China
| | - Atta Ur Rehman Khan
- Department of Biotechnology, The University of Azad Jammu & Kashmir, Muzaffarabad, Pakistan
| | - Xiumei Mo
- Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, P. R. China
| |
Collapse
|
|
38
|
Xie JL, Wang XR, Li MM, Tao ZH, Teng WW, Saijilafu. Mesenchymal Stromal Cell Therapy in Spinal Cord Injury: Mechanisms and Prospects. Front Cell Neurosci 2022; 16:862673. [PMID: 35722621 PMCID: PMC9204037 DOI: 10.3389/fncel.2022.862673] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/09/2022] [Indexed: 12/13/2022] Open
Abstract
Spinal cord injury (SCI) often leads to severe motor, sensory, and autonomic dysfunction in patients and imposes a huge economic cost to individuals and society. Due to its complicated pathophysiological mechanism, there is not yet an optimal treatment available for SCI. Mesenchymal stromal cells (MSCs) are promising candidate transplant cells for use in SCI treatment. The multipotency of MSCs, as well as their rich trophic and immunomodulatory abilities through paracrine signaling, are expected to play an important role in neural repair. At the same time, the simplicity of MSCs isolation and culture and the bypassing of ethical barriers to stem cell transplantation make them more attractive. However, the MSCs concept has evolved in a specific research context to encompass different populations of cells with a variety of biological characteristics, and failure to understand this can undermine the quality of research in the field. Here, we review the development of the concept of MSCs in order to clarify misconceptions and discuss the controversy in MSCs neural differentiation. We also summarize a potential role of MSCs in SCI treatment, including their migration and trophic and immunomodulatory effects, and their ability to relieve neuropathic pain, and we also highlight directions for future research.
Collapse
Affiliation(s)
- Ji-Le Xie
- Department of Orthopaedics, The First Affiliated Hospital, Soochow University, Suzhou, China,Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Xing-Ran Wang
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Mei-Mei Li
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Zi-Han Tao
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Wen-Wen Teng
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Saijilafu
- Department of Orthopaedics, The First Affiliated Hospital, Soochow University, Suzhou, China,Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China,*Correspondence: Saijilafu,
| |
Collapse
|
|
39
|
Yeo-Teh NSL, Tang BL. Moral obligations in conducting stem cell-based therapy trials for autism spectrum disorder. JOURNAL OF MEDICAL ETHICS 2022; 48:343-348. [PMID: 33858947 DOI: 10.1136/medethics-2020-107106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/04/2021] [Accepted: 03/20/2021] [Indexed: 06/12/2023]
Abstract
Unregulated patient treatments and approved clinical trials have been conducted with haematopoietic stem cells and mesenchymal stem cells for children with autism spectrum disorder (ASD). While the former direct-to-consumer practice is usually considered rogue and should be legally constrained, regulated clinical trials could also be ethically questionable. Here, we outline principal objections against these trials as they are currently conducted. Notably, these often lack a clear rationale for how transplanted cells may confer a therapeutic benefit in ASD, and thus, have ill-defined therapeutic outcomes. We posit that ambiguous and unsubstantiated descriptions of outcome from such clinical trials may nonetheless appeal to the lay public as being based on authentic scientific findings. These may further fuel caregivers of patients with ASD to pursue unregulated direct-to-consumer treatments, thus exposing them to unnecessary risks. There is, therefore, a moral obligation on the part of those regulating and conducting clinical trials of stem cell-based therapeutic for ASD minors to incorporate clear therapeutic targets, scientific rigour and reporting accuracy in their work. Any further stem cell-based trials for ASD unsupported by significant preclinical advances and particularly sound scientific hypothesis and aims would be ethically indefensible.
Collapse
Affiliation(s)
| | - Bor Luen Tang
- Research Compliance and Integrity Office, National University of Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore
| |
Collapse
|
|
40
|
Laycock C, Kieser D, Fitz-Gerald C, Soltani S, Frampton C. A systematic review of large animal and human studies of stem cell therapeutics for acute adult traumatic spinal cord injury. JOURNAL OF ORTHOPAEDICS, TRAUMA AND REHABILITATION 2022. [DOI: 10.1177/22104917221087401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Traumatic spinal cord injury (TSCI) is a devastating condition and the search for a cure remains one of the most tenacious healthcare challenges to date. Current therapies are limited in their efficacy to restore full neurological function – resulting in lifelong disability and loss of autonomy. Whilst there remains a necessity to refine therapeutic protocols, stem cell (SC) studies have shown promise in the mending and re-establishment of the spinal cord neuroanatomy. Objectives: We conducted a systematic review of functional outcomes in stem cell therapeutics over the last three decades in large animals and humans. Methods: Medline, Embase, Cochrane and SCOPUS databases were searched for potentially pertinent articles from 1990 to 2020. Studies published in English were included if the stem cells were directly injected into the intraspinal, epidural or intrathecal compartments within two weeks of a traumatic mechanism of injury, including acute intervertebral disc prolapse. The participants were either large animals – defined as canine, porcine or non-human primate in-vivo models – or human patients. Results: Nine studies were included in this review. Statistically significant improvements in motor function and deep pain perception were seen at 8 weeks to 6 months post-SC injection compared to controls. Limitations: Functional outcomes are variably measured across studies. Almost all studies used experimentally induced trauma, which may not accurately represent the complexity of human spinal cord injury. Due to the exclusion criteria, there were no non-human primate studies included, yet these animal models are considered a closer anatomical match to humans than other large mammals. No human studies were included. Conclusions and Implications: Autologous and allogeneic stem cells have been trialled for the reconstitution of damaged and lost cells, remyelination of axons and remodelling of the pathophysiological microenvironment within the injured spinal cord, with some promising outcome data. This may translate to more successful future Phase I/II human clinical trials into the use of stem cells after TSCI in adults.
Collapse
Affiliation(s)
- Charlotte Laycock
- University of Oxford Medical School, John Radcliffe Hospital, Oxford, UK
| | - David Kieser
- Department of Orthopaedics and Musculoskeletal Medicine, University of Otago, Christchurch School of Medicine, Christchurch, New Zealand
| | - Connor Fitz-Gerald
- Department of Orthopaedics and Musculoskeletal Medicine, University of Otago, Christchurch School of Medicine, Christchurch, New Zealand
| | - Sherry Soltani
- University of Oxford Medical School, John Radcliffe Hospital, Oxford, UK
| | - Chris Frampton
- Department of Orthopaedics and Musculoskeletal Medicine, University of Otago, Christchurch School of Medicine, Christchurch, New Zealand
| |
Collapse
|
|
41
|
Progression in translational research on spinal cord injury based on microenvironment imbalance. Bone Res 2022; 10:35. [PMID: 35396505 PMCID: PMC8993811 DOI: 10.1038/s41413-022-00199-9] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 11/14/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
Spinal cord injury (SCI) leads to loss of motor and sensory function below the injury level and imposes a considerable burden on patients, families, and society. Repair of the injured spinal cord has been recognized as a global medical challenge for many years. Significant progress has been made in research on the pathological mechanism of spinal cord injury. In particular, with the development of gene regulation, cell sequencing, and cell tracing technologies, in-depth explorations of the SCI microenvironment have become more feasible. However, translational studies related to repair of the injured spinal cord have not yielded significant results. This review summarizes the latest research progress on two aspects of SCI pathology: intraneuronal microenvironment imbalance and regenerative microenvironment imbalance. We also review repair strategies for the injured spinal cord based on microenvironment imbalance, including medications, cell transplantation, exosomes, tissue engineering, cell reprogramming, and rehabilitation. The current state of translational research on SCI and future directions are also discussed. The development of a combined, precise, and multitemporal strategy for repairing the injured spinal cord is a potential future direction.
Collapse
|
|
42
|
Clinical Trials Using Mesenchymal Stem Cells for Spinal Cord Injury: Challenges in Generating Evidence. Cells 2022; 11:cells11061019. [PMID: 35326470 PMCID: PMC8946989 DOI: 10.3390/cells11061019] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 12/12/2022] Open
Abstract
Spinal cord injury (SCI) remains an important public health problem which often causes permanent loss of muscle strength, sensation, and function below the site of the injury, generating physical, psychological, and social impacts throughout the lives of the affected individuals, since there are no effective treatments available. The use of stem cells has been investigated as a therapeutic approach for the treatment of SCI. Although a significant number of studies have been conducted in pre-clinical and clinical settings, so far there is no established cell therapy for the treatment of SCI. One aspect that makes it difficult to evaluate the efficacy is the heterogeneity of experimental designs in the clinical trials that have been published. Cell transplantation methods vary widely among the trials, and there are still no standardized protocols or recommendations for the therapeutic use of stem cells in SCI. Among the different cell types, mesenchymal stem/stromal cells (MSCs) are the most frequently tested in clinical trials for SCI treatment. This study reviews the clinical applications of MSCs for SCI, focusing on the critical analysis of 17 clinical trials published thus far, with emphasis on their design and quality. Moreover, it highlights the need for more evidence-based studies designed as randomized controlled trials and potential challenges to be addressed in context of stem cell therapies for SCI.
Collapse
|
|
43
|
Gao T, Huang F, Wang W, Xie Y, Wang B. Interleukin-10 genetically modified clinical-grade mesenchymal stromal cells markedly reinforced functional recovery after spinal cord injury via directing alternative activation of macrophages. Cell Mol Biol Lett 2022; 27:27. [PMID: 35300585 PMCID: PMC8931978 DOI: 10.1186/s11658-022-00325-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/22/2022] [Indexed: 12/19/2022] Open
Abstract
Background After spinal cord injury (SCI), dysregulated or nonresolving inflammatory processes can severely disturb neuronal homeostasis and drive neurodegeneration. Although mesenchymal stromal cell (MSC)-based therapies have showed certain therapeutic efficacy, no MSC therapy has reached its full clinical goal. In this study, we examine interleukin-10 (IL10) genetically modified clinical-grade MSCs (IL10-MSCs) and evaluate their clinical safety, effectiveness, and therapeutic mechanism in a completely transected SCI mouse model. Methods We established stable IL10-overexpressing human umbilical-cord-derived MSCs through electric transduction and screened out clinical-grade IL10-MSCs according to the criteria of cell-based therapeutic products, which were applied to mice with completely transected SCI by repeated tail intravenous injections. Then we comprehensively investigated the motor function, histological structure, and nerve regeneration in SCI mice, and further explored the potential therapeutic mechanism after IL10-MSC treatment. Results IL10-MSC treatment markedly reinforced locomotor improvement, accompanied with decreased lesion volume, regeneration of axons, and preservation of neurons, compared with naïve unmodified MSCs. Further, IL10-MSC transplantation increased the ratio of microglia to infiltrated alternatively activated macrophages (M2), and reduced the ratio of classically activated macrophages (M1) at the injured spinal cord, meanwhile increasing the percentage of Treg and Th2 cells, and reducing the percentage of Th1 cells in the peripheral circulatory system. In addition, IL10-MSC administration could prevent apoptosis and promote neuron differentiation of neural stem cells (NSCs) under inflammatory conditions in vitro. Conclusions IL10-MSCs exhibited a reliable safety profile and demonstrated promising therapeutic efficacy in SCI compared with naïve MSCs, providing solid support for future clinical application of genetically engineered MSCs. Supplementary Information The online version contains supplementary material available at 10.1186/s11658-022-00325-9.
Collapse
Affiliation(s)
- Tianyun Gao
- Center for Clinic Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Feifei Huang
- Center for Clinic Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Wenqing Wang
- Center for Clinic Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Yuanyuan Xie
- Center for Clinic Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Bin Wang
- Center for Clinic Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China.
| |
Collapse
|
|
44
|
Huang H, Chen L, Moviglia G, Sharma A, Al Zoubi ZM, He X, Chen D. Advances and prospects of cell therapy for spinal cord injury patients. JOURNAL OF NEURORESTORATOLOGY 2022. [DOI: 10.26599/jnr.2022.9040007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
|
|
45
|
Abstract
Traumatic injury of the central nervous system (CNS) is a worldwide health problem affecting millions of people. Trauma of the CNS, that is, traumatic brain injury (TBI) and spinal cord injury (SCI), lead to massive and progressive cell loss and axonal degeneration, usually with very limited regeneration. At present, there are no treatments to protect injured CNS tissue or to replace the lost tissue. Stem cells are a cell type that by definition can self-renew and give rise to multiple cell lineages. In recent years, therapies using stem and progenitor cells have shown promising effects in experimental CNS trauma, particularly in the acute-subacute stage, but also in chronic injuries. However, the therapeutic mechanisms by which transplanted cells achieve the structural and/or functional improvements are often not clear. Stem cell therapies for CNS trauma can be categorized into 2 main concepts, transplantation of exogenous neural stem cells and neural progenitor cells and recruitment of endogenous stem and progenitor cells. In this review, focusing on the advances during the last decade, we will discuss the major cell therapies, the pros and cons of these 2 concepts for TBI and SCI, and the treatment strategies we believe will be successful.
Collapse
Affiliation(s)
- Xiaofei Li
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Erik Sundström
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Corresponding author: Erik Sundström, Department of Neurobiology, Care Sciences and Society (NVS), BioClinicum J9:20, Karolinska University Hospital, S17164 Solna, Sweden.
| |
Collapse
|
|
46
|
Tang QR, Xue H, Zhang Q, Guo Y, Xu H, Liu Y, Liu JM. Evaluation of the Clinical Efficacy of Stem Cell Transplantation in the Treatment of Spinal Cord Injury: A Systematic Review and Meta-analysis. Cell Transplant 2021; 30:9636897211067804. [PMID: 34939443 PMCID: PMC8725233 DOI: 10.1177/09636897211067804] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Stem cell transplantation has been applied to treat spinal cord injury (SCI) in
clinical trials for many years. However, the clinical efficacies of stem cell
transplantation in SCI have been quite diverse. The purpose of our study was to
systematically investigate the efficacy of stem cell transplantation in patients
with SCI. The PubMed, Web of Science, Ovid-Medline, Cochrane Library, China
National Knowledge Infrastructure, VIP, Wanfang, and SinoMed databases were
searched until October 27, 2020. Quantitative and qualitative data were analyzed
by Review Manager 5.3 and R. Nine studies (n = 328) were
included, and the overall risk of bias was moderate. The ASIA Impairment Scale
(AIS) grading improvement rate was analyzed in favor of stem cell
transplantation group [odds ratio (OR) = 6.06, 95% confidence interval (CI):
3.16–11.62, P < 0.00001]. Urodynamic indices also showed
improvement in bladder function. In subgroup analyses, the results indicated
that in patients with complete (AIS A) SCI, with the application of cell numbers
between n*(107–108), two cell types
(i.e., bone marrow–derived mesenchymal stem cells and bone marrow mononuclears),
and treatment time of more than 6 months, stem cell transplantation was more
beneficial for sensorimotor function (P < 0.05 for all
groups). The risk of fever incidence in the stem cell transplantation group was
4.22 (95% CI: 1.7–10.22, P = 0.001), and principal component
analysis (PCA) suggested it was more related to transplanted cell numbers. Thus,
stem cell transplantation can promote functional recovery in SCI patients.
Moreover, the type and quantity of transplanted stem cells and treatment time
are important factors affecting the therapeutic effect of stem cell
transplantation in SCI. Further studies are needed to evaluate the effects and
elucidate the mechanisms of these factors on stem cell therapy in SCI.
Collapse
Affiliation(s)
- Qiao-Rui Tang
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Hui Xue
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Qiao Zhang
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Ying Guo
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Hao Xu
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Ying Liu
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Jia-Mei Liu
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
- Ying Liu, Department of Histology and
Embryology, College of Basic Medical Sciences, Jilin University, Changchun
130021, Jilin Province, P.R. China.
| |
Collapse
|
|
47
|
Liu S, Zhang H, Wang H, Huang J, Yang Y, Li G, Yu K, Yang L. A comparative study of different stem cells transplantation for spinal cord injury: a systematic review and network meta-analysis. World Neurosurg 2021; 159:e232-e243. [PMID: 34954058 DOI: 10.1016/j.wneu.2021.12.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 10/19/2022]
Abstract
OBJECTIVE This study aimed to evaluate the efficacy and safety of different stem cell types for spinal cord injury (SCI) therapy and find out the superior treatment for SCI. METHODS A systematic literature search was performed using PubMed, Embase, the Cochrane Library, Web of Science, VIP, CNKI, and Wan Fang from database initiation to January 30, 2021. A Bayesian network meta-analysis was performed using ADDIS software. The PROSPERO registration number was CRD42020129635. RESULTS Twelve studies with 642 patients were enrolled in this study. Network meta-analysis revealed that bone mesenchymal stem cells combined with rehabilitation training (BMSCs + R) were significantly more effective than rehabilitation training alone (R) in improving American Spinal Injury Association (ASIA) impairment scale (AIS)-grading improvement rate (OR=94.25, 95% CI: 6.71 to 9321.95), ASIA motor score (WMD=6.67, 95% CI: 0.83 to 12.73), ASIA Sensory Functional score (WMD=12.41, 95%CI: 3.42 to 21.72), and Barthel Index (BI) score (WMD=7.24, 95% CI: 0.21 to 14.30). However, no statistically significant differences were observed between marrow mononuclear cells combined with rehabilitation training (MNCs + R), umbilical cord-derived mesenchymal stem cells combined with rehabilitation training (UCMSCs + R), or UCMSCs alone and R on all indicators. In terms of safety, there were no serious and permanent adverse effects after transplantation of BMSCs, MNCs, or UCMSCs. CONCLUSION BMSCs + R may be superior to the other stem cell treatments for SCI in improving AIS grading, ASIA motor score, ASIA Sensory Functional score, and BI score. The therapeutic effects of UCMSCs and MNCs remain to be confirmed.
Collapse
Affiliation(s)
- Shuangyan Liu
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Huai Zhang
- Medical School, Hangzhou Normal University, Hangzhou 310000, China
| | - Haiyan Wang
- Medical School, Hangzhou Normal University, Hangzhou 310000, China
| | - Juan Huang
- Medical School, Hangzhou Normal University, Hangzhou 310000, China
| | - Yi Yang
- Medical School, Hangzhou Normal University, Hangzhou 310000, China
| | - Guoxiang Li
- Medical School, Shihezi University, Shihezi 832000, China
| | - Kuai Yu
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Lei Yang
- Medical School, Hangzhou Normal University, Hangzhou 310000, China.
| |
Collapse
|
|
48
|
Kim GU, Sung SE, Kang KK, Choi JH, Lee S, Sung M, Yang SY, Kim SK, Kim YI, Lim JH, Seo MS, Lee GW. Therapeutic Potential of Mesenchymal Stem Cells (MSCs) and MSC-Derived Extracellular Vesicles for the Treatment of Spinal Cord Injury. Int J Mol Sci 2021; 22:13672. [PMID: 34948463 PMCID: PMC8703906 DOI: 10.3390/ijms222413672] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/14/2021] [Accepted: 12/18/2021] [Indexed: 12/15/2022] Open
Abstract
Spinal cord injury (SCI) is a life-threatening condition that leads to permanent disability with partial or complete loss of motor, sensory, and autonomic functions. SCI is usually caused by initial mechanical insult, followed by a cascade of several neuroinflammation and structural changes. For ameliorating the neuroinflammatory cascades, MSC has been regarded as a therapeutic agent. The animal SCI research has demonstrated that MSC can be a valuable therapeutic agent with several growth factors and cytokines that may induce anti-inflammatory and regenerative effects. However, the therapeutic efficacy of MSCs in animal SCI models is inconsistent, and the optimal method of MSCs remains debatable. Moreover, there are several limitations to developing these therapeutic agents for humans. Therefore, identifying novel agents for regenerative medicine is necessary. Extracellular vesicles are a novel source for regenerative medicine; they possess nucleic acids, functional proteins, and bioactive lipids and perform various functions, including damaged tissue repair, immune response regulation, and reduction of inflammation. MSC-derived exosomes have advantages over MSCs, including small dimensions, low immunogenicity, and no need for additional procedures for culture expansion or delivery. Certain studies have demonstrated that MSC-derived extracellular vesicles (EVs), including exosomes, exhibit outstanding chondroprotective and anti-inflammatory effects. Therefore, we reviewed the principles and patho-mechanisms and summarized the research outcomes of MSCs and MSC-derived EVs for SCI, reported to date.
Collapse
Affiliation(s)
- Gang-Un Kim
- Department of Orthopedic Surgery, Hanil General Hospital, 308 Uicheon-ro, Dobong-gu, Seoul 01450, Korea;
| | - Soo-Eun Sung
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Kyung-Ku Kang
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Joo-Hee Choi
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Sijoon Lee
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Minkyoung Sung
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Seung Yun Yang
- Department of Biomaterials Science, Life and Industry Convergence Institute, Pusan National University, Miryang 50463, Korea;
| | - Seul-Ki Kim
- Efficacy Evaluation Team, Food Science R&D Center, KolmarBNH CO., LTD, 61Heolleungro 8-gil, Seocho-gu, Seoul 06800, Korea;
| | | | - Ju-Hyeon Lim
- New Drug Development Center, Osong Medical Innovation Foundation, Chungbuk 28160, Korea;
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea
| | - Min-Soo Seo
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Gun Woo Lee
- Cellexobio, Co. Ltd., Daegu 42415, Korea;
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea
| |
Collapse
|
|
49
|
Muthu S, Kartheek RR, Jeyaraman N, Rajendran RL, Khanna M, Jeyaraman M, Packkyarathinam RP, Gangadaran P, Ahn BC. Is Culture Expansion Necessary in Autologous Mesenchymal Stromal Cell Therapy to Obtain Superior Results in the Management of Knee Osteoarthritis?-Meta-Analysis of Randomized Controlled Trials. Bioengineering (Basel) 2021; 8:220. [PMID: 34940373 PMCID: PMC8698637 DOI: 10.3390/bioengineering8120220] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/10/2021] [Accepted: 12/15/2021] [Indexed: 02/05/2023] Open
Abstract
Study Design: Meta-analysis. Objectives: We aimed to analyze the impact of cultured expansion of autologous mesenchymal stromal cells (MSCs) in the management of osteoarthritis of the knee from randomized controlled trials (RCTs) available in the literature. Materials and Methods: We conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library until August 2021 for RCTs analyzing the efficacy and safety of culture-expanded compared to non-cultured autologous MSCs in the management of knee osteoarthritis. The Visual Analog Score (VAS) for pain, Western Ontario McMaster University's Osteoarthritis Index (WOMAC), Lysholm score, Knee Osteoarthritis Outcome Score (KOOS), and adverse events were the analyzed outcomes. Analysis was performed in R-platform using OpenMeta [Analyst] software. Results: Overall, 17 studies involving 767 patients were included for analysis. None of the studies made a direct comparison of the culture expanded and non-cultured MSCs, hence we pooled the results of all the included studies of non-cultured and cultured types of MSC sources and made a comparative analysis of the outcomes. At six months, culture expanded MSCs showed significantly better improvement (p < 0.001) in VAS outcome. Uncultured MSCs, on the other hand, demonstrated significant VAS improvement in the long term (12 months) in VAS (p < 0.001), WOMAC (p = 0.025), KOOS score (p = 0.016) where cultured-expanded MSCs failed to demonstrate a significant change. Culturing of MSCs did not significantly increase the complications noted (p = 0.485). On sub-group analysis, adipose-derived uncultured MSCs outperformed culture-expanded MSCs at both short term (six months) and long term (12 months) in functional outcome parameters such as WOMAC (p < 0.001, p = 0.025), Lysholm (p < 0.006), and KOOS (p < 0.003) scores, respectively, compared to their controls. Conclusions: We identified a void in literature evaluating the impact of culture expansion of MSCs for use in knee osteoarthritis. Our indirect analysis of literature showed that culture expansion of autologous MSCs is not a necessary factor to obtain superior results in the management of knee osteoarthritis. Moreover, while using uncultured autologous MSCs, we recommend MSCs of adipose origin to obtain superior functional outcomes. However, we urge future trials of sufficient quality to validate our findings to arrive at a consensus on the need for culture expansion of MSCs for use in cellular therapy of knee osteoarthritis.
Collapse
Affiliation(s)
- Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul 624001, Tamil Nadu, India;
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
| | - Randhi Rama Kartheek
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow 226010, Uttar Pradesh, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedics, Atlas Hospitals, Tiruchirappalli 620002, Tamil Nadu, India
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Department of Orthopaedics, Prasad Institute of Medical Sciences, Lucknow 226401, Uttar Pradesh, India
| | - Madhan Jeyaraman
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Department of Orthopaedics, Faculty of Medicine—Sri Lalithambigai Medical College and Hospital, Dr. MGR Educational and Research Institute, Chennai 600095, Tamil Nadu, India
| | - Rathinavelpandian Perunchezhian Packkyarathinam
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Department of Orthopaedics, Government Medical College, Omandurar Government Estate, Chennai 600002, Tamil Nadu, India
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| |
Collapse
|
|
50
|
Clinical application of stem cell therapy in neurogenic bladder: a systematic review and meta-analysis. Int Urogynecol J 2021; 33:2081-2097. [PMID: 34767058 DOI: 10.1007/s00192-021-04986-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/23/2021] [Indexed: 01/26/2023]
Abstract
INTRODUCTION AND HYPOTHESIS This review aims to investigate the effect of stem cell (SC) therapy on the management of neurogenic bladder (NGB) in four neurological diseases, including spinal cord injury (SCI), Parkinson's disease (PD), multiple sclerosis (MS), and stroke, in the clinical setting. METHODS An electronic database search was conducted in the Cochrane Library, EMBASE, Proquest, Clinicaltrial.gov , WHO, Google Scholar, MEDLINE via PubMed, Ovid, Web of Science, Scopus, ongoing trial registers, and conference proceedings in June 2019 and updated by hand searching on 1 February 2021. All randomized controlled trials (RCTs), quasi RCTs, phase I/II clinical trials, case-control, retrospective cohorts, and comprehensive case series that evaluated the regenerative potential of SCs on the management of NGB were included. Cochrane appraisal risk of bias checklist and the standardized critical appraisal instrument from the JBI Meta-Analysis of Statistics, Assessment, and Review Instrument (JBI-MAStARI) were used to appraise the studies. RESULTS Twenty-six studies among 1282 relevant publications met our inclusion criteria. Only SC therapy was applied for SCI or MS patients. Phase I/II clinical trials (without control arm) were the most conducted studies, and only four were RCTs. Four studies with 153 participants were included in the meta-analysis. The main route of transplantation was via lumbar puncture. There were no serious adverse events. Only nine studies in SCI and one in MS have used urodynamics, and the others have reported improvement based on patient satisfaction. SC therapy did not significantly improve residual urine volume, detrusor pressure, and maximum bladder capacity. Also, the quality of these publications was low or unclear. CONCLUSION Although most clinical trials provide evidence of the safety and effectiveness of MSCs on the management of NGB, the meta-analysis results did not show a significant improvement; however, the interpretation of study results is difficult because of the lack of placebo controls.
Collapse
|