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Saeedi P, Nilchiani LS, Zand B, Hajimirghasemi M, Halabian R. An overview of stem cells and cell products involved in trauma injury. Regen Ther 2025; 29:60-76. [PMID: 40143930 PMCID: PMC11938091 DOI: 10.1016/j.reth.2025.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/01/2025] [Accepted: 02/20/2025] [Indexed: 03/28/2025] Open
Abstract
Trauma injuries represent a significant public health burden worldwide, often leading to long-term disability and reduced quality of life. This review provides a comprehensive overview of the therapeutic potential of stem cells and cell products for traumatic injuries. The extraordinary characteristics of stem cells, such as self-renewal and transdifferentiation, make them definitive candidates for tissue regeneration. Mesenchymal stem cells (MSCs), neural stem cells (NSCs), and hematopoietic stem cells (HSCs) have been tested in preclinical studies for treating distinct traumatic injuries. Stem cell mechanisms of action are addressed through paracrine signaling, immunomodulation, differentiation, and neuroprotection. Cell products such as conditioned media, exosomes, and secretomes offer cell-free resources, thereby avoiding the risks of live cell transplantation. Clinical trials have reported many effective outcomes; however, variability exists across trauma types. Some challenges include tumorigenicity, standardized protocols, and regulatory issues. Collaboration and interdisciplinary research are being conducted to harness stem cells and products for trauma treatment. This emerging field is promising for improving patient recovery and quality of life after traumatic injuries.
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Affiliation(s)
- Pardis Saeedi
- Research Center for Health Management in Mass Gathering, Red Crescent Society of the Islamic Republic of Iran, Tehran, Iran
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Leila Sadat Nilchiani
- Department of Molecular and Cell Biology, Faculty of Advanced Sciences and Technology, Islamic Azad University Tehran Medical Sciences, Tehran, Iran
| | - Bita Zand
- Department of Molecular and Cell Biology, Faculty of Advanced Sciences and Technology, Islamic Azad University Tehran Medical Sciences, Tehran, Iran
| | - Maryam Hajimirghasemi
- Department of Internal Medicine, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Raheleh Halabian
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Lana JF, Navani A, Jeyaraman M, Santos N, Pires L, Santos GS, Rodrigues IJ, Santos D, Mosaner T, Azzini G, da Fonseca LF, de Macedo AP, Huber SC, de Moraes Ferreira Jorge D, Purita J. Sacral Bioneuromodulation: The Role of Bone Marrow Aspirate in Spinal Cord Injuries. Bioengineering (Basel) 2024; 11:461. [PMID: 38790327 PMCID: PMC11118755 DOI: 10.3390/bioengineering11050461] [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: 03/13/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 05/26/2024] Open
Abstract
Spinal cord injury (SCI) represents a severe trauma to the nervous system, leading to significant neurological damage, chronic inflammation, and persistent neuropathic pain. Current treatments, including pharmacotherapy, immobilization, physical therapy, and surgical interventions, often fall short in fully addressing the underlying pathophysiology and resultant disabilities. Emerging research in the field of regenerative medicine has introduced innovative approaches such as autologous orthobiologic therapies, with bone marrow aspirate (BMA) being particularly notable for its regenerative and anti-inflammatory properties. This review focuses on the potential of BMA to modulate inflammatory pathways, enhance tissue regeneration, and restore neurological function disrupted by SCI. We hypothesize that BMA's bioactive components may stimulate reparative processes at the cellular level, particularly when applied at strategic sites like the sacral hiatus to influence lumbar centers and higher neurological structures. By exploring the mechanisms through which BMA influences spinal repair, this review aims to establish a foundation for its application in clinical settings, potentially offering a transformative approach to SCI management that extends beyond symptomatic relief to promoting functional recovery.
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Affiliation(s)
- José Fábio Lana
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
- Clinical Research, Anna Vitória Lana Institute (IAVL), Indaiatuba 13334-170, SP, Brazil
- Medical School, Max Planck University Center (UniMAX), Indaiatuba 13343-060, SP, Brazil
| | - Annu Navani
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
- Medical School, Max Planck University Center (UniMAX), Indaiatuba 13343-060, SP, Brazil
- Comprehensive Spine & Sports Center, Campbell, CA 95008, USA
| | - Madhan Jeyaraman
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
- Department of Orthopaedics, ACS Medical College and Hospital, Chennai 600077, Tamil Nadu, India
| | - Napoliane Santos
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
| | - Luyddy Pires
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
| | - Gabriel Silva Santos
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
| | - Izair Jefthé Rodrigues
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
| | - Douglas Santos
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
| | - Tomas Mosaner
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
| | - Gabriel Azzini
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
| | - Lucas Furtado da Fonseca
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
- Medical School, Federal University of São Paulo (UNIFESP), São Paulo 04024-002, SP, Brazil
| | - Alex Pontes de Macedo
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
| | - Stephany Cares Huber
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
| | - Daniel de Moraes Ferreira Jorge
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (J.F.L.); (N.S.); (L.P.); (I.J.R.); (D.S.); (T.M.); (G.A.); (L.F.d.F.); (A.P.d.M.); (S.C.H.); (D.d.M.F.J.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
| | - Joseph Purita
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (A.N.); (J.P.)
- Medical School, Max Planck University Center (UniMAX), Indaiatuba 13343-060, SP, Brazil
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Cox CS, Notrica DM, Juranek J, Miller JH, Triolo F, Kosmach S, Savitz SI, Adelson PD, Pedroza C, Olson SD, Scott MC, Kumar A, Aertker BM, Caplan HW, Jackson ML, Gill BS, Hetz RA, Lavoie MS, Ewing-Cobbs L. Autologous bone marrow mononuclear cells to treat severe traumatic brain injury in children. Brain 2024; 147:1914-1925. [PMID: 38181433 PMCID: PMC11068104 DOI: 10.1093/brain/awae005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/29/2023] [Accepted: 12/30/2023] [Indexed: 01/07/2024] Open
Abstract
Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural CNS preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at two children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17 years of age with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation and infusion were completed by 48 h post-injury. A Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between two doses. Primary end points were quantitative brain volumes using MRI and microstructural integrity of the corpus callosum (diffusivity and oedema measurements) at 6 months and 12 months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1 year in the BMMNC group was significantly preserved compared to placebo [decrease of 19 891 versus 40 491, respectively; mean difference of -20 600, 95% confidence interval (CI): -35 868 to -5332; P = 0.01], and the number of corpus callosum streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved corpus callosum connectivity in the treated groups (-431 streamlines placebo versus -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 h after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to: (i) shorter intensive care duration and decreased ICU intensity; (ii) white matter structural preservation; and (iii) enhanced corpus callosum connectivity and improved microstructural metrics.
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Affiliation(s)
- Charles S Cox
- Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
- Program in Pediatric Regenerative Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - David M Notrica
- Department of Pediatric Surgery, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
| | - Jenifer Juranek
- Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
- Program in Pediatric Regenerative Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Jeffrey H Miller
- Department of Radiology, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
| | - Fabio Triolo
- Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
- Program in Pediatric Regenerative Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Steven Kosmach
- Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Sean I Savitz
- Department of Neurology, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - P David Adelson
- Department of Pediatric Neurosurgery, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
| | - Claudia Pedroza
- Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Scott D Olson
- Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
- Program in Pediatric Regenerative Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Michael C Scott
- Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Akshita Kumar
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Benjamin M Aertker
- Department of Neurology, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Henry W Caplan
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Margaret L Jackson
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Brijesh S Gill
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Robert A Hetz
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
| | - Michael S Lavoie
- Department of Psychology, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
| | - Linda Ewing-Cobbs
- Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX 77030, USA
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Zhang X, Kuang Q, Xu J, Lin Q, Chi H, Yu D. MSC-Based Cell Therapy in Neurological Diseases: A Concise Review of the Literature in Pre-Clinical and Clinical Research. Biomolecules 2024; 14:538. [PMID: 38785945 PMCID: PMC11117494 DOI: 10.3390/biom14050538] [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: 03/25/2024] [Revised: 04/17/2024] [Accepted: 04/22/2024] [Indexed: 05/25/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells with the ability to self-renew and multi-directional differentiation potential. Exogenously administered MSCs can migrate to damaged tissue sites and participate in the repair of damaged tissues. A large number of pre-clinical studies and clinical trials have demonstrated that MSCs have the potential to treat the abnormalities of congenital nervous system and neurodegenerative diseases. Therefore, MSCs hold great promise in the treatment of neurological diseases. Here, we summarize and highlight current progress in the understanding of the underlying mechanisms and strategies of MSC application in neurological diseases.
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Affiliation(s)
- Xiaorui Zhang
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Qihong Kuang
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Jianguang Xu
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Qing Lin
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Haoming Chi
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Daojin Yu
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
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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.
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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
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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.
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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
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Paresishvili T, Kakabadze Z. Freeze-Dried Mesenchymal Stem Cells: From Bench to Bedside. Review. Adv Biol (Weinh) 2024; 8:e2300155. [PMID: 37990389 DOI: 10.1002/adbi.202300155] [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: 04/21/2023] [Revised: 06/09/2023] [Indexed: 11/23/2023]
Abstract
This review describes the freeze-dried mesenchymal stem cells (MSCs) and their ability to restore damaged tissues and organs. An analysis of the literature shows that after the lyophilization MSCs retain >80% of paracrine factors and that the mechanism of their action on the restoration of damaged tissues and organs is similar to the mechanism of action of paracrine factors in fresh and cryopreserved mesenchymal stem cells. Based on the own materials, the use of paracrine factors of freeze-dried MSCs in vivo and in vitro for the treatment of various diseases of organs and tissues has shown to be effective. The study also discusses about the advantages and disadvantages of freeze-dried MSCs versus cryopreserved MSCs. However, for the effective use of freeze-dried MSCs in clinical practice, a more detailed study of the mechanism of interaction of paracrine factors of freeze-dried MSCs with target cells and tissues is required. It is also necessary to identify possible other specific paracrine factors of freeze-dried MSCs. In addition, develop new therapeutic strategies for the use of freeze-dried MSCs in regenerative medicine and tissue bioengineering.
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Affiliation(s)
- Teona Paresishvili
- Department of Clinical Anatomy, Tbilisi State Medical University, Tbilisi, 0186, Georgia
| | - Zurab Kakabadze
- Department of Clinical Anatomy, Tbilisi State Medical University, Tbilisi, 0186, Georgia
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Vij R, Kim H, Park H, Cheng T, Lotfi D, Chang D. Functional recovery of a 41-year-old quadriplegic spinal cord injury patient following multiple intravenous infusions of autologous adipose-derived mesenchymal stem cells: a case report. FRONTIERS IN TRANSPLANTATION 2023; 2:1287508. [PMID: 38993875 PMCID: PMC11235215 DOI: 10.3389/frtra.2023.1287508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 11/23/2023] [Indexed: 07/13/2024]
Abstract
Spinal cord injury (SCI) is a debilitating disease with clinical manifestations ranging from incomplete neurological deficits affecting sensory and motor functions to complete paralysis. Recent advancements in stem cell research have elucidated the therapeutic potential of mesenchymal stem cells (MSCs) for the treatment of patients with SCI. Here, we present a case of a 41-year-old quadriplegic male individual who experienced a traumatic C-5 incomplete SCI, after slipping off a boat in Florida Keys on August 4, 2017. He was diagnosed with C5-C6 Grade 2 anterolisthesis with flexion teardrop fracture of the anterior C6 with jumped facet on the right and perched facet on the left at C5-C6 with spinal canal stenosis. On September 12, 2019, an Individual Expanded Access Protocol was approved for administration of multiple infusions of autologous, adipose-derived MSCs (adMSCs) for the treatment of this quadriplegic incomplete C5-6 SCI patient. Thirty-four (34) recurrent infusions each with 200 million cells were administered, over a period of ∼2.5 years, which resulted in significant improvements in his quality-of-life as demonstrated by substantial improvements in SCIM-III (Spinal Cord Independence Measure III) scores. Additionally, electromyography/nerve conduction velocity (EMG/NCV) studies showed improvements in the patient's motor and sensory function. No safety concerns were presented, and no serious adverse events were reported during the entire course of treatment. Multiple intravenous infusions of autologous HB-adMSCs for treatment of SCI demonstrated significant enhancements in the patient's neurological function with improved quality-of-life. Further research is needed to evaluate the results of this study.
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Affiliation(s)
- Ridhima Vij
- Clinical Research, Hope Biosciences Research Foundation, Sugar Land, TX, United States
| | - Hosu Kim
- Cell Production, Hope Biosciences, Sugar Land, TX, United States
| | - Hyeonggeun Park
- Cell Production, Hope Biosciences, Sugar Land, TX, United States
| | - Thanh Cheng
- Clinical Research, Hope Biosciences Research Foundation, Sugar Land, TX, United States
| | - Djamchid Lotfi
- Clinical Research, Hope Biosciences Research Foundation, Sugar Land, TX, United States
| | - Donna Chang
- Clinical Research, Hope Biosciences Research Foundation, Sugar Land, TX, United States
- Cell Production, Hope Biosciences, Sugar Land, TX, United States
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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.
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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
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Huang LY, Sun X, Pan HX, Wang L, He CQ, Wei Q. Cell transplantation therapies for spinal cord injury focusing on bone marrow mesenchymal stem cells: Advances and challenges. World J Stem Cells 2023; 15:385-399. [PMID: 37342219 PMCID: PMC10277963 DOI: 10.4252/wjsc.v15.i5.385] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/17/2023] [Accepted: 03/21/2023] [Indexed: 05/26/2023] Open
Abstract
Spinal cord injury (SCI) is a devastating condition with complex pathological mechanisms that lead to sensory, motor, and autonomic dysfunction below the site of injury. To date, no effective therapy is available for the treatment of SCI. Recently, bone marrow-derived mesenchymal stem cells (BMMSCs) have been considered to be the most promising source for cellular therapies following SCI. The objective of the present review is to summarize the most recent insights into the cellular and molecular mechanism using BMMSC therapy to treat SCI. In this work, we review the specific mechanism of BMMSCs in SCI repair mainly from the following aspects: Neuroprotection, axon sprouting and/or regeneration, myelin regeneration, inhibitory microenvironments, glial scar formation, immunomodulation, and angiogenesis. Additionally, we summarize the latest evidence on the application of BMMSCs in clinical trials and further discuss the challenges and future directions for stem cell therapy in SCI models.
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Affiliation(s)
- Li-Yi Huang
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Xin Sun
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Hong-Xia Pan
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Lu Wang
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Cheng-Qi He
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Quan Wei
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
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11
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Clinical characteristics and treatment of spinal cord injury in children and adolescents. Chin J Traumatol 2023; 26:8-13. [PMID: 35478089 PMCID: PMC9912187 DOI: 10.1016/j.cjtee.2022.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/24/2022] [Accepted: 03/29/2022] [Indexed: 02/04/2023] Open
Abstract
Pediatric and adult spinal cord injuries (SCI) are distinct entities. Children and adolescents with SCI must suffer from lifelong disabilities, which is a heavy burden on patients, their families and the society. There are differences in Chinese and foreign literature reports on the incidence, injury mechanism and prognosis of SCI in children and adolescents. In addition to traumatic injuries such as car accidents and falls, the proportion of sports injuries is increasing. The most common sports injury is the backbend during dance practice. Compared with adults, children and adolescents are considered to have a greater potential for neurological improvement. The pathogenesis and treatment of pediatric SCI remains unclear. The mainstream view is that the mechanism of nerve damage in pediatric SCI include flexion, hyperextension, longitudinal distraction and ischemia. We also discuss the advantages and disadvantages of drugs such as methylprednisolone in the treatment of pediatric SCI and the indications and timing of surgery. In addition, the complications of pediatric SCI are also worthy of attention. New imaging techniques such as diffusion tensor imaging and diffusion tensor tractography may be used for diagnosis and assessment of prognosis. This article reviews the epidemiology, pathogenesis, imaging, clinical characteristics, treatment and complications of SCI in children and adolescents. Although current treatment cannot completely restore neurological function, patient quality of life can be enhanced. Continued developments and advances in the research of SCI may eventually provide a cure for children and adolescents with this kind of injury.
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12
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Yin Z, Yin J, Huo Y, Gu G, Yu J, Li A, Tang J. KCC2 overexpressed exosomes meditated spinal cord injury recovery in mice. Biomed Mater 2022; 17. [PMID: 36263707 DOI: 10.1088/1748-605x/ac956b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/27/2022] [Indexed: 11/11/2022]
Abstract
Exosomes show great potential in treating diseases of the central nervous system including spinal cord injury (SCI), still better engineered exosomes have more advantages. In this study, we purified exosomes from K+-Cl-co-transporter (KCC2) overexpressed bone marrow mesenchymal stem cells (ExoKCC2), to investigate the effect of ExoKCC2on neural differentiationin vitroand the repairing function of ExoKCC2in SCI micein vivo. Compared to bone marrow mesenchymal stem cells (BMSC)-derived exosomes (Exo), ExoKCC2could better promote neural stem cell differentiated into neurons, ameliorate the function recovery of SCI mice, and accelerate the neural regeneration at the lesion site. Altogether, engineered ExoKCC2may prove to be an advantageous strategy for SCI treatment.
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Affiliation(s)
- Zhaoyang Yin
- Department of Orthopedics, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, People's Republic of China
| | - Jian Yin
- Department of Orthopedics, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, People's Republic of China
| | - Yongfeng Huo
- Department of Orthopedics, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, People's Republic of China
| | - Guangxue Gu
- Department of Orthopedics, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, People's Republic of China
| | - Jian Yu
- Department of Orthopedics, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, People's Republic of China
| | - Aimin Li
- Department of Orthopedics, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, People's Republic of China
| | - Jinhai Tang
- The First Affiliated Hospital with Nanjing Medical University, Nanjing, People's Republic of China
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13
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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.
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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
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14
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Somuncu D, Gartenberg A, Cho W. Investigational Therapies for Gunshot Wounds to the Spine: A Narrative Review. Clin Spine Surg 2022; 35:233-240. [PMID: 34670987 DOI: 10.1097/bsd.0000000000001258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 09/15/2021] [Indexed: 11/26/2022]
Abstract
STUDY DESIGN This was a narrative review. OBJECTIVE The objective of this study was to review the standards of care and triage protocol for gunshot wounds to the spine, highlighting innovative future treatment options that may be implemented in patients with spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA With the increased availability of firearms among the United States population, gunshot wounds to the spine are becoming a clinically relevant and devastating issue. Such injuries result in severe and diverse complications. SCIs due to gunshot wounds are the leading cause of morbidity and mortality, as they often result in complete or incomplete paraplegia. Current standards of care focus on preventing further damage rather than total cure or treatment of SCI. METHODS A literature review was performed on the standards of care, triage protocol, associated conditions, current therapeutic options, and innovative treatment options for patients with gunshot wounds to the spine. RESULTS The general standards of care for spinal gunshot wounds involve maintaining or renewal of mechanical spinal steadiness and neurological activity while limiting complications of treatment. Current treatment options include management of mean arterial pressure goals, drug therapies consisting of antibiotics, and surgical approaches. With recent innovations in molecular biology and cell transplantation, potentially new and promising treatment options for patients with SCI exist. These options include cell transplantation therapies, platelet-rich plasma administration, exosomal treatments, and mitochondrial-targeted therapeutics. Stem cell transplantation is promising, as several clinical studies have been completed. However, loss-to-follow-up, lack of long-term evaluation, and questionable randomization has limited the use of stem cells in the standard of care practice. Although not studied on human models to a gunshot wound, exosomal and mitochondrial-based treatment options have been studied both in vitro and in animal models with SCI. CONCLUSION Newly emerging molecular and cellular therapy modalities for SCI contribute to the recovery process and may be utilized in conjunction with the current modalities for better outcomes.
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Affiliation(s)
- Doruk Somuncu
- Bahçeşehir University School of Medicine, Istanbul, Turkey
| | - Ariella Gartenberg
- Department of Orthopaedic Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY
| | - Woojin Cho
- Department of Orthopaedic Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY
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15
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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
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16
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Kakabadze MZ, Paresishvili T, Mardaleishvili K, Vadachkoria Z, Kipshidze N, Jangavadze M, Karalashvili L, Ghambashidze K, Chakhunashvili D, Kakabadze Z. Local drug delivery system for the treatment of tongue squamous cell carcinoma in rats. Oncol Lett 2021; 23:13. [PMID: 34820012 PMCID: PMC8607325 DOI: 10.3892/ol.2021.13131] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022] Open
Abstract
The present study describes a local drug delivery system with two functions, which can suppress tumor growth and accelerate wound healing. Thе system consists of a two-layer multicomponent fibrin-based gel (MCPFTG). The internal layer of MCPFTG, which is in direct contact with the wound surface, contains cisplatin placed on a CultiSpher-S collagen microcarrier. The external layer of MCPFTG consists of a CultiSpher-S microcarrier with lyophilized bone marrow stem cells (BMSCs). The efficacy of MCPFTG was evaluated in a rat model of squamous cell carcinoma of the tongue created with 4-nitroquinoline 1-oxide. The results of the study showed that, within 20–25 days, a non-healing wound of the tongue was formed in animals that underwent only 85% resection of squamous cell carcinoma, while rapid progression of the residual tumor was concomitantly observed. Immunohistochemical methods revealed high expression of cyclin D1 and low expression of E-cadherin in these animals. Additionally, high expression of p63 and Ki-67 was noted. In 80% of animals with squamous cell carcinoma of the tongue that were treated with MCPFTG after 85% tumor resection, a noticeable suppression of tumor growth was evident throughout 150 days, and tumor recurrence was not detected. Immunohistochemistry revealed low or moderate expression of cyclin D1, and high expression of E-cadherin throughout the whole observation period. The MCPFTG-based local drug delivery system was shown to be effective in suppressing tumor growth and preventing recurrence. MCPFTG decreased the toxicity of cisplatin and enhanced its antitumor activity. In addition, lyophilized paracrine BMSC factors present in MCPFTG accelerated wound healing after tumor removal. Thus, the present study suggests novel opportunities for the development of a multifunctional drug delivery system for the treatment of squamous cell carcinoma.
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Affiliation(s)
- Mariam Z Kakabadze
- Department of Clinical Anatomy and Operative Surgery, Iv. Javakhishvili Tbilisi State University, 0179 Tbilisi, Georgia
| | - Teona Paresishvili
- Department of Clinical Anatomy, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | | | - Zurab Vadachkoria
- Department of Child and Adolescent Maxillo-facial Surgery and Surgical Stomatology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | - Nicholas Kipshidze
- Department of Interventional Cardiology, Cardiovascular Research Foundation, New York, NY 10019, USA
| | - Mikheil Jangavadze
- Department of Clinical Anatomy and Operative Surgery, Iv. Javakhishvili Tbilisi State University, 0179 Tbilisi, Georgia
| | - Lia Karalashvili
- Department of Clinical Anatomy, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | - Ketevan Ghambashidze
- Department of Clinical Anatomy, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | - David Chakhunashvili
- Department of Clinical Anatomy, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | - Zurab Kakabadze
- Department of Clinical Anatomy, Tbilisi State Medical University, 0186 Tbilisi, Georgia
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17
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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.
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18
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Alavi SNR, Neishaboori AM, Yousefifard M. Extracorporeal shockwave therapy in spinal cord injury, early to advance to clinical trials? A systematic review and meta-analysis on animal studies. Neuroradiol J 2021; 34:552-561. [PMID: 34224252 DOI: 10.1177/19714009211026899] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND As there is no consensus over the efficacy of extracorporeal shockwave therapy in the management of spinal cord injury complications, the current meta-analysis aims to investigate preclinical evidence on the matter. METHODS The search strategy was developed based on keywords related to 'spinal cord injury' and 'extracorporeal shockwave therapy'. A primary search was conducted in Medline, Embase, Scopus and Web of Science until the end of 2020. Studies which administered extracorporeal shockwave therapy on spinal cord injury animal models and evaluated motor function and/or histological findings were included. The standardised mean difference with a 95% confidence interval (CI) were calculated. RESULTS Seven articles were included. Locomotion was significantly improved in the extracorporeal shockwave therapy treated group (standardised mean difference 1.68, 95% CI 1.05-2.31, P=0.032). It seems that the efficacy of extracorporeal shockwave therapy with an energy flux density of 0.1 mJ/mm2 is higher than 0.04 mJ/mm2 (P=0.044). Shockwave therapy was found to increase axonal sprouting (standardised mean difference 1.31, 95% CI 0.65, 1.96), vascular endothelial growth factor tissue levels (standardised mean difference 1.36, 95% CI 0.54, 2.18) and cell survival (standardised mean difference 2.49, 95% CI 0.93, 4.04). It also significantly prevents axonal degeneration (standardised mean difference 2.25, 95% CI 1.47, 3.02). CONCLUSION Extracorporeal shockwave therapy significantly improves locomotor recovery in spinal cord injury animal models through neural tissue regeneration. Nonetheless, in spite of the promising results and clinical application of extracorporeal shockwave therapy in various conditions, current evidence implies that designing clinical trials on extracorporeal shockwave therapy in the management of spinal cord injury may not be soon. Hence, further preclinical studies with the effort to reach the safest and the most efficient treatment protocol are needed.
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Affiliation(s)
| | | | - Mahmoud Yousefifard
- Physiology Research Center, 440827Iran University of Medical Sciences, Tehran, Iran
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19
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Abstract
Traumatic spinal cord injury (SCI) results in direct and indirect damage to neural tissues, which results in motor and sensory dysfunction, dystonia, and pathological reflex that ultimately lead to paraplegia or tetraplegia. A loss of cells, axon regeneration failure, and time-sensitive pathophysiology make tissue repair difficult. Despite various medical developments, there are currently no effective regenerative treatments. Stem cell therapy is a promising treatment for SCI due to its multiple targets and reactivity benefits. The present review focuses on SCI stem cell therapy, including bone marrow mesenchymal stem cells, umbilical mesenchymal stem cells, adipose-derived mesenchymal stem cells, neural stem cells, neural progenitor cells, embryonic stem cells, induced pluripotent stem cells, and extracellular vesicles. Each cell type targets certain features of SCI pathology and shows therapeutic effects via cell replacement, nutritional support, scaffolds, and immunomodulation mechanisms. However, many preclinical studies and a growing number of clinical trials found that single-cell treatments had only limited benefits for SCI. SCI damage is multifaceted, and there is a growing consensus that a combined treatment is needed.
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Affiliation(s)
- Liyi Huang
- Department of Rehabilitation Medicine Center, 34753West China Hospital/West China School of Medicine, Sichuan University, Chengdu, Sichuan, PR China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Sichuan University, Chengdu, Sichuan Province, PR China
| | - Chenying Fu
- State Key Laboratory of Biotherapy, 34753West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Feng Xiong
- Department of Rehabilitation Medicine Center, 34753West China Hospital/West China School of Medicine, Sichuan University, Chengdu, Sichuan, PR China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Sichuan University, Chengdu, Sichuan Province, PR China
| | - Chengqi He
- Department of Rehabilitation Medicine Center, 34753West China Hospital/West China School of Medicine, Sichuan University, Chengdu, Sichuan, PR China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Sichuan University, Chengdu, Sichuan Province, PR China
| | - Quan Wei
- Department of Rehabilitation Medicine Center, 34753West China Hospital/West China School of Medicine, Sichuan University, Chengdu, Sichuan, PR China.,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Sichuan University, Chengdu, Sichuan Province, PR China
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Huang H, Chen L, Mao G, Sharma HS. Clinical neurorestorative cell therapies: Developmental process, current state and future prospective. JOURNAL OF NEURORESTORATOLOGY 2020. [DOI: 10.26599/jnr.2020.9040009] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Clinical cell therapies (CTs) for neurological diseases and cellular damage have been explored for more than 2 decades. According to the United States Food and Drug Administration, there are 2 types of cell categories for therapy, namely stem cell-derived CT products and mature/functionally differentiated cell-derived CT products. However, regardless of the type of CT used, the majority of reports of clinical CTs from either small sample sizes based on single-center phase 1 or 2 unblinded trials or retrospective clinical studies showed effects on neurological improvement and the ability to either partially or temporarily thwart the deteriorating cellular processes of the neurodegenerative diseases. There have been only a few prospective, multicenter, randomized, double- blind placebo-control clinical trials of CTs so far in this developing novel area that have shown negative results, and more clinical trials are needed. This will expand our knowledge in exploring the type of cells that yield promising results and restore damaged neurological structure and functions of the central nervous system based on higher level evidence-based medical data. In this review, we briefly introduce the developmental process, current state, and future prospective for clinical neurorestorative CT.
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Yang Y, Pang M, Chen YY, Zhang LM, Liu H, Tan J, Liu B, Rong LM. Human umbilical cord mesenchymal stem cells to treat spinal cord injury in the early chronic phase: study protocol for a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial. Neural Regen Res 2020; 15:1532-1538. [PMID: 31997819 PMCID: PMC7059580 DOI: 10.4103/1673-5374.274347] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Human umbilical cord mesenchymal stem cells (hUC-MSCs) support revascularization, inhibition of inflammation, regulation of apoptosis, and promotion of the release of beneficial factors. Thus, they are regarded as a promising candidate for the treatment of intractable spinal cord injury (SCI). Clinical studies on patients with early chronic SCI (from 2 months to 1 year post-injury), which is clinically common, are rare; therefore, we will conduct a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial at the Third Affiliated Hospital of Sun Yat-sen University, West China Hospital of Sichuan University, and Shanghai East Hospital, Tongji University School of Medicine, China. The trial plans to recruit 66 early chronic SCI patients. Eligible patients will undergo randomization at a 2:1 ratio to two arms: the observation group and the control group. Subjects in the observation group will receive four intrathecal transplantations of stem cells, with a dosage of 1 × 106/kg, at one calendar month intervals. Subjects in the control group will receive intrathecal administrations of 10 mL sterile normal saline in place of the stem cell transplantations. Clinical safety will be assessed by the analysis of adverse events and laboratory tests. The American Spinal Injury Association (ASIA) total score will be the primary efficacy endpoint, and the secondary efficacy outcomes will be the following: ASIA impairment scale, International Association of Neural Restoration-Spinal Cord Injury Functional Rating Scale, muscle tension, electromyogram, cortical motor and cortical sensory evoked potentials, residual urine volume, magnetic resonance imaging-diffusion tensor imaging, T cell subtypes in serum, neurotrophic factors and inflammatory factors in both serum and cerebrospinal fluid. All evaluations will be performed at 1, 3, 6, and 12 months following the final intrathecal administration. During the entire study procedure, all adverse events will be reported as soon as they are noted. This trial is designed to evaluate the clinical safety and efficacy of subarachnoid transplantation of hUC-MSCs to treat early chronic SCI. Moreover, it will establish whether cytotherapy can ameliorate local hostile microenvironments, promote tracking fiber regeneration, and strengthen spinal conduction ability, thus improving overall motor, sensory, and micturition/defecation function in patients with early chronic SCI. This study was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University, China (approval No. [2018]-02) on March 30, 2018, and was registered with ClinicalTrials.gov (registration No. NCT03521323) on April 12, 2018. The revised trial protocol (protocol version 4.0) was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University, China (approval No. [2019]-10) on February 25, 2019, and released on ClinicalTrials.gov on April 29, 2019.
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Affiliation(s)
- Yang Yang
- Department of Spine Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
| | - Mao Pang
- Department of Spine Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
| | - Yu-Yong Chen
- Department of Spine Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
| | - Liang-Ming Zhang
- Department of Spine Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
| | - Hao Liu
- Department of Orthopedics, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Jun Tan
- Department of Orthopedics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bin Liu
- Department of Spine Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
| | - Li-Min Rong
- Department of Spine Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
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22
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Sharma A, Sane H, Gokulchandran N, Kulkarni P, Jose A, Nair V, Das R, Lakhanpal V, Badhe P. Intrathecal transplantation of autologous bone marrow mononuclear cells in patients with sub-acute and chronic spinal cord injury: An open-label study. Int J Health Sci (Qassim) 2020; 14:24-32. [PMID: 32206057 PMCID: PMC7069665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE The objective of the study was to analyze the effect of intrathecal transplantation of autologous bone marrow-derived mononuclear cells (BMMNCs) in functional recovery of spinal cord injury (SCI) patients along with neurorehabilitation and to evaluate various factors influencing the outcome of cellular therapy. METHODS We conducted an open-label study including 180 sub-acute and chronic SCI patients. All patients received intrathecal autologous BMMNCs along with neurorehabilitation. 80-100 mL of bone marrow was aspirated and BMMNCs were obtained using density gradient separation. An average of 1.06 × 108 cells with 97% viability was administered through lumbar puncture immediately. After transplantation, all patients underwent neurorehabilitation. Patients were followed up after an average of 9 ± 7 months. They were assessed for functional symptomatic changes and the outcome measures used were functional independence measure (FIM) and walking index for SCI (WISCI). RESULTS Patients showed symptomatic improvement in sitting/standing balance, bed mobility, trunk stability, upper limb function, mobility, sensation, bowel/bladder functions, and activities of daily living with no serious adverse events. Scores on FIM and WISCI showed statistically significant improvement. On subgroup analysis, it was found that early intervention and more than one dose of BMMNCs demonstrate a better functional outcome. Younger patients demonstrated better improvements in functional independence. Both cervical and dorsolumbar levels of injury show significant improvements in motor and sensory deficits. CONCLUSIONS Autologous BMMNC transplantation with neurorehabilitation is safe, effective, enhances functional recovery, and improves the quality of life of SCI patients in sub-acute and chronic stage.
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Affiliation(s)
- Alok Sharma
- Department of Medical Services and Clinical Research, NeuroGen Brain and Spine Institute, Mumbai, Maharashtra, India
| | - Hemangi Sane
- Department of Research and Development, NeuroGen Brain and Spine Institute, India
| | - Nandini Gokulchandran
- Department of Medical Services and Clinical Research, NeuroGen Brain and Spine Institute, Mumbai, Maharashtra, India
| | - Pooja Kulkarni
- Department of Research and Development, NeuroGen Brain and Spine Institute, India
| | - Alitta Jose
- Department of Research and Development, NeuroGen Brain and Spine Institute, India,
Address for correspondence: Ms. Alitta Jose, NeuroGen Brain and Spine Institute, Palm Beach Road, Seawoods (W), Navi Mumbai - 400 706, Maharashtra, India. Tel.: +91-22-41136565. E-mail:
| | - Vivek Nair
- Department of Neurorehabilitation, NeuroGen Brain and Spine Institute, Mumbai, Maharashtra, India
| | - Rohit Das
- Department of Neurorehabilitation, NeuroGen Brain and Spine Institute, Mumbai, Maharashtra, India
| | - Vaibhav Lakhanpal
- Department of Research and Development, NeuroGen Brain and Spine Institute, India
| | - Prerna Badhe
- Department of Regenerative Laboratory Services, NeuroGen Brain and Spine Institute, Mumbai, Maharashtra, India
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23
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Spinal cord injury: pathophysiology, treatment strategies, associated challenges, and future implications. Cell Tissue Res 2019; 377:125-151. [PMID: 31065801 DOI: 10.1007/s00441-019-03039-1] [Citation(s) in RCA: 131] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 04/01/2019] [Indexed: 12/16/2022]
Abstract
Axonal regeneration and formation of tripartite (axo-glial) junctions at damaged sites is a prerequisite for early repair of injured spinal cord. Transplantation of stem cells at such sites of damage which can generate both neuronal and glial population has gained impact in terms of recuperation upon infliction with spinal cord injury. In spite of the fact that a copious number of pre-clinical studies using different stem/progenitor cells have shown promising results at acute and subacute stages, at the chronic stages of injury their recovery rates have shown a drastic decline. Therefore, developing novel therapeutic strategies are the need of the hour in order to assuage secondary morbidity and effectuate improvement of the spinal cord injury (SCI)-afflicted patients' quality of life. The present review aims at providing an overview of the current treatment strategies and also gives an insight into the potential cell-based therapies for the treatment of SCI.
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24
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Yu Z, Xu N, Zhang N, Xiong Y, Wang Z, Liang S, Zhao D, Huang F, Zhang C. Repair of Peripheral Nerve Sensory Impairments via the Transplantation of Bone Marrow Neural Tissue-Committed Stem Cell-Derived Sensory Neurons. Cell Mol Neurobiol 2019; 39:341-353. [PMID: 30684112 PMCID: PMC11469867 DOI: 10.1007/s10571-019-00650-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 01/04/2019] [Indexed: 01/20/2023]
Abstract
The present study aimed to investigate the efficacy of transplantation of bone marrow neural tissue-committed stem cell-derived sensory neuron-like cells for the repair of peripheral nerve sensory impairments in rats. Bone marrow was isolated and cultured to obtain the neural tissue-committed stem cells (NTCSCs), and the differentiation of these cells into sensory neuron-like cells was induced. Bone marrow mesenchymal stem cells (BMSCs), bone marrow NTCSCs, and bone marrow NTCSC-derived sensory neurons (NTCSC-SNs) were transplanted by microinjection into the L4 and L5 dorsal root ganglions (DRGs) in an animal model of sensory defect. On the 2nd, 4th, 8th, and 12th week after the transplantation, the effects of the three types of stem cells on the repair of the sensory functional defect were analyzed via behavioral observation, sensory function evaluation, electrophysiological examination of the sciatic nerve, and morphological observation of the DRGs. The results revealed that the transplanted BMSCs, NTCSCs, and NTCSC-SNs were all able to repair the sensory nerves. In addition, the effect of the NTCSC-SNs was significantly better than that of the other two types of stem cells. The general posture and gait of the animals in the sensory defect model exhibited evident improvement over time. Plantar temperature sensitivity and pain sensitivity gradually recovered, and the sensation latency was reduced, with faster sensory nerve conduction velocity. Transplantation of NTCSC-SNs can improve the repair of peripheral nerve sensory defects in rats.
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Affiliation(s)
- Zhenhai Yu
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
- Department of Human Anatomy, College of Basic Medical Sciences, Second Military Medical University, Shanghai, 200433, People's Republic of China
| | - Ning Xu
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264100, People's Republic of China
| | - Naili Zhang
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Yanlian Xiong
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Zhiqiang Wang
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Shaohua Liang
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Dongmei Zhao
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Fei Huang
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China.
| | - Chuansen Zhang
- Department of Human Anatomy, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China.
- Department of Human Anatomy, College of Basic Medical Sciences, Second Military Medical University, Shanghai, 200433, People's Republic of China.
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Salehi-pourmehr H, Rahbarghazi R, Mahmoudi J, Roshangar L, Chapple CR, Hajebrahimi S, Abolhasanpour N, Azghani MR. Intra-bladder wall transplantation of bone marrow mesenchymal stem cells improved urinary bladder dysfunction following spinal cord injury. Life Sci 2019; 221:20-28. [PMID: 30735734 DOI: 10.1016/j.lfs.2019.02.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/25/2019] [Accepted: 02/04/2019] [Indexed: 12/14/2022]
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26
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Santamaría AJ, Benavides FD, DiFede DL, Khan A, Pujol MV, Dietrich WD, Marttos A, Green BA, Hare JM, Guest JD. Clinical and Neurophysiological Changes after Targeted Intrathecal Injections of Bone Marrow Stem Cells in a C3 Tetraplegic Subject. J Neurotrauma 2018; 36:500-516. [PMID: 29790404 DOI: 10.1089/neu.2018.5716] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
High-level quadriplegia is a devastating condition with limited treatment options. Bone marrow derived stem cells (BMSCs) are reported to have immunomodulatory and neurotrophic effects in spinal cord injury (SCI). We report a subject with complete C2 SCI who received three anatomically targeted intrathecal infusions of BMSCs under a single-patient expanded access investigational new drug (IND). She underwent intensive physical therapy and was followed for >2 years. At end-point, her American Spinal Injury Association Impairment Scale (AIS) grade improved from A to B, and she recovered focal pressure touch sensation over several body areas. We conducted serial neurophysiological testing to monitor changes in residual connectivity. Motor, sensory, and autonomic system testing included motor evoked potentials (MEPs), somatosensory evoked potentials (SSEPs), electromyography (EMG) recordings, F waves, galvanic skin responses, and tilt-table responses. The quality and magnitude of voluntary EMG activations increased over time, but remained below the threshold of clinically obvious movement. Unexpectedly, at 14 months post-injury, deep inspiratory maneuvers triggered respiratory-like EMG bursting in the biceps and several other muscles. This finding means that connections between respiratory neurons and motor neurons were newly established, or unmasked. We also report serial analysis of MRI, International Standards for Neurological Classification of SCI (ISNCSCI), pulmonary function, pain scores, cerebrospinal fluid (CSF) cytokines, and bladder assessment. As a single case, the linkage of the clinical and neurophysiological changes to either natural history or to the BMSC infusions cannot be resolved. Nevertheless, such detailed neurophysiological assessment of high cervical SCI patients is rarely performed. Our findings indicate that electrophysiology studies are sensitive to define both residual connectivity and new plasticity.
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Affiliation(s)
- Andrea J Santamaría
- 1 The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, Florida
| | - Francisco D Benavides
- 1 The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, Florida
| | - Darcy L DiFede
- 2 Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida
| | - Aisha Khan
- 2 Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida
| | - Marietsy V Pujol
- 2 Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida
| | - W Dalton Dietrich
- 1 The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, Florida.,3 Department of Neurological Surgery, University of Miami, Miller School of Medicine, Miami, Florida
| | - Antonio Marttos
- 4 Surgical Critical Care, University of Miami, Miller School of Medicine, Miami, Florida
| | - Barth A Green
- 3 Department of Neurological Surgery, University of Miami, Miller School of Medicine, Miami, Florida
| | - Joshua M Hare
- 2 Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida
| | - James D Guest
- 1 The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, Florida.,3 Department of Neurological Surgery, University of Miami, Miller School of Medicine, Miami, Florida
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27
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Singh A, Srivastava RN, Agrahari A, Singh S, Raj S, Chatterji T, Mahdi AA, Garg RK, Roy R. Proton NMR based serum metabolic profile correlates with the neurological recovery in treated acute spinal cord injury (ASCI) subjects: A pilot study. Clin Chim Acta 2018; 480:150-160. [DOI: 10.1016/j.cca.2018.02.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 02/07/2018] [Accepted: 02/13/2018] [Indexed: 01/09/2023]
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28
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Huang H, Young W, Chen L, Feng S, Zoubi ZMA, Sharma HS, Saberi H, Moviglia GA, He X, Muresanu DF, Sharma A, Otom A, Andrews RJ, Al-Zoubi A, Bryukhovetskiy AS, Chernykh ER, Domańska-Janik K, Jafar E, Johnson WE, Li Y, Li D, Luan Z, Mao G, Shetty AK, Siniscalco D, Skaper S, Sun T, Wang Y, Wiklund L, Xue Q, You SW, Zheng Z, Dimitrijevic MR, Masri WSE, Sanberg PR, Xu Q, Luan G, Chopp M, Cho KS, Zhou XF, Wu P, Liu K, Mobasheri H, Ohtori S, Tanaka H, Han F, Feng Y, Zhang S, Lu Y, Zhang Z, Rao Y, Tang Z, Xi H, Wu L, Shen S, Xue M, Xiang G, Guo X, Yang X, Hao Y, Hu Y, Li J, AO Q, Wang B, Zhang Z, Lu M, Li T. Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017). Cell Transplant 2018; 27:310-324. [PMID: 29637817 PMCID: PMC5898693 DOI: 10.1177/0963689717746999] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 07/22/2017] [Accepted: 11/13/2017] [Indexed: 12/11/2022] Open
Abstract
Cell therapy has been shown to be a key clinical therapeutic option for central nervous system diseases or damage. Standardization of clinical cell therapy procedures is an important task for professional associations devoted to cell therapy. The Chinese Branch of the International Association of Neurorestoratology (IANR) completed the first set of guidelines governing the clinical application of neurorestoration in 2011. The IANR and the Chinese Association of Neurorestoratology (CANR) collaborated to propose the current version "Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)". The IANR council board members and CANR committee members approved this proposal on September 1, 2016, and recommend it to clinical practitioners of cellular therapy. These guidelines include items of cell type nomenclature, cell quality control, minimal suggested cell doses, patient-informed consent, indications for undergoing cell therapy, contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility.
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Affiliation(s)
- Hongyun Huang
- Institute of Neurorestoratology, General Hospital of Armed Police Forces, Beijing, People’s Republic of China
| | - Wise Young
- W. M. Keck Center for Collaborative Neuroscience, Rutgers, State University of New Jersey, Piscataway, NJ, USA
| | - Lin Chen
- Department of Neurosurgery, Tsinghua University Yuquan Hospital, Beijing, People’s Republic of China
| | - Shiqing Feng
- Department of Orthopaedics, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
| | - Ziad M. Al Zoubi
- Jordan Ortho and Spinal Centre, Al-Saif Medical Center, Amman, Jordan
| | - Hari Shanker Sharma
- Intensive Experimental CNS Injury and Repair, University Hospital, Uppsala University, Uppsala, Sweden
| | - Hooshang Saberi
- Department of Neurosurgery, Brain and Spinal Injury Research center, Tehran University of Medical Sciences, Tehran, Iran
| | - Gustavo A. Moviglia
- Center of Research and Engineer of Tissues and Cellular Therapy, Maimonides University, Buenos Aires, Argentina
| | - Xijing He
- Department of Orthopaedics, Second Affiliated Hospital of Xi’an Jiaotong University, Xian, People’s Republic of China
| | - Dafin F. Muresanu
- Department of Neurosciences “Iuliu Hatieganu,” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Alok Sharma
- Department of Neurosurgery, LTM Medical College, LTMG Hospital, Mumbai, Mumbai, India
| | - Ali Otom
- Royal Rehabilitation Center, King Hussein Medical Centre-RJRC Amman, Jordan
| | - Russell J. Andrews
- Nanotechnology & Smart Systems, NASA Ames Research Center, Silicon Valley, CA, USA
| | - Adeeb Al-Zoubi
- The University of Illinois College of Medicine in Peoria, Peoria, IL, USA
| | - Andrey S. Bryukhovetskiy
- NeuroVita Clinic of Interventional and Restorative Neurology and Therapy, Kashirskoye shosse, Moscow, Russia
| | - Elena R. Chernykh
- Lab of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | | | - Emad Jafar
- Jordan Ortho and Spinal Centre, Al-Saif Medical Center, Amman, Jordan
| | - W. Eustace Johnson
- Stem Cells and Regenerative Biology, Faculty of Medicine Dentistry and Life Sciences, University of Chester, Chester, United Kingdom
| | - Ying Li
- Spinal Repair Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, United Kingdom
| | - Daqing Li
- Spinal Repair Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, United Kingdom
| | - Zuo Luan
- Department of Pediatrics, Navy General Hospital of PLA, Beijing, People’s Republic of China
| | - Gengsheng Mao
- Institute of Neurorestoratology, General Hospital of Armed Police Forces, Beijing, People’s Republic of China
| | - Ashok K. Shetty
- Department of Molecular and Cellular Medicine, Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA
| | - Dario Siniscalco
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli,” Naples, Italy
| | - Stephen Skaper
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
| | - Tiansheng Sun
- Department of orthopedics, PLA Army General Hospital, Beijing, People’s Republic of China
| | - Yunliang Wang
- Department of Neurology, 148th Hospital, Zibo, Shandong, People’s Republic of China
| | - Lars Wiklund
- Unit of Neurology, Department of Pharmacology and Clinical Neuroscience, Umea University, Ostersund, Sweden
| | - Qun Xue
- Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou Jiangsu, People’s Republic of China
| | - Si-Wei You
- Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China
| | - Zuncheng Zheng
- Department of Rehabilitation Medicine, The Central Hospital of Taian, Taian, Shandong, People’s Republic of China
| | | | - W. S. El Masri
- Spinal Injuries Unit, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, United Kingdom
| | - Paul R. Sanberg
- Center of Excellence for Aging & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Qunyuan Xu
- Institute of Neuroscience, Capital Medical University, Beijing, People’s Republic of China
| | - Guoming Luan
- Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Michael Chopp
- Henry Ford Hospital, Henry Ford Health System, Neurology Research, Detroit, MI, USA
| | - Kyoung-Suok Cho
- Department of Neurosurgery, Uijongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijongbu, South Korea
| | - Xin-Fu Zhou
- Division of Health Sciences, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia
| | - Ping Wu
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA
| | - Kai Liu
- Division of Life Science, The Hong Kong University of Science and Technology, Kowloon, Hong Kong
| | - Hamid Mobasheri
- Biomaterials Research Center, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Seiji Ohtori
- Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroyuki Tanaka
- Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Fabin Han
- Centre for Stem Cells and Regenerative Medicine, Liaocheng University/Liaocheng People’s Hospital, Liaocheng, Shandong, People’s Republic of China
| | - Yaping Feng
- Department of Neurosurgery, Kunming General Hospital of Chengdu Military Command of Chinese PLA, Kunming, Yunnan, People’s Republic of China
| | - Shaocheng Zhang
- Department of Orthopedics, Changhai Hospital, The Second Military Medical University, Shanghai, People’s Republic of China
| | - Yingjie Lu
- Department of Neurosurgery, Chengde Dadu Hospital, Weichang, Hebei, People’s Republic of China
| | - Zhicheng Zhang
- Department of orthopedics, PLA Army General Hospital, Beijing, People’s Republic of China
| | - Yaojian Rao
- Department of Spinal Surgery, Luoyang Orthopedic Hospital of Henan Province, Luoyang, Henan, People’s Republic of China
| | - Zhouping Tang
- Department of Neurology, Tongji Medical College of HUST, Tongji Hospital, Wuhan, People’s Republic of China
| | - Haitao Xi
- Department of Neurology, Beijing Rehabilitation Hospital of Capital Medical University, Beijing, People’s Republic of China
| | - Liang Wu
- Center of Rehabilitation, Beijing Xiaotangshan Rehabilitation Hospital, Beijing, People’s Republic of China
| | - Shunji Shen
- Department of Rehabilitation, Weihai Municipal Hospital, Weihai, Shandong, People’s Republic of China
| | - Mengzhou Xue
- Department of Neurorehabilitation, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Guanghong Xiang
- Brain Hospital of Hunan Province, Changsha, Hunan, People’s Republic of China
| | - Xiaoling Guo
- Department of Neurology, PLA Army 266 Hospital, Chengde, Hebei, People’s Republic of China
| | - Xiaofeng Yang
- Department of Neurosurgery, The First Affiliated Hospital of Zhejiang University Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Yujun Hao
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Yong Hu
- Department of Orthopaedic and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong
| | - Jinfeng Li
- Unit of Neurology, Department of Pharmacology and Clinical Neuroscience, Umea University, Ostersund, Sweden
| | - Qiang AO
- Department of tissue engineering, China Medical University, Shenyang, Liaoning, People’s Republic of China
| | - Bin Wang
- Department of Traumatology, The Second Affiliated Hospital of Guangzhou Medical University, Haizhu District, Guangzhou, People’s Republic of China
| | - Zhiwen Zhang
- Department of Neurosurgery, First Affiliated Hospital of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Ming Lu
- Department of Neurosurgery, Second Affiliated Hospital of Hunan Normal University (163 Hospital of PLA), Changsha, Hunan, People’s Republic of China
| | - Tong Li
- Department of Neurology, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
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Yu X, Wu H, Zhao Y, Guo Y, Chen Y, Dong P, Mu Q, Wang X, Wang X. Bone marrow mesenchymal stromal cells alleviate brain white matter injury via the enhanced proliferation of oligodendrocyte progenitor cells in focal cerebral ischemic rats. Brain Res 2017; 1680:127-136. [PMID: 29258846 DOI: 10.1016/j.brainres.2017.12.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 12/11/2017] [Accepted: 12/13/2017] [Indexed: 02/05/2023]
Abstract
The effects of transplanting bone marrow mesenchymal stromal cells (BMSCs) for the treatment of white matter damage are not well understood, nor are the underlying mechanisms. Recent studies showed that endogenous oligodendrocyte progenitor cells (OPCs) can be stimulated to proliferate. Therefore, we explore the effects of BMSCs transplantation on white matter damage and the proliferation of OPCs in transient focal cerebral ischemic rats. BMSCs were transplanted into a group of rats that had undergone middle cerebral artery occlusion (MCAO) 24 h after reperfusion. The ratswere examined by MRI-T2 and DTI sequencesdynamically. The proliferating cells were labeled by 5-Bromo-2'-deoxyuridine (BrdU). The effects of BMSC transplantation on neurons, axons, myelination, and proliferating OPCs were examined by Nissl staining, MBP/NF-H and BrdU/NG2 immunofluorescence staining7 days after transplantation. More Nissl-stained neuronswere found and the FA value of MRI-DTI was significantly higher in the MCAO + BMSCs group than in the MCAOgroup (both P < .01). The fold change of MBP protein was significantly higher in the MCAO + BMSCs group than in the MCAO group (P < .01); the same was true of NF-H protein. Additionally, there were more BrdU+NG2+ cells in the SVZ areas of the MCAO + BMSCs group than in the MCAO group (P < .01). BMSCs thus were shown to alleviate neuronal/axonal injury and promote the proliferation of OPCs and formation of myelin sheath, significantly alleviating white matter damage in focal cerebral ischemic rats.
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Affiliation(s)
- Xiaohe Yu
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Hongjuan Wu
- Clinical Medical Institute, Weifang Medical University, Weifang 261053, PR China
| | - Yansong Zhao
- Department of Ophthalmology, Weifang Medical University Affiliated Hospital, Clinical Medical Institute, Weifang Medical University, Weifang 261053, PR China
| | - Yuanyuan Guo
- Department of Medical Imaging, Weifang Medical University, Weifang 261053, PR China
| | - Yuxi Chen
- Department of Medical Imaging, Weifang Medical University, Weifang 261053, PR China
| | - Peng Dong
- Department of Medical Imaging, Weifang Medical University, Weifang 261053, PR China
| | - Qingjie Mu
- Department of Hematology, Clinical Medical Institute, Weifang Medical University, Weifang 261053, PR China
| | - Xin Wang
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Xiaoli Wang
- Department of Medical Imaging, Weifang Medical University, Weifang 261053, PR China.
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Ganz J, Shor E, Guo S, Sheinin A, Arie I, Michaelevski I, Pitaru S, Offen D, Levenberg S. Implantation of 3D Constructs Embedded with Oral Mucosa-Derived Cells Induces Functional Recovery in Rats with Complete Spinal Cord Transection. Front Neurosci 2017; 11:589. [PMID: 29163001 PMCID: PMC5671470 DOI: 10.3389/fnins.2017.00589] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 10/06/2017] [Indexed: 12/23/2022] Open
Abstract
Spinal cord injury (SCI), involving damaged axons and glial scar tissue, often culminates in irreversible impairments. Achieving substantial recovery following complete spinal cord transection remains an unmet challenge. Here, we report of implantation of an engineered 3D construct embedded with human oral mucosa stem cells (hOMSC) induced to secrete neuroprotective, immunomodulatory, and axonal elongation-associated factors, in a complete spinal cord transection rat model. Rats implanted with induced tissue engineering constructs regained fine motor control, coordination and walking pattern in sharp contrast to the untreated group that remained paralyzed (42 vs. 0%). Immunofluorescence, CLARITY, MRI, and electrophysiological assessments demonstrated a reconnection bridging the injured area, as well as presence of increased number of myelinated axons, neural precursors, and reduced glial scar tissue in recovered animals treated with the induced cell-embedded constructs. Finally, this construct is made of bio-compatible, clinically approved materials and utilizes a safe and easily extractable cell population. The results warrant further research with regards to the effectiveness of this treatment in addressing spinal cord injury.
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Affiliation(s)
- Javier Ganz
- Department of Human Molecular Genetics and Biochemistry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Erez Shor
- Department of Biomedical Engineering, Technion, Haifa, Israel
| | - Shaowei Guo
- Department of Biomedical Engineering, Technion, Haifa, Israel
| | - Anton Sheinin
- Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Ina Arie
- Department of Oral Biology, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Izhak Michaelevski
- Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.,Department of Molecular Biology, Faculty of Natural Sciences, Ariel University, Ariel, Israel
| | - Sandu Pitaru
- Department of Oral Biology, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Daniel Offen
- Department of Human Molecular Genetics and Biochemistry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Yuan W, Cui L, Li G, Wang N, Zhang P, Zhang Y, Yu N, Wang H, Zhu J, Yang L, Huang J. Recombinant neuritin affects the senescence, apoptosis, proliferation, and migration of rat bone marrow-derived mesenchymal stem cells. Biotechnol Lett 2017; 39:1649-1655. [DOI: 10.1007/s10529-017-2411-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 08/18/2017] [Indexed: 12/01/2022]
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Xavier-Elsas P, Ferreira RN, Gaspar-Elsas MIC. Surgical and immune reconstitution murine models in bone marrow research: Potential for exploring mechanisms in sepsis, trauma and allergy. World J Exp Med 2017; 7:58-77. [PMID: 28890868 PMCID: PMC5571450 DOI: 10.5493/wjem.v7.i3.58] [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: 03/27/2017] [Revised: 06/11/2017] [Accepted: 06/30/2017] [Indexed: 02/06/2023] Open
Abstract
Bone marrow, the vital organ which maintains lifelong hemopoiesis, currently receives considerable attention, as a source of multiple cell types which may play important roles in repair at distant sites. This emerging function, distinct from, but closely related to, bone marrow roles in innate immunity and inflammation, has been characterized through a number of strategies. However, the use of surgical models in this endeavour has hitherto been limited. Surgical strategies allow the experimenter to predetermine the site, timing, severity and invasiveness of injury; to add or remove aggravating factors (such as infection and defects in immunity) in controlled ways; and to manipulate the context of repair, including reconstitution with selected immune cell subpopulations. This endows surgical models overall with great potential for exploring bone marrow responses to injury, inflammation and infection, and its roles in repair and regeneration. We review three different murine surgical models, which variously combine trauma with infection, antigenic stimulation, or immune reconstitution, thereby illuminating different aspects of the bone marrow response to systemic injury in sepsis, trauma and allergy. They are: (1) cecal ligation and puncture, a versatile model of polymicrobial sepsis; (2) egg white implant, an intriguing model of eosinophilia induced by a combination of trauma and sensitization to insoluble allergen; and (3) ectopic lung tissue transplantation, which allows us to dissect afferent and efferent mechanisms leading to accumulation of hemopoietic cells in the lungs. These models highlight the gain in analytical power provided by the association of surgical and immunological strategies.
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Hou XQ, Wang L, Wang FG, Zhao XM, Zhang HT. Combination of RNA Interference and Stem Cells for Treatment of Central Nervous System Diseases. Genes (Basel) 2017; 8:genes8050135. [PMID: 28481269 PMCID: PMC5448009 DOI: 10.3390/genes8050135] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 04/27/2017] [Accepted: 04/28/2017] [Indexed: 12/31/2022] Open
Abstract
RNA interference (RNAi), including microRNAs, is an important player in the mediation of differentiation and migration of stem cells via target genes. It is used as a potential strategy for gene therapy for central nervous system (CNS) diseases. Stem cells are considered vectors of RNAi due to their capacity to deliver RNAi to other cells. In this review, we discuss the recent advances in studies of RNAi pathways in controlling neuronal differentiation and migration of stem cells. We also highlight the utilization of a combination of RNAi and stem cells in treatment of CNS diseases.
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Affiliation(s)
- Xue-Qin Hou
- Institute of Pharmacology, Taishan Medical University, Taian 271016, Shandong, China.
| | - Lei Wang
- Institute of Pharmacology, Taishan Medical University, Taian 271016, Shandong, China.
| | - Fu-Gang Wang
- Institute of Pharmacology, Taishan Medical University, Taian 271016, Shandong, China.
| | - Xiao-Min Zhao
- Institute of Pharmacology, Taishan Medical University, Taian 271016, Shandong, China.
| | - Han-Ting Zhang
- Institute of Pharmacology, Taishan Medical University, Taian 271016, Shandong, China.
- Departments of Behavioral Medicine & Psychiatry and Physiology & Pharmacology, Blanchette Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA.
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Multichannel polymer scaffold seeded with activated Schwann cells and bone mesenchymal stem cells improves axonal regeneration and functional recovery after rat spinal cord injury. Acta Pharmacol Sin 2017; 38:623-637. [PMID: 28392569 DOI: 10.1038/aps.2017.11] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 01/23/2017] [Indexed: 12/17/2022]
Abstract
The adult mammalian CNS has a limited capacity to regenerate after traumatic injury. In this study, a combinatorial strategy to promote axonal regeneration and functional recovery after spinal cord injury (SCI) was evaluated in adult rats. The rats were subjected to a complete transection in the thoracic spinal cord, and multichannel scaffolds seeded with activated Schwann cells (ASCs) and/or rat bone marrow-derived mesenchymal stem cells (MSCs) were acutely grafted into the 3-mm-wide transection gap. At 4 weeks post-transplantation and thereafter, the rats receiving scaffolds seeded with ASCs and MSCs exhibited significant recovery of nerve function as shown by the Basso, Beattie and Bresnahan (BBB) score and electrophysiological test results. Immunohistochemical analyses at 4 and 8 weeks after transplantation revealed that the implanted MSCs at the lesion/graft site survived and differentiated into neuron-like cells and co-localized with host neurons. Robust bundles of regenerated fibers were identified in the lesion/graft site in the ASC and MSC co-transplantation rats, and neurofilament 200 (NF) staining confirmed that these fibers were axons. Furthermore, myelin basic protein (MBP)-positive myelin sheaths were also identified at the lesion/graft site and confirmed via electron microscopy. In addition to expressing mature neuronal markers, sparse MSC-derived neuron-like cells expressed choline acetyltransferase (ChAT) at the injury site of the ASC and MSC co-transplantation rats. These findings suggest that co-transplantation of ASCs and MSCs in a multichannel polymer scaffold may represent a novel combinatorial strategy for the treatment of spinal cord injury.
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Abstract
INTRODUCTION Spinal cord injury (SCI) is a devastating condition, where regenerative failure and cell loss lead to paralysis. The heterogeneous and time-sensitive pathophysiology has made it difficult to target tissue repair. Despite many medical advances, there are no effective regenerative therapies. As stem cells offer multi-targeted and environmentally responsive benefits, cell therapy is a promising treatment approach. Areas covered: This review highlights the cell therapies being investigated for SCI, including Schwann cells, olfactory ensheathing cells, mensenchymal stem/stromal cells, neural precursors, oligodendrocyte progenitors, embryonic stem cells, and induced pluripotent stem cells. Through mechanisms of cell replacement, scaffolding, trophic support and immune modulation, each approach targets unique features of SCI pathology. However, as the injury is multifaceted, it is increasingly recognized that a combinatorial approach will be necessary to treat SCI. Expert opinion: Most preclinical studies, and an increasing number of clinical trials, are finding that single cell therapies have only modest benefits after SCI. These considerations, alongside issues of therapy cost-effectiveness, need to be addressed at the bench. In addition to exploring combinatorial strategies, researchers should consider cell reproducibility and storage parameters when designing animal experiments. Equally important, clinical trials must follow strict regulatory guidelines that will enable transparency of results.
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Affiliation(s)
- Anna Badner
- a Department of Genetics and Development , Krembil Research Institute, University Health Network , Toronto , ON , Canada.,b Institute of Medical Sciences , University of Toronto , Toronto , ON , Canada
| | - Ahad M Siddiqui
- a Department of Genetics and Development , Krembil Research Institute, University Health Network , Toronto , ON , Canada
| | - Michael G Fehlings
- a Department of Genetics and Development , Krembil Research Institute, University Health Network , Toronto , ON , Canada.,b Institute of Medical Sciences , University of Toronto , Toronto , ON , Canada.,c Canada Spinal Program , University Health Network, Toronto Western Hospital , Toronto , ON , Canada
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Abstract
Stem cells, especially neural stem cells (NSCs), are a very attractive cell source for potential reconstruction of injured spinal cord though either neuroprotection, neural regeneration, remyelination, replacement of lost neural cells, or reconnection of disrupted axons. The later have great potential since recent studies demonstrate long-distance growth and connectivity of axons derived from transplanted NSCs after spinal cord injury (SCI). In addition, transplanted NSCs constitute a permissive environment for host axonal regeneration and serve as new targets for host axonal connection. This reciprocal connection between grafted neurons and host neurons constitutes a neuronal relay formation that could restore functional connectivity after SCI.
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Salem N, Salem MY, Elmaghrabi MM, Elawady MA, Elawady MA, Sabry D, Shamaa A, Elkasapy AHH, Ibrhim N, Elamir A. Does vitamin C have the ability to augment the therapeutic effect of bone marrow-derived mesenchymal stem cells on spinal cord injury? Neural Regen Res 2017; 12:2050-2058. [PMID: 29323045 PMCID: PMC5784354 DOI: 10.4103/1673-5374.221163] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Methylprednisolone (MP) is currently the only drug confirmed to exhibit a neuroprotective effect on acute spinal cord injury (SCI). Vitamin C (VC) is a natural water-soluble antioxidant that exerts neuroprotective effects through eliminating free radical damage to nerve cells. Bone marrow mesenchymal stem cells (BMMSCs), as multipotent stem cells, are promising candidates in SCI repair. To evaluate the therapeutic effects of MP, VC and BMMSCs on traumatic SCI, 80 adult male rats were randomly divided into seven groups: control, SCI (SCI induction by weight-drop method), MP (SCI induction, followed by administration of 30 mg/kg MP via the tail vein, once every other 6 hours, for five times), VC (SCI induction, followed by intraperitoneal administration of 100 mg/kg VC once a day, for 28 days), MP + VC (SCI induction, followed by administration of MP and VC as the former), BMMSCs (SCI induction, followed by injection of 3 × 106 BMMSCs at the injury site), and BMMSCs + VC (SCI induction, followed by BMMSCs injection and VC administration as the former). Locomotor recovery was assessed using the Basso Mouse Scale. Injured spinal cord tissue was evaluated using hematoxylin-eosin staining and immunohistochemical staining. Expression of transforming growth factor-beta, tumor necrosis factor-alpha, and matrix metalloproteinase-2 genes was determined using real-time quantitative PCR. BMMSCs intervention better promoted recovery of nerve function of rats with SCI, mitigated nerve cell damage, and decreased expression of transforming growth factor-beta, tumor necrosis factor-alpha, and matrix metalloproteinase-2 genes than MP and/or VC. More importantly, BMMSCs in combination with VC induced more obvious improvements. These results suggest that VC can enhance the neuroprotective effects of BMMSCs against SCI.
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Affiliation(s)
- Nesrine Salem
- Department of Histology and Cell Biology, Faculty of Medicine, Banha University, Banha, Egypt
| | - Mohamed Y Salem
- Department of Histology and Cell Biology, Faculty of Medicine, Banha University, Banha, Egypt
| | | | - Moataz A Elawady
- Department of Neurosurgery, Faculty of Medicine, Banha University, Banha, Egypt
| | - Mona A Elawady
- Department of Community Medicine, Faculty of Medicine, Banha University, Banha, Egypt
| | - Dina Sabry
- Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Ashraf Shamaa
- Department of Surgery and Radiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | | | - Noha Ibrhim
- Department of Medical Physiology, Faculty of Medicine, Banha University, Banha, Egypt
| | - Azza Elamir
- Department of Medical Biochemistry, Faculty of Medicine, El Fayoum University, Egyptian, Egypt
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Vyshka G, Muzha D, Papajani M, Basho M. Recent advances on acute paraplegia. JOURNAL OF ACUTE DISEASE 2016; 5:445-449. [DOI: 10.1016/j.joad.2016.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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