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Aldali F, Deng C, Nie M, Chen H. Advances in therapies using mesenchymal stem cells and their exosomes for treatment of peripheral nerve injury: state of the art and future perspectives. Neural Regen Res 2025; 20:3151-3171. [PMID: 39435603 PMCID: PMC11881730 DOI: 10.4103/nrr.nrr-d-24-00235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 07/26/2024] [Accepted: 08/26/2024] [Indexed: 10/23/2024] Open
Abstract
"Peripheral nerve injury" refers to damage or trauma affecting nerves outside the brain and spinal cord. Peripheral nerve injury results in movements or sensation impairments, and represents a serious public health problem. Although severed peripheral nerves have been effectively joined and various therapies have been offered, recovery of sensory or motor functions remains limited, and efficacious therapies for complete repair of a nerve injury remain elusive. The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function. Mesenchymal stem cells, as large living cells responsive to the environment, secrete various factors and exosomes. The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins, microRNA, and messenger RNA derived from parent mesenchymal stem cells. Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function, offering solutions to changes associated with cell-based therapies. Despite ongoing investigations, mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage. A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation. This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury, exploring the underlying mechanisms. Subsequently, it provides an overview of the current status of mesenchymal stem cell and exosome-based therapies in clinical trials, followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes. Finally, the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes, offering potential solutions and guiding future directions.
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Affiliation(s)
- Fatima Aldali
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Chunchu Deng
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Mingbo Nie
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hong Chen
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Zou XF, Zhang BZ, Qian WW, Cheng FM. Bone marrow mesenchymal stem cells in treatment of peripheral nerve injury. World J Stem Cells 2024; 16:799-810. [PMID: 39219723 PMCID: PMC11362854 DOI: 10.4252/wjsc.v16.i8.799] [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: 03/07/2024] [Revised: 05/20/2024] [Accepted: 08/05/2024] [Indexed: 08/26/2024] Open
Abstract
Peripheral nerve injury (PNI) is a common neurological disorder and complete functional recovery is difficult to achieve. In recent years, bone marrow mesenchymal stem cells (BMSCs) have emerged as ideal seed cells for PNI treatment due to their strong differentiation potential and autologous transplantation ability. This review aims to summarize the molecular mechanisms by which BMSCs mediate nerve repair in PNI. The key mechanisms discussed include the differentiation of BMSCs into multiple types of nerve cells to promote repair of nerve injury. BMSCs also create a microenvironment suitable for neuronal survival and regeneration through the secretion of neurotrophic factors, extracellular matrix molecules, and adhesion molecules. Additionally, BMSCs release pro-angiogenic factors to promote the formation of new blood vessels. They modulate cytokine expression and regulate macrophage polarization, leading to immunomodulation. Furthermore, BMSCs synthesize and release proteins related to myelin sheath formation and axonal regeneration, thereby promoting neuronal repair and regeneration. Moreover, this review explores methods of applying BMSCs in PNI treatment, including direct cell transplantation into the injured neural tissue, implantation of BMSCs into nerve conduits providing support, and the application of genetically modified BMSCs, among others. These findings confirm the potential of BMSCs in treating PNI. However, with the development of this field, it is crucial to address issues related to BMSC therapy, including establishing standards for extracting, identifying, and cultivating BMSCs, as well as selecting application methods for BMSCs in PNI such as direct transplantation, tissue engineering, and genetic engineering. Addressing these issues will help translate current preclinical research results into clinical practice, providing new and effective treatment strategies for patients with PNI.
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Affiliation(s)
- Xiong-Fei Zou
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
| | - Bao-Zhong Zhang
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China.
| | - Wen-Wei Qian
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
| | - Florence Mei Cheng
- College of Nursing, The Ohio State University, Ohio, OH 43210, United States
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Sharifi M, Kamalabadi-Farahani M, Salehi M, Ebrahimi-Brough S, Alizadeh M. Recent perspectives on the synergy of mesenchymal stem cells with micro/nano strategies in peripheral nerve regeneration-a review. Front Bioeng Biotechnol 2024; 12:1401512. [PMID: 39050683 PMCID: PMC11266111 DOI: 10.3389/fbioe.2024.1401512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/19/2024] [Indexed: 07/27/2024] Open
Abstract
Despite the intrinsic repair of peripheral nerve injury (PNI), it is important to carefully monitor the process of peripheral nerve repair, as peripheral nerve regeneration is slow and incomplete in large traumatic lesions. Hence, mesenchymal stem cells (MSCs) with protective and regenerative functions are utilized in synergy with innovative micro/nano technologies to enhance the regeneration process of peripheral nerves. Nonetheless, as MSCs are assessed using standard regenerative criteria including sensory-motor indices, structural features, and morphology, it is challenging to differentiate between the protective and regenerative impacts of MSCs on neural tissue. This study aims to analyze the process of nerve regeneration, particularly the performance of MSCs with and without synergistic approaches. It also focuses on the paracrine secretions of MSCs and their conversion into neurons with functional properties that influence nerve regeneration after PNI. Furthermore, the study explores new ideas for nerve regeneration after PNI by considering the synergistic effect of MSCs and therapeutic compounds, neuronal cell derivatives, biological or polymeric conduits, organic/inorganic nanoparticles, and electrical stimulation. Finally, the study highlights the main obstacles to developing synergy in nerve regeneration after PNI and aims to open new windows based on recent advances in neural tissue regeneration.
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Affiliation(s)
- Majid Sharifi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mohammad Kamalabadi-Farahani
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Majid Salehi
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
- Health Technology Incubator Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Somayeh Ebrahimi-Brough
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Alizadeh
- Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
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Wu SH, Liao YT, Huang CH, Chen YC, Chiang ER, Wang JP. Comparison of the Confluence-Initiated Neurogenic Differentiation Tendency of Adipose-Derived and Bone Marrow-Derived Mesenchymal Stem Cells. Biomedicines 2021; 9:biomedicines9111503. [PMID: 34829732 PMCID: PMC8615071 DOI: 10.3390/biomedicines9111503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 12/27/2022] Open
Abstract
Adipose-derived mesenchymal stem cells (ADSCs), which tended to neurogenically differentiate spontaneously after achieving high confluence, were observed. Human ADSCs reaching 80% confluence were cultured in DMEM without an inducing factor for 24 h and then maintained in DMEM plus 1% FBS medium for 7 days. The neurogenic, adipogenic, and osteogenic genes of the factor-induced and confluence-initiated differentiation of the ADSCs and bone marrow-derived mesenchymal stem cells (BMSCs) at passages 3 to 5 were determined and compared using RT-qPCR, and the neurogenic differentiation was confirmed using immunofluorescent staining. In vitro tests revealed that the RNA and protein expression of neuronal markers, including class III β-tubulin (TUBB3), microtubule-associated protein 2 (MAP2), neurofilament medium polypeptide (NEFM), neurofilament heavy polypeptide (NEFH), and neurofilament light polypeptide (NEFL), had been enhanced in the confluence-initiated differentiation of the ADSCs. In addition, the expressions of neurotrophins, such as the nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), were also elevated in the confluence-initiated differentiation of the ADSCs. However, the confluent ADSCs did not show a tendency toward spontaneous adipogenic and osteogenic differentiation. Moreover, compared with the confluent ADSCs, the tendency of spontaneous neurogenic, adipogenic, and osteogenic differentiation of the confluent human bone marrow mesenchymal stem cells (BMSCs) was not observed. The results indicated that ADSCs had the potential to spontaneously differentiate into neuron-like cells during the confluent culture period; however, this tendency was not observed in BMSCs.
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Affiliation(s)
- Szu-Hsien Wu
- Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan; (S.-H.W.); (C.-H.H.)
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, National Defense Medical Center, Taipei 112, Taiwan
| | - Yu-Ting Liao
- Department of Orthopaedics & Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan;
| | - Chi-Han Huang
- Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan; (S.-H.W.); (C.-H.H.)
| | - Yi-Chou Chen
- Department of Orthopedics, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330, Taiwan;
| | - En-Rung Chiang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Department of Orthopaedics & Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan;
| | - Jung-Pan Wang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Department of Orthopaedics & Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan;
- Correspondence: ; Tel.: +886-2-2875-7557; Fax: +886-2-2875-7657
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Zhang RC, Du WQ, Zhang JY, Yu SX, Lu FZ, Ding HM, Cheng YB, Ren C, Geng DQ. Mesenchymal stem cell treatment for peripheral nerve injury: a narrative review. Neural Regen Res 2021; 16:2170-2176. [PMID: 33818489 PMCID: PMC8354135 DOI: 10.4103/1673-5374.310941] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Peripheral nerve injuries occur as the result of sudden trauma and lead to reduced quality of life. The peripheral nervous system has an inherent capability to regenerate axons. However, peripheral nerve regeneration following injury is generally slow and incomplete that results in poor functional outcomes such as muscle atrophy. Although conventional surgical procedures for peripheral nerve injuries present many benefits, there are still several limitations including scarring, difficult accessibility to donor nerve, neuroma formation and a need to sacrifice the autologous nerve. For many years, other therapeutic approaches for peripheral nerve injuries have been explored, the most notable being the replacement of Schwann cells, the glial cells responsible for clearing out debris from the site of injury. Introducing cultured Schwann cells to the injured sites showed great benefits in promoting axonal regeneration and functional recovery. However, there are limited sources of Schwann cells for extraction and difficulties in culturing Schwann cells in vitro. Therefore, novel therapeutic avenues that offer maximum benefits for the treatment of peripheral nerve injuries should be investigated. This review focused on strategies using mesenchymal stem cells to promote peripheral nerve regeneration including exosomes of mesenchymal stem cells, nerve engineering using the nerve guidance conduits containing mesenchymal stem cells, and genetically engineered mesenchymal stem cells. We present the current progress of mesenchymal stem cell treatment of peripheral nerve injuries.
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Affiliation(s)
- Rui-Cheng Zhang
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Wen-Qi Du
- Department of Human Anatomy, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Jing-Yuan Zhang
- Department of Neurosurgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, China
| | - Shao-Xia Yu
- Department of Neurology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, China
| | - Fang-Zhi Lu
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Hong-Mei Ding
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Yan-Bo Cheng
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Chao Ren
- Department of Neurology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, China
| | - De-Qin Geng
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
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Wang JP, Liao YT, Wu SH, Chiang ER, Hsu SH, Tseng TC, Hung SC. Mesenchymal stem cells from a hypoxic culture improve nerve regeneration. J Tissue Eng Regen Med 2020; 14:1804-1814. [PMID: 32976700 DOI: 10.1002/term.3136] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/27/2020] [Accepted: 09/10/2020] [Indexed: 12/31/2022]
Abstract
Repairing the peripheral nerves following a segmental defect injury remains surgically challenging. Because of some disadvantages of nerve grafts, nerve regeneration, such as conduits combined with bone marrow-derived mesenchymal stem cells (BMSCs), may serve as an alternative. BMSCs expand under hypoxic conditions, decrease in senescence, and increase in proliferation and differentiation potential into the bone, fat, and cartilage. The purpose of this study was to investigate whether BMSCs increased the neuronal differentiation potential following expansion under hypoxic conditions. Isolated human BMSCs (hBMSCs) expand under hypoxia or normoxia, and neuronal differentiation proceeds under normoxia. in vitro tests revealed hypoxia culture enhanced the RNA and protein expression of neuronal markers. The electrophysiology of hBMSC-differentiated neuron-like cells was also enhanced by the hypoxia culturing. Our animal model indicated that the potential treatment of hypoxic rat BMSCs (rBMSCs) was better than that of normoxic rBMSCs because the conduit with the hypoxic rBMSCs injection demonstrated the highest recovery rate of gastrocnemius muscle weights. There were more toluidine blue-stained myelinated nerve fibers in the hypoxic rBMSCs group than in the normoxic group. To sum up, BMSCs cultured under hypoxia increased the potential of neuronal differentiation both in vivo and in vitro.
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Affiliation(s)
- Jung-Pan Wang
- Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yu-Ting Liao
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Szu-Hsien Wu
- Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - En-Rung Chiang
- Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shan-Hui Hsu
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan
| | - Ting-Chen Tseng
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan
| | - Shih-Chieh Hung
- Graduate Institute of New Drug Development, Biomedical Sciences, China Medical University, Taichung, Taiwan
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Electrically conductive biomaterials based on natural polysaccharides: Challenges and applications in tissue engineering. Int J Biol Macromol 2019; 141:636-662. [DOI: 10.1016/j.ijbiomac.2019.09.020] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/03/2019] [Accepted: 09/04/2019] [Indexed: 01/01/2023]
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Yen CM, Shen CC, Yang YC, Liu BS, Lee HT, Sheu ML, Tsai MH, Cheng WY. Novel electrospun poly(ε-caprolactone)/type I collagen nanofiber conduits for repair of peripheral nerve injury. Neural Regen Res 2019; 14:1617-1625. [PMID: 31089062 PMCID: PMC6557087 DOI: 10.4103/1673-5374.255997] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Recent studies have shown the potential of artificially synthesized conduits in the repair of peripheral nerve injury. Natural biopolymers have received much attention because of their biocompatibility. To investigate the effects of novel electrospun absorbable poly(ε-caprolactone)/type I collagen nanofiber conduits (biopolymer nanofiber conduits) on the repair of peripheral nerve injury, we bridged 10-mm-long sciatic nerve defects with electrospun absorbable biopolymer nanofiber conduits, poly(ε-caprolactone) or silicone conduits in Sprague-Dawley rats. Rat neurologica1 function was weekly evaluated using sciatic function index within 8 weeks after repair. Eight weeks after repair, sciatic nerve myelin sheaths and axon morphology were observed by osmium tetroxide staining, hematoxylin-eosin staining, and transmission electron microscopy. S-100 (Schwann cell marker) and CD4 (inflammatory marker) immunoreactivities in sciatic nerve were detected by immunohistochemistry. In rats subjected to repair with electrospun absorbable biopolymer nanofiber conduits, no serious inflammatory reactions were observed in rat hind limbs, the morphology of myelin sheaths in the injured sciatic nerve was close to normal. CD4 immunoreactivity was obviously weaker in rats subjected to repair with electrospun absorbable biopolymer nanofiber conduits than in those subjected to repair with poly(ε-caprolactone) or silicone. Rats subjected to repair with electrospun absorbable biopolymer nanofiber conduits tended to have greater sciatic nerve function recovery than those receiving poly(ε-caprolactone) or silicone repair. These results suggest that electrospun absorbable poly(ε-caprolactone)/type I collagen nanofiber conduits have the potential of repairing sciatic nerve defects and exhibit good biocompatibility. All experimental procedures were approved by Institutional Animal Care and Use Committee of Taichung Veteran General Hospital, Taiwan, China (La-1031218) on October 2, 2014.
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Affiliation(s)
- Chun-Ming Yen
- Department of Neurosurgery, Neurological Institute, Taichung Veterans General Hospital; Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan, China
| | - Chiung-Chyi Shen
- Department of Neurosurgery, Neurological Institute, Taichung Veterans General Hospital; Department of Physical Therapy, Hungkuang University; Basic Medical Education Center, Central Taiwan University of Science and Technology, Taichung, Taiwan, China
| | - Yi-Chin Yang
- Department of Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan, China
| | - Bai-Shuan Liu
- Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung, Taiwan, China
| | - Hsu-Tung Lee
- Department of Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan, China
| | - Meei-Ling Sheu
- Institute of Biomedical Sciences, National Chung Hsing University; Department of Medical Research, Taichung Veterans General Hospital; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan, China
| | - Meng-Hsiun Tsai
- Department of Management Information System, National Chung Hsing University, Taichung, Taiwan, China
| | - Wen-Yu Cheng
- Department of Neurosurgery, Neurological Institute, Taichung Veterans General Hospital; Department of Physical Therapy, Hungkuang University, Taichung, Taiwan, China
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Sarker M, Naghieh S, McInnes AD, Schreyer DJ, Chen X. Regeneration of peripheral nerves by nerve guidance conduits: Influence of design, biopolymers, cells, growth factors, and physical stimuli. Prog Neurobiol 2018; 171:125-150. [DOI: 10.1016/j.pneurobio.2018.07.002] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 07/24/2018] [Accepted: 07/26/2018] [Indexed: 01/10/2023]
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Dos Santos FP, Peruch T, Katami SJV, Martini APR, Crestani TA, Quintiliano K, Maurmann N, Sanches EF, Netto CA, Pranke P, de Souza Pagnussat A. Poly (lactide-co-glycolide) (PLGA) Scaffold Induces Short-term Nerve Regeneration and Functional Recovery Following Sciatic Nerve Transection in Rats. Neuroscience 2018; 396:94-107. [PMID: 30452974 DOI: 10.1016/j.neuroscience.2018.11.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/06/2018] [Accepted: 11/08/2018] [Indexed: 01/27/2023]
Abstract
Peripheral nerve injury is an important cause of incapability and has limited available treatment. Autologous donor nerve implant is the golden standard treatment, however, may cause secondary deficits. Stem cells show positive results in preclinical settings, preserving tissue and function. We tested the efficacy of stem cells derived from human exfoliated deciduous teeth seeded in poly (lactide-co-glycolide) scaffolds in sciatic nerve transection model. Seventy-two adult male Wistar rats had 7-mm nerve gap bridge using scaffolds with (or without) stem cells. Animals were randomly divided into: sham-operated; sham-operated without scaffold; sham-operated + scaffold + stem cells; sciatic transection + no treatment; sciatic transection + acellular scaffolds; sciatic transection + scaffold + stem cells. Sciatic Functional Index and Ladder Rung Walking tests were performed before (-1), 14 and 28 days after surgery. Morphometric nerve measurement and muscle weights were assessed. Scaffolds with stem cells improved function in Sciatic Functional Index. Acellular scaffold was effective, promoting functional recovery and nerve regeneration following nerve injury. Scaffolds provide better nerve regeneration and functional recovery after sciatic transection. Despite cell therapy promoting faster recovery after sciatic transection in the Sciatic Index Score, stem cells did not improve functional and morphological recovery after nerve injury. This is the first study testing the potential use of scaffolds combined with stem cells in the early stages after injury. Scaffolds with stem cells could accelerate nerve recovery and favor adjuvant therapies, evidencing the need for further studies to increase the knowledge about stem cells' mechanisms.
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Affiliation(s)
- Franciele Pereira Dos Santos
- Post-graduation Program in Health Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Thais Peruch
- Department of Physical Therapy, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | | | - Ana Paula Rodrigues Martini
- Post-graduation Program in Neuroscience, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Thayane Antoniolli Crestani
- Hematology and Stem Cell Laboratory, Faculty of Pharmacy, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-graduation Program in Neuroscience, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Kerlin Quintiliano
- Hematology and Stem Cell Laboratory, Faculty of Pharmacy, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-graduation Program in Neuroscience, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Natasha Maurmann
- Hematology and Stem Cell Laboratory, Faculty of Pharmacy, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-graduation Program in Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Eduardo Farias Sanches
- Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Post-graduation Program in Neuroscience, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
| | - Carlos Alexandre Netto
- Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Patricia Pranke
- Hematology and Stem Cell Laboratory, Faculty of Pharmacy, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-graduation Program in Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Stem Cell Research Institute (SCRI), Porto Alegre, RS, Brazil
| | - Aline de Souza Pagnussat
- Post-graduation Program in Rehabilitation Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil; Department of Physical Therapy, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil; Post-graduation Program in Health Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
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Uz M, Das SR, Ding S, Sakaguchi DS, Claussen JC, Mallapragada SK. Advances in Controlling Differentiation of Adult Stem Cells for Peripheral Nerve Regeneration. Adv Healthc Mater 2018; 7:e1701046. [PMID: 29656561 DOI: 10.1002/adhm.201701046] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 01/08/2018] [Indexed: 01/01/2023]
Abstract
Adult stems cells, possessing the ability to grow, migrate, proliferate, and transdifferentiate into various specific phenotypes, constitute a great asset for peripheral nerve regeneration. Adult stem cells' ability to undergo transdifferentiation is sensitive to various cell-to-cell interactions and external stimuli involving interactions with physical, mechanical, and chemical cues within their microenvironment. Various studies have employed different techniques for transdifferentiating adult stem cells from distinct sources into specific lineages (e.g., glial cells and neurons). These techniques include chemical and/or electrical induction as well as cell-to-cell interactions via co-culture along with the use of various 3D conduit/scaffold designs. Such scaffolds consist of unique materials that possess controllable physical/mechanical properties mimicking cells' natural extracellular matrix. However, current limitations regarding non-scalable transdifferentiation protocols, fate commitment of transdifferentiated stem cells, and conduit/scaffold design have required new strategies for effective stem cells transdifferentiation and implantation. In this progress report, a comprehensive review of recent advances in the transdifferentiation of adult stem cells via different approaches along with multifunctional conduit/scaffolds designs is presented for peripheral nerve regeneration. Potential cellular mechanisms and signaling pathways associated with differentiation are also included. The discussion with current challenges in the field and an outlook toward future research directions is concluded.
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Affiliation(s)
- Metin Uz
- Department of Chemical and Biological Engineering Iowa State University Ames IA 50011 USA
| | - Suprem R. Das
- Department of Mechanical Engineering Iowa State University Ames IA 50011 USA
- Division of Materials Science and Engineering Ames Laboratory Ames IA 50011 USA
| | - Shaowei Ding
- Department of Mechanical Engineering Iowa State University Ames IA 50011 USA
| | - Donald S. Sakaguchi
- Neuroscience Program Iowa State University Ames IA 50011 USA
- Department of Genetics Development and Cell Biology Iowa State University Ames IA 50011 USA
| | - Jonathan C. Claussen
- Department of Mechanical Engineering Iowa State University Ames IA 50011 USA
- Division of Materials Science and Engineering Ames Laboratory Ames IA 50011 USA
| | - Surya K. Mallapragada
- Department of Chemical and Biological Engineering Iowa State University Ames IA 50011 USA
- Department of Genetics Development and Cell Biology Iowa State University Ames IA 50011 USA
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Chan KM, Beveridge J, Webber CA. Adipose-derived stem cells: From mice to man. Muscle Nerve 2018; 58:186-188. [PMID: 29742793 DOI: 10.1002/mus.26154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 04/27/2018] [Accepted: 05/05/2018] [Indexed: 11/06/2022]
Affiliation(s)
- K Ming Chan
- Division of Physical Medicine and Rehabilitation, 5005, Katz Group Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2E1.,Division of Plastic Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Julie Beveridge
- Division of Plastic Surgery, University of Alberta, Edmonton, Alberta, Canada
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Fernandes M, Valente SG, Sabongi RG, Gomes dos Santos JB, Leite VM, Ulrich H, Nery AA, da Silva Fernandes MJ. Bone marrow-derived mesenchymal stem cells versus adipose-derived mesenchymal stem cells for peripheral nerve regeneration. Neural Regen Res 2018; 13:100-104. [PMID: 29451213 PMCID: PMC5840974 DOI: 10.4103/1673-5374.224378] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2017] [Indexed: 12/15/2022] Open
Abstract
Studies have confirmed that bone marrow-derived mesenchymal stem cells (MSCs) can be used for treatment of several nervous system diseases. However, isolation of bone marrow-derived MSCs (BMSCs) is an invasive and painful process and the yield is very low. Therefore, there is a need to search for other alterative stem cell sources. Adipose-derived MSCs (ADSCs) have phenotypic and gene expression profiles similar to those of BMSCs. The production of ADSCs is greater than that of BMSCs, and ADSCs proliferate faster than BMSCs. To compare the effects of venous grafts containing BMSCs or ADSCs on sciatic nerve injury, in this study, rats were randomly divided into four groups: sham (only sciatic nerve exposed), Matrigel (MG; sciatic nerve injury + intravenous transplantation of MG vehicle), ADSCs (sciatic nerve injury + intravenous MG containing ADSCs), and BMSCs (sciatic nerve injury + intravenous MG containing BMSCs) groups. Sciatic functional index was calculated to evaluate the function of injured sciatic nerve. Morphologic characteristics of nerves distal to the lesion were observed by toluidine blue staining. Spinal motor neurons labeled with Fluoro-Gold were quantitatively assessed. Compared with sham-operated rats, sciatic functional index was lower, the density of small-diameter fibers was significantly increased, and the number of motor neurons significantly decreased in rats with sciatic nerve injury. Neither ADSCs nor BMSCs significantly improved the sciatic nerve function of rats with sciatic nerve injury, increased fiber density, fiber diameters, axonal diameters, myelin sheath thickness, and G ratios (axonal diameter/fiber diameter ratios) in the sciatic nerve distal to the lesion site. There was no significant difference in the number of spinal motor neurons among ADSCs, BMSCs and MG groups. These results suggest that neither BMSCs nor ADSCs provide satisfactory results for peripheral nerve repair when using MG as the conductor for engraftment.
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Affiliation(s)
- Marcela Fernandes
- Division of Hand and Upper Limb Surgery, Department of Orthopedics and Traumatology, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Sandra Gomes Valente
- Division of Hand and Upper Limb Surgery, Department of Orthopedics and Traumatology, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Rodrigo Guerra Sabongi
- Division of Hand and Upper Limb Surgery, Department of Orthopedics and Traumatology, Universidade Federal de São Paulo, São Paulo, Brazil
| | - João Baptista Gomes dos Santos
- Division of Hand and Upper Limb Surgery, Department of Orthopedics and Traumatology, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Vilnei Mattioli Leite
- Division of Hand and Upper Limb Surgery, Department of Orthopedics and Traumatology, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, Universidade de São Paulo, São Paulo, Brazil
| | - Arthur Andrade Nery
- Department of Biochemistry, Institute of Chemistry, Universidade de São Paulo, São Paulo, Brazil
| | - Maria José da Silva Fernandes
- Division of Neurosciences, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, São Paulo, Brazil
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Chitosan nerve conduits seeded with autologous bone marrow mononuclear cells for 30 mm goat peroneal nerve defect. Sci Rep 2017; 7:44002. [PMID: 28287100 PMCID: PMC5347120 DOI: 10.1038/srep44002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 02/03/2017] [Indexed: 01/01/2023] Open
Abstract
In the current research, to find if the combination of chitosan nerve conduits seeded with autologous bone marrow mononuclear cells (BM-MNCs) can be used to bridge 30 mm long peroneal nerve defects in goats, 15 animals were separated into BM-MNC group (n = 5), vehicle group (n = 5), and autologous nerve graft group (n = 5). 12 months after the surgery, animals were evaluated by behavioral observation, magnetic resonance imaging tests, histomorphological and electrophysiological analysis. Results revealed that animals in BM-MNC group and autologous nerve graft group achieved fine functional recovery; magnetic resonance imaging tests and histomorphometry analysis showed that the nerve defect was bridged by myelinated nerve axons in those animals. No significant difference was found between the two groups concerning myelinated axon density, axon diameter, myelin sheath thickness and peroneal nerve action potential. Animals in vehicle group failed to achieve significant functional recovery. The results indicated that chitosan nerve conduits seeded with autologous bone marrow mononuclear cells have strong potential in bridging long peripheral nerve defects and could be applied in future clinical trials.
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Knowlton S, Cho Y, Li XJ, Khademhosseini A, Tasoglu S. Utilizing stem cells for three-dimensional neural tissue engineering. Biomater Sci 2016; 4:768-84. [DOI: 10.1039/c5bm00324e] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Three-dimensional neural tissue engineering has significantly advanced the development of neural disease models and replacement tissues for patients by leveraging the unique capabilities of stem cells.
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Affiliation(s)
| | - Yongku Cho
- Department of Chemical & Biomolecular Engineering
- University of Connecticut
- Storrs
- USA
| | - Xue-Jun Li
- Department of Neuroscience
- University of Connecticut Health Center
- Farmington
- USA
| | - Ali Khademhosseini
- Center for Biomedical Engineering
- Department of Medicine
- Brigham and Women's Hospital Harvard Medical School
- Harvard-MIT Division of Health Sciences and Technology Massachusetts Institute of Technology
- Cambridge
| | - Savas Tasoglu
- Department of Biomedical Engineering
- University of Connecticut
- Storrs
- USA
- Department of Mechanical Engineering
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Fairbairn NG, Meppelink AM, Ng-Glazier J, Randolph MA, Winograd JM. Augmenting peripheral nerve regeneration using stem cells: A review of current opinion. World J Stem Cells 2015; 7:11-26. [PMID: 25621102 PMCID: PMC4300921 DOI: 10.4252/wjsc.v7.i1.11] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 09/18/2014] [Accepted: 10/27/2014] [Indexed: 02/06/2023] Open
Abstract
Outcomes following peripheral nerve injury remain frustratingly poor. The reasons for this are multifactorial, although maintaining a growth permissive environment in the distal nerve stump following repair is arguably the most important. The optimal environment for axonal regeneration relies on the synthesis and release of many biochemical mediators that are temporally and spatially regulated with a high level of incompletely understood complexity. The Schwann cell (SC) has emerged as a key player in this process. Prolonged periods of distal nerve stump denervation, characteristic of large gaps and proximal injuries, have been associated with a reduction in SC number and ability to support regenerating axons. Cell based therapy offers a potential therapy for the improvement of outcomes following peripheral nerve reconstruction. Stem cells have the potential to increase the number of SCs and prolong their ability to support regeneration. They may also have the ability to rescue and replenish populations of chromatolytic and apoptotic neurons following axotomy. Finally, they can be used in non-physiologic ways to preserve injured tissues such as denervated muscle while neuronal ingrowth has not yet occurred. Aside from stem cell type, careful consideration must be given to differentiation status, how stem cells are supported following transplantation and how they will be delivered to the site of injury. It is the aim of this article to review current opinions on the strategies of stem cell based therapy for the augmentation of peripheral nerve regeneration.
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Huang L, Li R, Liu W, Dai J, Du Z, Wang X, Ma J, Zhao J. Dynamic culture of a thermosensitive collagen hydrogel as an extracellular matrix improves the construction of tissue-engineered peripheral nerve. Neural Regen Res 2014; 9:1371-8. [PMID: 25221594 PMCID: PMC4160868 DOI: 10.4103/1673-5374.137590] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2014] [Indexed: 12/15/2022] Open
Abstract
Tissue engineering technologies offer new treatment strategies for the repair of peripheral nerve injury, but cell loss between seeding and adhesion to the scaffold remains inevitable. A thermosensitive collagen hydrogel was used as an extracellular matrix in this study and combined with bone marrow mesenchymal stem cells to construct tissue-engineered peripheral nerve composites in vitro. Dynamic culture was performed at an oscillating frequency of 0.5 Hz and 35° swing angle above and below the horizontal plane. The results demonstrated that bone marrow mesenchymal stem cells formed membrane-like structures around the poly-L-lactic acid scaffolds and exhibited regular alignment on the composite surface. Collagen was used to fill in the pores, and seeded cells adhered onto the poly-L-lactic acid fibers. The DNA content of the bone marrow mesenchymal stem cells was higher in the composites constructed with a thermosensitive collagen hydrogel compared with that in collagen I scaffold controls. The cellular DNA content was also higher in the thermosensitive collagen hydrogel composites constructed with the thermosensitive collagen hydrogel in dynamic culture than that in static culture. These results indicate that tissue-engineered composites formed with thermosensitive collagen hydrogel in dynamic culture can maintain larger numbers of seeded cells by avoiding cell loss during the initial adhesion stage. Moreover, seeded cells were distributed throughout the material.
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Affiliation(s)
- Lanfeng Huang
- Department of Joint Surgery, Orthopedics Hospital of the Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Rui Li
- Centre of Hand & Foot Surgery and Reparative & Reconstructive Surgery, Orthopedics Hospital of the Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Wanguo Liu
- Department of Orthopedics Surgery, the Third Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jin Dai
- Department of Joint Surgery, Orthopedics Hospital of the Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Zhenwu Du
- Institute of Orthopedics, the Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiaonan Wang
- Department of Joint Surgery, Orthopedics Hospital of the Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jianchao Ma
- Department of Joint Surgery, Orthopedics Hospital of the Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jinsong Zhao
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, Jilin Province, China
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Shakhbazau A, Archibald SJ, Shcharbin D, Bryszewska M, Midha R. Aligned collagen-GAG matrix as a 3D substrate for Schwann cell migration and dendrimer-based gene delivery. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2014; 25:1979-1989. [PMID: 24801062 DOI: 10.1007/s10856-014-5224-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 04/21/2014] [Indexed: 06/03/2023]
Abstract
The development of artificial off-the-shelf conduits that facilitate effective nerve regeneration and recovery after repair of traumatic nerve injury gaps is of fundamental importance. Collagen-glycosaminoglycan (GAG) matrix mimicking Schwann cell (SC) basal lamina has been proposed as a suitable and biologically rational substrate for nerve regeneration. In the present study, we have focused on the permissiveness of this matrix type for SC migration and repopulation, as these events play an essential role in nerve remodeling. We have also demonstrated that SCs cultured within collagen-GAG matrix are compatible with non-viral dendrimer-based gene delivery, that may allow conditioning of matrix-embedded cells for future gene therapy applications.
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Affiliation(s)
- Antos Shakhbazau
- Department of Clinical Neuroscience, Faculty of Medicine, University of Calgary, HMRB 109-3330 Hospital Drive NW, Calgary, AB, T2N4N1, Canada,
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Hernández-Cortés P, Toledo-Romero MA, Delgado M, Sánchez-González CE, Martin F, Galindo-Moreno P, O’Valle F. Peripheral nerve reconstruction with epsilon-caprolactone conduits seeded with vasoactive intestinal peptide gene-transfected mesenchymal stem cells in a rat model. J Neural Eng 2014; 11:046024. [DOI: 10.1088/1741-2560/11/4/046024] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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20
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Carriers in cell-based therapies for neurological disorders. Int J Mol Sci 2014; 15:10669-723. [PMID: 24933636 PMCID: PMC4100175 DOI: 10.3390/ijms150610669] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 05/19/2014] [Accepted: 05/30/2014] [Indexed: 02/07/2023] Open
Abstract
There is a pressing need for long-term neuroprotective and neuroregenerative therapies to promote full function recovery of injuries in the human nervous system resulting from trauma, stroke or degenerative diseases. Although cell-based therapies are promising in supporting repair and regeneration, direct introduction to the injury site is plagued by problems such as low transplanted cell survival rate, limited graft integration, immunorejection, and tumor formation. Neural tissue engineering offers an integrative and multifaceted approach to tackle these complex neurological disorders. Synergistic therapeutic effects can be obtained from combining customized biomaterial scaffolds with cell-based therapies. Current scaffold-facilitated cell transplantation strategies aim to achieve structural and functional rescue via offering a three-dimensional permissive and instructive environment for sustainable neuroactive factor production for prolonged periods and/or cell replacement at the target site. In this review, we intend to highlight important considerations in biomaterial selection and to review major biodegradable or non-biodegradable scaffolds used for cell transplantation to the central and peripheral nervous system in preclinical and clinical trials. Expanded knowledge in biomaterial properties and their prolonged interaction with transplanted and host cells have greatly expanded the possibilities for designing suitable carrier systems and the potential of cell therapies in the nervous system.
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Ribeiro J, Gartner A, Pereira T, Gomes R, Lopes MA, Gonçalves C, Varejão A, Luís AL, Maurício AC. Perspectives of employing mesenchymal stem cells from the Wharton's jelly of the umbilical cord for peripheral nerve repair. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2014; 108:79-120. [PMID: 24083432 DOI: 10.1016/b978-0-12-410499-0.00004-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Mesenchymal stem cells (MSCs) from Wharton's jelly present high plasticity and low immunogenicity, turning them into a desirable form of cell therapy for the injured nervous system. Their isolation, expansion, and characterization have been performed from cryopreserved umbilical cord tissue. Great concern has been dedicated to the collection, preservation, and transport protocols of the umbilical cord after the parturition to the laboratory in order to obtain samples with higher number of viable MSCs without microbiological contamination. Different biomaterials like chitosan-silicate hybrid, collagen, PLGA90:10, poly(DL-lactide-ɛ-caprolactone), and poly(vinyl alcohol) loaded with electrical conductive materials, associated to MSCs have also been tested in the rat sciatic nerve in axonotmesis and neurotmesis lesions. The in vitro studies of the scaffolds included citocompatibility evaluation of the biomaterials used and cell characterization by imunocytochemistry, karyotype analysis, differentiation capacity into neuroglial-like cells, and flow cytometry. The regeneration process follow-up has been performed by functional analysis and the repaired nerves processed for stereological studies permitted the morphologic regeneration evaluation. The MSCs from Wharton's jelly delivered through tested biomaterials should be regarded a potentially valuable tool to improve clinical outcome especially after trauma to sensory nerves. In addition, these cells represent a noncontroversial source of primitive mesenchymal progenitor cells, which can be harvested after birth, cryogenically stored, thawed, and expanded for therapeutic uses. The importance of a longitudinal study concerning tissue engineering of the peripheral nerve, which includes a multidisciplinary team able to develop biomaterials associated to cell therapies, to perform preclinical trials concerning animal welfare and the appropriate animal model is here enhanced.
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Affiliation(s)
- Jorge Ribeiro
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Porto, Portugal; Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências e Tecnologias Agrárias e Agro-Alimentares (ICETA), Universidade do Porto (UP), Porto, Portugal
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Gärtner A, Pereira T, Armada-da-Silva P, Amado S, Veloso A, Amorim I, Ribeiro J, Santos J, Bárcia R, Cruz P, Cruz H, Luís A, Santos J, Geuna S, Maurício A. Effects of umbilical cord tissue mesenchymal stem cells (UCX®) on rat sciatic nerve regeneration after neurotmesis injuries. J Stem Cells Regen Med 2014. [PMID: 25075157 PMCID: PMC4112274 DOI: 10.46582/jsrm.1001004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Peripheral nerves have the intrinsic capacity of self-regeneration after traumatic injury but the extent of the regeneration is often very poor. Increasing evidence demonstrates that mesenchymal stem/stromal cells (MSCs) may play an important role in tissue regeneration through the secretion of soluble trophic factors that enhance and assist in repair by paracrine activation of surrounding cells. In the present study, the therapeutic value of a population of umbilical cord tissue-derived MSCs, obtained by a proprietary method (UCX®), was evaluated on end-to-end rat sciatic nerve repair. Furthermore, in order to promote both, end-to-end nerve fiber contacts and MSC cell-cell interaction, as well as reduce the flush away effect of the cells after administration, a commercially available haemostatic sealant, Floseal®, was used as vehicle. Both, functional and morphologic recoveries were evaluated along the healing period using extensor postural thrust (EPT), withdrawal reflex latency (WRL), ankle kinematics analysis, and either histological analysis or stereology, in the hyper-acute, acute and chronic phases of healing. The histological analysis of the hyper-acute and acute phase studies revealed that in the group treated with UCX® alone the Wallerian degeneration was improved for the subsequent process of regeneration, the fiber organization was higher, and the extent of fibrosis was lower. The chronic phase experimental groups revealed that treatment with UCX® induced an increased number of regenerated fibers and thickening of the myelin sheet. Kinematics analysis showed that the ankle joint angle determined for untreated animals was significantly different from any of the treated groups at the instant of initial contact (IC). At opposite toe off (OT) and heel rise (HR), differences were found between untreated animals and the groups treated with either uCx® alone or UCX® administered with Floseal®. Overall, the UCX® application presented positive effects in functional and morphologic recovery, in both the acute and chronic phases of the regeneration process. Kinematics analysis has revealed positive synergistic effects brought by Floseal® as vehicle for MSCs.
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Affiliation(s)
- A Gärtner
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS) , Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal. ; Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências e Tecnologias Agrárias e Agro-Alimentares (ICETA) , Rua D. Manuel II, Apartado 55142, 4051-401, Porto, Portugal. ; These authors contributed equally for the results present in this research work
| | - T Pereira
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS) , Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal. ; Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências e Tecnologias Agrárias e Agro-Alimentares (ICETA) , Rua D. Manuel II, Apartado 55142, 4051-401, Porto, Portugal. ; These authors contributed equally for the results present in this research work
| | - Pas Armada-da-Silva
- Faculdade de Motricidade Humana (FMH), Universidade de Lisboa (UL) , Estrada da Costa, 1499-002, Cruz Quebrada - Dafundo, Portugal. ; CIPER-FMH: Centro Interdisciplinar de Estudo de Performance Humana, Faculdade de Motricidade Humana (FMH) , Universidade de Lisboa (UL), Estrada da Costa, 1499-002, Cruz Quebrada - Dafundo, Portugal
| | - S Amado
- CIPER-FMH: Centro Interdisciplinar de Estudo de Performance Humana, Faculdade de Motricidade Humana (FMH) , Universidade de Lisboa (UL), Estrada da Costa, 1499-002, Cruz Quebrada - Dafundo, Portugal. ; UIS-IPL: Unidade de Investigação em Saúde da Escola Superior de Saúde de Leiria , Instituto Politécnico de Leiria, Portugal
| | - Ap Veloso
- Faculdade de Motricidade Humana (FMH), Universidade de Lisboa (UL) , Estrada da Costa, 1499-002, Cruz Quebrada - Dafundo, Portugal. ; CIPER-FMH: Centro Interdisciplinar de Estudo de Performance Humana, Faculdade de Motricidade Humana (FMH) , Universidade de Lisboa (UL), Estrada da Costa, 1499-002, Cruz Quebrada - Dafundo, Portugal
| | - I Amorim
- Departamento de Patologia e de Imunologia Molecular, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS) , Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal. ; Instituto Português de Patologia e Imunologia Molecular da niversidade do Porto (IPATIMUP) , Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal
| | - J Ribeiro
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS) , Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal. ; Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências e Tecnologias Agrárias e Agro-Alimentares (ICETA) , Rua D. Manuel II, Apartado 55142, 4051-401, Porto, Portugal. ; UPVET, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS) , Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Jd Santos
- CEMUC, Departamento de Engenharia Metalúrgica e Materiais, Faculdade de Engenharia , Universidade do Porto, Rua Dr Roberto Frias, 4200-465 Porto, Portugal
| | - Rn Bárcia
- ECBio - Research and Development in Biotechnology S.A. , Rua Henrique Paiva Couceiro, 27, 2700-451 Amadora, Portugal
| | - P Cruz
- ECBio - Research and Development in Biotechnology S.A. , Rua Henrique Paiva Couceiro, 27, 2700-451 Amadora, Portugal
| | - H Cruz
- ECBio - Research and Development in Biotechnology S.A. , Rua Henrique Paiva Couceiro, 27, 2700-451 Amadora, Portugal
| | - Al Luís
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS) , Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal. ; Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS) , Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Jm Santos
- ECBio - Research and Development in Biotechnology S.A. , Rua Henrique Paiva Couceiro, 27, 2700-451 Amadora, Portugal
| | - S Geuna
- Neuroscience Institute of the Cavalieri Ottolenghi Foundation , Turin, Italy. ; Department of Clinical and Biological Sciences , University of Turin, Italy
| | - Ac Maurício
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS) , Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal. ; Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências e Tecnologias Agrárias e Agro-Alimentares (ICETA) , Rua D. Manuel II, Apartado 55142, 4051-401, Porto, Portugal
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Martinez AMB, Goulart CDO, Ramalho BDS, Oliveira JT, Almeida FM. Neurotrauma and mesenchymal stem cells treatment: From experimental studies to clinical trials. World J Stem Cells 2014; 6:179-94. [PMID: 24772245 PMCID: PMC3999776 DOI: 10.4252/wjsc.v6.i2.179] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/26/2014] [Accepted: 03/11/2014] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell (MSC) therapy has attracted the attention of scientists and clinicians around the world. Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spinal cord and peripheral nerve injury. These effects are believed to be due to their ability to differentiate into other cell lineages, modulate inflammatory and immunomodulatory responses, reduce cell apoptosis, secrete several neurotrophic factors and respond to tissue injury, among others. There are many pre-clinical studies on MSC treatment for spinal cord injury (SCI) and peripheral nerve injuries. However, the same is not true for clinical trials, particularly those concerned with nerve trauma, indicating the necessity of more well-constructed studies showing the benefits that cell therapy can provide for individuals suffering the consequences of nerve lesions. As for clinical trials for SCI treatment the results obtained so far are not as beneficial as those described in experimental studies. For these reasons basic and pre-clinical studies dealing with MSC therapy should emphasize the standardization of protocols that could be translated to the clinical set with consistent and positive outcomes. This review is based on pre-clinical studies and clinical trials available in the literature from 2010 until now. At the time of writing this article there were 43 and 36 pre-clinical and 19 and 1 clinical trials on injured spinal cord and peripheral nerves, respectively.
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Affiliation(s)
- Ana Maria Blanco Martinez
- Ana Maria Blanco Martinez, Camila de Oliveira Goulart, Bruna dos Santos Ramalho, Júlia Teixeira Oliveira, Fernanda Martins Almeida, Laboratory of Neurodegeneration and Repair, Institute of Biomedical Sciences, Health Science Center, 21941-902, Rio de Janeiro, Brazil
| | - Camila de Oliveira Goulart
- Ana Maria Blanco Martinez, Camila de Oliveira Goulart, Bruna dos Santos Ramalho, Júlia Teixeira Oliveira, Fernanda Martins Almeida, Laboratory of Neurodegeneration and Repair, Institute of Biomedical Sciences, Health Science Center, 21941-902, Rio de Janeiro, Brazil
| | - Bruna Dos Santos Ramalho
- Ana Maria Blanco Martinez, Camila de Oliveira Goulart, Bruna dos Santos Ramalho, Júlia Teixeira Oliveira, Fernanda Martins Almeida, Laboratory of Neurodegeneration and Repair, Institute of Biomedical Sciences, Health Science Center, 21941-902, Rio de Janeiro, Brazil
| | - Júlia Teixeira Oliveira
- Ana Maria Blanco Martinez, Camila de Oliveira Goulart, Bruna dos Santos Ramalho, Júlia Teixeira Oliveira, Fernanda Martins Almeida, Laboratory of Neurodegeneration and Repair, Institute of Biomedical Sciences, Health Science Center, 21941-902, Rio de Janeiro, Brazil
| | - Fernanda Martins Almeida
- Ana Maria Blanco Martinez, Camila de Oliveira Goulart, Bruna dos Santos Ramalho, Júlia Teixeira Oliveira, Fernanda Martins Almeida, Laboratory of Neurodegeneration and Repair, Institute of Biomedical Sciences, Health Science Center, 21941-902, Rio de Janeiro, Brazil
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Widgerow AD, Salibian AA, Lalezari S, Evans GRD. Neuromodulatory nerve regeneration: adipose tissue-derived stem cells and neurotrophic mediation in peripheral nerve regeneration. J Neurosci Res 2013; 91:1517-24. [PMID: 24105674 DOI: 10.1002/jnr.23284] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Revised: 07/17/2013] [Accepted: 07/18/2013] [Indexed: 12/17/2022]
Abstract
Peripheral nerve injury requiring nerve gap reconstruction remains a major problem. In the quest to find an alternative to autogenous nerve graft procedures, attempts have been made to differentiate mesenchymal stem cells into neuronal lineages in vitro and utilize these cellular constructs for nerve regeneration. Unfortunately, this has produced mixed results, with no definitive procedure matching or surpassing traditional nerve grafting procedures. This review presents a different approach to nerve regeneration. The literature was reviewed to evaluate current methods of using adipose-derived stem cells (ADSCs) for peripheral nerve regeneration in in vivo models of animal peripheral nerve injury. The authors present cited evidence for directing nerve regeneration through paracrine effects of ADSCs rather than through in vitro nerve regeneration. The paracrine effects rely mainly, but not solely, on the elaboration of nerve growth factors and neurotrophic mediators that influence surrounding host cells to orchestrate in vivo nerve regeneration. Although this paradigm has been indirectly referred to in a host of publications, few major efforts for this type of neuromodulatory nerve regeneration have been forthcoming. The ADSCs are initially "primed" in vitro using specialized controlled medium (not for neuronal differentiation but for sustainability) and then incorporated into a hydrogel base matrix designed for this purpose. This core matrix is then introduced into a natural collagen-based nerve conduit. The prototype design concepts, evidence for paracrine influences, and regulatory hurdles that are avoided using this approach are discussed.
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Affiliation(s)
- Alan D Widgerow
- Institute of Aesthetic and Plastic Surgery, University of California Irvine, Irvine, California
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Gnavi S, Barwig C, Freier T, Haastert-Talini K, Grothe C, Geuna S. The use of chitosan-based scaffolds to enhance regeneration in the nervous system. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2013; 109:1-62. [PMID: 24093605 DOI: 10.1016/b978-0-12-420045-6.00001-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Various biomaterials have been proposed to build up scaffolds for promoting neural repair. Among them, chitosan, a derivative of chitin, has been raising more and more interest among basic and clinical scientists. A number of studies with neuronal and glial cell cultures have shown that this biomaterial has biomimetic properties, which make it a good candidate for developing innovative devices for neural repair. Yet, in vivo experimental studies have shown that chitosan can be successfully used to create scaffolds that promote regeneration both in the central and in the peripheral nervous system. In this review, the relevant literature on the use of chitosan in the nervous tissue, either alone or in combination with other components, is overviewed. Altogether, the promising in vitro and in vivo experimental results make it possible to foresee that time for clinical trials with chitosan-based nerve regeneration-promoting devices is approaching quickly.
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Affiliation(s)
- Sara Gnavi
- Department of Clinical and Biological Sciences, Neuroscience Institute of the Cavalieri Ottolenghi Foundation (NICO), University of Turin, Ospedale San Luigi, Regione Gonzole 10, Orbassano (TO), Italy
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