|
1
|
Yuan Y, Liu H, Dai Z, He C, Qin S, Su Z. From Physiology to Pathology of Astrocytes: Highlighting Their Potential as Therapeutic Targets for CNS Injury. Neurosci Bull 2025; 41:131-154. [PMID: 39080102 PMCID: PMC11748647 DOI: 10.1007/s12264-024-01258-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 03/15/2024] [Indexed: 01/19/2025] Open
Abstract
In the mammalian central nervous system (CNS), astrocytes are the ubiquitous glial cells that have complex morphological and molecular characteristics. These fascinating cells play essential neurosupportive and homeostatic roles in the healthy CNS and undergo morphological, molecular, and functional changes to adopt so-called 'reactive' states in response to CNS injury or disease. In recent years, interest in astrocyte research has increased dramatically and some new biological features and roles of astrocytes in physiological and pathological conditions have been discovered thanks to technological advances. Here, we will review and discuss the well-established and emerging astroglial biology and functions, with emphasis on their potential as therapeutic targets for CNS injury, including traumatic and ischemic injury. This review article will highlight the importance of astrocytes in the neuropathological process and repair of CNS injury.
Collapse
Affiliation(s)
- Yimin Yuan
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai, 200433, China
- Department of Pain Medicine, School of Anesthesiology, Naval Medical University, Shanghai, 200433, China
| | - Hong Liu
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai, 200433, China
| | - Ziwei Dai
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai, 200433, China
| | - Cheng He
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai, 200433, China
| | - Shangyao Qin
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai, 200433, China.
| | - Zhida Su
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai, 200433, China.
| |
Collapse
|
|
2
|
Dill-Macky AS, Lee EN, Wertheim JA, Koss KM. Glia in tissue engineering: From biomaterial tools to transplantation. Acta Biomater 2024; 190:24-49. [PMID: 39396630 DOI: 10.1016/j.actbio.2024.10.017] [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: 02/16/2024] [Revised: 10/01/2024] [Accepted: 10/10/2024] [Indexed: 10/15/2024]
Abstract
Glia are imperative in nearly every function of the nervous system, including neurotransmission, neuronal repair, development, immunity, and myelination. Recently, the reparative roles of glia in the central and peripheral nervous systems have been elucidated, suggesting a tremendous potential for these cells as novel treatments to central nervous system disorders. Glial cells often behave as 'double-edged swords' in neuroinflammation, ultimately deciding the life or death of resident cells. Compared to glia, neuronal cells have limited mobility, lack the ability to divide and self-renew, and are generally more delicate. Glia have been candidates for therapeutic use in many successful grafting studies, which have been largely focused on restoring myelin with Schwann cells, olfactory ensheathing glia, and oligodendrocytes with support from astrocytes. However, few therapeutics of this class have succeeded past clinical trials. Several tools and materials are being developed to understand and re-engineer these grafting concepts for greater success, such as extra cellular matrix-based scaffolds, bioactive peptides, biomolecular delivery systems, biomolecular discovery for neuroinflammatory mediation, composite microstructures such as artificial channels for cell trafficking, and graft enhanced electrical stimulation. Furthermore, advances in stem cell-derived cortical/cerebral organoid differentiation protocols have allowed for the generation of patient-derived glia comparable to those acquired from tissues requiring highly invasive procedures or are otherwise inaccessible. However, research on bioengineered tools that manipulate glial cells is nowhere near as comprehensive as that for systems of neurons and neural stem cells. This article explores the therapeutic potential of glia in transplantation with an emphasis on novel bioengineered tools for enhancement of their reparative properties. STATEMENT OF SIGNIFICANCE: Neural glia are responsible for a host of developmental, homeostatic, and reparative roles in the central nervous system but are often a major cause of tissue damage and cellular loss in insults and degenerative pathologies. Most glial grafts have employed Schwann cells for remyelination, but other glial with novel biomaterials have been employed, emphasizing their diverse functionality. Promising strategies have emerged, including neuroimmune mediation of glial scar tissues and facilitated migration and differentiation of stem cells for neural replacement. Herein, a comprehensive review of biomaterial tools for glia in transplantation is presented, highlighting Schwann cells, astrocytes, olfactory ensheating glia, oligodendrocytes, microglia, and ependymal cells.
Collapse
Affiliation(s)
- A S Dill-Macky
- Department of Surgery, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724, United States
| | - E N Lee
- Department of Surgery, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724, United States
| | - J A Wertheim
- Department of Surgery, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724, United States
| | - K M Koss
- Department of Neurobiology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0625, United States; Sealy Institute for Drug Discovery, University of Texas Medical Branch, 105 11th Street Galveston, TX 77555-1110, United States.
| |
Collapse
|
|
3
|
Hosseini SM, Nemati S, Karimi-Abdolrezaee S. Astrocytes originated from neural stem cells drive the regenerative remodeling of pathologic CSPGs in spinal cord injury. Stem Cell Reports 2024; 19:1451-1473. [PMID: 39303705 PMCID: PMC11561464 DOI: 10.1016/j.stemcr.2024.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 08/20/2024] [Accepted: 08/21/2024] [Indexed: 09/22/2024] Open
Abstract
Neural degeneration is a hallmark of spinal cord injury (SCI). Multipotent neural precursor cells (NPCs) have the potential to reconstruct the damaged neuron-glia network due to their tri-lineage capacity to generate neurons, astrocytes, and oligodendrocytes. However, astrogenesis is the predominant fate of resident or transplanted NPCs in the SCI milieu adding to the abundant number of resident astrocytes in the lesion. How NPC-derived astrocytes respond to the inflammatory milieu of SCI and the mechanisms by which they contribute to the post-injury recovery processes remain largely unknown. Here, we uncover that activated NPC-derived astrocytes exhibit distinct molecular signature that is immune modulatory and foster neurogenesis, neuronal maturity, and synaptogenesis. Mechanistically, NPC-derived astrocytes perform regenerative matrix remodeling by clearing inhibitory chondroitin sulfate proteoglycans (CSPGs) from the injury milieu through LAR and PTP-σ receptor-mediated endocytosis and the production of ADAMTS1 and ADAMTS9, while most resident astrocytes are pro-inflammatory and contribute to the pathologic deposition of CSPGs. These novel findings unravel critical mechanisms of NPC-mediated astrogenesis in SCI repair.
Collapse
Affiliation(s)
- Seyed Mojtaba Hosseini
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Manitoba Multiple Sclerosis Research Center, Winnipeg, MB, Canada
| | - Shiva Nemati
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Manitoba Multiple Sclerosis Research Center, Winnipeg, MB, Canada
| | - Soheila Karimi-Abdolrezaee
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Manitoba Multiple Sclerosis Research Center, Winnipeg, MB, Canada; Children Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.
| |
Collapse
|
|
4
|
Liu S, Wu Q, Wang L, Xing C, Guo J, Li B, Ma H, Zhong H, Zhou M, Zhu S, Zhu R, Ning G. Coordination function index: A novel indicator for assessing hindlimb locomotor recovery in spinal cord injury rats based on catwalk gait parameters. Behav Brain Res 2024; 459:114765. [PMID: 37992973 DOI: 10.1016/j.bbr.2023.114765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 11/24/2023]
Abstract
In preclinical studies of spinal cord injury (SCI), behavioral assessments are crucial for evaluating treatment effectiveness. Commonly used methods include Basso, Beattie, Bresnahan (BBB) score and the Louisville swim scale (LSS), relying on subjective observations. The CatWalk automated gait analysis system is also widely used in SCI studies, providing extensive gait parameters from footprints. However, these parameters are often used independently or combined simply without utilizing the vast amount of data provided by CatWalk. Therefore, it is necessary to develop a novel approach encompassing multiple CatWalk parameters for a comprehensive and objective assessment of locomotor function. In this work, we screened 208 CatWalk XT gait parameters and identified 38 suitable for assessing hindlimb motor function recovery in a rat thoracic contusion SCI model. Exploratory factor analysis was used to reveal structural relationships among these parameters. Weighted scores for Coordination effectively differentiated hindlimb motor function levels, termed as the Coordinated Function Index (CFI). CFI showed high reliability, exhibiting high correlations with BBB scores, LSS, and T2WI lesion area. Finally, we simplified CFI based on factor loadings and correlation analysis, obtaining a streamlined version with reliable assessment efficacy. In conclusion, we developed a systematic assessment indicator utilizing multiple CatWalk parameters to objectively evaluate hindlimb motor function recovery in rats after thoracic contusion SCI.
Collapse
Affiliation(s)
- Song Liu
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Qiang Wu
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Liyue Wang
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Cong Xing
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Junrui Guo
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Baicao Li
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Hongpeng Ma
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Hao Zhong
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Mi Zhou
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Shibo Zhu
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Rusen Zhu
- Department of Spine Surgery, Tianjin Union Medical Center, Nankai University, Tianjin, China
| | - Guangzhi Ning
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China.
| |
Collapse
|
|
5
|
Liu Y, Wang Y, Wang Y, Zhou J, Ding W. The growth status and functions of olfactory ensheathing cells cultured on randomly oriented and aligned type-I-collagen-based nanofibrous scaffolds. NANOTECHNOLOGY 2023; 35:035101. [PMID: 37905427 DOI: 10.1088/1361-6528/ad02a4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 10/11/2023] [Indexed: 11/02/2023]
Abstract
Aim. The potential of olfactory ensheathing cells (OECs) as a cell therapy for spinal cord reconstruction and regeneration after injury has drawn significant attention in recent years. This study attempted to investigate the influences of nano-fibrous scaffolds on the growth status and functional properties of OECs.Methods.The ultra-morphology of the scaffolds was visualized using scanning electron microscopy (SEM). To culture OECs, donated cells were subcultured and identified with p75. Cell proliferation, apoptosis, and survival rates were measured through MTT assay, Annexin-V/PI staining, and p75 cell counting, respectively. The adhesion of cells cultured on scaffolds was observed using SEM. Additionally, the functions of OECs cultured on scaffolds were assessed by testing gene expression levels through real time polymerase chain reaction.Results.The electrospun type I collagen-based nano-fibers exhibited a smooth surface and uniform distribution. It was indicated that the proliferation and survival rates of OECs cultured on both randomly oriented and aligned type I collagen-based nano-fibrous scaffolds were higher than those observed in the collagen-coated control. Conversely, apoptosis rates were lower in cells cultured on scaffolds. Furthermore, OEC adhesion was better on the scaffolds than on the control. The expression levels of target genes were significantly elevated in cells cultured on scaffolds versus the controls.Conclusion.As a whole, the utilization of aligned collagen nanofibers has demonstrated significant advantages in promoting cell growth and improving cell function. These findings have important implications for the field of regenerative medicine and suggest that the approach may hold promise for the future therapeutic applications.
Collapse
Affiliation(s)
- Yugang Liu
- Department of Spinal Surgery, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, 050051, People's Republic of China
- Department of Orthopedic Surgery, Affiliated Hospital of Hebei University of Engineering, 81 Congtai Road, Handan, 056002, People's Republic of China
| | - Yansong Wang
- Department of Spine Surgery, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150001, People's Republic of China
| | - Ying Wang
- Department of Orthopedic Surgery, Affiliated Hospital of Hebei University of Engineering, 81 Congtai Road, Handan, 056002, People's Republic of China
| | - Jihui Zhou
- Department of Spine Surgery, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150001, People's Republic of China
| | - Wenyuan Ding
- Department of Spinal Surgery, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, 050051, People's Republic of China
| |
Collapse
|
|
6
|
Costa G, Ribeiro FF, Sebastião AM, Muir EM, Vaz SH. Bridging the gap of axonal regeneration in the central nervous system: A state of the art review on central axonal regeneration. Front Neurosci 2022; 16:1003145. [PMID: 36440273 PMCID: PMC9682039 DOI: 10.3389/fnins.2022.1003145] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/19/2022] [Indexed: 08/26/2023] Open
Abstract
Neuronal regeneration in the central nervous system (CNS) is an important field of research with relevance to all types of neuronal injuries, including neurodegenerative diseases. The glial scar is a result of the astrocyte response to CNS injury. It is made up of many components creating a complex environment in which astrocytes play various key roles. The glial scar is heterogeneous, diverse and its composition depends upon the injury type and location. The heterogeneity of the glial scar observed in different situations of CNS damage and the consequent implications for axon regeneration have not been reviewed in depth. The gap in this knowledge will be addressed in this review which will also focus on our current understanding of central axonal regeneration and the molecular mechanisms involved. The multifactorial context of CNS regeneration is discussed, and we review newly identified roles for components previously thought to solely play an inhibitory role in central regeneration: astrocytes and p75NTR and discuss their potential and relevance for deciding therapeutic interventions. The article ends with a comprehensive review of promising new therapeutic targets identified for axonal regeneration in CNS and a discussion of novel ways of looking at therapeutic interventions for several brain diseases and injuries.
Collapse
Affiliation(s)
- Gonçalo Costa
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Filipa F. Ribeiro
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Ana M. Sebastião
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Elizabeth M. Muir
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Sandra H. Vaz
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| |
Collapse
|
|
7
|
Hall A, Fortino T, Spruance V, Niceforo A, Harrop JS, Phelps PE, Priest CA, Zholudeva LV, Lane MA. Cell transplantation to repair the injured spinal cord. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 166:79-158. [PMID: 36424097 PMCID: PMC10008620 DOI: 10.1016/bs.irn.2022.09.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Adam Hall
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - Tara Fortino
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - Victoria Spruance
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States; Division of Kidney, Urologic, & Hematologic Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Alessia Niceforo
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - James S Harrop
- Department of Neurological and Orthopedic Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Patricia E Phelps
- Department of Integrative Biology & Physiology, UCLA, Los Angeles, CA, United States
| | | | - Lyandysha V Zholudeva
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States; Gladstone Institutes, San Francisco, CA, United States
| | - Michael A Lane
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States.
| |
Collapse
|
|
8
|
Heinzel JC, Oberhauser V, Keibl C, Schädl B, Swiadek NV, Längle G, Frick H, Slezak C, Prahm C, Grillari J, Kolbenschlag J, Hercher D. ESWT Diminishes Axonal Regeneration following Repair of the Rat Median Nerve with Muscle-In-Vein Conduits but Not after Autologous Nerve Grafting. Biomedicines 2022; 10:biomedicines10081777. [PMID: 35892677 PMCID: PMC9394363 DOI: 10.3390/biomedicines10081777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/06/2022] [Accepted: 07/19/2022] [Indexed: 12/02/2022] Open
Abstract
Investigations reporting positive effects of extracorporeal shockwave therapy (ESWT) on nerve regeneration are limited to the rat sciatic nerve model. The effects of ESWT on muscle-in-vein conduits (MVCs) have also not been investigated yet. This study aimed to evaluate the effects of ESWT after repair of the rat median nerve with either autografts (ANGs) or MVCs. In male Lewis rats, a 7 mm segment of the right median nerve was reconstructed either with an ANG or an MVC. For each reconstructive technique, one group of animals received one application of ESWT while the other rats served as controls. The animals were observed for 12 weeks, and nerve regeneration was assessed using computerized gait analysis, the grasping test, electrophysiological evaluations and histological quantification of axons, blood vessels and lymphatic vasculature. Here, we provide for the first time a comprehensive analysis of ESWT effects on nerve regeneration in a rat model of median nerve injury. Furthermore, this study is among the first reporting the quantification of lymphatic vessels following peripheral nerve injury and reconstruction in vivo. While we found no significant direct positive effects of ESWT on peripheral nerve regeneration, results following nerve repair with MVCs were significantly inferior to those after ANG repair.
Collapse
Affiliation(s)
- Johannes C. Heinzel
- Department of Hand-, Plastic, Reconstructive and Burn Surgery, BG Klinik Tuebingen, University of Tuebingen, Schnarrenbergstraße 95, 72076 Tuebingen, Germany; (J.C.H.); (C.P.); (J.K.)
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Donaueschingenstraße 13, 1200 Vienna, Austria; (V.O.); (C.K.); (B.S.); (N.V.S.); (G.L.); (H.F.); (C.S.); (J.G.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Viola Oberhauser
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Donaueschingenstraße 13, 1200 Vienna, Austria; (V.O.); (C.K.); (B.S.); (N.V.S.); (G.L.); (H.F.); (C.S.); (J.G.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Claudia Keibl
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Donaueschingenstraße 13, 1200 Vienna, Austria; (V.O.); (C.K.); (B.S.); (N.V.S.); (G.L.); (H.F.); (C.S.); (J.G.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Barbara Schädl
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Donaueschingenstraße 13, 1200 Vienna, Austria; (V.O.); (C.K.); (B.S.); (N.V.S.); (G.L.); (H.F.); (C.S.); (J.G.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
- Core Facility Morphology, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria
| | - Nicole V. Swiadek
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Donaueschingenstraße 13, 1200 Vienna, Austria; (V.O.); (C.K.); (B.S.); (N.V.S.); (G.L.); (H.F.); (C.S.); (J.G.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Gregor Längle
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Donaueschingenstraße 13, 1200 Vienna, Austria; (V.O.); (C.K.); (B.S.); (N.V.S.); (G.L.); (H.F.); (C.S.); (J.G.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Helen Frick
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Donaueschingenstraße 13, 1200 Vienna, Austria; (V.O.); (C.K.); (B.S.); (N.V.S.); (G.L.); (H.F.); (C.S.); (J.G.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Cyrill Slezak
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Donaueschingenstraße 13, 1200 Vienna, Austria; (V.O.); (C.K.); (B.S.); (N.V.S.); (G.L.); (H.F.); (C.S.); (J.G.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
- Department of Physics, Utah Valley University, Orem, UT 84058, USA
| | - Cosima Prahm
- Department of Hand-, Plastic, Reconstructive and Burn Surgery, BG Klinik Tuebingen, University of Tuebingen, Schnarrenbergstraße 95, 72076 Tuebingen, Germany; (J.C.H.); (C.P.); (J.K.)
| | - Johannes Grillari
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Donaueschingenstraße 13, 1200 Vienna, Austria; (V.O.); (C.K.); (B.S.); (N.V.S.); (G.L.); (H.F.); (C.S.); (J.G.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
- Institute of Molecular Biotechnology, Department of Biotechnology, BOKU—University of Natural Resources and Life Sciences, Muthgasse 18, 1190 Vienna, Austria
| | - Jonas Kolbenschlag
- Department of Hand-, Plastic, Reconstructive and Burn Surgery, BG Klinik Tuebingen, University of Tuebingen, Schnarrenbergstraße 95, 72076 Tuebingen, Germany; (J.C.H.); (C.P.); (J.K.)
| | - David Hercher
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Donaueschingenstraße 13, 1200 Vienna, Austria; (V.O.); (C.K.); (B.S.); (N.V.S.); (G.L.); (H.F.); (C.S.); (J.G.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
- Correspondence:
| |
Collapse
|
|
9
|
Gao C, Song S, Lv Y, Huang J, Zhang Z. Recent Development of Conductive Hydrogels for Tissue Engineering: Review and Perspective. Macromol Biosci 2022; 22:e2200051. [PMID: 35472125 DOI: 10.1002/mabi.202200051] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/29/2022] [Indexed: 11/11/2022]
Abstract
In recent years, tissue engineering techniques have been rapidly developed and offer a new therapeutic approach to organ or tissue damage repair. However, most of tissue engineering scaffolds are nonconductive and cannot establish effective electrical coupling with tissue for the electroactive tissues. Electroconductive hydrogels (ECHs) have received increasing attention in tissue engineering owing to their electroconductivity, biocompatibility and high water content. In vitro, ECHs can not only promote the communication of electrical signals between cells, but also mediate the adhesion, proliferation, migration, and differentiation of different kinds of cells. In vivo, ECHs can transmit the electric signal to electroactive tissues and activate bioelectrical signaling pathways to promote tissue repair. As a result, implanting ECHs into damaged tissues can effectively reconstruct physiological functions related to electrical conduction. In this review, we first present an overview about the classifications and the fabrication methods of ECHs. And then, the applications of ECHs in tissue engineering, including cardiac, nerve, skin and skeletal muscle tissue, are highlighted. At last, we provide some rational guidelines for designing ECHs towards clinical applications. This article is protected by copyright. All rights reserved.
Collapse
Affiliation(s)
- Chen Gao
- CAS Key Laboratory for Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences, Suzhou, 215123, People's Republic of China
| | - Shaoshuai Song
- CAS Key Laboratory for Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences, Suzhou, 215123, People's Republic of China.,School of Nano-Tech and Nano-Bionics, University of Science and Technology of China (USTC), Hefei, 230026, People's Republic of China
| | - Yinjuan Lv
- CAS Key Laboratory for Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences, Suzhou, 215123, People's Republic of China
| | - Jie Huang
- CAS Key Laboratory for Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences, Suzhou, 215123, People's Republic of China.,School of Nano-Tech and Nano-Bionics, University of Science and Technology of China (USTC), Hefei, 230026, People's Republic of China
| | - Zhijun Zhang
- CAS Key Laboratory for Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences, Suzhou, 215123, People's Republic of China.,School of Nano-Tech and Nano-Bionics, University of Science and Technology of China (USTC), Hefei, 230026, People's Republic of China
| |
Collapse
|
|
10
|
Affiliation(s)
- Xiaolong Zheng
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Wei Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
- Key Laboratory of Neurological Diseases of Chinese Ministry of Education, the School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
- Wei Wang, Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei 430030, China. Tel: +86-27-83663657, E-mail:
| |
Collapse
|
|
11
|
Hastings N, Kuan WL, Osborne A, Kotter MRN. Therapeutic Potential of Astrocyte Transplantation. Cell Transplant 2022; 31:9636897221105499. [PMID: 35770772 PMCID: PMC9251977 DOI: 10.1177/09636897221105499] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cell transplantation is an attractive treatment strategy for a variety of brain disorders, as it promises to replenish lost functions and rejuvenate the brain. In particular, transplantation of astrocytes has come into light recently as a therapy for amyotrophic lateral sclerosis (ALS); moreover, grafting of astrocytes also showed positive results in models of other conditions ranging from neurodegenerative diseases of older age to traumatic injury and stroke. Despite clear differences in etiology, disorders such as ALS, Parkinson's, Alzheimer's, and Huntington's diseases, as well as traumatic injury and stroke, converge on a number of underlying astrocytic abnormalities, which include inflammatory changes, mitochondrial damage, calcium signaling disturbance, hemichannel opening, and loss of glutamate transporters. In this review, we examine these convergent pathways leading to astrocyte dysfunction, and explore the existing evidence for a therapeutic potential of transplantation of healthy astrocytes in various models. Existing literature presents a wide variety of methods to generate astrocytes, or relevant precursor cells, for subsequent transplantation, while described outcomes of this type of treatment also differ between studies. We take technical differences between methodologies into account to understand the variability of therapeutic benefits, or lack thereof, at a deeper level. We conclude by discussing some key requirements of an astrocyte graft that would be most suitable for clinical applications.
Collapse
Affiliation(s)
- Nataly Hastings
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.,Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Wei-Li Kuan
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Andrew Osborne
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Mark R N Kotter
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.,Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| |
Collapse
|
|
12
|
Soft surfaces promote astrocytic differentiation of mouse embryonic neural stem cells via dephosphorylation of MRLC in the absence of serum. Sci Rep 2021; 11:19574. [PMID: 34599241 PMCID: PMC8486742 DOI: 10.1038/s41598-021-99059-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 09/15/2021] [Indexed: 11/24/2022] Open
Abstract
Astrocytes, which can be obtained from neural stem cells (NSCs) by adding serum and/or recombinant proteins in culture media or by passaging NSCs repeatedly, are expected to be applicable in regenerative medicine for the treatment of neurodegenerative diseases. However, astrocytes obtained using existing methods are costly and have poor quality. The stiffness of culture surfaces has been reported to affect astrocytic differentiation of adult NSCs. However, the influence of surface stiffness on astrocytic differentiation of embryonic NSCs has not yet been reported. In this study, we showed that astrocytic differentiation of embryonic NSCs was increased on soft surfaces (1 kPa and 12 kPa) compared with the NSCs on stiff surfaces (2.8 GPa) in serum-free condition. Furthermore, di-phosphorylated myosin regulatory light chain (PP-MRLC) was decreased in embryonic NSCs cultured on the soft surfaces than the cells on the stiff surfaces. Additionally, astrocytic differentiation of embryonic NSCs was induced by a Ras homolog associated kinase (ROCK) inhibitor, which decreased PP-MRLC in NSCs. These results suggest that decreasing the PP-MRLC of embryonic NSCs on soft surfaces or treating NSCs with a ROCK inhibitor is a good method to prepare astrocytes for application in regenerative medicine.
Collapse
|
|
13
|
Hart CG, Karimi-Abdolrezaee S. Recent insights on astrocyte mechanisms in CNS homeostasis, pathology, and repair. J Neurosci Res 2021; 99:2427-2462. [PMID: 34259342 DOI: 10.1002/jnr.24922] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 06/06/2021] [Accepted: 06/24/2021] [Indexed: 12/20/2022]
Abstract
Astrocytes play essential roles in development, homeostasis, injury, and repair of the central nervous system (CNS). Their development is tightly regulated by distinct spatial and temporal cues during embryogenesis and into adulthood throughout the CNS. Astrocytes have several important responsibilities such as regulating blood flow and permeability of the blood-CNS barrier, glucose metabolism and storage, synapse formation and function, and axon myelination. In CNS pathologies, astrocytes also play critical parts in both injury and repair mechanisms. Upon injury, they undergo a robust phenotypic shift known as "reactive astrogliosis," which results in both constructive and deleterious outcomes. Astrocyte activation and migration at the site of injury provides an early defense mechanism to minimize the extent of injury by enveloping the lesion area. However, astrogliosis also contributes to the inhibitory microenvironment of CNS injury and potentiate secondary injury mechanisms, such as inflammation, oxidative stress, and glutamate excitotoxicity, which facilitate neurodegeneration in CNS pathologies. Intriguingly, reactive astrocytes are increasingly a focus in current therapeutic strategies as their activation can be modulated toward a neuroprotective and reparative phenotype. This review will discuss recent advancements in knowledge regarding the development and role of astrocytes in the healthy and pathological CNS. We will also review how astrocytes have been genetically modified to optimize their reparative potential after injury, and how they may be transdifferentiated into neurons and oligodendrocytes to promote repair after CNS injury and neurodegeneration.
Collapse
Affiliation(s)
- Christopher G Hart
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada
| | - Soheila Karimi-Abdolrezaee
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada
| |
Collapse
|
|
14
|
Tran AP, Warren PM, Silver J. New insights into glial scar formation after spinal cord injury. Cell Tissue Res 2021; 387:319-336. [PMID: 34076775 PMCID: PMC8975767 DOI: 10.1007/s00441-021-03477-w] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023]
Abstract
Severe spinal cord injury causes permanent loss of function and sensation throughout the body. The trauma causes a multifaceted torrent of pathophysiological processes which ultimately act to form a complex structure, permanently remodeling the cellular architecture and extracellular matrix. This structure is traditionally termed the glial/fibrotic scar. Similar cellular formations occur following stroke, infection, and neurodegenerative diseases of the central nervous system (CNS) signifying their fundamental importance to preservation of function. It is increasingly recognized that the scar performs multiple roles affecting recovery following traumatic injury. Innovative research into the properties of this structure is imperative to the development of treatment strategies to recover motor function and sensation following CNS trauma. In this review, we summarize how the regeneration potential of the CNS alters across phyla and age through formation of scar-like structures. We describe how new insights from next-generation sequencing technologies have yielded a more complex portrait of the molecular mechanisms governing the astrocyte, microglial, and neuronal responses to injury and development, especially of the glial component of the scar. Finally, we discuss possible combinatorial therapeutic approaches centering on scar modulation to restore function after severe CNS injury.
Collapse
Affiliation(s)
- Amanda Phuong Tran
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Philippa Mary Warren
- Wolfson Centre for Age Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Guy's Campus, London Bridge, London, UK
| | - Jerry Silver
- Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
| |
Collapse
|
|
15
|
Heinzel JC, Oberhauser V, Keibl C, Swiadek N, Längle G, Frick H, Kolbenschlag J, Prahm C, Grillari J, Hercher D. Evaluation of Functional Recovery in Rats After Median Nerve Resection and Autograft Repair Using Computerized Gait Analysis. Front Neurosci 2021; 14:593545. [PMID: 33551723 PMCID: PMC7859340 DOI: 10.3389/fnins.2020.593545] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022] Open
Abstract
Computerized gait analysis is a common evaluation method in rat models of hind limb nerve injuries, but its use remains unpublished in models of segmental nerve injury of the forelimb. It was the aim of this work to investigate if computerized gait analysis is a feasible evaluation method in a rat model of segmental median nerve injury and autograft repair. Ten male Lewis rats underwent 7-mm resection of the right median nerve with immediate autograft repair. The left median nerve was resected without repair and served as an internal control. Animals were assessed for 12 weeks after surgery via CatWalk (CW) gait analysis every 2 weeks. Evaluation of motor recovery by means of the grasping test was performed weekly while electrophysiological measurements were performed at the end of the observation period. CW data were correlated with grasping strength at each post-operative time point. CW data were also correlated with electrophysiology using linear regression analysis. Principal component analysis was performed to identify clusters of outcome metrics. Recovery of motor function was observable 4 weeks after surgery, but grasping strength was significantly reduced (p < 0.01) compared to baseline values until post-operative week 6. In terms of sensory recovery, the pain-related parameter Duty Cycle showed significant (p < 0.05) recovery starting from post-operative week 8. The Print Area of the right paw was significantly (p < 0.05) increased compared to the left side starting from post-operative week 10. Various parameters of gait correlated significantly (p < 0.05) with mean and maximum grasping strength. However, only Stand Index showed a significant correlation with compound muscle action potential (CMAP) amplitude (p < 0.05). With this work, we prove that computerized gait analysis is a valid and feasible method to evaluate functional recovery after autograft repair of the rat median nerve. We were able to identify parameters such as Print Area, Duty Cycle, and Stand Index, which allow assessment of nerve regeneration. The course of these parameters following nerve resection without repair was also assessed. Additionally, external paw rotation was identified as a valid parameter to evaluate motor reinnervation. In summary, computerized gait analysis is a valuable additional tool to study nerve regeneration in rats with median nerve injury.
Collapse
Affiliation(s)
- Johannes C Heinzel
- Department of Hand, Plastic, Reconstructive and Burn Surgery, BG Trauma Center Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany.,Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Viola Oberhauser
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Claudia Keibl
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Nicole Swiadek
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Gregor Längle
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Helen Frick
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Jonas Kolbenschlag
- Department of Hand, Plastic, Reconstructive and Burn Surgery, BG Trauma Center Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Cosima Prahm
- Department of Hand, Plastic, Reconstructive and Burn Surgery, BG Trauma Center Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Johannes Grillari
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria.,Department of Biotechnology, Institute of Molecular Biotechnology, BOKU-University of Natural Resources and Life Sciences Vienna, Vienna, Austria
| | - David Hercher
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| |
Collapse
|
|
16
|
Heinzel J, Längle G, Oberhauser V, Hausner T, Kolbenschlag J, Prahm C, Grillari J, Hercher D. Use of the CatWalk gait analysis system to assess functional recovery in rodent models of peripheral nerve injury - a systematic review. J Neurosci Methods 2020; 345:108889. [PMID: 32755615 DOI: 10.1016/j.jneumeth.2020.108889] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/28/2020] [Accepted: 07/28/2020] [Indexed: 02/07/2023]
Abstract
Injuries of the peripheral nervous system are common among the population affecting around 3% of all trauma patients. This high clinical need in the field of peripheral nerve injury and regeneration has been steadily driving experimental and epidemiological research. Thereby, it is crucial to determine the exact degree of recovery of end-organ function. Regeneration after nerve injuries is assessed by a wide variety of techniques and pre-clinical model systems, where rodent models are among the most widely used. However, results from rodents are difficult to translate to human patients in general, and reproducible and comparable assessment of functional recovery is of highest importance. Computerized gait analysis allows comprehensive acquisition of locomotor function. As the animals cross the recording device voluntarily, functional recovery is assessable with a minimum degree of human interference on their behavior. This article aims to give a detailed overview on the existing literature on CatWalk gait analysis in rodent models of peripheral nerve injuries of upper and lower extremities, e.g. axonotmesis, neurotmesis or fibrosis, with special emphasis on differences between models. Researchers interested in assessment of locomotor function in such models will especially benefit from this work as it will provide them with an overview of the various experimental setups and expected outcomes. This work also addresses potential pitfalls and hurdles in order to promote well designed, comparable studies allowing for accelerated development of therapeutic strategies in peripheral repair and regeneration.
Collapse
Affiliation(s)
- Johannes Heinzel
- Department of Hand-, Plastic, Reconstructive and Burn Surgery, BG Trauma Center Tuebingen, Eberhard Karls University, Tuebingen, Germany; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstraße 13, 1020, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Austria
| | - Gregor Längle
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstraße 13, 1020, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Austria
| | - Viola Oberhauser
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstraße 13, 1020, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Austria
| | - Thomas Hausner
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstraße 13, 1020, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Austria
| | - Jonas Kolbenschlag
- Department of Hand-, Plastic, Reconstructive and Burn Surgery, BG Trauma Center Tuebingen, Eberhard Karls University, Tuebingen, Germany
| | - Cosima Prahm
- Department of Hand-, Plastic, Reconstructive and Burn Surgery, BG Trauma Center Tuebingen, Eberhard Karls University, Tuebingen, Germany
| | - Johannes Grillari
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstraße 13, 1020, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Austria; Institute of Molecular Biotechnology, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190, Vienna, Austria
| | - David Hercher
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstraße 13, 1020, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Austria.
| |
Collapse
|
|
17
|
Fiker R, Kim LH, Molina LA, Chomiak T, Whelan PJ. Visual Gait Lab: A user-friendly approach to gait analysis. J Neurosci Methods 2020; 341:108775. [PMID: 32428621 DOI: 10.1016/j.jneumeth.2020.108775] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/09/2020] [Accepted: 05/09/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND Gait analysis forms a critical part of many lab workflows, ranging from those interested in preclinical neurological models to others who use locomotion as part of a standard battery of tests. Unfortunately, while paw detection can be semi-automated, it becomes generally a time-consuming process with error corrections. Improvement in paw tracking would aid in better gait analysis performance and experience. NEW METHOD Here we show the use of Visual Gait Lab (VGL), a high-level software with an intuitive, easy to use interface, that is built on DeepLabCut™. VGL is optimized to generate gait metrics and allows for quick manual error corrections. VGL comes with a single executable, streamlining setup on Windows systems. We demonstrate the use of VGL to analyze gait. RESULTS Training and evaluation of VGL were conducted using 200 frames (80/20 train-test split) of video from mice walking on a treadmill. The trained network was then used to visually track paw placements to compute gait metrics. These are processed and presented on the screen where the user can rapidly identify and correct errors. COMPARISON WITH EXISTING METHODS Gait analysis remains cumbersome, even with commercial software due to paw detection errors. DeepLabCut™ is an alternative that can improve visual tracking but is not optimized for gait analysis functionality. CONCLUSIONS VGL allows for gait analysis to be performed in a rapid, unbiased manner, with a set-up that can be easily implemented and executed by those without a background in computer programming.
Collapse
Affiliation(s)
- Robert Fiker
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Linda H Kim
- Department of Neuroscience, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Leonardo A Molina
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Taylor Chomiak
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Patrick J Whelan
- Department of Neuroscience, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada.
| |
Collapse
|
|
18
|
Heinzel JC, Hercher D, Redl H. The course of recovery of locomotor function over a 10-week observation period in a rat model of femoral nerve resection and autograft repair. Brain Behav 2020; 10:e01580. [PMID: 32097542 PMCID: PMC7177579 DOI: 10.1002/brb3.1580] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 12/26/2019] [Accepted: 01/30/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND A great extent of knowledge on peripheral nerve regeneration has been gathered using the rat sciatic nerve model. The femoral nerve model of the rat offers an interesting alternative, as it lacks disadvantageous features such as automutilation. For the analysis of locomotor behavior in rats after sciatic nerve injury, the CatWalk™ XT Gait Analysis System is often used. However, lesions of the femoral nerve in the rat have yet remained unstudied with this method. MATERIAL AND METHODS Ten male Sprague Dawley rats were evaluated with the CatWalk XT to study their gait after a 6-mm resection of the right femoral nerve and reconstruction with an autologous nerve graft. Animals were observed for 10 weeks after surgery. RESULTS Print Area, Print Length, Swing Speed, and Duty Cycle decreased to a minimum of 40% of baseline 2 weeks after surgery. Swing Time was elevated more than twofold at this time point. However, all these parameters recovered back to >90% of baseline values at 10 weeks after surgery. This degree of functional recovery has not been reported after sciatic nerve resection and autograft repair. Base of support varied minimally postoperatively in contrast to a strong decrement after sciatic nerve resection and repair. CONCLUSION We hereby provide a comprehensive in-depth analysis of how to study functional recovery after injury of the femoral nerve in the rat via the CatWalk XT. We place special emphasis on highlighting the differences between the femoral nerve and sciatic nerve injury model in this context.
Collapse
Affiliation(s)
- Johannes Christoph Heinzel
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Trauma Research Center, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - David Hercher
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Trauma Research Center, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Heinz Redl
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Trauma Research Center, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| |
Collapse
|
|
19
|
Saroia J, Yanen W, Wei Q, Zhang K, Lu T, Zhang B. A review on biocompatibility nature of hydrogels with 3D printing techniques, tissue engineering application and its future prospective. Biodes Manuf 2018. [DOI: 10.1007/s42242-018-0029-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
|
|
20
|
Tran AP, Warren PM, Silver J. The Biology of Regeneration Failure and Success After Spinal Cord Injury. Physiol Rev 2018. [PMID: 29513146 DOI: 10.1152/physrev.00017.2017] [Citation(s) in RCA: 568] [Impact Index Per Article: 81.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Since no approved therapies to restore mobility and sensation following spinal cord injury (SCI) currently exist, a better understanding of the cellular and molecular mechanisms following SCI that compromise regeneration or neuroplasticity is needed to develop new strategies to promote axonal regrowth and restore function. Physical trauma to the spinal cord results in vascular disruption that, in turn, causes blood-spinal cord barrier rupture leading to hemorrhage and ischemia, followed by rampant local cell death. As subsequent edema and inflammation occur, neuronal and glial necrosis and apoptosis spread well beyond the initial site of impact, ultimately resolving into a cavity surrounded by glial/fibrotic scarring. The glial scar, which stabilizes the spread of secondary injury, also acts as a chronic, physical, and chemo-entrapping barrier that prevents axonal regeneration. Understanding the formative events in glial scarring helps guide strategies towards the development of potential therapies to enhance axon regeneration and functional recovery at both acute and chronic stages following SCI. This review will also discuss the perineuronal net and how chondroitin sulfate proteoglycans (CSPGs) deposited in both the glial scar and net impede axonal outgrowth at the level of the growth cone. We will end the review with a summary of current CSPG-targeting strategies that help to foster axonal regeneration, neuroplasticity/sprouting, and functional recovery following SCI.
Collapse
Affiliation(s)
- Amanda Phuong Tran
- Department of Neurosciences, Case Western Reserve University , Cleveland, Ohio ; and School of Biomedical Sciences, University of Leeds , Leeds , United Kingdom
| | - Philippa Mary Warren
- Department of Neurosciences, Case Western Reserve University , Cleveland, Ohio ; and School of Biomedical Sciences, University of Leeds , Leeds , United Kingdom
| | - Jerry Silver
- Department of Neurosciences, Case Western Reserve University , Cleveland, Ohio ; and School of Biomedical Sciences, University of Leeds , Leeds , United Kingdom
| |
Collapse
|
|
21
|
Youngblood RL, Truong NF, Segura T, Shea LD. It's All in the Delivery: Designing Hydrogels for Cell and Non-viral Gene Therapies. Mol Ther 2018; 26:2087-2106. [PMID: 30107997 PMCID: PMC6127639 DOI: 10.1016/j.ymthe.2018.07.022] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 07/24/2018] [Accepted: 07/24/2018] [Indexed: 01/08/2023] Open
Abstract
Hydrogels provide a regenerative medicine platform with their ability to create an environment that supports transplanted or endogenous infiltrating cells and enables these cells to restore or replace the function of tissues lost to disease or trauma. Furthermore, these systems have been employed as delivery vehicles for therapeutic genes, which can direct and/or enhance the function of the transplanted or endogenous cells. Herein, we review recent advances in the development of hydrogels for cell and non-viral gene delivery through understanding the design parameters, including both physical and biological components, on promoting transgene expression, cell engraftment, and ultimately cell function. Furthermore, this review identifies emerging opportunities for combining cell and gene delivery approaches to overcome challenges to the field.
Collapse
Affiliation(s)
- Richard L Youngblood
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Norman F Truong
- Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Tatiana Segura
- Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
| |
Collapse
|
|
22
|
Tickle JA, Poptani H, Taylor A, Chari DM. Noninvasive imaging of nanoparticle-labeled transplant populations within polymer matrices for neural cell therapy. Nanomedicine (Lond) 2018; 13:1333-1348. [PMID: 29949467 PMCID: PMC6220152 DOI: 10.2217/nnm-2017-0347] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Accepted: 03/29/2018] [Indexed: 12/15/2022] Open
Abstract
AIM To develop a 3D neural cell construct for encapsulated delivery of transplant cells; develop hydrogels seeded with magnetic nanoparticle (MNP)-labeled cells suitable for cell tracking by MRI. MATERIALS & METHODS Astrocytes were exogenously labeled with MRI-compatible iron-oxide MNPs prior to intra-construct incorporation within a 3D collagen hydrogel. RESULTS A connective, complex cellular network was clearly observable within the 3D constructs, with high cellular viability. MNP accumulation in astrocytes provided a hypointense MRI signal at 24 h & 14 days. CONCLUSION Our findings support the concept of developing a 3D construct possessing the dual advantages of (i) support of long-term cell survival of neural populations with (ii) the potential for noninvasive MRI-tracking of intra-construct cells for neuroregenerative applications.
Collapse
Affiliation(s)
- Jacqueline A Tickle
- Institute for Science & Technology in Medicine, Keele University, Keele, ST5 5BG, UK
| | - Harish Poptani
- Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK
| | - Arthur Taylor
- Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK
| | - Divya M Chari
- Institute for Science & Technology in Medicine, Keele University, Keele, ST5 5BG, UK
| |
Collapse
|
|
23
|
Liu S, Schackel T, Weidner N, Puttagunta R. Biomaterial-Supported Cell Transplantation Treatments for Spinal Cord Injury: Challenges and Perspectives. Front Cell Neurosci 2018; 11:430. [PMID: 29375316 PMCID: PMC5768640 DOI: 10.3389/fncel.2017.00430] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 12/20/2017] [Indexed: 12/17/2022] Open
Abstract
Spinal cord injury (SCI), resulting in para- and tetraplegia caused by the partial or complete disruption of descending motor and ascending sensory neurons, represents a complex neurological condition that remains incurable. Following SCI, numerous obstacles comprising of the loss of neural tissue (neurons, astrocytes, and oligodendrocytes), formation of a cavity, inflammation, loss of neuronal circuitry and function must be overcome. Given the multifaceted primary and secondary injury events that occur with SCI treatment options are likely to require combinatorial therapies. While several methods have been explored, only the intersection of two, cell transplantation and biomaterial implantation, will be addressed in detail here. Owing to the constant advance of cell culture technologies, cell-based transplantation has come to the forefront of SCI treatment in order to replace/protect damaged tissue and provide physical as well as trophic support for axonal regrowth. Biomaterial scaffolds provide cells with a protected environment from the surrounding lesion, in addition to bridging extensive damage and providing physical and directional support for axonal regrowth. Moreover, in this combinatorial approach cell transplantation improves scaffold integration and therefore regenerative growth potential. Here, we review the advances in combinatorial therapies of Schwann cells (SCs), astrocytes, olfactory ensheathing cells (OECs), mesenchymal stem cells, as well as neural stem and progenitor cells (NSPCs) with various biomaterial scaffolds.
Collapse
Affiliation(s)
- Shengwen Liu
- Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Thomas Schackel
- Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany
| | - Norbert Weidner
- Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany
| | - Radhika Puttagunta
- Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany
| |
Collapse
|
|
24
|
Chuang CS, Chang JC, Cheng FC, Liu KH, Su HL, Liu CS. Modulation of mitochondrial dynamics by treadmill training to improve gait and mitochondrial deficiency in a rat model of Parkinson's disease. Life Sci 2017; 191:236-244. [DOI: 10.1016/j.lfs.2017.10.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 09/25/2017] [Accepted: 10/02/2017] [Indexed: 11/16/2022]
|
|
25
|
Functional Test Scales for Evaluating Cell-Based Therapies in Animal Models of Spinal Cord Injury. Stem Cells Int 2017; 2017:5160261. [PMID: 29109741 PMCID: PMC5646345 DOI: 10.1155/2017/5160261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 06/28/2017] [Accepted: 08/01/2017] [Indexed: 01/22/2023] Open
Abstract
Recently, spinal cord researchers have focused on multifaceted approaches for the treatment of spinal cord injury (SCI). However, as there is no cure for the deficits produced by SCI, various therapeutic strategies have been examined using animal models. Due to the lack of standardized functional assessment tools for use in such models, it is important to choose a suitable animal model and precise behavioral test when evaluating the efficacy of potential SCI treatments. In the present review, we discuss recent evidence regarding functional recovery in various animal models of SCI, summarize the representative models currently used, evaluate recent cell-based therapeutic approaches, and aim to identify the most precise and appropriate scales for functional assessment in such research.
Collapse
|
|
26
|
Biocompatibility of hydrogel-based scaffolds for tissue engineering applications. Biotechnol Adv 2017; 35:530-544. [DOI: 10.1016/j.biotechadv.2017.05.006] [Citation(s) in RCA: 407] [Impact Index Per Article: 50.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Revised: 05/08/2017] [Accepted: 05/22/2017] [Indexed: 12/15/2022]
|
|
27
|
Blaško J, Szekiova E, Slovinska L, Kafka J, Cizkova D. Axonal outgrowth stimulation after alginate/mesenchymal stem cell therapy in injured rat spinal cord. Acta Neurobiol Exp (Wars) 2017. [DOI: 10.21307/ane-2017-066] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
|
|
28
|
Tsou YH, Khoneisser J, Huang PC, Xu X. Hydrogel as a bioactive material to regulate stem cell fate. Bioact Mater 2016; 1:39-55. [PMID: 29744394 PMCID: PMC5883979 DOI: 10.1016/j.bioactmat.2016.05.001] [Citation(s) in RCA: 187] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 04/27/2016] [Accepted: 05/02/2016] [Indexed: 02/08/2023] Open
Abstract
The encapsulation of stem cells in a hydrogel substrate provides a promising future in biomedical applications. However, communications between hydrogels and stem cells is complicated; various factors such as porosity, different polymer types, stiffness, compatibility and degradation will lead to stem cell survival or death. Hydrogels mimic the three-dimensional extracellular matrix to provide a friendly environment for stem cells. On the other hand, stem cells can sense the surroundings to make the next progression, stretching out, proliferating or just to remain. As such, understanding the correlation between stem cells and hydrogels is crucial. In this Review, we first discuss the varying types of the hydrogels and stem cells, which are most commonly used in the biomedical fields and further investigate how hydrogels interact with stem cells from the perspective of their biomedical application, while providing insights into the design and development of hydrogels for drug delivery, tissue engineering and regenerative medicine purpose. In addition, we compare the results such as stiffness, degradation time and pore size as well as peptide types of hydrogels from respected journals. We also discussed most recently magnificent materials and their effects to regulate stem cell fate.
Hydrogels as Extracellular Matrix (ECM) mimics stem cells proliferation and differentiation. Discuss how hydrogels interact with stem cells from the perspective of their biomedical applications. Recent magnificent materials and their effects to regulate stem cells fate.
Collapse
Affiliation(s)
- Yung-Hao Tsou
- Department of Chemical, Biological, and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
| | - Joe Khoneisser
- Department of Chemical, Biological, and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
| | - Ping-Chun Huang
- Department of Chemical, Biological, and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
| | - Xiaoyang Xu
- Department of Chemical, Biological, and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
| |
Collapse
|
|
29
|
Chen C, Chan A, Wen H, Chung SH, Deng W, Jiang P. Stem and Progenitor Cell-Derived Astroglia Therapies for Neurological Diseases. Trends Mol Med 2015; 21:715-729. [PMID: 26443123 DOI: 10.1016/j.molmed.2015.09.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 09/04/2015] [Accepted: 09/08/2015] [Indexed: 02/07/2023]
Abstract
Astroglia are a major cellular constituent of the central nervous system (CNS) and play crucial roles in brain development, function, and integrity. Increasing evidence demonstrates that astroglia dysfunction occurs in a variety of neurological disorders ranging from CNS injuries to genetic diseases and chronic degenerative conditions. These new insights herald the concept that transplantation of astroglia could be of therapeutic value in treating the injured or diseased CNS. Recent technological advances in the generation of human astroglia from stem and progenitor cells have been prominent. We propose that a better understanding of the suitability of astroglial cells in transplantation as well as of their therapeutic effects in animal models may lead to the establishment of astroglia-based therapies to treat neurological diseases.
Collapse
Affiliation(s)
- Chen Chen
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA, USA
| | - Albert Chan
- Department of Pediatrics, University of California, Davis, CA, USA
| | - Han Wen
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA, USA
| | | | - Wenbin Deng
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA, USA.
| | - Peng Jiang
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA, USA; Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, NE, USA.
| |
Collapse
|
|
30
|
Tsintou M, Dalamagkas K, Seifalian AM. Advances in regenerative therapies for spinal cord injury: a biomaterials approach. Neural Regen Res 2015; 10:726-742. [PMID: 26109946 PMCID: PMC4468763 DOI: 10.4103/1673-5374.156966] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2015] [Indexed: 12/16/2022] Open
Abstract
Spinal cord injury results in the permanent loss of function, causing enormous personal, social and economic problems. Even though neural regeneration has been proven to be a natural mechanism, central nervous system repair mechanisms are ineffective due to the imbalance of the inhibitory and excitatory factors implicated in neuroregeneration. Therefore, there is growing research interest on discovering a novel therapeutic strategy for effective spinal cord injury repair. To this direction, cell-based delivery strategies, biomolecule delivery strategies as well as scaffold-based therapeutic strategies have been developed with a tendency to seek for the answer to a combinatorial approach of all the above. Here we review the recent advances on regenerative/neural engineering therapies for spinal cord injury, aiming at providing an insight to the most promising repair strategies, in order to facilitate future research conduction.
Collapse
Affiliation(s)
- Magdalini Tsintou
- UCL Centre for Nanotechnology & Regenerative Medicine, Division of Surgery and Interventional Science, University College of London, London, UK
| | - Kyriakos Dalamagkas
- UCL Centre for Nanotechnology & Regenerative Medicine, Division of Surgery and Interventional Science, University College of London, London, UK
| | - Alexander Marcus Seifalian
- UCL Centre for Nanotechnology & Regenerative Medicine, Division of Surgery and Interventional Science, University College of London, London, UK
- Royal Free London NHS Foundation Trust Hospital, London, UK
| |
Collapse
|
|
31
|
Nicaise C, Mitrecic D, Falnikar A, Lepore AC. Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury. World J Stem Cells 2015; 7:380-398. [PMID: 25815122 PMCID: PMC4369494 DOI: 10.4252/wjsc.v7.i2.380] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/07/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Neglected for years, astrocytes are now recognized to fulfill and support many, if not all, homeostatic functions of the healthy central nervous system (CNS). During neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI), astrocytes in the vicinity of degenerating areas undergo both morphological and functional changes that might compromise their intrinsic properties. Evidence from human and animal studies show that deficient astrocyte functions or loss-of-astrocytes largely contribute to increased susceptibility to cell death for neurons, oligodendrocytes and axons during ALS and SCI disease progression. Despite exciting advances in experimental CNS repair, most of current approaches that are translated into clinical trials focus on the replacement or support of spinal neurons through stem cell transplantation, while none focus on the specific replacement of astroglial populations. Knowing the important functions carried out by astrocytes in the CNS, astrocyte replacement-based therapies might be a promising approach to alleviate overall astrocyte dysfunction, deliver neurotrophic support to degenerating spinal tissue and stimulate endogenous CNS repair abilities. Enclosed in this review, we gathered experimental evidence that argue in favor of astrocyte transplantation during ALS and SCI. Based on their intrinsic properties and according to the cell type transplanted, astrocyte precursors or stem cell-derived astrocytes promote axonal growth, support mechanisms and cells involved in myelination, are able to modulate the host immune response, deliver neurotrophic factors and provide protective molecules against oxidative or excitotoxic insults, amongst many possible benefits. Embryonic or adult stem cells can even be genetically engineered in order to deliver missing gene products and therefore maximize the chance of neuroprotection and functional recovery. However, before broad clinical translation, further preclinical data on safety, reliability and therapeutic efficiency should be collected. Although several technical challenges need to be overcome, we discuss the major hurdles that have already been met or solved by targeting the astrocyte population in experimental ALS and SCI models and we discuss avenues for future directions based on latest molecular findings regarding astrocyte biology.
Collapse
|
|
32
|
Garcia-Ovejero D, González S, Paniagua-Torija B, Lima A, Molina-Holgado E, De Nicola AF, Labombarda F. Progesterone reduces secondary damage, preserves white matter, and improves locomotor outcome after spinal cord contusion. J Neurotrauma 2014; 31:857-71. [PMID: 24460450 DOI: 10.1089/neu.2013.3162] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Progesterone is an anti-inflammatory and promyelinating agent after spinal cord injury, but its effectiveness on functional recovery is still controversial. In the current study, we tested the effects of chronic progesterone administration on tissue preservation and functional recovery in a clinically relevant model of spinal cord lesion (thoracic contusion). Using magnetic resonance imaging, we observed that progesterone reduced both volume and rostrocaudal extension of the lesion at 60 days post-injury. In addition, progesterone increased the number of total mature oligodendrocytes, myelin basic protein immunoreactivity, and the number of axonal profiles at the epicenter of the lesion. Further, progesterone treatment significantly improved motor outcome as assessed using the Basso-Bresnahan-Beattie scale for locomotion and CatWalk gait analysis. These data suggest that progesterone could be considered a promising therapeutical candidate for spinal cord injury.
Collapse
Affiliation(s)
- Daniel Garcia-Ovejero
- 1 Laboratorio de Neuroinflamación, Hospital Nacional de Parapléjicos , Toledo, Spain
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Abstract
There is currently no standard pharmacological treatment for spinal cord injury. Here, we suggest that progesterone, a steroid hormone, may be a promising therapeutical candidate as it is already for traumatic brain injury, where it has reached phase II clinical trials. We rely on previous works showing anti-inflammatory, neuroprotective and promyelinating roles for progesterone after spinal cord injury and in our recent paper, in which we demonstrate that progesterone diminishes lesion, preserves white matter integrity and improves locomotor recovery in a clinically relevant model of spinal cord lesion.
Collapse
Affiliation(s)
- Florencia Labombarda
- Laboratory of Neuroendocrine Biochemistry, Institute of Biology and Experimental Medicine CONICET, Vuelta de Obligado 2490, Buenos Aires, Argentina ; Departament of Human Biochemistry, School of Medicine, Buenos Aires University, Paraguay 2155, Buenos Aires, Argentina
| | - Daniel Garcia-Ovejero
- Neuroinflammation Laboratory, National Hospital For Paraplegics, (SESCAM), Toledo, Spain
| |
Collapse
|
|
34
|
Falnikar A, Li K, Lepore AC. Therapeutically targeting astrocytes with stem and progenitor cell transplantation following traumatic spinal cord injury. Brain Res 2014; 1619:91-103. [PMID: 25251595 DOI: 10.1016/j.brainres.2014.09.037] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 09/10/2014] [Accepted: 09/15/2014] [Indexed: 12/12/2022]
Abstract
Replacement of lost and/or dysfunctional astrocytes via multipotent neural stem cell (NSC) and lineage-restricted neural progenitor cell (NPC) transplantation is a promising therapeutic approach for traumatic spinal cord injury (SCI). Cell transplantation in general offers the potential to replace central nervous system (CNS) cell types, achieve remyelination, deliver missing gene products, promote and guide axonal growth, modulate the host immune response, deliver neuroprotective factors, and provide a cellular substrate for bridging the lesion site, amongst other possible benefits. A host of cell types that differ in their developmental stage, CNS region and species of derivation, as well as in their phenotypic potential, have been tested in a variety of SCI animal models. Historically in the SCI field, most pre-clinical NSC and NPC transplantation studies have focused on neuronal and oligodendrocyte replacement. However, much less attention has been geared towards targeting astroglial dysfunction in the inured spinal cord, despite the integral roles played by astrocytes in both normal CNS function and in the diseased nervous system. Despite the relative lack of studies, cell transplantation-based targeting of astrocytes dates back to some of the earliest transplant studies in SCI animal models. In this review, we will describe the history of work involving cell transplantation for targeting astrocytes in models of SCI. We will also touch on the current state of affairs in the field, as well as on important future directions as we move forward in trying to develop this approach into a viable strategy for SCI patients. Practical issues such as timing of delivery, route of transplantation and immunesuppression needs are beyond the scope of this review. This article is part of a Special Issue entitled SI: Spinal cord injury.
Collapse
Affiliation(s)
- Aditi Falnikar
- Department of Neuroscience, Farber Institute for Neurosciences, Thomas Jefferson University Medical College, 900 Walnut Street, JHN 469, Philadelphia, PA 19107, United States
| | - Ke Li
- Department of Neuroscience, Farber Institute for Neurosciences, Thomas Jefferson University Medical College, 900 Walnut Street, JHN 469, Philadelphia, PA 19107, United States
| | - Angelo C Lepore
- Department of Neuroscience, Farber Institute for Neurosciences, Thomas Jefferson University Medical College, 900 Walnut Street, JHN 469, Philadelphia, PA 19107, United States.
| |
Collapse
|
|
35
|
Wu L, Li J, Chen L, Zhang H, Yuan L, Davies SJ. Combined transplantation of GDAs(BMP) and hr-decorin in spinal cord contusion repair. Neural Regen Res 2014; 8:2236-48. [PMID: 25206533 PMCID: PMC4146032 DOI: 10.3969/j.issn.1673-5374.2013.24.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 06/27/2013] [Indexed: 12/23/2022] Open
Abstract
Following spinal cord injury, astrocyte proliferation and scar formation are the main factors inhibiting the regeneration and growth of spinal cord axons. Recombinant decorin suppresses inflammatory reactions, inhibits glial scar formation, and promotes axonal growth. Rat models of T8 spinal cord contusion were created with the NYU impactor and these models were subjected to combined transplantation of bone morphogenetic protein-4-induced glial-restricted precursor-derived astrocytes and human recombinant decorin transplantation. At 28 days after spinal cord contusion, double-immunofluorescent histochemistry revealed that combined transplantation inhibited the early inflammatory response in injured rats. Furthermore, brain-derived neurotrophic factor, which was secreted by transplanted cells, protected injured axons. The combined transplantation promoted axonal regeneration and growth of injured motor and sensory neurons by inhibiting astrocyte proliferation and glial scar formation, with astrocytes forming a linear arrangement in the contused spinal cord, thus providing axonal regeneration channels.
Collapse
Affiliation(s)
- Liang Wu
- School of Rehabilitation Medicine, Capital Medical University, Beijing 100068, China ; Department of Neural Functional Reconstruction of Spine and Spinal Cord, China Rehabilitation Research Center, Beijing 100068, China ; Rehabilitation Center, Beijing Xiaotangshan Rehabilitation Hospital, Beijing 102211, China
| | - Jianjun Li
- School of Rehabilitation Medicine, Capital Medical University, Beijing 100068, China ; Department of Neural Functional Reconstruction of Spine and Spinal Cord, China Rehabilitation Research Center, Beijing 100068, China
| | - Liang Chen
- School of Rehabilitation Medicine, Capital Medical University, Beijing 100068, China ; Department of Neural Functional Reconstruction of Spine and Spinal Cord, China Rehabilitation Research Center, Beijing 100068, China
| | - Hong Zhang
- School of Rehabilitation Medicine, Capital Medical University, Beijing 100068, China
| | - Li Yuan
- School of Rehabilitation Medicine, Capital Medical University, Beijing 100068, China ; Department of Neural Functional Reconstruction of Spine and Spinal Cord, China Rehabilitation Research Center, Beijing 100068, China
| | - Stephen Ja Davies
- Department of Neurosurgery, University of Colorado Denver, 1250 14th Street Denver, Colorado 80217, USA
| |
Collapse
|
|
36
|
Chu T, Zhou H, Li F, Wang T, Lu L, Feng S. Astrocyte transplantation for spinal cord injury: current status and perspective. Brain Res Bull 2014; 107:18-30. [PMID: 24878447 DOI: 10.1016/j.brainresbull.2014.05.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Revised: 05/17/2014] [Accepted: 05/19/2014] [Indexed: 02/07/2023]
Abstract
Spinal cord injury (SCI) often causes incurable neurological dysfunction because axonal regeneration in adult spinal cord is rare. Astrocytes are gradually recognized as being necessary for the regeneration after SCI as they promote axonal growth under both physiological and pathophysiological conditions. Heterogeneous populations of astrocytes have been explored for structural and functional restoration. The results range from the early variable and modest effects of immature astrocyte transplantation to the later significant, but controversial, outcomes of glial-restricted precursor (GRP)-derived astrocyte (GDA) transplantation. However, the traditional neuron-centric view and the concerns about the inhibitory roles of astrocytes after SCI, along with the sporadic studies and the lack of a comprehensive review, have led to some confusion over the usefulness of astrocytes in SCI. It is the purpose of the review to discuss the current status of astrocyte transplantation for SCI based on a dialectical view of the context-dependent manner of astrocyte behavior and the time-associated characteristics of glial scarring. Critical issues are then analyzed to reveal the potential direction of future research.
Collapse
Affiliation(s)
- Tianci Chu
- Department of Orthopaedics, Tianjin Medical University General Hospital, Anshan Road No. 154, Heping District, Tianjin 300052, PR China.
| | - Hengxing Zhou
- Department of Orthopaedics, Tianjin Medical University General Hospital, Anshan Road No. 154, Heping District, Tianjin 300052, PR China.
| | - Fuyuan Li
- Department of Orthopaedics, Tianjin Medical University General Hospital, Anshan Road No. 154, Heping District, Tianjin 300052, PR China.
| | - Tianyi Wang
- Department of Orthopaedics, Tianjin Medical University General Hospital, Anshan Road No. 154, Heping District, Tianjin 300052, PR China.
| | - Lu Lu
- Department of Orthopaedics, Tianjin Medical University General Hospital, Anshan Road No. 154, Heping District, Tianjin 300052, PR China.
| | - Shiqing Feng
- Department of Orthopaedics, Tianjin Medical University General Hospital, Anshan Road No. 154, Heping District, Tianjin 300052, PR China.
| |
Collapse
|
|
37
|
Kanno H, Pressman Y, Moody A, Berg R, Muir EM, Rogers JH, Ozawa H, Itoi E, Pearse DD, Bunge MB. Combination of engineered Schwann cell grafts to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after spinal cord injury. J Neurosci 2014; 34:1838-55. [PMID: 24478364 PMCID: PMC3905147 DOI: 10.1523/jneurosci.2661-13.2014] [Citation(s) in RCA: 126] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 11/14/2013] [Accepted: 12/19/2013] [Indexed: 11/21/2022] Open
Abstract
Transplantation of Schwann cells (SCs) is a promising therapeutic strategy for spinal cord repair. SCs introduced into lesions support axon regeneration, but because these axons do not exit the transplant, additional approaches with SCs are needed. Here, we transplanted SCs genetically modified to secrete a bifunctional neurotrophin (D15A) and chondroitinase ABC (ChABC) into a subacute contusion injury in rats. We examined the effects of these modifications on graft volume, SC number, degradation of chondroitin sulfate proteoglycans (CSPGs), astrogliosis, SC myelination of axons, propriospinal and supraspinal axon numbers, locomotor outcome (BBB scoring, CatWalk gait analysis), and mechanical and thermal sensitivity on the hind paws. D15A secreted from transplanted SCs increased graft volume and SC number and myelinated axon number. SCs secreting ChABC significantly decreased CSPGs, led to some egress of SCs from the graft, and increased propriospinal and 5-HT-positive axons in the graft. SCs secreting both D15A and ChABC yielded the best responses: (1) the largest number of SC myelinated axons, (2) more propriospinal axons in the graft and host tissue around and caudal to it, (3) more corticospinal axons closer to the graft and around and caudal to it, (4) more brainstem neurons projecting caudal to the transplant, (5) increased 5-HT-positive axons in the graft and caudal to it, (6) significant improvement in aspects of locomotion, and (7) improvement in mechanical and thermal allodynia. This is the first evidence that the combination of SC transplants engineered to secrete neurotrophin and chondroitinase further improves axonal regeneration and locomotor and sensory function.
Collapse
Affiliation(s)
- Haruo Kanno
- Miami Project to Cure Paralysis
- Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan, 9808574
| | | | | | | | - Elizabeth M. Muir
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, United Kingdom, and
| | - John H. Rogers
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, United Kingdom, and
| | - Hiroshi Ozawa
- Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan, 9808574
| | - Eiji Itoi
- Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan, 9808574
| | - Damien D. Pearse
- Miami Project to Cure Paralysis
- Department of Neurological Surgery
- Neuroscience Program
- Interdisciplinary Stem Cell Institute, and
| | - Mary Bartlett Bunge
- Miami Project to Cure Paralysis
- Department of Neurological Surgery
- Neuroscience Program
- Interdisciplinary Stem Cell Institute, and
- Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida 33136
| |
Collapse
|
|
38
|
Abstract
The consequence of numerous neurological disorders is the significant loss of neural cells, which further results in multilevel dysfunction or severe functional deficits. The extracellular matrix (ECM) is of tremendous importance for neural regeneration mediating ambivalent functions: ECM serves as a growth-promoting substrate for neurons but, on the other hand, is a major constituent of the inhibitory scar, which results from traumatic injuries of the central nervous system. Therefore, cell and tissue replacement strategies on the basis of ECM mimetics are very promising therapeutic interventions. Numerous synthetic and natural materials have proven effective both in vitro and in vivo. The closer a material's physicochemical and molecular properties are to the original extracellular matrix, the more promising its effectiveness may be. Relevant factors that need to be taken into account when designing such materials for neural repair relate to receptor-mediated cell-matrix interactions, which are dependent on chemical and mechanical sensing. This chapter outlines important characteristics of natural and synthetic ECM materials (scaffolds) and provides an overview of recent advances in design and application of ECM materials for neural regeneration, both in therapeutic applications and in basic biological research.
Collapse
Affiliation(s)
- Veronica Estrada
- Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University Medical Center Düsseldorf, Düsseldorf, Germany
| | - Ayse Tekinay
- UNAM-National Nanotechnology Research Center, Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey
| | - Hans Werner Müller
- Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University Medical Center Düsseldorf, Düsseldorf, Germany.
| |
Collapse
|
|
39
|
The effect of a polyurethane-based reverse thermal gel on bone marrow stromal cell transplant survival and spinal cord repair. Biomaterials 2013; 35:1924-31. [PMID: 24331711 DOI: 10.1016/j.biomaterials.2013.11.062] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 11/21/2013] [Indexed: 01/09/2023]
Abstract
Cell therapy for nervous tissue repair is limited by low transplant survival. We investigated the effects of a polyurethane-based reverse thermal gel, poly(ethylene glycol)-poly(serinol hexamethylene urethane) (ESHU) on bone marrow stromal cell (BMSC) transplant survival and repair using a rat model of spinal cord contusion. Transplantation of BMSCs in ESHU at three days post-contusion resulted in a 3.5-fold increase in BMSC survival at one week post-injury and a 66% increase in spared nervous tissue volume at four weeks post-injury. These improvements were accompanied by enhanced hindlimb motor and sensorimotor recovery. In vitro, we found that ESHU protected BMSCs from hydrogen peroxide-mediated death, resulting in a four-fold increase in BMSC survival with two-fold fewer BMSCs expressing the apoptosis marker, caspase 3 and the DNA oxidation marker, 8-oxo-deoxyguanosine. We argue that ESHU protected BMSCs transplanted is a spinal cord contusion from death thereby augmenting their effects on neuroprotection leading to improved behavioral restoration. The data show that the repair effects of intraneural BMSC transplants depend on the degree of their survival and may have a widespread impact on cell-based regenerative medicine.
Collapse
|
|
40
|
El-Sherbiny IM, Yacoub MH. Hydrogel scaffolds for tissue engineering: Progress and challenges. Glob Cardiol Sci Pract 2013; 2013:316-42. [PMID: 24689032 PMCID: PMC3963751 DOI: 10.5339/gcsp.2013.38] [Citation(s) in RCA: 446] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Accepted: 10/11/2013] [Indexed: 12/18/2022] Open
Abstract
Designing of biologically active scaffolds with optimal characteristics is one of the key factors for successful tissue engineering. Recently, hydrogels have received a considerable interest as leading candidates for engineered tissue scaffolds due to their unique compositional and structural similarities to the natural extracellular matrix, in addition to their desirable framework for cellular proliferation and survival. More recently, the ability to control the shape, porosity, surface morphology, and size of hydrogel scaffolds has created new opportunities to overcome various challenges in tissue engineering such as vascularization, tissue architecture and simultaneous seeding of multiple cells. This review provides an overview of the different types of hydrogels, the approaches that can be used to fabricate hydrogel matrices with specific features and the recent applications of hydrogels in tissue engineering. Special attention was given to the various design considerations for an efficient hydrogel scaffold in tissue engineering. Also, the challenges associated with the use of hydrogel scaffolds were described.
Collapse
Affiliation(s)
- Ibrahim M El-Sherbiny
- Center for Materials Science, University of Science and Technology, Zewail City of Science and Technology, 6th October City, 12588 Giza, Egypt
| | - Magdi H Yacoub
- Harefield Heart Science Centre, National Heart and Lung Institute, Imperial College, London, UK
| |
Collapse
|
|
41
|
Sakiyama-Elbert S, Johnson PJ, Hodgetts SI, Plant GW, Harvey AR. Scaffolds to promote spinal cord regeneration. HANDBOOK OF CLINICAL NEUROLOGY 2013; 109:575-94. [PMID: 23098738 DOI: 10.1016/b978-0-444-52137-8.00036-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Substantial research effort in the spinal cord injury (SCI) field is directed towards reduction of secondary injury changes and enhancement of tissue sparing. However, pathway repair after complete transections, large lesions, or after chronic injury may require the implantation of some form of oriented bridging structure to restore tissue continuity across a trauma zone. These matrices or scaffolds should be biocompatible and create an environment that facilitates tissue growth and vascularization, and allow axons to regenerate through and beyond the implant in order to reconnect with "normal" tissue distal to the injury. The myelination of regrown axons is another important requirement. In this chapter, we describe recent advances in biomaterial technology designed to provide a terrain for regenerating axons to grow across the site of injury and/or create an environment for endogenous repair. Many different types of scaffold are under investigation; they can be biodegradable or nondegradable, natural or synthetic. Scaffolds can be designed to incorporate immobilized signaling molecules and/or used as devices for controlled release of therapeutic agents, including growth factors. These bridging structures can also be infiltrated with specific cell types deemed suitable for spinal cord repair.
Collapse
Affiliation(s)
- S Sakiyama-Elbert
- Department of Biomedical Engineering, Washington University, St. Louis, MO, USA
| | | | | | | | | |
Collapse
|
|
42
|
Haas C, Fischer I. Human astrocytes derived from glial restricted progenitors support regeneration of the injured spinal cord. J Neurotrauma 2013; 30:1035-52. [PMID: 23635322 DOI: 10.1089/neu.2013.2915] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Cellular transplantation using neural stem cells and progenitors is a promising therapeutic strategy that has the potential to replace lost cells, modulate the injury environment, and create a permissive environment for the regeneration of injured host axons. Our research has focused on the use of human glial restricted progenitors (hGRP) and derived astrocytes. In the current study, we examined the morphological and phenotypic properties of hGRP prepared from the fetal central nervous system by clinically-approved protocols, compared with astrocytes derived from hGRP prepared by treatment with ciliary neurotrophic factor or bone morphogenetic protein 4. These differentiation protocols generated astrocytes that showed morphological differences and could be classified along an immature to mature spectrum, respectively. Despite these differences, the cells retained morphological and phenotypic plasticity upon a challenge with an alternate differentiation protocol. Importantly, when hGRP and derived astrocytes were transplanted acutely into a cervical dorsal column lesion, they survived and promoted regeneration of long ascending host sensory axons into the graft/lesion site, with no differences among the groups. Further, hGRP taken directly from frozen stocks behaved similarly and also supported regeneration of host axons into the lesion. Our results underscore the dynamic and permissive properties of human fetal astrocytes to promote axonal regeneration. They also suggest that a time-consuming process of pre-differentiation may not be necessary for therapeutic efficacy, and that the banking of large quantities of readily available hGRP can be an appropriate source of permissive cells for transplantation.
Collapse
Affiliation(s)
- Christopher Haas
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | | |
Collapse
|
|
43
|
Krishna V, Konakondla S, Nicholas J, Varma A, Kindy M, Wen X. Biomaterial-based interventions for neuronal regeneration and functional recovery in rodent model of spinal cord injury: a systematic review. J Spinal Cord Med 2013; 36:174-90. [PMID: 23809587 PMCID: PMC3654443 DOI: 10.1179/2045772313y.0000000095] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
CONTEXT There is considerable interest in translating laboratory advances in neuronal regeneration following spinal cord injury (SCI). A multimodality approach has been advocated for successful functional neuronal regeneration. With this goal in mind several biomaterials have been employed as neuronal bridges either to support cellular transplants, to release neurotrophic factors, or to do both. A systematic review of this literature is lacking. Such a review may provide insight to strategies with a high potential for further investigation and potential clinical application. OBJECTIVE To systematically review the design strategies and outcomes after biomaterial-based multimodal interventions for neuronal regeneration in rodent SCI model. To analyse functional outcomes after implantation of biomaterial-based multimodal interventions and to identify predictors of functional outcomes. METHODS A broad PubMed, CINHAL, and a manual search of relevant literature databases yielded data from 24 publications; 14 of these articles included functional outcome information. Studies reporting behavioral data in rat model of SCI and employing biodegradable polymer-based multimodal intervention were included. For behavioral recovery, studies using severe injury models (transection or severe clip compression (>16.9 g) or contusion (50 g/cm)) were categorized separately from those investigating partial injury models (hemisection or moderate-to-severe clip compression or contusion). RESULTS The cumulative mean improvements in Basso, Beattie, and Bresnahan scores after biomaterial-based interventions are 5.93 (95% CI = 2.41 - 9.45) and 4.44 (95% CI = 2.65 - 6.24) for transection and hemisection models, respectively. Factors associated with improved outcomes include the type of polymer used and a follow-up period greater than 6 weeks. CONCLUSION The functional improvement after implantation of biopolymer-based multimodal implants is modest. The relationship with neuronal regeneration and functional outcome, the effects of inflammation at the site of injury, the prolonged survival of supporting cells, the differentiation of stem cells, the effective delivery of neurotrophic factors, and longer follow-up periods are all topics for future elucidation. Future investigations should strive to further define specific factors associated with improved functional outcomes in clinically relevant models.
Collapse
Affiliation(s)
- Vibhor Krishna
- Medical University of South Carolina, Charleston, SC, USA.
| | | | - Joyce Nicholas
- Medical University of South Carolina, Charleston, SC, USA
| | - Abhay Varma
- Medical University of South Carolina, Charleston, SC, USA
| | - Mark Kindy
- Medical University of South Carolina, Charleston, SC, USA
| | - Xuejun Wen
- Medical University of South Carolina, Charleston, SC, USA; and Department of Bioengineering, Clemson University, SC, USA
| |
Collapse
|
|
44
|
Volpato FZ, Führmann T, Migliaresi C, Hutmacher DW, Dalton PD. Using extracellular matrix for regenerative medicine in the spinal cord. Biomaterials 2013; 34:4945-55. [PMID: 23597407 DOI: 10.1016/j.biomaterials.2013.03.057] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 03/20/2013] [Indexed: 12/12/2022]
Abstract
Regeneration within the mammalian central nervous system (CNS) is limited, and traumatic injury often leads to permanent functional motor and sensory loss. The lack of regeneration following spinal cord injury (SCI) is mainly caused by the presence of glial scarring, cystic cavitation and a hostile environment to axonal growth at the lesion site. The more prominent experimental treatment strategies focus mainly on drug and cell therapies, however recent interest in biomaterial-based strategies are increasing in number and breadth. Outside the spinal cord, approaches that utilize the extracellular matrix (ECM) to promote tissue repair show tremendous potential for various application including vascular, skin, bone, cartilage, liver, lung, heart and peripheral nerve tissue engineering (TE). Experimentally, it is unknown if these approaches can be successfully translated to the CNS, either alone or in combination with synthetic biomaterial scaffolds. In this review we outline the first attempts to apply the potential of ECM-based biomaterials and combining cell-derived ECM with synthetic scaffolds.
Collapse
Affiliation(s)
- Fabio Zomer Volpato
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove 4059, Australia
| | | | | | | | | |
Collapse
|
|
45
|
Kubinová S, Syková E. Biomaterials combined with cell therapy for treatment of spinal cord injury. Regen Med 2012; 7:207-24. [PMID: 22397610 DOI: 10.2217/rme.11.121] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Spinal cord injury (SCI) is a devastating traumatic injury resulting in paralysis or sensory deficits due to tissue damage and the poor ability of axons to regenerate across the lesion. Despite extensive research, there is still no effective treatment that would restore lost function after SCI. A possible therapeutic approach would be to bridge the area of injury with a bioengineered scaffold that would create a stimulatory environment as well as provide guidance cues for the re-establishment of damaged axonal connections. Advanced scaffold design aims at the fabrication of complex materials providing the concomitant delivery of cells, neurotrophic factors or other bioactive substances to achieve a synergistic effect for treatment. This review summarizes the current utilization of scaffolding materials for SCI treatment in terms of their physicochemical properties and emphasizes their use in combination with various cell types, as well as with other combinatorial approaches promoting spinal cord repair.
Collapse
Affiliation(s)
- Sárka Kubinová
- Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
| | | |
Collapse
|
|
46
|
Joosten EAJ. Biodegradable biomatrices and bridging the injured spinal cord: the corticospinal tract as a proof of principle. Cell Tissue Res 2012; 349:375-95. [PMID: 22411698 PMCID: PMC3375422 DOI: 10.1007/s00441-012-1352-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Accepted: 01/27/2012] [Indexed: 12/12/2022]
Abstract
Important advances in the development of smart biodegradable implants for axonal regeneration after spinal cord injury have recently been reported. These advances are evaluated in this review with special emphasis on the regeneration of the corticospinal tract. The corticospinal tract is often considered the ultimate challenge in demonstrating whether a repair strategy has been successful in the regeneration of the injured mammalian spinal cord. The extensive know-how of factors and cells involved in the development of the corticospinal tract, and the advances made in material science and tissue engineering technology, have provided the foundations for the optimization of the biomatrices needed for repair. Based on the findings summarized in this review, the future development of smart biodegradable bridges for CST regrowth and regeneration in the injured spinal cord is discussed.
Collapse
Affiliation(s)
- Elbert A J Joosten
- Department of Anesthesiology, Pain Management and Research Center, Maastricht University Medical Hospital, Maastricht, The Netherlands.
| |
Collapse
|
|
47
|
Haas C, Neuhuber B, Yamagami T, Rao M, Fischer I. Phenotypic analysis of astrocytes derived from glial restricted precursors and their impact on axon regeneration. Exp Neurol 2012; 233:717-32. [PMID: 22101004 PMCID: PMC3272137 DOI: 10.1016/j.expneurol.2011.11.002] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 10/12/2011] [Accepted: 11/01/2011] [Indexed: 12/16/2022]
Abstract
Although astrocytes are involved in the production of an inhibitory glial scar following injury, they are also capable of providing neuroprotection and supporting axonal growth. There is growing appreciation for a diverse and dynamic population of astrocytes, specified by a variety of glial precursors, whose function is regulated regionally and temporally. Consequently, the therapeutic application of glial precursors and astrocytes by effective transplantation protocols requires a better understanding of their phenotypic and functional properties and effective protocols for their preparation. We present a systematic analysis of astrocyte differentiation using multiple preparations of glial-restricted precursors (GRP), evaluating their morphological and phenotypic properties following treatment with fetal bovine serum (FBS), bone morphogenetic protein 4 (BMP-4), or ciliary neurotrophic factor (CNTF) in comparison to controls treated with basic fibroblast growth factor (bFGF), which maintains undifferentiated GRP. We found that treatments with FBS or BMP-4 generated similar profiles of highly differentiated astrocytes that were A2B5-/GFAP+. Treatment with FBS generated the most mature astrocytes, with a distinct and near-homogeneous morphology of fibroblast-like flat cells, whereas BMP-4 derived astrocytes had a stellate, but heterogeneous morphology. Treatment with CNTF induced differentiation of GRP to an intermediate state of GFAP+cells that maintained immature markers and had relatively long processes. Furthermore, astrocytes generated by BMP-4 or CNTF showed considerable experimental plasticity, and their morphology and phenotypes could be reversed with complementary treatments along a wide range of mature-immature states. Importantly, when GRP or GRP treated with BMP-4 or CNTF were transplanted acutely into a dorsal column lesion of the spinal cord, cells from all 3 groups survived and generated permissive astrocytes that supported axon growth and regeneration of host sensory axons into, but not out of the lesion. Our study underscores the dynamic nature of astrocytes prepared from GRP and their permissive properties, and suggest that future therapeutic applications in restoring connectivity following CNS injury are likely to require a combination of treatments.
Collapse
Affiliation(s)
| | | | - Takaya Yamagami
- Department of Neurobiology & Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, Life Technologies, Frederick, MD
| | | | - Itzhak Fischer
- Department of Neurobiology & Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, Life Technologies, Frederick, MD
| |
Collapse
|
|
48
|
Abstract
Spinal cord injury (SCI) presents a complex regenerative problem due to the multiple facets of growth inhibition that occur following trauma to the cord parenchyma and stroma. Clinically, SCI is further complicated by the heterogeneity in the size, shape and extent of human injuries. Many of these injuries do not breach the dura mater and have continuous viable axons through the injury site that can later lead to some degree of functional recovery. In these cases, surgical manipulation of the spinal cord by implanting a preformed scaffold or drug delivery device may lead to further damage. Given these circumstances, in situ-forming scaffolds are an attractive approach for SCI regeneration. These synthetic and natural polymers undergo a rapid transformation from liquid to gel upon injection into the cord tissue, conforming to the individual lesion site and directly integrating with the host tissue. Injectable materials can be formulated to have mechanical properties that closely match the native spinal cord extracellular matrix, and this may enhance axonal ingrowth. Such materials can also be loaded with cellular and molecular therapeutics to modulate the wound environment and enhance regeneration. This review will focus on the current status of in situ-forming materials for spinal cord repair. The advantages of, and requirements for, such polymers will be presented, and examples of the behavior of such systems in vitro and in vivo will be presented. There are helpful lessons to be learned from the investigations of injectable hydrogels for the treatment of SCI that apply to the use of these biomaterials for the treatment of lesions in other central nervous system tissues and in organs comprising other tissue types.
Collapse
Affiliation(s)
- D Macaya
- Tissue Engineering, VA Boston Healthcare System, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | | |
Collapse
|
|
49
|
Noble M, Davies JE, Mayer-Pröschel M, Pröschel C, Davies SJA. Precursor cell biology and the development of astrocyte transplantation therapies: lessons from spinal cord injury. Neurotherapeutics 2011; 8:677-93. [PMID: 21918888 PMCID: PMC3210359 DOI: 10.1007/s13311-011-0071-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
This review summarizes current progress on development of astrocyte transplantation therapies for repair of the damaged central nervous system. Replacement of neurons in the injured or diseased central nervous system is currently one of the most popular therapeutic goals, but if neuronal replacement is attempted in the absence of appropriate supporting cells (astrocytes and oligodendrocytes), then the chances of restoring neurological functional are greatly reduced. Although the past 20 years have offered great progress on oligodendrocyte replacement therapies, astrocyte transplantation therapies have been both less explored and comparatively less successful. We have now developed successful astrocyte transplantation therapies by pre-differentiating glial restricted precursor (GRP) cells into a specific population of GRP cell-derived astrocytes (GDAs) by exposing the GRP cells to bone morphogenetic protein-4 (BMP) prior to transplantation. When transplanted into transected rat spinal cord, rat and human GDAs(BMP) promote extensive axonal regeneration, rescue neuronal cell survival, realign tissue structure, and restore behavior to pre-injury levels on a grid-walk analysis of volitional foot placement. Such benefits are not provided by GRP cells themselves, demonstrating that the lesion environment does not direct differentiation in a manner optimally beneficial for the restoration of function. Such benefits also are not provided by transplantation of a different population of astrocytes generated from GRP cells exposed to ciliary neurotrophic factor (GDAs(CNTF)), thus providing the first transplantation-based evidence of functional heterogeneity in astrocyte populations. Moreover, lessons learned from the study of rat cells are strongly predictive of outcomes using human cells. Thus, these studies provide successful strategies for the use of astrocyte transplantation therapies for restoration of function following spinal cord injury.
Collapse
Affiliation(s)
- Mark Noble
- University of Rochester Stem Cell and Regenerative Medicine Institute and Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
| | | | | | | | | |
Collapse
|
|
50
|
Davies SJA, Shih CH, Noble M, Mayer-Proschel M, Davies JE, Proschel C. Transplantation of specific human astrocytes promotes functional recovery after spinal cord injury. PLoS One 2011; 6:e17328. [PMID: 21407803 PMCID: PMC3047562 DOI: 10.1371/journal.pone.0017328] [Citation(s) in RCA: 110] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2010] [Accepted: 01/24/2011] [Indexed: 12/13/2022] Open
Abstract
Repairing trauma to the central nervous system by replacement of glial support cells is an increasingly attractive therapeutic strategy. We have focused on the less-studied replacement of astrocytes, the major support cell in the central nervous system, by generating astrocytes from embryonic human glial precursor cells using two different astrocyte differentiation inducing factors. The resulting astrocytes differed in expression of multiple proteins thought to either promote or inhibit central nervous system homeostasis and regeneration. When transplanted into acute transection injuries of the adult rat spinal cord, astrocytes generated by exposing human glial precursor cells to bone morphogenetic protein promoted significant recovery of volitional foot placement, axonal growth and notably robust increases in neuronal survival in multiple spinal cord laminae. In marked contrast, human glial precursor cells and astrocytes generated from these cells by exposure to ciliary neurotrophic factor both failed to promote significant behavioral recovery or similarly robust neuronal survival and support of axon growth at sites of injury. Our studies thus demonstrate functional differences between human astrocyte populations and suggest that pre-differentiation of precursor cells into a specific astrocyte subtype is required to optimize astrocyte replacement therapies. To our knowledge, this study is the first to show functional differences in ability to promote repair of the injured adult central nervous system between two distinct subtypes of human astrocytes derived from a common fetal glial precursor population. These findings are consistent with our previous studies of transplanting specific subtypes of rodent glial precursor derived astrocytes into sites of spinal cord injury, and indicate a remarkable conservation from rat to human of functional differences between astrocyte subtypes. In addition, our studies provide a specific population of human astrocytes that appears to be particularly suitable for further development towards clinical application in treating the traumatically injured or diseased human central nervous system.
Collapse
Affiliation(s)
- Stephen J. A. Davies
- Department of Neurosurgery, University of
Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, United States of
America
| | - Chung-Hsuan Shih
- Department of Biomedical Genetics, Institute
for Stem Cell and Regenerative Medicine, University of Rochester Medical Center,
Rochester, New York, United States of America
| | - Mark Noble
- Department of Biomedical Genetics, Institute
for Stem Cell and Regenerative Medicine, University of Rochester Medical Center,
Rochester, New York, United States of America
| | - Margot Mayer-Proschel
- Department of Biomedical Genetics, Institute
for Stem Cell and Regenerative Medicine, University of Rochester Medical Center,
Rochester, New York, United States of America
| | - Jeannette E. Davies
- Department of Neurosurgery, University of
Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, United States of
America
| | - Christoph Proschel
- Department of Biomedical Genetics, Institute
for Stem Cell and Regenerative Medicine, University of Rochester Medical Center,
Rochester, New York, United States of America
| |
Collapse
|