|
1
|
Tang X, Deng P, Li L, He Y, Wang J, Hao D, Yang H. Advances in genetically modified neural stem cell therapy for central nervous system injury and neurological diseases. Stem Cell Res Ther 2024; 15:482. [PMID: 39696712 DOI: 10.1186/s13287-024-04089-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 12/03/2024] [Indexed: 12/20/2024] Open
Abstract
Neural stem cells (NSCs) have increasingly been recognized as the most promising candidates for cell-based therapies for the central nervous system (CNS) injuries, primarily due to their pluripotent differentiation capabilities, as well as their remarkable secretory and homing properties. In recent years, extensive research efforts have been initiated to explore the therapeutic potential of NSC transplantation for CNS injuries, yielding significant advancements. Nevertheless, owing to the formation of adverse microenvironment at post-injury leading to suboptimal survival, differentiation, and integration within the host neural network of transplanted NSCs, NSC-based transplantation therapies often fall short of achieving optimal therapeutic outcomes. To address this challenge, genetic modification has been developed an attractive strategy to improve the outcomes of NSC therapies. This is mainly attributed to its potential to not only enhance the differentiation capacity of NSCs but also to boost a range of biological activities, such as the secretion of bioactive factors, anti-inflammatory effects, anti-apoptotic properties, immunomodulation, antioxidative functions, and angiogenesis. Furthermore, genetic modification empowers NSCs to play a more robust neuroprotective role in the context of nerve injury. In this review, we will provide an overview of recent advances in the roles and mechanisms of NSCs genetically modified with various therapeutic genes in the treatment of neural injuries and neural disorders. Also, an update on current technical parameters suitable for NSC transplantation and functional recovery in clinical studies are summarized.
Collapse
Affiliation(s)
- Xiangwen Tang
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Peng Deng
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
- Basic Medical School Academy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Lin Li
- Basic Medical School Academy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Yuqing He
- Basic Medical School Academy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Jinchao Wang
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Dingjun Hao
- Department of Spine Surgery, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Hao Yang
- Translational Medicine Center, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China.
| |
Collapse
|
|
2
|
Stepanova OV, Fursa GA, Andretsova SS, Shishkina VS, Voronova AD, Chadin AV, Karsuntseva EK, Reshetov IV, Chekhonin VP. Prospects for the use of olfactory mucosa cells in bioprinting for the treatment of spinal cord injuries. World J Clin Cases 2023; 11:322-331. [PMID: 36686356 PMCID: PMC9850961 DOI: 10.12998/wjcc.v11.i2.322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/28/2022] [Accepted: 01/05/2023] [Indexed: 01/12/2023] Open
Abstract
The review focuses on the most important areas of cell therapy for spinal cord injuries. Olfactory mucosa cells are promising for transplantation. Obtaining these cells is safe for patients. The use of olfactory mucosa cells is effective in restoring motor function due to the remyelination and regeneration of axons after spinal cord injuries. These cells express neurotrophic factors that play an important role in the functional recovery of nerve tissue after spinal cord injuries. In addition, it is possible to increase the content of neurotrophic factors, at the site of injury, exogenously by the direct injection of neurotrophic factors or their delivery using gene therapy. The advantages of olfactory mucosa cells, in combination with neurotrophic factors, open up wide possibilities for their application in three-dimensional and four-dimensional bioprinting technology treating spinal cord injuries.
Collapse
Affiliation(s)
- Olga Vladislavovna Stepanova
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
- Department of Neurohumoral and Immunological Research, National Medical Research Center of Cardiology, Moscow 121552, Russia
| | - Grigorii Andreevich Fursa
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
| | - Svetlana Sergeevna Andretsova
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
- Department of Biology, Moscow State University, Moscow 119991, Russia
| | - Valentina Sergeevna Shishkina
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
| | - Anastasia Denisovna Voronova
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
| | - Andrey Viktorovich Chadin
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
| | | | | | - Vladimir Pavlovich Chekhonin
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
- Department of Medical Nanobiotechnologу, N.I. Pirogov Russian National Research Medical University, Moscow 117997, Russia
| |
Collapse
|
|
3
|
Jaloux C, Bonnet M, Vogtensperger M, Witters M, Veran J, Giraudo L, Sabatier F, Michel J, Legré R, Guiraudie-Capraz G, Féron F. Human nasal olfactory stem cells, purified as advanced therapy medicinal products, improve neuronal differentiation. Front Neurosci 2022; 16:1042276. [PMID: 36466172 PMCID: PMC9713000 DOI: 10.3389/fnins.2022.1042276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/04/2022] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND Olfactory ecto-mesenchymal stem cells (OE-MSC) are mesenchymal stem cells derived from the lamina propria of the nasal mucosa. They display neurogenic and immunomodulatory properties and were shown to induce recovery in animal models of spinal cord trauma, hearing loss, Parkinsons's disease, amnesia, and peripheral nerve injury. As a step toward clinical practice, we sought to (i) devise a culture protocol that meets the requirements set by human health agencies and (ii) assess the efficacy of stem cells on neuron differentiation. METHODS Nasal olfactory mucosa biopsies from three donors were used to design and validate the good manufacturing process for purifying stem cells. All processes and procedures were performed by expert staff from the cell therapy laboratory of the public hospital of Marseille (AP-HM), according to aseptic handling manipulations. Premises, materials and air were kept clean at all times to avoid cross-contamination, accidents, or even fatalities. Purified stem cells were cultivated for 24 or 48 h and conditioned media were collected before being added to the culture medium of the neuroblastoma cell line Neuro2a. RESULTS Compared to the explant culture-based protocol, enzymatic digestion provides higher cell numbers more rapidly and is less prone to contamination. The use of platelet lysate in place of fetal calf serum is effective in promoting higher cell proliferation (the percentage of CFU-F progenitors is 15.5%), with the optimal percentage of platelet lysate being 10%. Cultured OE-MSCs do not show chromosomal rearrangement and, as expected, express the usual phenotypic markers of mesenchymal stem cells. When incorporated in standard culture medium, the conditioned medium of purified OE-MSCs promotes cell differentiation of Neuro2a neuroblastoma cells. CONCLUSION We developed a safer and more efficient manufacturing process for clinical grade olfactory stem cells. With this protocol, human OE-MSCs will soon be used in a Phase I clinical based on their autologous transplantation in digital nerves with a neglected injury. However, further studies are required to unveil the underlying mechanisms of action.
Collapse
Affiliation(s)
- Charlotte Jaloux
- CNRS, INP, UMR 7051, Institut de Neuropathophysiologie, Equipe Nasal Olfactory Stemness and Epigenesis (NOSE), Aix Marseille University, Marseille, France
- Department of Hand Surgery and Reconstructive Surgery of the Limbs, La Timone University Hospital, Assistance Publique Hôpitaux de Marseille, Marseille, France
| | - Maxime Bonnet
- CNRS, INP, UMR 7051, Institut de Neuropathophysiologie, Equipe Nasal Olfactory Stemness and Epigenesis (NOSE), Aix Marseille University, Marseille, France
- Faculté des Sciences du Sport de Marseille, CNRS, ISM, UMR 7287, Institut des Sciences du Mouvement Etienne-Jules MAREY, Equipe Plasticité des Systèmes Nerveux et Musculaire (PSNM), Parc Scientifique et Technologique de Luminy, Aix Marseille University, Marseille, France
| | - Marie Vogtensperger
- Cell Therapy Department, Hôpital de la Conception, AP-HM, INSERM CIC BT 1409, Marseille, France
| | - Marie Witters
- CNRS, INP, UMR 7051, Institut de Neuropathophysiologie, Equipe Nasal Olfactory Stemness and Epigenesis (NOSE), Aix Marseille University, Marseille, France
- Department of Hand Surgery and Reconstructive Surgery of the Limbs, La Timone University Hospital, Assistance Publique Hôpitaux de Marseille, Marseille, France
| | - Julie Veran
- Cell Therapy Department, Hôpital de la Conception, AP-HM, INSERM CIC BT 1409, Marseille, France
| | - Laurent Giraudo
- Cell Therapy Department, Hôpital de la Conception, AP-HM, INSERM CIC BT 1409, Marseille, France
| | - Florence Sabatier
- Cell Therapy Department, Hôpital de la Conception, AP-HM, INSERM CIC BT 1409, Marseille, France
- Aix-Marseille Université, C2VN, UMR-1263, INSERM, INRA 1260, UFR de Pharmacie, Marseille, France
| | - Justin Michel
- Department of Otorhinolaryngology and Head and Neck Surgery, Assistance Publique des Hôpitaux de Marseille, Institut Universitaire des Systèmes Thermiques Industriels, La Conception University Hospital, Aix Marseille University, Marseille, France
| | - Regis Legré
- Department of Hand Surgery and Reconstructive Surgery of the Limbs, La Timone University Hospital, Assistance Publique Hôpitaux de Marseille, Marseille, France
| | - Gaëlle Guiraudie-Capraz
- CNRS, INP, UMR 7051, Institut de Neuropathophysiologie, Equipe Nasal Olfactory Stemness and Epigenesis (NOSE), Aix Marseille University, Marseille, France
| | - François Féron
- CNRS, INP, UMR 7051, Institut de Neuropathophysiologie, Equipe Nasal Olfactory Stemness and Epigenesis (NOSE), Aix Marseille University, Marseille, France
| |
Collapse
|
|
4
|
Yang R, Pan J, Wang Y, Xia P, Tai M, Jiang Z, Chen G. Application and prospects of somatic cell reprogramming technology for spinal cord injury treatment. Front Cell Neurosci 2022; 16:1005399. [PMID: 36467604 PMCID: PMC9712200 DOI: 10.3389/fncel.2022.1005399] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 11/02/2022] [Indexed: 08/10/2023] Open
Abstract
Spinal cord injury (SCI) is a serious neurological trauma that is challenging to treat. After SCI, many neurons in the injured area die due to necrosis or apoptosis, and astrocytes, oligodendrocytes, microglia and other non-neuronal cells become dysfunctional, hindering the repair of the injured spinal cord. Corrective surgery and biological, physical and pharmacological therapies are commonly used treatment modalities for SCI; however, no current therapeutic strategies can achieve complete recovery. Somatic cell reprogramming is a promising technology that has gradually become a feasible therapeutic approach for repairing the injured spinal cord. This revolutionary technology can reprogram fibroblasts, astrocytes, NG2 cells and neural progenitor cells into neurons or oligodendrocytes for spinal cord repair. In this review, we provide an overview of the transcription factors, genes, microRNAs (miRNAs), small molecules and combinations of these factors that can mediate somatic cell reprogramming to repair the injured spinal cord. Although many challenges and questions related to this technique remain, we believe that the beneficial effect of somatic cell reprogramming provides new ideas for achieving functional recovery after SCI and a direction for the development of treatments for SCI.
Collapse
Affiliation(s)
- Riyun Yang
- Department of Histology and Embryology, Medical School of Nantong University, Nantong, China
| | - Jingying Pan
- Department of Histology and Embryology, Medical School of Nantong University, Nantong, China
| | - Yankai Wang
- Center for Basic Medical Research, Medical School of Nantong University, Nantong, China
| | - Panhui Xia
- Center for Basic Medical Research, Medical School of Nantong University, Nantong, China
| | - Mingliang Tai
- Center for Basic Medical Research, Medical School of Nantong University, Nantong, China
| | - Zhihao Jiang
- Center for Basic Medical Research, Medical School of Nantong University, Nantong, China
| | - Gang Chen
- Center for Basic Medical Research, Medical School of Nantong University, Nantong, China
- Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
| |
Collapse
|
|
5
|
Guo W, Zhang X, Zhai J, Xue J. The roles and applications of neural stem cells in spinal cord injury repair. Front Bioeng Biotechnol 2022; 10:966866. [PMID: 36105599 PMCID: PMC9465243 DOI: 10.3389/fbioe.2022.966866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 07/28/2022] [Indexed: 12/05/2022] Open
Abstract
Spinal cord injury (SCI), which has no current cure, places a severe burden on patients. Stem cell-based therapies are considered promising in attempts to repair injured spinal cords; such options include neural stem cells (NSCs). NSCs are multipotent stem cells that differentiate into neuronal and neuroglial lineages. This feature makes NSCs suitable candidates for regenerating injured spinal cords. Many studies have revealed the therapeutic potential of NSCs. In this review, we discuss from an integrated view how NSCs can help SCI repair. We will discuss the sources and therapeutic potential of NSCs, as well as representative pre-clinical studies and clinical trials of NSC-based therapies for SCI repair.
Collapse
Affiliation(s)
- Wen Guo
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xindan Zhang
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, China
| | - Jiliang Zhai
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Beijing, China
- *Correspondence: Jiliang Zhai, ; Jiajia Xue,
| | - Jiajia Xue
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, China
- *Correspondence: Jiliang Zhai, ; Jiajia Xue,
| |
Collapse
|
|
6
|
Feng Y, Peng Y, Jie J, Yang Y, Yang P. The immune microenvironment and tissue engineering strategies for spinal cord regeneration. Front Cell Neurosci 2022; 16:969002. [PMID: 35990891 PMCID: PMC9385973 DOI: 10.3389/fncel.2022.969002] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Regeneration of neural tissue is limited following spinal cord injury (SCI). Successful regeneration of injured nerves requires the intrinsic regenerative capability of the neurons and a suitable microenvironment. However, the local microenvironment is damaged, including insufficient intraneural vascularization, prolonged immune responses, overactive immune responses, dysregulated bioenergetic metabolism and terminated bioelectrical conduction. Among them, the immune microenvironment formed by immune cells and cytokines plays a dual role in inflammation and regeneration. Few studies have focused on the role of the immune microenvironment in spinal cord regeneration. Here, we summarize those findings involving various immune cells (neutrophils, monocytes, microglia and T lymphocytes) after SCI. The pathological changes that occur in the local microenvironment and the function of immune cells are described. We also summarize and discuss the current strategies for treating SCI with tissue-engineered biomaterials from the perspective of the immune microenvironment.
Collapse
Affiliation(s)
- Yuan Feng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Yong Peng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Jing Jie
- Department of Clinical Laboratory, The First People’s Hospital of Nantong, The Second Affiliated Hospital of Nantong University, Nantong, China
- Jing Jie,
| | - Yumin Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
- Yumin Yang,
| | - Pengxiang Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
- Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin Medical University, Harbin, China
- *Correspondence: Pengxiang Yang,
| |
Collapse
|
|
7
|
Rövekamp M, von Glinski A, Volkenstein S, Dazert S, Sengstock C, Schildhauer TA, Breisch M. Olfactory Stem Cells for the Treatment of Spinal Cord Injury - a new pathway to the cure? World Neurosurg 2022; 161:e408-e416. [PMID: 35149247 DOI: 10.1016/j.wneu.2022.02.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 02/03/2022] [Accepted: 02/03/2022] [Indexed: 11/28/2022]
Abstract
OBJECTIVE Since full functional recovery after spinal cord injuries (SCI) remains a major challenge, stem cell therapies represent promising strategies to improve neurological functions after SCI. The olfactory mucosa (OM) displays an attractive source of multipotent cells for regenerative approaches and is easily accessible by biopsies due to its exposed location. The regenerative capacity of the resident olfactory stem cells (OSC) has been demonstrated in animal as well as clinical studies. This study aims to demonstrate the feasibility of isolation, purification and cultivation of OSC. METHODS OM specimens were taken dorso-posterior from nasal middle turbinate. OSC were isolated and purified using the neurosphere assay. Differentiation capacity of the OSC in neural lineage and their behavior in a plasma clot matrix were investigated. RESULTS Our study demonstrated that OSC differentiated into neural lineage and were positive for GFAP as well as β-III tubulin. Furthermore, OSC were viable and proliferated in a plasma clot matrix. CONCLUSION Since there are no standard methods for purification, characterization, and delivery of OSC to the injury site, which is a prerequisite for the clinical approval, this study focuses on the establishment of appropriate methods and underlies the high potential of the OM for autologous cell therapeutical approaches.
Collapse
Affiliation(s)
- Markus Rövekamp
- Surgical Research, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany.
| | - Alexander von Glinski
- Deparment of General and Trauma Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Stefan Volkenstein
- Department of Otorhinolaryngology, Head- and Neck Surgery/ St. Elisabeth-Hospital, Ruhr University Bochum, Bleichstraße 15, 44787 Bochum, Germany
| | - Stefan Dazert
- Department of Otorhinolaryngology, Head- and Neck Surgery/ St. Elisabeth-Hospital, Ruhr University Bochum, Bleichstraße 15, 44787 Bochum, Germany
| | - Christina Sengstock
- Leibniz-Institut für Analytische Wissenschaften -ISAS- e.V., Bunsen-Kirchhoff-Straße 11, 44139 Dortmund, Germany
| | - Thomas Armin Schildhauer
- Deparment of General and Trauma Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| | - Marina Breisch
- Surgical Research, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bürkle-de-la-Camp Platz 1, 44789 Bochum, Germany
| |
Collapse
|
|
8
|
Preparation of Adhesion Culture of Neural Stem/Progenitor Cells of the Olfactory Mucosa for the Treatment of Spinal Cord Injuries. Bull Exp Biol Med 2020; 170:158-163. [PMID: 33231802 DOI: 10.1007/s10517-020-05023-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Indexed: 10/22/2022]
Abstract
In this work, an optimal protocol was developed for obtaining adhesion culture of neural stem/progenitor cells (NSPC) of rat olfactory mucosa. During the development of the protocol, the conditions for cell culturing on adhesion substrates fibronectin and laminin in DMEM/F-12 and neurobasal media with the same culture additives were compared. Cell proliferation was maximum during culturing on both substrates in the neurobasal medium. Using the immunofluorescence method, we found that culturing on fibronectin in the neurobasal medium ensured maximum (52.22%) content of nestin-positive cells in comparison with other culturing conditions. The highest percentage of βIII-tubulin-positive cells was detected in cultures growing on fibronectin in the neurobasal medium and in DMEM/F-12 (79.11 and 83.52%, respectively). Culturing in adhesion cultures in the neurobasal medium on fibronectin allowed obtaining cultures enriched with NSPC and neurons differentiating from them in a quantity sufficient for further transplantation. The developed protocol can be recommended for obtaining NPSC from human olfactory mucosa for the treatment of spinal cord injuries.
Collapse
|