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Kuwar R, Zhang N, McQuiston A, Wen X, Sun D. Generation of induced pluripotent stem cells from rat fibroblasts and optimization of its differentiation into mature functional neurons. J Neurosci Methods 2024; 406:110114. [PMID: 38522633 PMCID: PMC11060920 DOI: 10.1016/j.jneumeth.2024.110114] [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: 12/01/2023] [Revised: 03/11/2024] [Accepted: 03/20/2024] [Indexed: 03/26/2024]
Abstract
BACKGROUND Induced pluripotent stem cells (iPSCs) derived neural stem cells (NSCs) provide a potential for autologous neural transplantation therapy following neurological insults. Thus far, in preclinical studies the donor iPSCs-NSCs are mostly of human or mouse origin with concerns centering around graft rejection when applied to rat brain injury models. For better survival and integration of transplanted cells in the injured brain in rat models, use of rat-iPSC-NSCs and in combination with biomaterials is of advantageous. Herein, we report a detailed method in generating rat iPSCs with improved reprogramming efficiency and differentiation into neurons. NEW METHOD Rat fibroblasts were reprogrammed into iPSCs with polybrene and EF1α-STEMCCA-LoxP lentivirus vector. Pluripotency characterization, differentiation into neuronal linage cells were assessed with RT-qPCR, Western blotting, immunostaining and patch-clamp methods. Cells were cultured in a custom-designed integrin array system as well as in a hydrogel-based 3D condition. RESULTS We describe a thorough method for the generation of rat-iPSC-NSCs, and identify integrin αvβ8 as a substrate for the optimal growth of rat-iPSC-NSCs. Furthermore, with hydrogel as the supporting biomaterial in the 3-D culture, when combined with integrin αvβ8 binding peptide, it forms a conducive environment for optimal growth and differentiation of iPSC-NSCs into mature neurons. COMPARISON WITH EXISTING METHODS Published studies about rat-iPSC-NSCs are rare. This study provides a detailed protocol for the generation of rat iPSC-NSCs and optimal growth conditions for neuronal differentiation. Our method is useable for studies to assess the utility of rat iPSC-NSCs for neural transplantation in rat brain injury models.
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Affiliation(s)
- Ram Kuwar
- Department of Anatomy and Neurobiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Ning Zhang
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Adam McQuiston
- Department of Anatomy and Neurobiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Xuejun Wen
- Department of Chemical and Life Science Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Dong Sun
- Department of Anatomy and Neurobiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
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Fan Y, Li J, Fang B. A Tale of Two: When Neural Stem Cells Encounter Hypoxia. Cell Mol Neurobiol 2023; 43:1799-1816. [PMID: 36308642 PMCID: PMC11412202 DOI: 10.1007/s10571-022-01293-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 10/02/2022] [Indexed: 11/12/2022]
Abstract
Normoxia is defined as an oxygen concentration of 20.9%, as in room air, whereas hypoxia refers to any oxygen concentration less than this. Any physiological oxygen deficiency or tissue oxygen deficiency relative to demand is called hypoxia. Neural stem cells (NSCs) are multipotent stem cells that can differentiate into multiple cell lines such as neurons, oligodendrocytes, and astrocytes. Under hypoxic conditions, the apoptosis rate of NSCs increases remarkably in vitro or in vivo. However, some hypoxia promotes the proliferation and differentiation of NSCs. The difference is related to the oxygen concentration, the duration of hypoxia, the hypoxia tolerance threshold of the NSCs, and the tissue source of the NSCs. The main mechanism of hypoxia-induced proliferation and differentiation involves an increase in cyclin and erythropoietin concentrations, and hypoxia-inducible factors play a key role. Multiple molecular pathways are activated during hypoxia, including Notch, Wnt/β-catenin, PI3K/Akt, and altered microRNA expression. In addition, we review the protective effect of exogenous NSCs transplantation on ischemic or anoxic organs, the therapeutic potential of hypoxic preconditioning on exogenous NSCs and clinical application of NSCs.
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Affiliation(s)
- Yiting Fan
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| | - Jinshi Li
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| | - Bo Fang
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China.
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Survival and Neurogenesis-Promoting Effects of the Co-Overexpression of BCLXL and BDNF Genes on Wharton’s Jelly-Derived Mesenchymal Stem Cells. Life (Basel) 2022; 12:life12091406. [PMID: 36143442 PMCID: PMC9501059 DOI: 10.3390/life12091406] [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: 08/17/2022] [Revised: 09/05/2022] [Accepted: 09/07/2022] [Indexed: 12/02/2022] Open
Abstract
The main problem with using MSC (mesenchymal stem cells) to treat the deficient diseases of the central nervous system is the low cell survival rate after the transplant procedure and their low ability to spontaneously differentiate into functional neurons. The aim of this study was to investigate the effects of genetically modifying MSC. A co-overexpression of two genes was performed: BCLXL was supposed to increase the resistance of the cells to the toxic agents and BDNF was supposed to direct cells into the neuronal differentiation pathway. As a result, it was possible to obtain the functional overexpression of the BCLXL and BDNF genes. These cells had an increased resistance to apoptosis-inducing toxicants (staurosporine, doxorubicin and H2O2). At the same time, the genes of the neuronal pathway (CHAT, TPH1) were overexpressed. The genetically modified MSC increased the survival rate under toxic conditions, which increased the chance of surviving a transplant procedure. The obtained cells can be treated as neural cell progenitors, which makes them a universal material that can be used in various disease models. The production of neurotransmitters suggests that cells transplanted into the brain and subjected to the additional influence of the brain’s microenvironment, will be able to form synapses and become functional neurons.
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Adugna DG, Aragie H, Kibret AA, Belay DG. Therapeutic Application of Stem Cells in the Repair of Traumatic Brain Injury. Stem Cells Cloning 2022; 15:53-61. [PMID: 35859889 PMCID: PMC9289752 DOI: 10.2147/sccaa.s369577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/10/2022] [Indexed: 12/03/2022] Open
Abstract
Traumatic brain injury is the main cause of injury-related deaths and disabilities throughout the world, which is characterized by a disruption of the normal physiology of the brain following trauma. It can potentially cause severe complications such as physical, cognitive, and emotional impairment. In addition to understanding traumatic brain injury pathophysiology, this review explains the therapeutic potential of stem cells following brain injury in two pathways: response of endogenous neurogenic cells and transplantation of exogenous stem cell therapy. After traumatic brain injuries, clinical evidence indicated that endogenous neural progenitor cells might play an important role in regenerative medicine to treat brain injury. This is due to an increased neurogenic regeneration ability of these cells following brain injury. Besides, exogenous stem cell transplantation has also accelerated immature neuronal development and increased endogenous cellular proliferation in the damaged brain region. Therefore, a better understanding of the endogenous neural stem cell’s regenerative ability and the effect of exogenous stem cells on proliferation and differentiation ability may help researchers to understand how to increase functional recovery and tissue repair following injury.
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Affiliation(s)
- Dagnew Getnet Adugna
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Amhara Region, Ethiopia
| | - Hailu Aragie
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Amhara Region, Ethiopia
| | - Anteneh Ayelign Kibret
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Amhara Region, Ethiopia
| | - Daniel Gashaneh Belay
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Amhara Region, Ethiopia.,Department of Epidemiology, Institution of Public Health, College of Medicine and Health Science, University of Gondar, Gondar, Amhara Region, Ethiopia
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Zhao L, Liu JW, Shi HY, Ma YM. Neural stem cell therapy for brain disease. World J Stem Cells 2021; 13:1278-1292. [PMID: 34630862 PMCID: PMC8474718 DOI: 10.4252/wjsc.v13.i9.1278] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/28/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
Brain diseases, including brain tumors, neurodegenerative disorders, cerebrovascular diseases, and traumatic brain injuries, are among the major disorders influencing human health, currently with no effective therapy. Due to the low regeneration capacity of neurons, insufficient secretion of neurotrophic factors, and the aggravation of ischemia and hypoxia after nerve injury, irreversible loss of functional neurons and nerve tissue damage occurs. This damage is difficult to repair and regenerate the central nervous system after injury. Neural stem cells (NSCs) are pluripotent stem cells that only exist in the central nervous system. They have good self-renewal potential and ability to differentiate into neurons, astrocytes, and oligodendrocytes and improve the cellular microenvironment. NSC transplantation approaches have been made for various neurodegenerative disorders based on their regenerative potential. This review summarizes and discusses the characteristics of NSCs, and the advantages and effects of NSCs in the treatment of brain diseases and limitations of NSC transplantation that need to be addressed for the treatment of brain diseases in the future.
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Affiliation(s)
- Lan Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
| | - Jian-Wei Liu
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hui-Yan Shi
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Ya-Min Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
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Tu T, Peng J, Jiang Y. FNDC5/Irisin: A New Protagonist in Acute Brain Injury. Stem Cells Dev 2020; 29:533-543. [PMID: 31914844 DOI: 10.1089/scd.2019.0232] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Tianqi Tu
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jianhua Peng
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Neurosurgical Clinical Research Center of Sichuan Province, Luzhou, China
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yong Jiang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Neurosurgical Clinical Research Center of Sichuan Province, Luzhou, China
- Laboratory of Neurological Diseases and Brain Functions, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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Zhu B, Eom J, Hunt RF. Transplanted interneurons improve memory precision after traumatic brain injury. Nat Commun 2019; 10:5156. [PMID: 31727894 PMCID: PMC6856380 DOI: 10.1038/s41467-019-13170-w] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 10/23/2019] [Indexed: 12/26/2022] Open
Abstract
Repair of the traumatically injured brain has been envisioned for decades, but regenerating new neurons at the site of brain injury has been challenging. We show GABAergic progenitors, derived from the embryonic medial ganglionic eminence, migrate long distances following transplantation into the hippocampus of adult mice with traumatic brain injury, functionally integrate as mature inhibitory interneurons and restore post-traumatic decreases in synaptic inhibition. Grafted animals had improvements in memory precision that were reversed by chemogenetic silencing of the transplanted neurons and a long-lasting reduction in spontaneous seizures. Our results reveal a striking ability of transplanted interneurons for incorporating into injured brain circuits, and this approach is a powerful therapeutic strategy for correcting post-traumatic memory and seizure disorders.
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Affiliation(s)
- Bingyao Zhu
- Department of Anatomy & Neurobiology, University of California, Irvine, CA, 92697, USA
| | - Jisu Eom
- Department of Anatomy & Neurobiology, University of California, Irvine, CA, 92697, USA
| | - Robert F Hunt
- Department of Anatomy & Neurobiology, University of California, Irvine, CA, 92697, USA. .,Center for the Neurobiology of Learning and Memory, University of California, Irvine, CA, 92697, USA. .,Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, 92697, USA.
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Ahlfors JE, Azimi A, El-Ayoubi R, Velumian A, Vonderwalde I, Boscher C, Mihai O, Mani S, Samoilova M, Khazaei M, Fehlings MG, Morshead CM. Examining the fundamental biology of a novel population of directly reprogrammed human neural precursor cells. Stem Cell Res Ther 2019; 10:166. [PMID: 31196173 PMCID: PMC6567617 DOI: 10.1186/s13287-019-1255-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 04/29/2019] [Accepted: 05/06/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Cell reprogramming is a promising avenue for cell-based therapies as it allows for the generation of multipotent, unipotent, or mature somatic cells without going through a pluripotent state. While the use of autologous cells is considered ideal, key challenges for their clinical translation include the ability to reproducibly generate sufficient quantities of cells within a therapeutically relevant time window. METHODS We performed transfection of three distinct human somatic starting populations of cells with a non-integrating synthetic plasmid expressing Musashi 1 (MSI1), Neurogenin 2 (NGN2), and Methyl-CpG-Binding Domain 2 (MBD2). The resulting directly reprogrammed neural precursor cells (drNPCs) were examined in vitro using RT-qPCR, karyotype analysis, immunohistochemistry, and FACS at early and late time post-transfection. Electrophysiology (patch clamp) was performed on drNPC-derived neurons to determine their capacity to generate action potentials. In vivo characterization was performed following transplantation of drNPCs into two animal models (Shiverer and SCID/Beige mice), and the numbers, location, and differentiation profile of the transplanted cells were examined using immunohistochemistry. RESULTS Human somatic cells can be directly reprogrammed within two weeks to neural precursor cells (drNPCs) by transient exposure to Msi1, Ngn2, and MBD2 using non-viral constructs. The drNPCs generate all three neural cell types (astrocytes, oligodendrocytes, and neurons) and can be passaged in vitro to generate large numbers of cells within four weeks. drNPCs can respond to in vivo differentiation and migration cues as demonstrated by their migration to the olfactory bulb and contribution to neurogenesis in vivo. Differentiation profiles of transplanted cells onto the corpus callosum of myelin-deficient mice reveal the production of oligodendrocytes and astrocytes. CONCLUSIONS Human drNPCs can be efficiently and rapidly produced from donor somatic cells and possess all the important characteristics of native neural multipotent cells including differentiation into neurons, astrocytes, and oligodendrocytes, and in vivo neurogenesis and myelination.
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Affiliation(s)
| | - Ashkan Azimi
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8 Canada
- Division of Anatomy, Department of Surgery, University of Toronto, Ontario, M5S 1A8 Canada
| | | | - Alexander Velumian
- Division of Neurosurgery, Department of Surgery, University of Toronto, Ontario, M5T 1P5 Canada
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario M5T 2S8 Canada
| | - Ilan Vonderwalde
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3G9 Canada
| | | | - Oana Mihai
- New World Laboratories, Laval, Quebec, H7V 5B7 Canada
| | - Sarathi Mani
- New World Laboratories, Laval, Quebec, H7V 5B7 Canada
| | - Marina Samoilova
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario M5T 2S8 Canada
| | - Mohamad Khazaei
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario M5T 2S8 Canada
| | - Michael G. Fehlings
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8 Canada
- Division of Neurosurgery, Department of Surgery, University of Toronto, Ontario, M5T 1P5 Canada
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario M5T 2S8 Canada
| | - Cindi M Morshead
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8 Canada
- Division of Anatomy, Department of Surgery, University of Toronto, Ontario, M5S 1A8 Canada
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3G9 Canada
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S3E1 Canada
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Kuwar R, Rolfe A, Di L, Xu H, He L, Jiang Y, Zhang S, Sun D. A novel small molecular NLRP3 inflammasome inhibitor alleviates neuroinflammatory response following traumatic brain injury. J Neuroinflammation 2019; 16:81. [PMID: 30975164 PMCID: PMC6458637 DOI: 10.1186/s12974-019-1471-y] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 03/29/2019] [Indexed: 01/03/2023] Open
Abstract
Background Neuroinflammation is an essential player in many neurological diseases including traumatic brain injury (TBI). Recent studies have identified that inflammasome complexes are responsible for inflammatory responses in many pathological conditions. Inflammasomes are intracellular multiprotein complexes which regulate the innate immune response, activation of caspase-1, production of pro-inflammatory cytokines IL-1β and IL-18, and induction of cell death (pyroptosis). Among inflammasome family members, the nucleotide-binding domain leucine-rich repeats family protein 3 (NLRP3) is the most extensively studied and its activation is induced following TBI. As a novel target, drug development targeting the formation and activation of NLRP3 inflammasome is a prospective therapy for TBI. We have recently developed a small molecule JC124 with specificity on NLRP3 inflammasome. In this study, we explored the therapeutic value of JC124 for TBI treatment. Methods Adult male Sprague-Dawley rats were subjected to a moderate cortical impact injury. Following TBI, animals received 4 doses of JC124 treatment with the first dose starting at 30 min, the second dose at 6 h after TBI, the third and fourth doses at 24 or 30 h following TBI, respectively. Animals were sacrificed at 2 days post-injury. Brain tissues were processed either for ELISA and western blotting analysis for inflammatory response, or for histological examination to assess degenerative neurons, acute inflammatory cell response and lesion volume. Results We found that post-injury treatment with JC124 significantly decreased the number of injury-induced degenerating neurons, inflammatory cell response in the injured brain, and cortical lesion volume. Injured animals treated with JC124 also had significantly reduced protein expression levels of NLRP3, ASC, IL-1 beta, TNFα, iNOS, and caspase-1. Conclusion Our data suggest that our novel NLRP3 inhibitor has a specific anti-inflammatory effect to protect the injured brain following TBI.
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Affiliation(s)
- Ram Kuwar
- Department of Anatomy and Neurobiology, School of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298-0709, USA
| | - Andrew Rolfe
- Department of Anatomy and Neurobiology, School of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298-0709, USA
| | - Long Di
- Department of Anatomy and Neurobiology, School of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298-0709, USA
| | - Hongyu Xu
- Department of Anatomy and Neurobiology, School of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298-0709, USA
| | - Liu He
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298-0709, USA
| | - Yuqi Jiang
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298-0709, USA
| | - Shijun Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298-0709, USA
| | - Dong Sun
- Department of Anatomy and Neurobiology, School of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298-0709, USA.
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Skop NB, Singh S, Antikainen H, Saqcena C, Calderon F, Rothbard DE, Cho CH, Gandhi CD, Levison SW, Dobrowolski R. Subacute Transplantation of Native and Genetically Engineered Neural Progenitors Seeded on Microsphere Scaffolds Promote Repair and Functional Recovery After Traumatic Brain Injury. ASN Neuro 2019; 11:1759091419830186. [PMID: 30818968 PMCID: PMC6399762 DOI: 10.1177/1759091419830186] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 12/11/2018] [Accepted: 12/18/2018] [Indexed: 01/09/2023] Open
Abstract
There is intense interest and effort toward regenerating the brain after severe injury. Stem cell transplantation after insult to the central nervous system has been regarded as the most promising approach for repair; however, engrafting cells alone might not be sufficient for effective regeneration. In this study, we have compared neural progenitors (NPs) from the fetal ventricular zone (VZ), the postnatal subventricular zone, and an immortalized radial glia (RG) cell line engineered to conditionally secrete the trophic factor insulin-like growth factor 1 (IGF-1). Upon differentiation in vitro, the VZ cells were able to generate a greater number of neurons than subventricular zone cells. Furthermore, differentiated VZ cells generated pyramidal neurons . In vitro, doxycycline-driven secretion of IGF-1 strongly promoted neuronal differentiation of cells with hippocampal, interneuron and cortical specificity. Accordingly, VZ and engineered RG-IGF-1-hemagglutinin (HA) cells were selected for subsequent in vivo experiments. To increase cell survival, we delivered the NPs attached to a multifunctional chitosan-based scaffold. The microspheres containing adherent NPs were injected subacutely into the lesion cavity of adult rat brains that had sustained controlled cortical impact injury. At 2 weeks posttransplantation, the exogenously introduced cells showed a reduction in stem cell or progenitor markers and acquired mature neuronal and glial markers. In beam walking tests assessing sensorimotor recovery, transplanted RG cells secreting IGF-1 contributed significantly to functional improvement while native VZ or RG cells did not promote significant recovery. Altogether, these results support the therapeutic potential of chitosan-based multifunctional microsphere scaffolds seeded with genetically modified NPs expressing IGF-1 to promote repair and functional recovery after traumatic brain injuries.
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Affiliation(s)
- Nolan B. Skop
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Newark, NJ, USA
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, USA
| | - Sweta Singh
- Department of Biological Sciences, Rutgers University, Newark, NJ, USA
- Stem Cell and Gene Therapy Research Group, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - Henri Antikainen
- Department of Biological Sciences, Rutgers University, Newark, NJ, USA
| | - Chaitali Saqcena
- Department of Biological Sciences, Rutgers University, Newark, NJ, USA
| | - Frances Calderon
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Newark, NJ, USA
| | - Deborah E. Rothbard
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Newark, NJ, USA
| | - Cheul H. Cho
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, USA
| | - Chirag D. Gandhi
- Department of Neurosurgery, Westchester Medical Center at NY Medical College, Valhalla, NY, USA
| | - Steven W. Levison
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Newark, NJ, USA
| | - Radek Dobrowolski
- Department of Biological Sciences, Rutgers University, Newark, NJ, USA
- Department of Cell Systems and Anatomy, University of Texas Health San Antonio, TX, USA
- Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, TX, USA
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Mundim MV, Zamproni LN, Pinto AAS, Galindo LT, Xavier AM, Glezer I, Porcionatto M. A new function for Prokineticin 2: Recruitment of SVZ-derived neuroblasts to the injured cortex in a mouse model of traumatic brain injury. Mol Cell Neurosci 2018; 94:1-10. [PMID: 30391355 DOI: 10.1016/j.mcn.2018.10.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 10/13/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023] Open
Abstract
Traumatic brain injury is an important cause of global morbidity and mortality. After an initial injury, there is a cascade of cellular and molecular events that ultimately lead to cell death. Therapies aim to both counteract these mechanisms and replenish the lost cell population in order to improve recovery. The adult mammal brain has at least two neurogenic regions that maintain physiological functions: the subgranular zone of the dentate gyrus in the hippocampus, which produces neurons that integrate locally, and the subventricular zone (SVZ) adjacent to the lateral ventricles, which produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulbs. Brain injuries, as well as neurodegenerative diseases, induce the SVZ to respond by increasing cell proliferation and migration to the injured areas. Here we report that cells migrate from the SVZ and RMS to the injured cortex after traumatic brain injury in mice, and that the physiological RMS migration is not impaired. We also show that Prokineticin 2 (PROK2), a chemokine important for the olfactory bulb neurogenesis, expressed exclusively by cortical microglia in the cortex as early as 24 h after injury. We then show that administration of a PROK2 receptor antagonist decreases the number of SVZ cells that reach the injured cortex, while injection of recombinant PROK2 into the cortex of uninjured mice attracts SVZ cells. We also demonstrate that cells expressing PROK2 in vitro directionally attract SVZ cells. These data suggest that PROK2 could be utilized in regeneration efforts for the acutely injured mammalian cortex.
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Affiliation(s)
- Mayara Vieira Mundim
- Department of Biochemistry, Laboratory of Neurobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 3o andar, São Paulo, SP 04039-032, Brazil
| | - Laura Nicoleti Zamproni
- Department of Biochemistry, Laboratory of Neurobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 3o andar, São Paulo, SP 04039-032, Brazil
| | - Agnes Araújo Sardinha Pinto
- Department of Biochemistry, Laboratory of Neurobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 3o andar, São Paulo, SP 04039-032, Brazil
| | - Layla Testa Galindo
- Department of Biochemistry, Laboratory of Neurobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 3o andar, São Paulo, SP 04039-032, Brazil
| | - André Machado Xavier
- Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua 3 de Maio, 100 - 4o andar, São Paulo, SP 04044-020, Brazil
| | - Isaias Glezer
- Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua 3 de Maio, 100 - 4o andar, São Paulo, SP 04044-020, Brazil
| | - Marimélia Porcionatto
- Department of Biochemistry, Laboratory of Neurobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 3o andar, São Paulo, SP 04039-032, Brazil.
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Nasser M, Ballout N, Mantash S, Bejjani F, Najdi F, Ramadan N, Soueid J, Zibara K, Kobeissy F. Transplantation of Embryonic Neural Stem Cells and Differentiated Cells in a Controlled Cortical Impact (CCI) Model of Adult Mouse Somatosensory Cortex. Front Neurol 2018; 9:895. [PMID: 30405520 PMCID: PMC6208009 DOI: 10.3389/fneur.2018.00895] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 10/02/2018] [Indexed: 12/11/2022] Open
Abstract
Traumatic brain injury (TBI) is a major cause of death worldwide. Depending on the severity of the injury, TBI can reflect a broad range of consequences such as speech impairment, memory disturbances, and premature death. In this study, embryonic neural stem cells (ENSC) were isolated from E14 mouse embryos and cultured to produce neurospheres which were induced to generate differentiated cells (DC). As a cell replacement treatment option, we aimed to transplant ENSC or DC into the adult injured C57BL/6 mouse cortex controlled cortical impact (CCI) model, 7 days post-trauma, in comparison to saline injection (control). The effect of grafted cells on neuroinflammation and neurogenesis was investigated at 1 and 4 weeks post-transplantation. Results showed that microglia were activated following mild CCI, but not enhanced after engraftment of ENSC or DC. Indeed, ipsilateral lesioned somatosensory area expressed high levels of Iba-1+ microglia within the different groups after 1 and 4 weeks. On the other hand, treatment with ENSC or DC demonstrated a significant reduction in astrogliosis. The levels of GFAP expressing astrocytes started decreasing early (1 week) in the ENSC group and then were similarly low at 4 weeks in both ENSC and DC. Moreover, neurogenesis was significantly enhanced in ENSC and DC groups. Indeed, a significant increase in the number of DCX expressing progenitor cells was observed at 1 week in the ENSC group, and in DC and ENSC groups at 4 weeks. Furthermore, the number of mature neuronal cells (NeuN+) significantly increased in DC group at 4 weeks whereas they decreased in ENSC group at 1 week. Therefore, injection of ENSC or DC post-CCI caused decreased astrogliosis and suggested an increased neurogenesis via inducing neural progenitor proliferation and expression rather than neuronal maturation. Thus, ENSC may play a role in replacing lost cells and brain repair following TBI by improving neurogenesis and reducing neuroinflammation, reflecting an optimal environment for transplanted and newly born cells.
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Affiliation(s)
- Mohammad Nasser
- Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.,ER045, PRASE, DSST, Lebanese University, Beirut, Lebanon
| | | | - Sarah Mantash
- ER045, PRASE, DSST, Lebanese University, Beirut, Lebanon
| | | | - Farah Najdi
- ER045, PRASE, DSST, Lebanese University, Beirut, Lebanon
| | - Naify Ramadan
- ER045, PRASE, DSST, Lebanese University, Beirut, Lebanon.,Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Jihane Soueid
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Kazem Zibara
- Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.,ER045, PRASE, DSST, Lebanese University, Beirut, Lebanon
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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13
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Zibara K, Ballout N, Mondello S, Karnib N, Ramadan N, Omais S, Nabbouh A, Caliz D, Clavijo A, Hu Z, Ghanem N, Gajavelli S, Kobeissy F. Combination of drug and stem cells neurotherapy: Potential interventions in neurotrauma and traumatic brain injury. Neuropharmacology 2018; 145:177-198. [PMID: 30267729 DOI: 10.1016/j.neuropharm.2018.09.032] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 09/17/2018] [Accepted: 09/21/2018] [Indexed: 12/12/2022]
Abstract
Traumatic brain injury (TBI) has been recognized as one of the major public health issues that leads to devastating neurological disability. As a consequence of primary and secondary injury phases, neuronal loss following brain trauma leads to pathophysiological alterations on the molecular and cellular levels that severely impact the neuropsycho-behavioral and motor outcomes. Thus, to mitigate the neuropathological sequelae post-TBI such as cerebral edema, inflammation and neural degeneration, several neurotherapeutic options have been investigated including drug intervention, stem cell use and combinational therapies. These treatments aim to ameliorate cellular degeneration, motor decline, cognitive and behavioral deficits. Recently, the use of neural stem cells (NSCs) coupled with selective drug therapy has emerged as an alternative treatment option for neural regeneration and behavioral rehabilitation post-neural injury. Given their neuroprotective abilities, NSC-based neurotherapy has been widely investigated and well-reported in numerous disease models, notably in trauma studies. In this review, we will elaborate on current updates in cell replacement therapy in the area of neurotrauma. In addition, we will discuss novel combination drug therapy treatments that have been investigated in conjunction with stem cells to overcome the limitations associated with stem cell transplantation. Understanding the regenerative capacities of stem cell and drug combination therapy will help improve functional recovery and brain repair post-TBI. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".
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Affiliation(s)
- Kazem Zibara
- ER045, Laboratory of Stem Cells, PRASE, Lebanese University, Beirut, Lebanon; Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Nissrine Ballout
- ER045, Laboratory of Stem Cells, PRASE, Lebanese University, Beirut, Lebanon
| | - Stefania Mondello
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Nabil Karnib
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon
| | - Naify Ramadan
- Department of Women's and Children's Health (KBH), Division of Clinical Pediatrics, Karolinska Institute, Sweden
| | - Saad Omais
- Department of Biology, American University of Beirut, Beirut, Lebanon
| | - Ali Nabbouh
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon
| | - Daniela Caliz
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA
| | - Angelica Clavijo
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA
| | - Zhen Hu
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA
| | - Noël Ghanem
- Department of Biology, American University of Beirut, Beirut, Lebanon
| | - Shyam Gajavelli
- Lois Pope LIFE Center, Neurosurgery, University of Miami, 33136, Miami, FL, USA.
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon; Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Department of Emergency Medicine, University of Florida, Gainesville, FL, 32611, USA.
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14
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Ghazale H, Ramadan N, Mantash S, Zibara K, El-Sitt S, Darwish H, Chamaa F, Boustany RM, Mondello S, Abou-Kheir W, Soueid J, Kobeissy F. Docosahexaenoic acid (DHA) enhances the therapeutic potential of neonatal neural stem cell transplantation post-Traumatic brain injury. Behav Brain Res 2018; 340:1-13. [PMID: 29126932 DOI: 10.1016/j.bbr.2017.11.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 10/27/2017] [Accepted: 11/06/2017] [Indexed: 12/25/2022]
Abstract
Traumatic Brain Injury (TBI) is a major cause of death and disability worldwide with 1.5 million people inflicted yearly. Several neurotherapeutic interventions have been proposed including drug administration as well as cellular therapy involving neural stem cells (NSCs). Among the proposed drugs is docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibiting neuroprotective properties. In this study, we utilized an innovative intervention of neonatal NSCs transplantation in combination with DHA injections in order to ameliorate brain damage and promote functional recovery in an experimental model of TBI. Thus, NSCs derived from the subventricular zone of neonatal pups were cultured into neurospheres and transplanted in the cortex of an experimentally controlled cortical impact mouse model of TBI. The effect of NSC transplantation was assessed alone and/or in combination with DHA administration. Motor deficits were evaluated using pole climbing and rotarod tests. Using immunohistochemistry, the effect of transplanted NSCs and DHA treatment was used to assess astrocytic (Glial fibrillary acidic protein, GFAP) and microglial (ionized calcium binding adaptor molecule-1, IBA-1) activity. In addition, we quantified neuroblasts (doublecortin; DCX) and dopaminergic neurons (tyrosine hydroxylase; TH) expression levels. Combined NSC transplantation and DHA injections significantly attenuated TBI-induced motor function deficits (pole climbing test), promoted neurogenesis, coupled with an increase in glial reactivity at the cortical site of injury. In addition, the number of tyrosine hydroxylase positive neurons was found to increase markedly in the ventral tegmental area and substantia nigra in the combination therapy group. Immunoblotting analysis indicated that DHA+NSCs treated animals showed decreased levels of 38kDa GFAP-BDP (breakdown product) and 145kDa αII-spectrin SBDP indicative of attenuated calpain/caspase activation. These data demonstrate that prior treatment with DHA may be a desirable strategy to improve the therapeutic efficacy of NSC transplantation in TBI.
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Affiliation(s)
- Hussein Ghazale
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon
| | - Naify Ramadan
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon
| | - Sara Mantash
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon
| | - Kazem Zibara
- ER045, Laboratory of Stem Cells, DSST, Lebanese University, Beirut, Lebanon; Department of Biology, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Sally El-Sitt
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon
| | - Hala Darwish
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon
| | - Farah Chamaa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Rose Mary Boustany
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon; American University of Beirut Medical Center Special Kids Clinic, Neurogenetics Program and Division of Pediatric Neurology, Departments of Pediatrics and Adolescent Medicine, Beirut, Lebanon
| | - Stefania Mondello
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, A.O.U. "Policlinico G. Martino", Via Consolare Valeria, Messina, 98125, Italy
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
| | - Jihane Soueid
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon.
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon; Department of Psychiatry, Center for Neuroproteomics and Biomarkers Research, University of Florida, Gainesville, FL, USA.
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15
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Implantation of Neuronal Stem Cells Enhances Object Recognition without Increasing Neurogenesis after Lateral Fluid Percussion Injury in Mice. Stem Cells Int 2018. [PMID: 29531536 PMCID: PMC5818962 DOI: 10.1155/2018/4209821] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cognitive deficits after traumatic brain injury (TBI) are debilitating and contribute to the morbidity and loss of productivity of over 10 million people worldwide. Cell transplantation has been linked to enhanced cognitive function after experimental traumatic brain injury, yet the mechanism of recovery is poorly understood. Since the hippocampus is a critical structure for learning and memory, supports adult neurogenesis, and is particularly vulnerable after TBI, we hypothesized that stem cell transplantation after TBI enhances cognitive recovery by modulation of endogenous hippocampal neurogenesis. We performed lateral fluid percussion injury (LFPI) in adult mice and transplanted embryonic stem cell-derived neural progenitor cells (NPC). Our data confirm an injury-induced cognitive deficit in novel object recognition, a hippocampal-dependent learning task, which is reversed one week after NPC transplantation. While LFPI alone promotes hippocampal neurogenesis, as revealed by doublecortin immunolabeling of immature neurons, subsequent NPC transplantation prevents increased neurogenesis and is not associated with morphological maturation of endogenous injury-induced immature neurons. Thus, NPC transplantation enhances cognitive recovery early after LFPI without a concomitant increase in neuron numbers or maturation.
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16
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Abstract
PURPOSE OF REVIEW Traumatic brain injury (TBI) is a global public health concern, with limited treatment options available. Despite improving survival rate after TBI, treatment is lacking for brain functional recovery and structural repair in clinic. Recent studies have suggested that the mature brain harbors neural stem cells which have regenerative capacity following brain insults. Much progress has been made in preclinical TBI model studies in understanding the behaviors, functions, and regulatory mechanisms of neural stem cells in the injured brain. Different strategies targeting these cell population have been assessed in TBI models. In parallel, cell transplantation strategy using a wide range of stem cells has been explored for TBI treatment in pre-clinical studies and some in clinical trials. This review summarized strategies which have been explored to enhance endogenous neural stem cell-mediated regeneration and recent development in cell transplantation studies for post-TBI brain repair. RECENT FINDINGS Thus far, neural regeneration through neural stem cells either by modulating endogenous neural stem cells or by stem cell transplantation has attracted much attention. It is highly speculated that targeting neural stem cells could be a potential strategy to repair and regenerate the injured brain. Neuroprotection and neuroregeneration are major aspects for TBI therapeutic development. With technique advancement, it is hoped that stem cell-based therapy targeting neuroregeneration will be able to translate to clinic in not so far future.
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Affiliation(s)
- Nicole M Weston
- Department of Anatomy and Neurobiology, School of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, P.O.Box 980709, Richmond, VA, 23298, USA
| | - Dong Sun
- Department of Anatomy and Neurobiology, School of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, P.O.Box 980709, Richmond, VA, 23298, USA.
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17
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Fang H, Song P, Shen Y, Shen C, Liu X. Bone mesenchymal stem cell-conditioned medium decreases the generation of astrocytes during the process of neural stem cells differentiation. J Spinal Cord Med 2018; 41. [PMID: 28649933 PMCID: PMC5810792 DOI: 10.1080/10790268.2017.1314880] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
OBJECTIVES The aim of this study was to investigate the effect of bone mesenchymal stem cell (BMSC) conditioned medium (CM) and Bone morphogenetic protein-4 (BMP-4) on the generation of astrocytes during the process of NSCs differentiation. DESIGN Neural stem cells (NSCs) were grown under different culture conditions. SETTING The First Affiliated Hospital of Anhui Medical University, Hefei, China. OUTCOME MEASURES The study consisted of four groups: NSCs cultured under control conditions (group 1) or with the addition of BMSC-CM (group 2);(BMP-4) (group 3) or both (group 4).The expression of glial fibrillary acidic protein (GFAP) was detected by immunocytochemical staining and Western blotting. RESULTS The expression of GFAP was higher in Group3 and lower in Group 2 compared to that in Group 1. The expression of GFAP in Group 4 was intermediate between that of Group 2 and Group 3. CONCLUSIONS These results suggest that BMSC-CM can decrease the generation of astrocytes and that the inhibition of the (BMP-4) /Smad1/5/8 signaling pathway may be the underlying mechanism. This phenomenon may be mediated by increasing the expression of Smad6.
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Affiliation(s)
- Huang Fang
- Department of Spinal Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Peiwen Song
- Department of Spinal Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuening Shen
- Department of Medical Imaging, Bengbu Medical College, Bengbu, China
| | - Cailiang Shen
- Department of Spinal Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China,Correspondence to: Cailiang Shen, Department of Spinal Surgery, The First Affiliated Hospital of Anhui Medical University, 210 Ji Xi Road, Hefei 230032, China.
| | - Xiaoying Liu
- School of Life Science, Anhui Medical University, Heifei, China
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18
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Traumatic Brain Injury and Stem Cell: Pathophysiology and Update on Recent Treatment Modalities. Stem Cells Int 2017; 2017:6392592. [PMID: 28852409 PMCID: PMC5568618 DOI: 10.1155/2017/6392592] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 07/26/2017] [Indexed: 12/30/2022] Open
Abstract
Traumatic brain injury (TBI) is a complex condition that presents with a wide spectrum of clinical symptoms caused by an initial insult to the brain through an external mechanical force to the skull. In the United States alone, TBI accounts for more than 50,000 deaths per year and is one of the leading causes of mortality among young adults in the developed world. Pathophysiology of TBI is complex and consists of acute and delayed injury. In the acute phase, brain tissue destroyed upon impact includes neurons, glia, and endothelial cells, the latter of which makes up the blood-brain barrier. In the delayed phase, “toxins” released from damaged cells set off cascades in neighboring cells eventually leading to exacerbation of primary injury. As researches further explore pathophysiology and molecular mechanisms underlying this debilitating condition, numerous potential therapeutic strategies, especially those involving stem cells, are emerging to improve recovery and possibly reverse damage. In addition to elucidating the most recent advances in the understanding of TBI pathophysiology, this review explores two primary pathways currently under investigation and are thought to yield the most viable therapeutic approach for treatment of TBI: manipulation of endogenous neural cell response and administration of exogenous stem cell therapy.
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19
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Paterno R, Folweiler KA, Cohen AS. Pathophysiology and Treatment of Memory Dysfunction After Traumatic Brain Injury. Curr Neurol Neurosci Rep 2017; 17:52. [PMID: 28500417 PMCID: PMC5861722 DOI: 10.1007/s11910-017-0762-x] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Memory is fundamental to everyday life, and cognitive impairments resulting from traumatic brain injury (TBI) have devastating effects on TBI survivors. A contributing component to memory impairments caused by TBI is alteration in the neural circuits associated with memory function. In this review, we aim to bring together experimental findings that characterize behavioral memory deficits and the underlying pathophysiology of memory-involved circuits after TBI. While there is little doubt that TBI causes memory and cognitive dysfunction, it is difficult to conclude which memory phase, i.e., encoding, maintenance, or retrieval, is specifically altered by TBI. This is most likely due to variation in behavioral protocols and experimental models. Additionally, we review a selection of experimental treatments that hold translational potential to mitigate memory dysfunction following injury.
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Affiliation(s)
- Rosalia Paterno
- Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Abramson Research Center, Rm. 816-h, Philadelphia, PA, 19104, USA.
| | - Kaitlin A Folweiler
- Department of Anesthesiology and Critical Care Medicine, Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Abramson Research Center, Rm. 816-h, Philadelphia, PA, 19104, USA
| | - Akiva S Cohen
- Department of Anesthesiology and Critical Care Medicine, Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Abramson Research Center, Rm. 816-h, Philadelphia, PA, 19104, USA
- Department of Anesthesiology and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Abramson Research Center, Rm. 816-h, Philadelphia, PA, 19104, USA
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20
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Zhou J, Cui H, Lu H, Xu Z, Feng W, Chen L, Jin X, Yang X, Qi Z. Muscle-derived stem cells in peripheral nerve regeneration: reality or illusion? Regen Med 2017. [PMID: 28621200 DOI: 10.2217/rme-2016-0165] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Owing to the complicated and time-consuming regenerative process, the repair of injured peripheral nerves depends largely on ongoing stem-cell therapy. Decades ago, researchers successfully isolated and identified muscle-derived stem cells (MDSCs) and discovered their potential for multidifferentiation. MDSCs play an important role in trauma repair associated with neuromuscular and vascular injury by simultaneously promoting tissue regrowth via direct differentiation and systematic secretion under physiological conditions. However, the isolation, culture, induction and application of MDSCs require further methodological analysis before clinical application. In this review, we comprehensively discuss the challenges associated with neural regeneration and reviewed the progress of stem cell based regenerative medicine, in an effort to realize the potential of MDSCs in nerve regeneration.
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Affiliation(s)
- Jing Zhou
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Haiyan Cui
- Department of Plastic & Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, PR China
| | - Haibin Lu
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Zhuqiu Xu
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Weifeng Feng
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Lulu Chen
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Xiaolei Jin
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Xiaonan Yang
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Zuoliang Qi
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
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21
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Dekmak A, Mantash S, Shaito A, Toutonji A, Ramadan N, Ghazale H, Kassem N, Darwish H, Zibara K. Stem cells and combination therapy for the treatment of traumatic brain injury. Behav Brain Res 2016; 340:49-62. [PMID: 28043902 DOI: 10.1016/j.bbr.2016.12.039] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 10/30/2016] [Accepted: 12/29/2016] [Indexed: 12/15/2022]
Abstract
TBI is a nondegenerative, noncongenital insult to the brain from an external mechanical force; for instance a violent blow in a car accident. It is a complex injury with a broad spectrum of symptoms and has become a major cause of death and disability in addition to being a burden on public health and societies worldwide. As such, finding a therapy for TBI has become a major health concern for many countries, which has led to the emergence of many monotherapies that have shown promising effects in animal models of TBI, but have not yet proven any significant efficacy in clinical trials. In this paper, we will review existing and novel TBI treatment options. We will first shed light on the complex pathophysiology and molecular mechanisms of this disorder, understanding of which is a necessity for launching any treatment option. We will then review most of the currently available treatments for TBI including the recent approaches in the field of stem cell therapy as an optimal solution to treat TBI. Therapy using endogenous stem cells will be reviewed, followed by therapies utilizing exogenous stem cells from embryonic, induced pluripotent, mesenchymal, and neural origin. Combination therapy is also discussed as an emergent novel approach to treat TBI. Two approaches are highlighted, an approach concerning growth factors and another using ROCK inhibitors. These approaches are highlighted with regard to their benefits in minimizing the outcomes of TBI. Finally, we focus on the consequent improvements in motor and cognitive functions after stem cell therapy. Overall, this review will cover existing treatment options and recent advancements in TBI therapy, with a focus on the potential application of these strategies as a solution to improve the functional outcomes of TBI.
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Affiliation(s)
- AmiraSan Dekmak
- ER045, Laboratory of Stem Cells, Faculty of Sciences, DSST, PRASE, Lebanese University, Beirut, Lebanon
| | - Sarah Mantash
- ER045, Laboratory of Stem Cells, Faculty of Sciences, DSST, PRASE, Lebanese University, Beirut, Lebanon; Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
| | - Abdullah Shaito
- Department of Biological and Chemical Sciences, Lebanese International University, Beirut, Lebanon
| | - Amer Toutonji
- Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
| | - Naify Ramadan
- ER045, Laboratory of Stem Cells, Faculty of Sciences, DSST, PRASE, Lebanese University, Beirut, Lebanon; Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
| | - Hussein Ghazale
- Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
| | - Nouhad Kassem
- ER045, Laboratory of Stem Cells, Faculty of Sciences, DSST, PRASE, Lebanese University, Beirut, Lebanon
| | - Hala Darwish
- Faculty of Medicine, Hariri School of Nursing, American University of Beirut, Beirut, Lebanon
| | - Kazem Zibara
- ER045, Laboratory of Stem Cells, Faculty of Sciences, DSST, PRASE, Lebanese University, Beirut, Lebanon; Laboratory of Cardiovascular Diseases and Stem Cells, Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.
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22
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Sun D. The potential of neural transplantation for brain repair and regeneration following traumatic brain injury. Neural Regen Res 2016; 11:18-22. [PMID: 26981070 PMCID: PMC4774215 DOI: 10.4103/1673-5374.169605] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Traumatic brain injury is a major health problem worldwide. Currently, there is no effective treatment to improve neural structural repair and functional recovery of patients in the clinic. Cell transplantation is a potential strategy to repair and regenerate the injured brain. This review article summarized recent development in cell transplantation studies for post-traumatic brain injury brain repair with varying types of cell sources. It also discussed the potential of neural transplantation to repair/promote recovery of the injured brain following traumatic brain injury.
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Affiliation(s)
- Dong Sun
- Department of Neurosurgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
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23
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Yousefifard M, Nasirinezhad F, Shardi Manaheji H, Janzadeh A, Hosseini M, Keshavarz M. Human bone marrow-derived and umbilical cord-derived mesenchymal stem cells for alleviating neuropathic pain in a spinal cord injury model. Stem Cell Res Ther 2016; 7:36. [PMID: 26957122 PMCID: PMC4784350 DOI: 10.1186/s13287-016-0295-2] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 02/03/2016] [Accepted: 02/17/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Stem cell therapy can be used for alleviating the neuropathic pain induced by spinal cord injuries (SCIs). However, survival and differentiation of stem cells following their transplantation vary depending on the host and intrinsic factors of the cell. Therefore, the present study aimed to determine the effect of stem cells derived from bone marrow (BM-MSC) and umbilical cord (UC-MSC) on neuropathic pain relief. METHODS A compression model was used to induce SCI in a rat model. A week after SCI, about 1 million cells were transplanted into the spinal cord. Behavioral tests, including motor function recovery, mechanical allodynia, cold allodynia, mechanical hyperalgesia, and thermal hyperalgesia, were carried out every week for 8 weeks after SCI induction. A single unit recording and histological evaluation were then performed. RESULTS We show that BM-MSC and UC-MSC transplantations led to improving functional recovery, allodynia, and hyperalgesia. No difference was seen between the two cell groups regarding motor recovery and alleviating the allodynia and hyperalgesia. These cells survived in the tissue at least 8 weeks and prevented cavity formation due to SCI. However, survival rate of UC-MSC was significantly higher than BM-MSC. Electrophysiological evaluations showed that transplantation of UC-MSC brings about better results than BM-MSCs in wind up of wide dynamic range neurons. CONCLUSIONS The results of the present study show that BM-MSC and UC-MSC transplantations alleviated the symptoms of neuropathic pain and resulted in subsequent motor recovery after SCI. However, survival rate and electrophysiological findings of UC-MSC were significantly better than BM-MSC.
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Affiliation(s)
- Mahmoud Yousefifard
- Electrophysiology Research Center, Tehran University of Medical Sciences, Tehran, Iran. .,Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Farinaz Nasirinezhad
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran. .,Department of Physiology, Iran University of Medical Sciences, Tehran, Iran.
| | - Homa Shardi Manaheji
- Department of Physiology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Atousa Janzadeh
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Mostafa Hosseini
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. .,Pediatric Chronic Kidney Disease Research Center, Childrens Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mansoor Keshavarz
- Electrophysiology Research Center, Tehran University of Medical Sciences, Tehran, Iran. .,Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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24
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Yousefifard M, Rahimi-Movaghar V, Nasirinezhad F, Baikpour M, Safari S, Saadat S, Moghadas Jafari A, Asady H, Razavi Tousi SMT, Hosseini M. Neural stem/progenitor cell transplantation for spinal cord injury treatment; A systematic review and meta-analysis. Neuroscience 2016; 322:377-97. [PMID: 26917272 DOI: 10.1016/j.neuroscience.2016.02.034] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 02/15/2016] [Accepted: 02/16/2016] [Indexed: 12/21/2022]
Abstract
Despite the vast improvements of cell therapy in spinal cord injury treatment, no optimum protocol has been developed for application of neural stem/progenitor cells. In this regard, the present meta-analysis showed that the efficacy of the neural stem/progenitor cell (NSPC) transplantation depends mainly on injury model, intervention phase, transplanted cell count, immunosuppressive use, and probably stem cell source. Improved functional recovery post NSPC transplantation was found to be higher in transection and contusion models. Moreover, NSPC transplantation in acute phase of spinal injury was found to have better functional recovery. Higher doses (>3×10(6)cell/kg) were also shown to be optimum for transplantation, but immunosuppressive agent administration negatively affected the motor function recovery. Scaffold use in NSPC transplantation could also effectively raise functional recovery.
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Affiliation(s)
- M Yousefifard
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - V Rahimi-Movaghar
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - F Nasirinezhad
- Physiology Research Center, Department of Physiology, Iran University of Medical Sciences, Tehran, Iran
| | - M Baikpour
- Department of Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - S Safari
- Department of Emergency Medicine, Shohadaye Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - S Saadat
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - A Moghadas Jafari
- Department of Emergency Medicine, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - H Asady
- Department of Occupational Health Engineering, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - S M T Razavi Tousi
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - M Hosseini
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Pediatric Chronic Kidney Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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25
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Rocamonde B, Paradells S, Garcia Esparza MA, Vives MS, Sauro S, Ramos CM, Pradas MM, Soria JM. Combined application of polyacrylate scaffold and lipoic acid treatment promotes neural tissue reparation after brain injury. Brain Inj 2016; 30:208-16. [PMID: 26745450 DOI: 10.3109/02699052.2015.1091505] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PRIMARY OBJECTIVE The aim of this study was to investigate the reparative potential of a polymeric scaffold designed for brain tissue repair in combination with lipoic acid. RESEARCH DESIGN Histological, cytological and structural analysis of a combined treatment after a brain cryo-injury model in rats. METHODS AND PROCEDURES Adult Wistar rats were subjected to cryogenic brain injury. A channelled-porous scaffold of ethyl acrylate and hydroxyethylacrylate, p(EA-co-HEA) was grafted into cerebral penumbra alone or combined with intraperitoneal LA administration. Histological and cytological evaluation was performed after 15 and 60 days and structural magnetic resonance (MRI) assessment was performed at 2 and 6 months after the surgery. MAIN OUTCOMES AND RESULTS The scaffold was suitable for the establishment of different cellular types. The results obtained suggest that this strategy promotes blood vessels formation, decreased microglial response and neuron migration, particularly when LA was administrated. CONCLUSIONS These evidences demonstrated that the combination of a channelled polymer scaffold with LA administration may represent a potential treatment for neural tissue repair after brain injury.
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Affiliation(s)
- Brenda Rocamonde
- a Facultad Ciencias de la Salud, Universidad CEU-Cardenal Herrera , Valencia , Spain
| | - Sara Paradells
- a Facultad Ciencias de la Salud, Universidad CEU-Cardenal Herrera , Valencia , Spain
| | | | - Mavi Sánchez Vives
- b Institut D'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS , Barcelona , Spain
| | - Salvatore Sauro
- a Facultad Ciencias de la Salud, Universidad CEU-Cardenal Herrera , Valencia , Spain
| | - Cristina Martínez Ramos
- c Centro de Biomateriales e Ingeniería Tisular, Universidad Politécnica de Valencia , Valencia , Spain
| | - Manuel Monleón Pradas
- c Centro de Biomateriales e Ingeniería Tisular, Universidad Politécnica de Valencia , Valencia , Spain
| | - José Miguel Soria
- a Facultad Ciencias de la Salud, Universidad CEU-Cardenal Herrera , Valencia , Spain.,d Instituto de Ciencias Biomédicas, Universidad CEU-Cardenal Herrera , Moncada , Valencia , Spain
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26
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Skop NB, Calderon F, Cho CH, Gandhi CD, Levison SW. Improvements in biomaterial matrices for neural precursor cell transplantation. MOLECULAR AND CELLULAR THERAPIES 2014; 2:19. [PMID: 26056586 PMCID: PMC4452047 DOI: 10.1186/2052-8426-2-19] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 06/05/2014] [Indexed: 12/24/2022]
Abstract
Progress is being made in developing neuroprotective strategies for traumatic brain injuries; however, there will never be a therapy that will fully preserve neurons that are injured from moderate to severe head injuries. Therefore, to restore neurological function, regenerative strategies will be required. Given the limited regenerative capacity of the resident neural precursors of the CNS, many investigators have evaluated the regenerative potential of transplanted precursors. Unfortunately, these precursors do not thrive when engrafted without a biomaterial scaffold. In this article we review the types of natural and synthetic materials that are being used in brain tissue engineering applications for traumatic brain injury and stroke. We also analyze modifications of the scaffolds including immobilizing drugs, growth factors and extracellular matrix molecules to improve CNS regeneration and functional recovery. We conclude with a discussion of some of the challenges that remain to be solved towards repairing and regenerating the brain.
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Affiliation(s)
- Nolan B Skop
- Department of Neurology & Neurosciences, Rutgers University-New Jersey Medical School, NJMS-Cancer Center, H-1226, 205 South Orange Ave., Newark, NJ 07103 USA ; Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102 USA
| | - Frances Calderon
- Department of Neurology & Neurosciences, Rutgers University-New Jersey Medical School, NJMS-Cancer Center, H-1226, 205 South Orange Ave., Newark, NJ 07103 USA
| | - Cheul H Cho
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102 USA
| | - Chirag D Gandhi
- Department of Neurology & Neurosciences, Rutgers University-New Jersey Medical School, NJMS-Cancer Center, H-1226, 205 South Orange Ave., Newark, NJ 07103 USA ; Department of Neurological Surgery, Rutgers University-New Jersey Medical School, New Jersey Medical School, Newark, NJ 07103 USA
| | - Steven W Levison
- Department of Neurology & Neurosciences, Rutgers University-New Jersey Medical School, NJMS-Cancer Center, H-1226, 205 South Orange Ave., Newark, NJ 07103 USA
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27
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Skop NB, Calderon F, Cho CH, Gandhi CD, Levison SW. Improvements in biomaterial matrices for neural precursor cell transplantation. MOLECULAR AND CELLULAR THERAPIES 2014; 2:19. [PMID: 26056586 PMCID: PMC4452047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 06/05/2014] [Indexed: 11/21/2023]
Abstract
Progress is being made in developing neuroprotective strategies for traumatic brain injuries; however, there will never be a therapy that will fully preserve neurons that are injured from moderate to severe head injuries. Therefore, to restore neurological function, regenerative strategies will be required. Given the limited regenerative capacity of the resident neural precursors of the CNS, many investigators have evaluated the regenerative potential of transplanted precursors. Unfortunately, these precursors do not thrive when engrafted without a biomaterial scaffold. In this article we review the types of natural and synthetic materials that are being used in brain tissue engineering applications for traumatic brain injury and stroke. We also analyze modifications of the scaffolds including immobilizing drugs, growth factors and extracellular matrix molecules to improve CNS regeneration and functional recovery. We conclude with a discussion of some of the challenges that remain to be solved towards repairing and regenerating the brain.
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Affiliation(s)
- Nolan B Skop
- />Department of Neurology & Neurosciences, Rutgers University-New Jersey Medical School, NJMS-Cancer Center, H-1226, 205 South Orange Ave., Newark, NJ 07103 USA
- />Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102 USA
| | - Frances Calderon
- />Department of Neurology & Neurosciences, Rutgers University-New Jersey Medical School, NJMS-Cancer Center, H-1226, 205 South Orange Ave., Newark, NJ 07103 USA
| | - Cheul H Cho
- />Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102 USA
| | - Chirag D Gandhi
- />Department of Neurology & Neurosciences, Rutgers University-New Jersey Medical School, NJMS-Cancer Center, H-1226, 205 South Orange Ave., Newark, NJ 07103 USA
- />Department of Neurological Surgery, Rutgers University-New Jersey Medical School, New Jersey Medical School, Newark, NJ 07103 USA
| | - Steven W Levison
- />Department of Neurology & Neurosciences, Rutgers University-New Jersey Medical School, NJMS-Cancer Center, H-1226, 205 South Orange Ave., Newark, NJ 07103 USA
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28
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Rossignol J, Fink K, Davis K, Clerc S, Crane A, Matchynski J, Lowrance S, Bombard M, DeKorver N, Lescaudron L, Dunbar GL. Transplants of Adult Mesenchymal and Neural Stem Cells Provide Neuroprotection and Behavioral Sparing in a Transgenic Rat Model of Huntington's Disease. Stem Cells 2014; 32:500-9. [DOI: 10.1002/stem.1508] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 07/16/2013] [Accepted: 07/27/2013] [Indexed: 02/06/2023]
Affiliation(s)
- Julien Rossignol
- Department of Psychology; Central Michigan University; Mount Pleasant Michigan USA
- Program in Neuroscience; Central Michigan University; Mount Pleasant Michigan USA
- College of Medicine; Central Michigan University; Mount Pleasant Michigan USA
- Field Neurosciences Institute; Saginaw Michigan USA
| | - Kyle Fink
- Program in Neuroscience; Central Michigan University; Mount Pleasant Michigan USA
| | - Kendra Davis
- Program in Neuroscience; Central Michigan University; Mount Pleasant Michigan USA
| | - Steven Clerc
- Program in Neuroscience; Central Michigan University; Mount Pleasant Michigan USA
| | - Andrew Crane
- Program in Neuroscience; Central Michigan University; Mount Pleasant Michigan USA
| | - Jessica Matchynski
- Program in Neuroscience; Central Michigan University; Mount Pleasant Michigan USA
| | - Steven Lowrance
- Program in Neuroscience; Central Michigan University; Mount Pleasant Michigan USA
| | - Matthew Bombard
- Program in Neuroscience; Central Michigan University; Mount Pleasant Michigan USA
| | - Nicholas DeKorver
- Program in Neuroscience; Central Michigan University; Mount Pleasant Michigan USA
| | - Laurent Lescaudron
- INSERM UMR 643; Nantes France
- ITUN, Institut Transplantation Urologie Nephrologie; CHU Nantes France
- Université de Nantes; UFR des Sciences et des Techniques; Nantes France
| | - Gary L. Dunbar
- Department of Psychology; Central Michigan University; Mount Pleasant Michigan USA
- Program in Neuroscience; Central Michigan University; Mount Pleasant Michigan USA
- College of Medicine; Central Michigan University; Mount Pleasant Michigan USA
- Field Neurosciences Institute; Saginaw Michigan USA
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29
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Skop NB, Calderon F, Cho CH, Gandhi CD, Levison SW. Optimizing a multifunctional microsphere scaffold to improve neural precursor cell transplantation for traumatic brain injury repair. J Tissue Eng Regen Med 2013; 10:E419-E432. [DOI: 10.1002/term.1832] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 06/12/2013] [Accepted: 09/02/2013] [Indexed: 12/16/2022]
Affiliation(s)
- Nolan B. Skop
- Department of Neurology and Neurosciences; Rutgers-New Jersey Medical School; Newark NJ USA
- Department of Neurological Surgery; Rutgers-New Jersey Medical School; Newark NJ USA
| | - Frances Calderon
- Department of Neurology and Neurosciences; Rutgers-New Jersey Medical School; Newark NJ USA
| | - Cheul H. Cho
- Department of Biomedical Engineering; New Jersey Institute of Technology; Newark NJ USA
| | - Chirag D. Gandhi
- Department of Neurological Surgery; Rutgers-New Jersey Medical School; Newark NJ USA
| | - Steven W. Levison
- Department of Neurology and Neurosciences; Rutgers-New Jersey Medical School; Newark NJ USA
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30
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Nong Y, Zhang C, Wei L, Zhang Z, Cheng J, Wen L, Song Z. In situ investigation of allografted mouse HCN4 gene–transfected rat bone marrow mesenchymal stromal cells with the use of patch-clamp recording of ventricular slices. Cytotherapy 2013; 15:905-19. [DOI: 10.1016/j.jcyt.2013.03.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 02/21/2013] [Accepted: 03/24/2013] [Indexed: 01/01/2023]
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