Central nervous system injury leads to irreversible neuronal loss and glial scar formation, which ultimately results in persistent neurological dysfunction. Regenerative medicine suggests that replenishing missing neurons may be an ideal approach to repair the damage. Recent researches showed that many mature cells could be transdifferentiated into functional neurons by reprogramming. Therefore, reprogramming endogenous glia in situ to produce functional neurons shows great potential and unique advantage for repairing neuronal damage and treating neurodegenerative diseases. The present review summarized the current research progress on in situ transdifferentiation in the central nervous system, focusing on the cell types, characteristics and research progress of glial cells that could be transdifferentiated in situ, in order to provide theoretical basis for the development of new therapeutic strategies of neuronal injury and further clinical application.
Cell Transdifferentiation ; Cellular Reprogramming ; Central Nervous System ; cytology ; Humans ; Neurodegenerative Diseases ; Neuroglia ; cytology ; Neurons ; cytology

Spinal cord injury (SCI), which is much in the public eye, is still a refractory disease compromising the well-being of both patients and society. In spite of there being many methods dealing with the lesion, there is still a deficiency in comprehensive strategies covering all facets of this damage. Further, we should also mention the structure called the corticospinal tract (CST) which plays a crucial role in the motor responses of organisms, and it will be the focal point of our attention. In this review, we discuss a variety of strategies targeting different dimensions following SCI and some treatments that are especially efficacious to the CST are emphasized. Over recent decades, researchers have developed many effective tactics involving five approaches: (1) tackle more extensive regions; (2) provide a regenerative microenvironment; (3) provide a glial microenvironment; (4) transplantation; and (5) other auxiliary methods, for instance, rehabilitation training and electrical stimulation. We review the basic knowledge on this disease and correlative treatments. In addition, some well-formulated perspectives and hypotheses have been delineated. We emphasize that such a multifaceted problem needs combinatorial approaches, and we analyze some discrepancies in past studies. Finally, for the future, we present numerous brand-new latent tactics which have great promise for curbing SCI.
Animals ; Astrocytes/cytology* ; Axons/physiology* ; Cell Transplantation ; Disease Models, Animal ; Electric Stimulation ; Humans ; Microglia/cytology* ; Motor Neurons/cytology* ; Nerve Regeneration ; Neuroglia/cytology* ; Neuronal Plasticity ; Neurons/cytology* ; Oligodendroglia/cytology* ; Pyramidal Tracts/pathology* ; Recovery of Function ; Regenerative Medicine/methods* ; Spinal Cord Injuries/therapy*

OBJECTIVETo observe the time course of proliferation and differentiation of neural stem cells (NSCs) in the subventricular zone (SVZ) of rats following traumatic craniocerebral injury (TBI).

METHODSForty-eight SD rats were randomized into 3 groups, namely the control group without any treatment, the sham-operated group with scalp incision and preparation of a cranial window, and TBI group with craniocerebral injury induced by Feeney's method. With nestin and BrdU as two cell markers, NSE as the neuron-specific marker and GFAP as the glial cell marker, immunofluorescence assay with double labeled antibodies was performed to examine the proliferation and differentiation of endogenous NSCs in the SVZ at different time points after TBI.

RESULTSs The numbers of cells positive for nestin/NSE, nestin/GFAP, BrdU/NSE, and BrdU/GFAP in the SVZ of the rats increased significantly after TBI. The positive cells began to increase at 1 day after TBI, reached the peak level at day 3 and became normal at day 14, showing significant differences between the time points of measurement following TBI and from the cell numbers in the control group measured at the same time points. The cells positive for nestin/ GFAP showed the most distinct increase in the SVZ of the rats with TBI.

CONCLUSIONTBI results in mobilization of the NSCs in the SVZ on the injured side to cause the proliferation and differentiation of the endogenous NSCs. The SVZ is one of the most important germinal centers of NSC proliferation and differentiation.

Animals ; Bromodeoxyuridine ; metabolism ; Cell Differentiation ; Cell Proliferation ; Craniocerebral Trauma ; pathology ; Glial Fibrillary Acidic Protein ; metabolism ; Lateral Ventricles ; cytology ; Nestin ; metabolism ; Neural Stem Cells ; cytology ; Neuroglia ; cytology ; Neurons ; cytology ; Phosphopyruvate Hydratase ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley

OBJECTIVEDuring the process of tissue remodeling in human tumor transplantation models, the roles of the inoculated tumor cells and host tissue in tumor progression is still largely unknown. The aim of this study was to investigate the relationships and interactions between these two sides using GFP-RFP double fluorescence tracing technique.

METHODSRed fluorescence protein (RFP) gene was stably transfected into glioma stem cell line SU3, then SU3-RFP cells were transplanted into the brain of athymic nude mice with green fluorescence protein (GFP) expression. After the intracerebral tumors were formed, the relationship and interaction between GFP cells and RFP cells were analyzed. Highly proliferative GFP cells were screened out, and monocloned with micro-pipetting. DNA content assay, chromosome banding and carcinogenicity test of the GFP cells were performed to observe the GFP cells' cancerous phenotype in nude mice.

RESULTSIn the transplantable tumor tissue, besides a great quantity of RFP cells, there were still a proportion of GFP cells and GFP/RFP fusion cells. The proportion of RFP cells, GFP cells and GFP/RFP cells were (88.99 ± 1.46)%, (5.59 ± 1.00)%, and (4.11 ± 1.020)%, respectively. Two monoclonal host GFP cells (H1 and H9) were cloned, which demonstrated the properties of immortality, loss of contact inhibition, and ultra-tetraploid when cultured in vitro. Both H1 and H9 cells expressed CNP, a specific marker of oligodendrocytes. The GFP cells also demonstrated 100% tumorigenic rate and high invasive properties in vivo.

CONCLUSIONSIn this glioma transplantation model, the transplanted tumor tissues contained not only transplanted glioma stem cells but also cancerous host GFP cells. Our findings offer important clues to further research on the relationships among different members in the tumor microenvironment.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase ; metabolism ; Animals ; Brain ; cytology ; metabolism ; Cell Communication ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Glioma ; metabolism ; pathology ; Green Fluorescent Proteins ; metabolism ; Humans ; Intermediate Filament Proteins ; metabolism ; Luminescent Proteins ; genetics ; metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasm Transplantation ; Neoplastic Stem Cells ; cytology ; metabolism ; Nerve Tissue Proteins ; metabolism ; Nestin ; Neuroglia ; cytology ; metabolism ; Transfection ; Tumor Microenvironment

Glial cells play a critical role in morphine tolerance, resulting from repeated administration of morphine. Both the development and the expression of tolerance are suppressed by the analgesic lamotrigine. This study investigated the relationship between the ability of lamotrigine to maintain the antinociceptive effect of morphine during tolerance development and glial cell activation in the spinal cord. In a rat model, morphine (15 microg) was intrathecally injected once daily for 7 days to induce morphine tolerance. Lamotrigine (200 microg) was co-administered with morphine either for 7 days or the first or last 3 days of this 7 day period. Thermal nociception was measured. OX-42 and GFAP immunoreactivity, indicating spinal microglial and astrocytic activation were evaluated on day 8. Tolerance developed after 7 days of intrathecal morphine administration; however, this was completely blocked and reversed by co-administration of lamotrigine. When lamotrigine was coinjected with morphine on days 5-7, the morphine effect was partially restored. Glial cell activation increased with the development of morphine tolerance but was clearly inhibited in the presence of lamotrigine. These results suggest that, in association with the suppression of spinal glial cell activity, intrathecally coadministered lamotrigine attenuates antinociceptive tolerance to morphine.
Analgesics/*pharmacology ; Animals ; Antigens, CD11b/metabolism ; Astrocytes/cytology ; Drug Tolerance ; Immunohistochemistry ; Male ; Microglia/cytology ; Morphine/*pharmacology ; Nerve Tissue Proteins/metabolism ; Neuroglia/cytology/*metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*cytology ; Triazines/*pharmacology

Angelica ; chemistry ; Animals ; Animals, Newborn ; Cell Count ; Female ; Fetal Hypoxia ; pathology ; Hippocampus ; cytology ; drug effects ; Male ; Neuroglia ; cytology ; Neurons ; cytology ; Pregnancy ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the effects of Ginkgo biloba extract 50 (GBE50) on inflammatory cytokines and glia cell injury in the prefrontal cortex and hippocampus of aging rats and its probable mechanism. Methods Totally 45 male SD rats were randomly divided into 4 groups, i.e., the normal control group (n=12), the model group (n=11), the low dose GBE50 group (n=10), and the high dose GBE50 group (n=12). The aging rat model was intraperitoneally injected with D-galactose to establish the aging model for 42 days. Starting from the 22nd day of modeling, rats in the low dose GBE50 group and the high dose GBE50 group were administered by gastrogavage with 75 mg/kg and 150 mg/kg respectively. The protein contents and mRNA expressions of IL-1beta, IL-6, and TNF-a in the prefrontal cortex and hippocampus of rats were detected by radioimmunoassay and Real-time fluorescence quantitative PCR assay respectively. The ultrastructural changes of glia cells in the hippocampal CA1 region were observed by transmission electron microscope. Results The protein contents and mRNA expressions of IL-1beta and TNF-alpha in the prefrontal cortex and the hippocampus of aging rats obviously increased when compared with the normal control group (P < 0.05, P < 0.01). The content of IL-6 in the hippocampus of aging rats obviously decreased (P < 0.01). Compared with the model group, the protein content and mRNA expression of IL-1beta in the prefrontal cortex and the hippocampus were obviously downregulated in the low and high dose GBE50 groups. The content of TNF-alpha in the prefrontal cortex was obviously downregulated in the low and high dose GBE50 groups, the content of TNF-alpha in the hippocampus was obviously downregulated in the low dose GBE50 group (P < 0.05, P < 0.01). The content of IL-6 in the prefrontal cortex of the low dose GBE50 group was up-regulated. The content of IL-6 in the hippocampus of the high dose GBE50 group was also upregulated. The mRNA expression of IL-6 in the prefrontal cortex of the low and high dose GBE50 groups obviously increased (P < 0.05, P < 0.01). Low and high dose GBE50 showed obvious recovery on the ultrastructural damage of glia cells in the hippocampal CA1 region.

CONCLUSIONSGBE50 showed inhibitive effects on the inflammatory reaction of nerves of aging rats. Its mechanism might be possibly correlated with its regulatory effects on the cytokines in the prefrontal cortex and the hippocampus, as well as the ultrastructures of glia cells in the prefrontal cortex and hippocampus to some degree.

Aging ; Animals ; Cytokines ; metabolism ; Ginkgo biloba ; Hippocampus ; cytology ; drug effects ; Interleukin-1beta ; metabolism ; Interleukin-6 ; metabolism ; Male ; Neuroglia ; ultrastructure ; Plant Extracts ; pharmacology ; Prefrontal Cortex ; cytology ; drug effects ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; metabolism

Derived from neural stem cells (NSCs) and progenitor cells originated from the neuroectoderm, the nervous system presents an unprecedented degree of cellular diversity, interwoven to ensure correct connections for propagating information and responding to environmental cues. NSCs and progenitor cells must integrate cell-intrinsic programs and environmental cues to achieve production of appropriate types of neurons and glia at appropriate times and places during development. These developmental dynamics are reflected in changes in gene expression, which is regulated by transcription factors and at the epigenetic level. From early commitment of neural lineage to functional plasticity in terminal differentiated neurons, epigenetic regulation is involved in every step of neural development. Here we focus on the recent advance in our understanding of epigenetic regulation on orderly generation of diverse neural cell types in the mammalian nervous system, an important aspect of neural development and regenerative medicine.
Chromatin ; metabolism ; DNA Methylation ; Epigenomics ; Histones ; genetics ; metabolism ; Humans ; Neural Stem Cells ; cytology ; metabolism ; Neurogenesis ; Neuroglia ; cytology ; metabolism ; RNA, Untranslated ; metabolism

The process of cortical expansion in the central nervous system is a key step of mammalian brain development to ensure its physiological function. Radial glial (RG) cells are a glial cell type contributing to this progress as intermediate neural progenitor cells responsible for an increase in the number of cortical neurons. In this review, we discuss the current understanding of RG cells during neurogenesis and provide further information on the mechanisms of neurodevelopmental diseases and stem cell-related brain tumorigenesis. Knowledge of neuronal stem cell and relative diseases will bridge benchmark research through translational studies to clinical therapeutic treatments of these diseases.
Biomarkers, Tumor ; metabolism ; Brain ; growth & development ; physiology ; Brain Neoplasms ; metabolism ; pathology ; therapy ; Glioma ; metabolism ; pathology ; therapy ; Humans ; Intercellular Signaling Peptides and Proteins ; chemistry ; metabolism ; Lissencephaly ; metabolism ; pathology ; Microcephaly ; metabolism ; pathology ; Neoplastic Stem Cells ; cytology ; metabolism ; Neurogenesis ; drug effects ; Neuroglia ; cytology ; metabolism ; Protein Kinase Inhibitors ; chemistry ; pharmacology

Human pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) hold great promise in regenerative medicine as they are an important source of functional cells for potential cell replacement. These human PSCs, similar to their counterparts of mouse, have the full potential to give rise to any type of cells in the body. However, for the promise to be fulfilled, it is necessary to convert these PSCs into functional specialized cells. Using the developmental principles of neural lineage specification, human ESCs and iPSCs have been effectively differentiated to regional and functional specific neurons and glia, such as striatal gama-aminobutyric acid (GABA)-ergic neurons, spinal motor neurons and myelin sheath forming oligodendrocytes. The human PSCs, in general differentiate after the similar developmental program as that of the mouse: they use the same set of cell signaling to tune the cell fate and they share a conserved transcriptional program that directs the cell fate transition. However, the human PSCs, unlike their counterparts of mouse, tend to respond divergently to the same set of extracellular signals at certain stages of differentiation, which will be a critical consideration to translate the animal model based studies to clinical application.
Astrocytes ; cytology ; Cell Differentiation ; Embryonic Stem Cells ; cytology ; Humans ; Neuroglia ; cytology ; Neurons ; cytology ; Pluripotent Stem Cells ; cytology