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

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

The treatment of spinal cord injury is always a stubborn problem for neurosurgeons because nerve cell cannot regenerate and the glia scar can prevent the axonal regeneration. Olfactory ensheathing cells (OECs) is a kind of especial glia cell, which possesses the character of horizontal cell of central nervous system and schwann cell. Many foundational and clinical studies showed that the olfactory ensheathing cellscan promote axonal regeneration and prove axonal growth, some progress is made and this is bringing hope for treatment of spine injury.
Animals ; Cell Transplantation ; Cells, Cultured ; Humans ; Nerve Regeneration ; Neuroglia ; cytology ; transplantation ; Olfactory Mucosa ; cytology ; transplantation ; Spinal Cord Injuries ; therapy

The cell body or soma in the dosal root ganglion (DRG) is normally excitable and this excitability can increase and persist after an injury of peripheral sensory neurons. In a rat model of radicular pain, an intraforaminal implantation of a rod that chronically compressed the lumbar DRG ("CCD" model) resulted in neuronal somal hyperexcitability and spontaneous activity that was accompanied by hyperalgesia in the ipsilateral hind paw. By the 5th day after onset of CCD, there was a novel upregulation in neuronal expression of the chemokine, monocyte chemoattractant protein-1 (MCP-1 or CCL2) and also its receptor, CCR2. The neurons developed, in response to topically applied MCP-1, an excitatory response that they normally do not have. CCD also activated non-neuronal cells including, for example, the endothelial cells as evidenced by angiogenesis in the form of an increased number of capillaries in the DRG after 7 days. A working hypothesis is that the CCD induced changes in neurons and non-neuronal cells that may act together to promote the survival of the injured tissue. The release of ligands such as CCL2, in addition to possibly activating nociceptive neurons (maintaining the pain), may also act to preserve injured cells in the face of ischemia and hypoxia, for example, by promoting angiogenesis. Thus, somal hyperexcitability, as often said of inflammation, may represent a double edged sword.
Animals ; Chemokine CCL2 ; metabolism ; Ganglia, Spinal ; cytology ; pathology ; Hyperalgesia ; pathology ; Neuroglia ; cytology ; Nociceptors ; cytology ; Pain ; pathology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord Compression ; physiopathology ; Up-Regulation

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

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*

To study the effect of lysophosphatidic acid (LPA) on the differentiation of embryonic neural stem cells (NSCs) into neuroglial cells in rats in vitro, both oligodendrocytes and astrocytes were detected by their marker proteins galactocerebroside (Gal-C) and glial fibrillary acidic protein (GFAP), respectively, using double-labeling immunocytochemistry. RT-PCR assay was also used for analyzing the expression of LPA receptors in NSCs. Our results showed that: (1) LPA at different concentrations (0.01-3.0 mumol/L) was added to culture medium and cell counting was carried out on the 7th day in all groups. Exposure to LPA led to a dose-dependent increase of oligodendrocytes with the response peaked at 1.0 mumol/L, with an increased percentage of 32.6% (P<0.01) of total cells as compared to that of 8.5% in the vehicle group. (2) LPA showed no effect on the differentiation of NSCs into astrocytes. (3) RT-PCR assay showed that LPA(1) and LPA(3) receptors were strongly expressed while LPA(2) receptor expressed weakly in NSCs. These results suggest that LPA at low concentration might act as an extracellular signal through the receptors in NSCs, mainly LPA(1) and LPA(3) receptors, to promote the differentiation of NSCs into oligodendrocytes, while it exhibits little, if any, conceivable effect on the differentiation of NSCs into astrocytes.
Animals ; Cell Differentiation ; drug effects ; Cells, Cultured ; Lysophospholipids ; pharmacology ; Neural Stem Cells ; cytology ; drug effects ; Neuroglia ; cytology ; Rats ; Receptors, Lysophosphatidic Acid ; metabolism

OBJECTIVETo investigate whether or not allografted olfactory mucosa gliacytes could repair peripheral nerve injure.

METHODSOlfactory mucosa gliacytes had been cultured in vitro for 2 weeks, then purified and condensed for later transplantation.Sixty adult female Wistar rats were randomized into 2 groups of 30 rats each, A (control) and B (test). Rats' left sciatic nerves were excised 25 mm long axons and retained epineurium lumen anastomosed to proximal ends. Culture mediums, and olfactory mucosa gliacytes were transplanted into epineurium lumen of A and B groups respectively. At 3 months postoperatively, the regenerations of injured sciatic nerves were evaluated by methods of macroscopy, photomicroscopy, transmission electron microscopy, retro-marked fluorescence red, the condensation of glial fibre acid protein (GFAP) and nerve growth factors (NF) assayed by immunofluorescence, and the concentration of myelin basic protein (MBP) and neurofilament protein (NF) assayed by enzyme linked immunosorbent assay.

RESULTSThe regenerations of injured sciatic nerves were superior in B group to in A group; the transportation distance of retro-marked fluorescence red were longer in B group than in A group (P < 0.01). The condensations of GFAP and NGF were more dense in B group than in A group. The concentrations of MBP and NF were more high in B group than in A group (P < 0.01). The function scores of injured limbs were superior in B group to in A group (P < 0.01). The quantifications of nerve fibers and myelin fibers of injured sciatic nerve were larger in B group than in A group (P < 0.01).

CONCLUSIONAllografted olfactory mucosa gliacytes could repair injured nerve defect.

Animals ; Cell Transplantation ; Cells, Cultured ; Disease Models, Animal ; Female ; Nerve Regeneration ; Neuroglia ; cytology ; Olfactory Mucosa ; cytology ; Random Allocation ; Rats ; Rats, Wistar ; Sciatic Nerve ; injuries ; Transplantation, Homologous

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

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