Many in vivo and in vitro studies have demonstrated the targeted migration of neural stem cells (NSC) to infiltrating brain tumors, including malignant glioma, highlighting a potential therapeutic approach. However, there is not enough information to apply this approach to clinical therapy. The most important things in stem cell therapy for brain tumors involve selecting the appropriate neural progenitor type and optimizing the efficiency of the cell engraftment. By histological analysis using two different live-dyes, human NSCs were shown to migrate away from the transplanted site in the direction of the expanding C6 glioma and to intermix with the tumor bed, especially with the tumor core. This intermixing occurred within 7 days when NSCs were implanted into glioma model. The time course of migratory HB1.F5 with the greatest mobility of three NSC lines was as follows. As early as 3 days after transplantation, several NSCs were found leaving the implant site, primarily approaching microsatellites and frontier cells located near the site of NSC implantation. Through 7 days post-transplantation, massive numbers of NSCs continued to be attracted to and interspersed with C6 glioma, and were finally distributed extensively throughout the whole tumor bed, including the core and penumbra of the tumor mass. However, NSCs appeared to penetrate into the tumor mass very well, whereas normal fibroblast cells could not migrate. These findings strengthen the potential for human NSCs as attractive vehicles to improve therapeutic gene delivery to cancer or glioma if they are optimized to selectively kill neoplastic cells.
Animals ; Brain/*cytology/*pathology ; Brain Neoplasms/*pathology ; *Cell Movement ; Female ; Glioma/*pathology ; Humans ; Mice ; NIH 3T3 Cells ; Neurons/*cytology ; Rats ; Rats, Sprague-Dawley ; Stem Cells/*cytology

We have tracked the response of host and transplanted neural progenitors or stem cells to hypoxic-ischemic (HI) brain injury, and explored the therapeutic potential of neural stem cells (NSCs) injected into mice brains subjected to focal HI injury. Such cells may integrace appropriately into the degenerating central nervous system (CNS), and showed robust engraftment and foreign gene expression within the region of HI inury. They appeared to have migrated preferentially to the site of ischemia, experienced limited proliferation, and differentiated into neural cells lost to injury, trying to repopulate the damaged brain area. The transplantation of exogenous NSCs may, in fact, augment a natural self-repair process in which the damaged CNS "attempts" to mobilize its own pool of stem cells. Providing additional NSCs and trophic factors may optimize this response. Therefore, NSCs may provide a novel approach to reconstituting brains damaged by HI brain injury. Preliminary data in animal models of stroke lends support to these hypotheses.
Animal ; Brain/pathology ; Brain Diseases/therapy* ; Brain Diseases/pathology ; Brain Ischemia/therapy* ; Brain Ischemia/pathology ; Gene Therapy* ; Human ; Nerve Tissue/cytology* ; Stem Cells/transplantation* ; Tissue Therapy*

OBJECTIVETo simulate the chemical microenvironment of injured brain tissue, and to explore the effect of this chemical microenvironment on temperature sensitive umbilical cord mesenchymal stem cells (tsUC).

METHODSRat models of traumatic brain injury (TBI) were made by fluid percussion injury, and then the brain tissue extracts of the injured regions were acquired. Human umbilical cord mesenchymal stem cells (UC) were isolated and cultured, and the tsUC were obtained through the infection of temperature-sensitive Simian 40 Large T- antigen (ts-SV40LT) retrovirus. After that, both the two kinds of cells were cultured on the polyacrylamide gels which mimicking the elastic modulus of brain. Four groups were included: UC cultured under normal temperature (UC group), UC cultured added brain tissue extract under normal temperature (UC plus extract group), tsUC cultured under mild hypothermia (tsUC group), and tsUC added brain tissue extract under mild hypothermia for 3 days, then normal temperature for 4 days (tsUC plus extract group). After 24 hours, the apoptosis level was checked. Cell growth and morphological changes in each group were given dynamic observation. Seven days later, cell immunofluorescences were implemented for examining neural differentiation level.

RESULTSCompared with UC plus extract group, the apoptosis and proliferation in UC plus extract group were significantly reduced (P < 0.01) and increased (P < 0.01) respectively. Cell immunofluorescence showed that the both GFAP and Neuron positive cells were significantly enhanced in UC plus extract group than those in tsUC plus extract group.

CONCLUSIONtsUC combining with mild hypothermia could significantly reverse injury induced cell apoptosis, improve cell proliferation and neural differentiation under chemical microenvironment after brain injury, which confirmed the adaptation and resistance of tsUC under mild hypothermia after TBI.

Animals ; Apoptosis ; Brain ; cytology ; pathology ; Brain Injuries ; pathology ; Cell Proliferation ; Humans ; Mesenchymal Stromal Cells ; chemistry ; Neurons ; cytology ; Rats ; Temperature ; Umbilical Cord ; cytology

Neurogenesis occurs in the adult brain, and neural stem cells (NSCs) reside in the adult central nervous system (CNS). In the adult brain, newly generated neuronal cells would originate from a population of glial cells with stem cells properties, and be involved in processes such as learning and memory, depression, and in regenerative attempts in the diseased brain and after injuries. In human, a recent study reported no evidence of migrating neural progenitor cells along the subventricular zone (SVZ) to the olfactory bulb (OB), contrary to other species, highlighting the particularity of adult neurogenesis in human. Though the origin and contribution of newly generated neuronal cells to CNS pathophysiology remain to be fully understood, the discovery that NSCs reside in the adult CNS force us to re-evaluate our knowledge and understanding of brain functioning, and suggest that the adult CNS may be amenable to repair. In this manuscript,we will review the recent data, debates and controversies on the identification, origin and function of newly generated neuronal cells in the adult brain, in human and in other species. We will discuss their contribution and significance to CNS pathophysiology, and for cellular therapy.
Adult Stem Cells ; cytology ; transplantation ; Aging ; Animals ; Brain ; cytology ; Central Nervous System ; cytology ; growth & development ; Central Nervous System Diseases ; pathology ; surgery ; Humans ; Stem Cell Transplantation ; methods

OBJECTIVETo investigate the effects of hypoxia-ischemia (HI) on different neural cells and their survival in subventricular zone (SVZ) of human fetus in mid trimester of pregnancy and thus to explore the pathogenesis of hypoxic-ischemic brain damage on the cellular level.

METHODSAcutely dissociated SVZ cells, prepared from five fetuses of human embryos aborted voluntarily at 17 to 22 weeks of gestational age, were cultured for a short time separately under HI (HI group) and normal condition (control group). HI injury was simulated by oxygen/glucose deprivation (OGD) and the dead cells were counted by staining with Trypan blue. The injury was evaluated by the survival rate before culturing. After culturing, all of the neural cells of SVZ, including neural stem cells (NSCs), neurons, astrocytes, oligodendrocyte progenitors and microglia cells were recognized separately by their special marker nestin, microtubule associated proteins 2 (MAP2), glial fibrillary acidic protein (GFAP), platelet derived growth factor receptor alpha (PDGFRalpha) and ricinus communis agglutinin (RCA120) with immunofluorescence cytochemistry. At the same time, all cell nuclei were stained with bisbenzimide. The percentages of SVZ cells were calculated and compared between HI and control groups.

RESULTSThe survival rate of HI SVZ cells, (63.41 +/- 0.06) percent, was much lower than that of control (98.9 +/- 0.01) percent (P < 0.001). The result indicated that SVZ cells were damaged obviously by HI. After culturing shortly the highest proportion of cells in HI group was astrocytes (56.48 +/- 0.03) percent, followed by NSCs (22.47 +/- 0.03) percent, and the lowest was oligodendrocyte progenitors. But in control group, the neurons accounted for (48.81 +/- 0.03) percent and astrocytes (32.31 +/- 0.03) percent, while the lowest was microglia cells.

CONCLUSIONSThere were NSCs, neurons, astrocytes, oligodendrocyte progenitors and microglial cells in SVZ of mid trimester of pregnancy. They were sensitive to HI and their survival rates were different: the NSCs and astrocytes showed higher survival rate than neurons and oligodendrocyte progenitors.

Cell Differentiation ; Cell Survival ; Cells, Cultured ; Cerebral Ventricles ; Female ; Fetus ; cytology ; pathology ; Humans ; Hypoxia-Ischemia, Brain ; pathology ; Neurons ; cytology ; Pregnancy ; Pregnancy Trimester, Second

Various studies have demonstrated the tremendous tropism of stem cells for malignant gliomas, making these cells a potential vehicle for delivery of therapeutic genes to disseminated glioma cells. However, little is known about the mechanisms underlying the glioma-induced tropism of stem cells. Soluble factors including chemokines or growth factors released and expressed by glioma cells at least mediate the tropism of stem cells for gliomas. Here we review the possible mechanisms of stem cells tropism for malignant gliomas.
Brain Neoplasms ; pathology ; therapy ; Cell Movement ; physiology ; Glioma ; pathology ; therapy ; Humans ; Neoplasm Invasiveness ; Neurons ; cytology ; Stem Cells ; classification ; cytology ; physiology ; Tropism ; physiology

OBJECTIVETo investigate the role of Bcl-2 in the cytoprotective effect of thyroid hormone against hippocampal cell apoptosis in rats with chronic cerebral ischemia.

METHODSFifty adult male SD rats were randomized into sham-operated group, 2-vessel occlusion (2VO) group and triiodothyronine (T3) treatment group. At 7 and 14 days after the operation, the tissue structure of the CA1 region was observed with Nissl staining, and TUNEL staining was used to determine the apoptosis index (AI) in the dentate gyrus; Western blotting was performed to detect the expression level of Bcl-2 in the hippocampus.

RESULTSIn the 2VO group, the CA1 region of the hippocampus showed obvious structural damages with reduced number of neurons, and these changes were significantly improved in T3 treatment group. At 7 days after the operation, no significant difference was found in AI between the sham-operated group (17.714∓2.553), 2VO group (20.868∓2.090) and T3 group (20.365∓1.055) (P=0.060); the expression level of Bcl-2 was higher in T3 group than in 2VO group. On day 14, AI was 66.532∓3.249 in 2VO group, significantly higher than that in T3 treatment group (56.153∓4.556, P=0.001); Bcl-2 expression was the highest in T3 group and the lowest in 2VO group.

CONCLUSIONThyroid hormone can reduce cell apoptosis in the hippocampus of rats with chronic cerebral ischemia possibly by up-regulating the expression of Bcl-2.

Animals ; Apoptosis ; drug effects ; Brain Ischemia ; pathology ; CA1 Region, Hippocampal ; cytology ; pathology ; Male ; Neurons ; cytology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Rats, Sprague-Dawley ; Triiodothyronine ; pharmacology

OBJECTIVETo explore the expression of autophagy after ischemia/reperfusion and its possible function in rats hippocampus neurons.

METHODSAfter 2 hours oxygen-glucose deprivation and different periods time of reperfusion (OGD/R) treatment in primary hippocampal neurons, neuron viability was evaluated by MTT assay, specific structure of autophagosome and specific protein of autophagy microtubule-associated protein 1 light chain 3 B (LC3B) were detected by transmission electron microscope and immunofluorescence respectively. The inhibitor of autophagy 3-Methyladenine (3-MA) was also used to exam the viability of neurons.

RESULTSTreatment by OGD/R markedly reduced neuronal viability. Compared to the control group, autophagy existed in different time periods after OGD/R shown both in transmission electron microscope and immunofluorescence. Application of 3-MA significantly reduced neuronal viability.

CONCLUSIONOxygen-glucose deprivation can activate autophagy in rat hippocampus neurons, which may resist the injury during ischemia/reperfusion.

Animals ; Autophagy ; physiology ; Brain Ischemia ; pathology ; Cell Hypoxia ; Culture Media, Serum-Free ; Hippocampus ; cytology ; pathology ; Male ; Neurons ; pathology ; Primary Cell Culture ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; pathology

Animals ; Apoptosis ; drug effects ; Brain Ischemia ; pathology ; Hippocampus ; cytology ; drug effects ; pathology ; Neurons ; drug effects ; pathology ; Rats ; Rats, Wistar ; Reperfusion Injury ; pathology ; Sulfinic Acids ; pharmacology

AIMTo evaluate N-acetylaspartate reflecting the neuronal lesion in middle cerebral artery occlusion and reperfusion rat by magnetic resonance spectroscopy (MRS).

METHODSSixteen adult Wistar rats with MCAO reperfusion and ten pseudooperation rats were performed MRS in vivo at the sixth weeks, then pathologic examination of HE staining and immunohistochemical staining were made. We compared hippocampus modality, cell density and immunohistochemical results with N-acetylaspartate, creatine changes and ration of NAA/Cr.

RESULTSThe values of NAA, Cr and NAA/Cr of ipsilateral hippocampus lesion in MCAO reperfusion rats (2.05 +/- 0.33, 2.42 +/- 0.41 and 0.86 +/- 0.10) were visiblly decreased than contralateral hippocampus (3.45 +/- 0.58, 3.10 +/- 0.93, 1.18 +/- 0.32) and control group (3.42 +/- 0.43, 3.57 +/- 0.47, 0.98 +/- 0.14). But the level of decreased NAA is not corresponding to the degree of neuronal death in ipsilateral region of hippocampus in histochemistry.

CONCLUSIONMRS has perfect explanation of cell metabolic changes in CA1 region. Decrease of NAA represented neuron delayed injury. But the decreased level of NAA is not perfectly corresponded to the degree of neuron lost. This change has closed correlation with reactive astrocytes proliferation.

Animals ; Aspartic Acid ; analogs & derivatives ; metabolism ; Brain Ischemia ; metabolism ; pathology ; Female ; Hippocampus ; cytology ; pathology ; Magnetic Resonance Spectroscopy ; methods ; Male ; Neurons ; metabolism ; pathology ; Rats ; Rats, Wistar