The mast cells of the mammalian central nervous system

Summary The uptake and turnover of the precursors of heparin and heparan sulphate (³⁵S), and of serotonin (³H-5-hydroxytryptophan; ³H-5-HTP) by mast cells (MCs) and neurolipomastocytoid cells (NLMs) of the mammalian CNS were studied. Rats of varying age from 1 day to early adulthood were injected with ³⁵S (as a solution of sodium sulphate) and ³H-5-HTP, and allowed to survive for different periods. Several fixatives, as well as lengths of exposure to photographic emulsion, were tested. The monoamine oxidase inhibitor, nialamide, needed to be given before uptake of ³H-5-HTP could be adequately demonstrated especially in the CNS. ³⁵S was taken up by structures known to contain a great deal of sulphate, viz., cartilage and goblet cells, as well as by MCs of adult liver and thymus, but not by MCs of adult CNS. All of these structures, including the MCs of CNS, took it up much more avidly in babies than in adults. ³H-5-HTP had a similar effect in that the MCs of younger animals took it up more strongly than did those of adults. In the MCs of the CNS uptake seemed to increase up to 15 days of age but then to decrease as maturity was reached. The MCs are located in the leptomeninges of the cerebral hemispheres as well as the choroid fissures and dorsal thalamus. The NLMs, ubiquitously distributed in the leptomeninges as well as perivascularly, showed less radioactivity with both markers in fewer cells and only in babies. The possible significance of these results is discussed. It is concluded that MCs, and to a lesser extent NLMs, of the CNS do permit entry of these markers, and that the more immature the cells, the heavier the load that enters. Adult cells do not seem to take up precursor suggesting little or no turnover.Supported in part by a grant from the Incentive Plan of the Medical School, American University of Beirut, and by Research Support Grant MA-004 from the College of Graduate Studies, University of Kuwait     

The mast cells of the mammalian central nervous system. IX. Development of the mast cells in the brain of the young rat

There are four potentially granular or frankly granular cells within the connective tissue compartment of the mammalian central nervous system, whether this is part of the surface leptomeninges or the leptomeningeal sleeves around parenchymal blood vessels larger than capillaries. These are: Cells that behave like macrophages, part of the mononuclear phagocyte system of the body; they are granular to varying degrees (containing lysosomes). Brown-pigmented granular cells which are mainly located on the surface but are also seen for varying distances along blood vessels as they pass inside the CNS of pigmented animals. Mast cells (MCs) which are granular and located especially prominently in surface leptomeninges of young mammals, and, in adults, are restricted to special parts of the CNS. Granular cells, referred to by me as neurolipomastocytoid cells (NLMs), are numerous, ubiquitously distributed, and seem to have morphological features in common with those of both MCs and macrophages. The exact identity of these NLMs still needs to established. One approach was to study the development of all three non-pigmented cells in the immature brain of the albino rat, especially at the ultrastructural level. This communication represents the findings regarding the MCs. The MCs appear to arise from a small mononuclear cell and to go through maturation stages identical to those described by others for MCs outside the CNS. The greatly flattened adjacent leptomeningeal cells are an easily identifiable entity especially due to their peculiar glycogen content in the young.     

Cancer stem cells in the mammalian central nervous system

Malignant tumours intrinsic to the central nervous system (CNS) are among the most difficult of neoplasms to treat effectively. The major biological features of these tumours that preclude successful therapy include their cellular heterogeneity, which renders them highly resistant to both chemotherapy and radiotherapy, and the propensity of the component tumour cells to invade, diffusely, the contiguous nervous tissues. The tumours are classified according to perceived cell of origin, gliomas being the most common generic group. In the 1970s transplacental administration of the potent neurocarcinogen, N-ethyl-N-nitrosourea (ENU), enabled investigation of the sequential development of brain and spinal neoplasms by electron microscopy and immunohistochemistry. The significance of the primitive cells of the subependymal plate in cellular origin and evolution of a variety of glial tumours was thereby established. Since then, the development of new cell culture methods, including the in vitro growth of neurospheres and multicellular tumour spheroids, and new antigenic markers of stem cells and glial/neuronal cell precursor cells, including nestin, Mushashi-1 and CD133, have led to a reappraisal of the histological classification and origins of CNS tumours. Moreover, neural stem cells may also provide new vectors in exciting novel therapeutic strategies for these tumours. In addition to the gliomas, stem cells may have been identified in paediatric tumours including cerebellar medulloblastoma, thought to be of external granule cell neuronal derivation. Interestingly, while the stem cell marker CD133 is expressed in these primitive neuroectodermal tumours (PNETs), the chondroitin sulphate proteoglycan neuronal/glial 2 (NG2), which appears to denote increased proliferative, but reduced migratory activity in adult gliomas, is rarely expressed. This is in contrast to the situation in the histologically similar supratentorial PNETs. A possible functional 'switch' between proliferation and migration in developing neural tumour cells may exist between NG2 and ganglioside GD3. The divergent pathways of differentiation of CNS tumours and the possibility of stem cell origin, for some, if not all, such neoplasms remain a matter for debate and continued research, but the presence of self-renewing neural stem cells in the CNS of both children and adults strongly suggests a role for these cells in tumour initiation and resistance to current therapeutic strategies.     

Stem cells in the adult mammalian central nervous system

Over the past year, evidence has accrued that adult CNS stem cells are a widespread progenitor cell type. These cells may normally replace neurons and/or glia in the adult brain and spinal cord. Advances have been made in understanding the signals that regulate stem cell proliferation and differentiation. A deeper understanding of the structure of germinal zones has helped us move towards identifying stem cells in vivo. Recent studies suggest that the fate of stem cell progeny in vivo may be linked to the complexity of the animal's environment.     

The mast cells of the mammalian central nervous system. III. Ultrastructural characteristics in the adult rat brain.

The brains of young adult male and female Sprague-Dawley rats were studied with the electron microscope to determine the full ultrastructural picture of two types of perivascular granular cell. One of these, referred to here as the type I cell and described by both light and electron microscopy by several authors, including ourselves, has been reported to be a mast cell (MC) almost identical to MCs outside the CNS. The other, referred to here as the type II cell and described by many authors under almost as many names, was dealt with fully by Ibrahim in several reports and regarded by him as a type of MC. It is felt that the results warrant the conclusions that the type I cells are indeed MCs, while the type II cells are closely allied to the type I cells and probably better adapted to the function they subserve in the CNS of mammals. The similarities between the two cell types probably outnumber the dissimilarities and even these have their counterparts in MCs outside the CNS. The problem of the possible confusion between the type II cells and macrophages, whether reportedly within vessel walls or in the form of modified or special 'pericytic' microglia, is discussed. It is concluded that there is no justification for regarding these cells as macrophages. Because of the similarity between the type II cells and MCs, and because of the high lipid content of the type II cells, it is suggested that these elements be called neurolipomastocytes or neurolipomastocytoid cells.     

The role of mast cells in virus-induced inflammation in the murine central nervous system

The mononuclear inflammatory response to Sindbis virus infection of the central nervous system is analogous to the cutaneous delayed-type hypersensitivity reaction. It is dependent on sensitized T cells for initiation, but many of the cells present are nonsensitized bone marrow-derived cells. Tissue mast cells have been shown to be important for the development of the delayed-type hypersensitivity reaction in the skin where capillary endothelial cells are joined by tight junctions. To determine whether mast cells are also important for the development of an immune-mediated inflammatory response across the endothelial tight junctions of the blood-brain barrier, the development of mononuclear inflammation in the central nervous system of reserpine-treated mice and mast cell-deficient mice (WBB6F1-W/Wv) was studied after infection with Sindbis virus. Three central nervous system compartments, the cerebrospinal fluid, the meninges, and the brain parenchyma, were evaluated for inflammation by counting the number of cells present, by grading the histopathologic lesions, and by labeling infiltrating cells with 125IUDR. By all parameters inflammation was reduced when mice were treated with reserpine or were deficient in mast cells. Antigen-specific humoral and cellular immune responses were depressed and virus clearance delayed in reserpine-treated mice, but not in mast cell deficient mice. It is concluded that the vasoactive amines released by mast cells in the central nervous system play a facilitating role in the development of the inflammatory response to Sindbis virus.     

The distribution of tau in the mammalian central nervous system

We have determined the biochemical and immunocytochemical localization of the heterogeneous microtubule-associated protein tau using a monoclonal antibody that binds to all of the tau polypeptides in both bovine and rat brain. Using immunoblot assays and competitive enzyme-linked immunosorbent assays, we have shown tau to be more abundant in bovine white matter extracts and microtubules than in extracts and microtubules from an enriched gray matter region of the brain. On a per mole basis, twice-cycled microtubules from white matter contained three times more tau than did twice-cycled microtubules from gray matter. Immunohistochemical studies that compared the localization of tau with that of MAP2 and tubulin demonstrated that tau was restricted to axons, extending the results of the biochemical studies. Tau localization was not observed in glia, which indicated that, at least in brain, tau is neuron specific. These observations indicate that tau may help define a subpopulation of microtubules that is restricted to axons. Furthermore, the monoclonal antibody described in this report should prove very useful to investigators studying axonal sprouting and growth because it is an exclusive axonal marker.     

Intracellular calcium recordings from isolated cells of the mammalian central nervous system

Measurements made with two different techniques of intracellular calcium levels from small isolated cells of the mammalian central nervous system are described and compared. Recordings in cultured mouse embryo spinal cord and dorsal root ganglion neurons, made with double-barrelled borosilicate Ca2+-selective microelectrodes yielded a mean Ca2+ level of 2.3 (SE +/- 0.54) microM for the lowest values recorded in 24 out of 46 cells. Intracellular Ca2+ dependence on membrane potential was apparent with levels of calcium greater than or equal to 4 microM (r = 0.371, n = 29). Both cyclic fluctuations induced by tetraethylammonium and an apparent increase in Ca2+ evoked by the depolarizing excitatory amino acid, L-aspartate, were observed. In contrast, estimates of intracellular Ca2+ obtained by spectrofluorimetry of suspensions of mouse embryo brain cells, loaded with the intracellular Ca-binding fluorescent probe, quin2 provided a approximately equal to 10-fold lower value, 152 (SE +/- 7) nM. This more closely resembles levels reported for large neurons where large-tip microelectrodes with greater sensitivity were used, and in spite of the heterogeneity of the cells this value is presumed to be a more accurate estimate of intraneuronal Ca2+ concentration. In these fluorescence studies KCl readily evoked increases in intracellular Ca2+ which could be blocked by verapamil and Cd2+ and were not induced in the absence of Ca2+. Increases were also produced by N-methyl-D-aspartate, but not by the kainate-like Lathyrus neurotoxin, L-3-oxalylamino-2-aminopropionic acid. These results provide preliminary evidence for both voltage-sensitive and receptor-activated Ca channels in embryonic brain cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Benzodiazepine receptors in the mammalian central nervous system

A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 20, No. 2, pp. 269–279, March–April, 1988.     

The contribution of mast cells to the histamine content of the central nervous system: A regional analysis

W/W^V mice are severely deficient in mast cells. The absence of mast cells in skin and salivary glands was found to be paralleled by a drastic decrease of the histamine levels in these tissues when compared to non-anemic +/+ control mice. Brains of W/W^V mice are also devoid of mast cells. A comparison of the histamine concentrations in several brain regions of W/W^V mice and controls revealed a moderate decrease in cerebral cortex, thalamus, hypothalamus and midbrain but no change in pons, medulla and cerebellum. These findings provide strong evidence that mast cells contribute to the histamine content in forebrain regions but not in hindbrain regions. It is speculated that there may exist histaminergic neurons intrinsic to the medulla and pons.     

成年哺乳动物中枢神经系统干细胞

神经干细胞广泛存在于成年哺乳动物的中枢神经系统。神经干细胞的增殖和分化受生长因子及功能活动等的调节。神经干细胞产生新的神经元可能与学习和记忆有关。     

The mast cells of the mammalian central nervous system V. The effect of compound 48|80 on the neurolipomastocytoid cells and related areas of the CNS: Early changes

Summary The response of the neurolipomastocytoid cells (NLMs) and elements in their vicinity within the central nervous system of various animal species was studied following injection of the animals with the specific mast cell (MC)-discharger compound 48/80. The observed alterations were grouped into those occurring early (0–21 days) and later (up to 18 months). In the present report, only the acute changes are described, light and electron microscopically.Most experimental animals developed prostration, scratching, acral-type reaction, signs of respiratory distress and salivation, and, in the monkey, uncontrollable somnolence. Within about 2 weeks after the injection some animals (especially guinea pigs) manifested various degrees of limb paralysis. The NLMs, like MCs outside the CNS, responded to injection by various degrees of degranulation, vacuolation, marked variation in granule size, apparent cell loss and sometimes an increase in number. Electron microscopically, particulate breakdown products of the granules of the NLMs appeared in the cytoplasm; occasionally there was suggestive evidence that they had passed inward across the vessel wall to reach the lumen, and also outward through the outermost basal lamina. Perivascular astrocytic feet showed swelling and vacuolation shortly after the injection, which was followed by evidence of gliosis and later scarring; occasionally, alterations in the mitochondria were observed. In the spinal cord of the guinea pig, capillary neoformation was observed with endothelial cells and adjacent NLMs taking up tritiated thymidine.The discussion centers on the partial similarity of response to compound 48/80 of the NLMs to that of MCs outside the CNS, and the probable involvement of NLM-damage in the parenchymal changes.The preliminary portion of this work was done with T. Wiedman at Ames Research Center, Moffett Field, California; a short communication has been published (Ibrahim 1970), and part of the study was presented at the Annual Meeting of the American Association of Anatomists (Ibrahim et al. 1976)Supported by a grant from the Incentive Plan of the Medical School, American University of Beirut, Lebanon, by Biomedical Research support Grant RR 05373 from the Biomedical Research Support Branch, Division of Research Facilities and Resources, National Institutes of Health, and by Research Grant No. MA 004 from the College of Graduate Studies, University of Kuwait     

Short interfering RNA-induced gene silencing is transmitted between cells from the mammalian central nervous system

Although short interfering RNA (siRNA)-induced gene silencing can be transmitted between cells in plants and in Caenorhabditis elegans, this phenomenon has been barely studied in mammalian cells. Both immortalized oligodendrocytes and SNB19 glioblastoma cells were transfected with siRNA constructs for phosphatase and tensin homolog deleted on chromosome 10 (PTEN) or Akt/protein kinase B (Akt). Co-cultures were established between silenced cells and non-silenced cells which were hygromycin resistant and/or expressed green fluorescent protein. After fluorescence sorting or hygromycin selection to remove the silenced cells, the expression of PTEN or Akt genes in the originally unsilenced cells was in all cases significantly decreased. Importantly, silencing did not occur in transwell culture studies, suggesting that transmission of the silencing signal requires a close association between cells. These results provide the first direct demonstration that an siRNA-induced silencing signal can be transmitted between mammalian CNS cells.     

Substance P receptors in mammalian central nervous system.

1. Multiple distinct affinity states or sites of substance P (SP) receptors exist in freshly-prepared rat brain membranes. 2. Substance P receptors may couple with islet-activating protein (pertussis toxin) sensitive GTP-binding protein(s). 3. Substance P receptors may be regulated Mg2+ and Na+ in an opposite manner. 4. Some important factor(s), in addition to GTP-binding protein, appear to be involved in SP binding activity. 5. An apparent molecular weight of the SP binding site is approximately 46,000 Da.