The origin of remyelinating cells in the adult central nervous system: the role of the mature oligodendrocyte

The sequence of events by which new oligodendrocytes are generated in the adult mammalian central nervous system has not been clearly defined. Here we review old evidence that remyelinating cells can arise from the division of mature oligodendrocytes. In addition, we report the results of a tissue culture study comparing oligodendrocytes and immature progenitors with regard to their capacity for proliferation, for the generation of new oligodendrocytes and for myelination. Monoclonal antibodies 04 and 01 were used to distinguish oligodendrocytes (04+01+) from progenitors (04+01-). Dissociated cell suspensions from adult rat spinal cord were separated by flow cytometry into 01+ and 01- cell fractions, at greater than 93% purity. The 01+ fraction contained approximately 0.7% 04+01- cells while the 01- fraction contained approximately 4.4% 04+01- cells. Cells from these fractions were plated onto cultures of purified dissociated dorsal root ganglion neurons. The cultures that received 01+ cells developed numerous expanding colonies of cells expressing both 01 and 04, or 04 only, by 8 days and were essentially covered by oligodendrocytes by 16 days. In marked contrast, oligodendrocyte colonies were rare in cultures receiving 01- cells. By 24 days, myelination was extensive in cultures receiving 01+ cells; in contrast, only a few myelin segments were observed in cultures receiving the 01- fraction. Thus, oligodendrocytes (01+ cells) appear more capable than progenitors (04+01-) of generating new myelinating oligodendrocytes in this culture system.     

Sulfhydryl-containing cells of the central nervous system

Summary Brains of several species were sectioned and stained by theBarrnett andSeligman technique for localizing sulfhydryl groups. Most of the cells of the brain react weakly, but in the phylogenetically older parts, e. g., hypothalamus, amygdaloid nucleus, and cingulate gyrus, certain astrocytes and microglia were observed which were highly reactive. They were observed in all species studied; they are not present at birth in the rat, but develop afterwards. Electrical stimulation of the cortex did not change their staining characteristics. The localization and possible significance of these cells was discussed.

---

Zusammenfassung Hirnschnitte verschiedener Tierarten wurden nachBarrnett undSeligman gefärbt um Sulfhydrylgruppen zu lokalisieren. Die meisten Hirnzellen lassen sich nur schwach färben, aber in den, phylogenetisch gesehen, älteren Teilen, z. B. dem Hypothalamus, dem Nucleus amygdalae und dem Gyrus cinguli, sind bestimmte Astrocyten und Mikroglia zu beobachten, die sehr stark gefärbt erscheinen. Diese wurden bei allen untersuchten Tierarten festgestellt. Bei der Ratte sind sie bei der Geburt nicht zu finden, entwickeln sich aber später. Ihre Affinität zu verschiedenen Farbstoffen ändert sich nicht durch elektrischen Reiz des Cortex. Die Lokalisation und mögliche Bedeutung dieser Zellen wird besprochen.

---

Résumé Des cerveaux de plusieurs espèces furent coupés et colorés selon la méthode deBarrnett etSeligman afin de localiser des groupements sulfhydryles. La plupart des noyaux cérébraux ne se colorent que faiblement, mais dans les parties philogéniquement plus vieilles comme par exemple dans l'hypothalamus, le faisceau de l'ourlet, la circonvolution, il y a quelques astrocytes et microglies donnant une réaction très vive. On les rencontrait dans toutes les espèces étudiées, ils ne sont pas présents dans les rats nouveau-nés, mais se développent plus tard. La stimulation électrique de l'écorce ne changeait pas leur réaction envers des colorants. La localisation et le rôle probable de ces noyaux sont évalués.

---

---

With 4 Figures     

Centronuclear myopathy: Possible central nervous system origin

The authors describe a case of myopathy characterized physically by limb weakness, eyelid ptosis, voluntary and reflex paralysis of vertical movements of gaze, and loss of deep tendon reflexes; and morphologically by the abnormal presence of centrally located nuclei in muscle fibers and type 1 fiber hypotrophy. The establishment in this case study of two particular findings–the probably nuclear or supranuclear ophthalmoplegia and the apparently impaired nuclear migration from the center of the muscle fiber toward its periphery–supports the hypothesis of a neuromuscular disorder whose level of severity depends on the degree of difficulty in the nuclear migration itself. This would be linked to a reduction in central nervous system influence.     

Immunoregulation of cells within the central nervous system

There is growing evidence that immunomodulators influence cellular events within the central nervous system. Microglia are one important class of effector cells in the brain which both respond to and secrete immunoregulatory factors. By controlling the proliferation, death, or differentiation of neighboring cells, microglia may regulate the structure and function of neural tissues during development and in response to injury. As described here, suppression of microglia offers a new approach in the treatment of neurologic diseases.     

Myelination and remyelination in the central nervous system by transplanted oligodendrocytes using the shiverer model. Discussion on the remyelinating cell population in adult mammals

In the early sixties, remyelination was first observed in animal models of demyelination and described a few years later in multiple sclerosis. The spontaneous remyelination process is now well documented. Remyelination by transplantation of myelin-forming cells has been attempted. Transplanted Schwann cells can myelinate a central nervous system lesion but the remyelination is limited to the area of implantation. Oligodendrocytes or precursor cells are much more invasive and have been shown to migrate from the implantation site to the lesion at a distance of several millimeters. Thus, remyelination by transplantation of myelin-forming cells is possible at least in animal models, the oligodendrocytes being more efficient.     

Angiitis of the central nervous system.

Angiitis of the central nervous system is a rare disease which may result from numerous causes responsible for the presence of inflammatory lesions of the vascular wall. These inflammatory lesions may sometimes be associated with necrosis. Cerebral vessels of all sizes may be involved. The clinical presentation is highly variable, with focal to diffuse manifestations and acute to chronic evolution. Angiography is the cornerstone diagnostic procedure, showing multiple segmental stenoses of the cerebral arteries sometimes separated by fusiform dilatations. Although suggestive, this angiographical pattern is not unequivocal and other causes must be carefully ruled out. Only cerebral and/or leptomeningeal biopsy can provide a definite diagnosis of cerebral angiitis but this invasive diagnostic procedure is not performed in the majority of cases. Among the numerous causes of cerebral angiitis, one can individualize infectious diseases, primary systemic angiitis with cerebral involvement, angiitis secondary to various systemic diseases and other miscellaneous causes such as drug abuse or neoplasm.     

Histoplasmosis of the central nervous system.

Histoplasma capsulatum infection of the central nervous system is extremely rare in the United Kingdom partly because the organism is not endemic. However, because the organism can remain quiescent in the lungs or the adrenal glands for over 40 years before dissemination, it increasingly needs to be considered in unexplained neurological disease particularly in people who lived in endemic areas as children. In this paper a rapidly progressive fatal myelopathy in an English man brought up in India was shown at necropsy to be due to histoplasmosis. The neurological features of this infection are reviewed.     

Catecholamine-containing cells in the central nervous system and periphery of Aplysia californica.

Previous studies have suggested the presence of numerous catecholamine-containing cells in both the central ganglia and peripheral tissues of Aplysia, but they often offered conflicting or incomplete accounts of numbers, locations, and morphologies. The current study combines aldehyde-induced histofluorescence and tyrosine hydroxylase-like immunoreactivity together with confocal microscopy to provide details of these cells. Approximately 35-50 neurones in the cerebral ganglia, 4-8 neurones in the pedal ganglia, 5 neurones in the buccal ganglia, and numerous small fibres in various nerve trunks exhibited both immunoreactivity and aldehyde-induced fluorescence. Approximately 20 cells in the pedal ganglia and 4 cells in the buccal ganglia exhibited only immunoreactivity whereas 15-20 neurons in the cerebral ganglia exhibited only aldehyde-induced fluorescence. No somata in the pleural or abdominal ganglia exhibited aldehyde-induced fluorescence or immunoreactivity. Both aldehyde-induced histofluorescence and immunoreactivity also labelled what appeared to be two classes of catecholamine-containing cells in the gill, siphon, oesophagus, rhinophore, tentacle, and reproductive organs. The more numerous, but smaller cells had subepithelial somata and processes penetrating the overlying body wall, thus suggesting a sensory function. Another class of neurones had larger somata, often located more deeply within the tissue, and occasionally appeared to be multipolar. Processes from these various peripheral cells appeared to comprise the major component of afferent fibres and to form an extensive peripheral plexus, often associated with various muscles. The morphologies of the peripheral cells thus suggest involvement in both local and centrally mediated reflexes and responses, but additional studies must test such hypothesised functions and determine the sensory modalities that the cells mediate.     

The penetration of anti-infectives into the central nervous system.

The blood-brain barrier, blood-cerebrospinal fluid (CSF) barrier, and meninges are a complex and difficult-to-study system charged with protecting the central nervous system (CNS) from toxins, including drugs. Current estimates of CNS drug exposure are limited to CSF to blood ratios, of which area-under-the curve (AUC) estimates provide the most robust measure of drug exposure. Different classes of drugs and individual drugs within classes have different CNS penetration potential that is dependent upon a variety of biologic and pharmacologic factors. Clinical data (AUC and point ratios) regarding the penetration of several anti-infective agents used for the treatment of CNS infections are provided in this article.     

The mast cells of the mammalian central nervous system. 2. The effect of proton irradiation in the monkey

Young adult monkeys (Macaca mulatta) were irradiated with protons variable in energy and dosage and given at different rates. They died or were killed at intervals and their brains and spinal cords were examined for several changes including the status of the mast cells (MCs) (see Ibrahim 1974). Depending on the animal and the dosage, initial changes in these cells included various combinations of partial or complete degranulation, anisogranulation, hypertrophy and moderate to marked increase in number. These changes are similar to changes recorded in the literature respecting MCs outside the CNS; they resolved, but incompletely, within a few days. When delayed radionecrosis occurred a few months later, the same changes recurred but generally more intensely and were sometimes accompanied by parenchymal perivascular or leptomeningeal mononuclear cell inflammatory infiltrates. Calcification and pigment transformation of some MCs occurred. Also, in 3 cases marked oligodendroglial proliferation in central white matter was seen accompanied by intense MC damage. This proliferation is of interest in relation to experimental and human demyelination. An aetiological relationship between MC changes and both early and delayed vascular and parenchymal damage is possible. The suggestion made by others, that many features of delayed radionecrosis are due to a delayed hypersensitivity reaction, is here reiterated, but in addition there seems also to be a possibility that the MCs are involved in providing the antigen either directly or indirectly. Vascular damage must be responsible for many features of delayed radionecrosis.     

Use of bromodeoxyuridine-immunohistochemistry to examine the proliferation, migration and time of origin of cells in the central nervous system

The use of an exogenously administered thymidine analog, 5-bromo-2'-deoxyuridine (BrdU), for studies of the proliferation, migration and time of origin of cells in the cerebral cortex was investigated and compared with [3H]thymidine [( 3H]dT) autoradiography. Pregnant rats or mice were injected with BrdU and/or [3H]dT and processed by standard immunohistochemical techniques using a primary antibody directed against BrdU in single-stranded DNA, autoradiographic methods, or both. In animals that survived only 1 h after the injection, BrdU-positive cells were distributed in the proliferative zones throughout the central nervous system (CNS). In animals killed 1-3 days after the BrdU injection, intensely immunoreactive cells were in the superficial cortical plate and less intensely labeled cells were scattered throughout the deep cortical plate, the intermediate zone, and the germinal zones. In adult animals, 60 days or more after an injection of BrdU on GD 19, BrdU-positive cells were located in layer II/III of neocortex, the hippocampal pyramidal layer, and the granule layer of the dentate gyrus. In the double-labeling studies, the distribution of BrdU-immunoreactive cells was identical to that of autoradiographically labeled cells, and all autoradiographically labeled neurons were BrdU positive. Thus, BrdU immunohistochemistry is suitable for developmental studies of the CNS; moreover, it provides several advantages over [3H]dT autoradiography.     

Extensive oligodendrocyte remyelination following injection of cultured central nervous system cells into demyelinating lesions in adult central nervous system

Following the injection of central nervous system (CNS) cell cultures, prepared from 1-day-old rats and maintained in vitro for 7 days, into irradiated, demyelinating lesions in the spinal cord of adult isologous animals, extensive remyelination of axons by oligodendrocytes was observed. In addition, astrocytes, within the transplanted cell suspension, established normal relationships with oligodendrocytes, axons and other tissue elements, which led to the establishment of large CNS territories throughout the lesions. Outside these CNS domains, Schwann cells, which are present in the transplanted cell suspension, myelinated groups of axons. These observations indicate that the irradiated, ethidium bromide lesion provides an in vivo environment, devoid of the influences of host glia, in which to examine the interactions of transplanted glial cells with demyelinating axons.     

Neuroinflammation in the central nervous system: Symphony of glial cells

Neuroinflammation in the central nervous system (CNS) is an important subject of neuroimmunological research. Emerging evidence suggests that neuroinflammation is a key player in various neurological disorders, including neurodegenerative diseases and CNS injury. Neuroinflammation is a complex and well-orchestrated process by various groups of glial cells in CNS and peripheral immune cells. The cross-talks between various groups of glial cells in CNS neuroinflammation is an extremely complex and dynamic process which resembles a well-orchestrated symphony. However, the understanding of how glial cells interact with each other to shape the distinctive immune responses of the CNS remains limited. In this review, we will discuss the joint actions of glial cells in three phases of neuroinflammation, including initiation, progression, and prognosis, the three movements of the symphony, as the role of each type of glial cells in neuroinflammation depends on the nature of inflammatory cues and specific course of diseases. This perspective of glial cells in neuroinflammation might provide helpful clues to the development of the early diagnosis and therapeutic intervention of the various CNS diseases.     

Rosai-Dorfman disease of the central nervous system.

Rosai-Dorfman disease (RDD) is an idiopathic, non-neoplastic, lymphoproliferative disorder characterized by sinus histiocytosis and massive lymphadenopathy. When RDD involves the central nervous system the lesion simulates a meningioma. Histological and immunohistochemical confirmation is essential for a definitive diagnosis. In this paper, ten cases of RDD confined to the central nervous system are reported. Another case with orbital RDD was excluded. Nine cases involved the cranial cavity alone; in one, the cervical extradural region was also involved. Treatment consisted of surgical excision or biopsy. Histology and immunohistochemistry revealed a mixed cell population of predominantly mature histiocytes with evidence of emperipolesis and strong positivity for S100 protein in all cases. No recurrence was observed during follow up ranging from three months to eight years.     

Fungal infections of the central nervous system.

This review discusses a practical approach to the patient with possible fungal infection of the central nervous system (CNS). Difficulties in establishing the diagnosis come from the nonspecific clinical syndromes (subacute meningitis, meningoencephalitis, and brain abscess) and the low isolation rate of fungi from cerebrospinal fluid (CSF). Helpful diagnostic clues often come from knowledge of the patient's geographic travels, risk factors, evidence of systemic organ infection, and fungal serologic tests. Standard and new antifungal agents are evaluated and the initial and suppressive drug management of the common fungal infections is presented.