Cells of the oligodendroglial lineage, myelination, and remyelination

Myelin is critical in maintaining electrical impulse conduction in the central nervous system. The oligodendrocyte is the cell type responsible for myelin production within this compartment. The mutual supply of trophic support between oligodendrocytes and the underlying axons may indicate why demyelinated axons undergo degeneration more readily; the latter contributes to the neural decline in multiple sclerosis (MS). Myelin repair, termed remyelination, occurs in acute inflammatory lesions in MS and is associated with functional recovery and clinical remittances. Animal models have demonstrated that remyelination is mediated by oligodendrocyte progenitor cells (OPCs) which have responded to chemotactic cues, migrated into the lesion, proliferated, differentiated into mature oligodendrocytes, and ensheathed demyelinated axons. The limited remyelination observed in more chronic MS lesions may reflect intrinsic properties of neural cells or extrinsic deterrents. Therapeutic strategies currently under development include transplantation of exogenous OPCs and promotion of remyelination by endogenous OPCs. All currently approved MS therapies are aimed at dampening the immune response and are not directly targeting neural processes.     

LINGO-1, a transmembrane signaling protein, inhibits oligodendrocyte differentiation and myelination through intercellular self-interactions

Overcoming remyelination failure is a major goal of new therapies for demyelinating diseases like multiple sclerosis. LINGO-1, a key negative regulator of myelination, is a transmembrane signaling protein expressed in both neurons and oligodendrocytes. In neurons, LINGO-1 is an integral component of the Nogo receptor complex, which inhibits axonal growth via RhoA. Because the only ligand-binding subunit of this complex, the Nogo receptor, is absent in oligodendrocytes, the extracellular signals that inhibit myelination through a LINGO-1-mediated mechanism are unknown. Here we show that LINGO-1 inhibits oligodendrocyte terminal differentiation through intercellular interactions and is capable of a self-association in trans. Consistent with previous reports, overexpression of full-length LINGO-1 inhibited differentiation of oligodendrocyte precursor cells (OPCs). Unexpectedly, treatment with a soluble recombinant LINGO-1 ectodomain also had an inhibitory effect on OPCs and decreased myelinated axonal segments in cocultures with neurons from dorsal root ganglia. We demonstrated LINGO-1-mediated inhibition of OPCs through intercellular signaling by using a surface-bound LINGO-1 construct expressed ectopically in astrocytes. Further investigation showed that the soluble LINGO-1 ectodomain can interact with itself in trans by binding to CHO cells expressing full-length LINGO-1. Finally, we observed that soluble LINGO-1 could activate RhoA in OPCs. We propose that LINGO-1 acts as both a ligand and a receptor and that the mechanism by which it negatively regulates OPC differentiation and myelination is mediated by a homophilic intercellular interaction. Disruption of this protein-protein interaction could lead to a decrease of LINGO-1 inhibition and an increase in myelination.     

Plasticity of Neurons and Glia Following Neonatal Hypoxic-Ischemic Brain Injury in Rats

Periventricular white matter injury in premature infants is linked to chronic neurological dysfunction. Periventricular white matter injury is caused by many mechanisms including hypoxia-ischemia (HI). Animal models of HI in the neonatal rodent brain can replicate some important features of periventricular white matter injury. Most rodent studies have focused upon early cellular and tissue events following unilateral neonatal HI that is elicited by unilateral carotid artery ligation and followed by timed exposure to moderate hypoxia. Milder hypoxic-ischemic insults elicit preferential white matter injury. Little information is available about long-term cellular effects of unilateral HI. One month after unilateral neonatal hypoxia ischemia, we show that all the components for structural reorganization of the brain are present in moderately injured rats. These components in the injured side include extensive influx of neurites, axonal and dendritic growth cones, abundant immature synapses, and myelination of many small axons. Surprisingly, this neural recovery is often found in and adjacent to cysts that have the ultrastructural features of bone extracellular matrix. In contrast, brains with severe hypoxia ischemia one month after injury still undergo massive neuronal degeneration. While massive destruction of neurons and glia are striking events shortly after brain HI, neural cells re-express their intrinsic properties and attempt an anatomical recovery long after injury. Special issue dedicated to Anthony Campagnoni.     

CNTF-Activated Astrocytes Release a Soluble Trophic Activity for Oligodendrocyte Progenitors

CNTF (ciliary neurotrophic factor) has been suggested to be an important survival factor for oligodendrocytes; however, this effect is inconsistently obtained and myelination appears normal in CNTF null animals. On the other hand, CNTF stimulates astrocytes to produce growth and trophic factors. Therefore, we tested the hypothesis that CNTF acts indirectly through astrocytes to promote oligodendrocyte survival. We show that CNTF-stimulated astrocytes release a trophic factor(s) that leads to more than double the number of oligodendrocyte progenitor cells (OPCs) by 48 h. The trophic activity fractionates at greater than 30 kD. By contrast, OPCs grown in CNTF supplemented chemically defined medium fared no better than cells grown without CNTF. Untreated astrocytes, and CNTF- and IL-1β -stimulated astrocytes all promoted the proliferation of OPCs to a similar extent, but only the CNTF-stimulated astrocyte conditioned media (CM) resulted in increased OPCs numbers. Cumulatively, these results confirm previous data indicating that astrocytes release potent mitogens for oligodendroglia, and demonstrate that CNTF stimulates astrocytes to release an OPC survival-promoting activity.     

Olig2在cuprizone介导的脱髓鞘动物模型中的表达变化

目的探讨Olig2在cuprizone诱导的急性脱髓鞘动物模型中的表达变化规律。方法应用含0.2%cuprizone饲料饲育小鼠,通过调控饲育时间,造成神经脱髓鞘及髓鞘再生,使用免疫荧光染色和实时定量PCR(qRT-PCR)的方法,观察模型髓鞘脱失后及髓鞘再生2周后Olig2、少突胶质细胞碱性髓鞘蛋白(MBP)及星形胶质细胞神经胶质酸性蛋白(GFAP)的表达变化。结果 Cuprizone饲育6周后,动物胼胝体白质内髓鞘脱失严重,在恢复正常饲料后,髓鞘逐渐恢复正常结构。正常小鼠大脑Olig2低水平表达。髓鞘脱失后Olig2、GFAP表达增高,并可见Olig2+/GFAP+细胞,MBP表达明显降低。髓鞘再生2周后Olig2表达降低,MBP、GFAP表达增高。结论 Olig2基因在cuprizone诱导的脱髓鞘模型中的表达变化,提示Olig2可能参与祖细胞向有活性的星形胶质细胞的分化过程,并与胶质瘢痕的形成有关。     

Transplantation of mature adipocyte-derived dedifferentiated fat cells promotes locomotor functional recovery by remyelination and glial scar reduction after spinal cord injury in mice

Mature adipocyte-derived dedifferentiated fat cells (DFAT) have a potential to be useful as new cell-source for cell-based therapy for spinal cord injury (SCI), but the mechanisms remain unclear. The objective of this study was to examine whether DFAT-induced functional recovery is achieved through remyelination and/or glial scar reduction in a mice model of SCI. To accomplish this we subjected adult female mice (n = 22) to SCI. On the 8th day post-injury locomotor tests were performed, and the mice were randomly divided into two groups (control and DFAT). The DFAT group received stereotaxic injection of DFAT, while the controls received DMEM medium. Functional tests were conducted at repeated intervals, until the 36th day, and immunohistochemistry or staining was performed on the spinal cord sections. DFAT transplantation significantly improved locomotor function of their hindlimbs, and promoted remyelination and glial scar reduction, when compared to the controls. There were significant and positive correlations between promotion of remyelination or/and reduction of glial scar, and recovery of locomotor function. Furthermore, transplanted DFAT expressed markers for neuron, astrocyte, and oligodendrocyte, along with neurotrophic factors, within the injured spinal cord. In conclusion, DFAT-induced functional recovery in mice after SCI is probably mediated by both cell-autonomous and cell-non-autonomous effects on remyelination of the injured spinal cord.     

Promoting remyelination: A case study in regenerative medicine

Therapeutics that modulate regenerative mechanisms by targeting the activity of endogenous (adult) stem cell populations have the potential to revolutionize medicine. In many human disease states, capacity to repair damaged tissue underlies progressive decline and disease progression. Recent insights derived from efforts aimed at promoting remyelination for the treatment of multiple sclerosis (MS) highlight the importance of considering the limiting factors and underlying mechanisms associated with all aspects of disease onset, progression and recovery, during both the discovery and clinical stages of developing a regenerative medicine. This perspective presents general considerations for the development of regenerative therapies, using remyelination as a case study.     

Nutritional factors and aging in demyelinating diseases

Demyelination is a pathological process characterized by the loss of myelin around axons. In the central nervous system, oligodendroglial damage and demyelination are common pathological features characterizing white matter and neurodegenerative disorders. Remyelination is a regenerative process by which myelin sheaths are restored to demyelinated axons, resolving functional deficits. This process is often deficient in demyelinating diseases such as multiple sclerosis (MS), and the reasons for the failure of repair mechanisms remain unclear. The characterization of these mechanisms and the factors involved in the proliferation, recruitment, and differentiation of oligodendroglial progenitor cells is key in designing strategies to improve remyelination in demyelinating disorders. First, a very dynamic combination of different molecules such as growth factors, cytokines, chemokines, and different signaling pathways is tightly regulated during the remyelination process. Second, factors unrelated to this pathology, i.e., age and genetic background, may impact disease progression either positively or negatively, and in particular, age-related remyelination failure has been proven to involve oligodendroglial cells aging and their intrinsic capacities among other factors. Third, nutrients may either help or hinder disease progression. Experimental evidence supports the anti-inflammatory role of omega-6 and omega-3 polyunsaturated fatty acids through the competitive inhibition of arachidonic acid, whose metabolites participate in inflammation, and the reduction in T cell proliferation. In turn, vitamin D intake and synthesis have been associated with lower MS incidence levels, while vitamin D–gene interactions might be involved in the pathogenesis of MS. Finally, dietary polyphenols have been reported to mitigate demyelination by modulating the immune response.     

Interferon-β Is a Potent Promoter of Nerve Growth Factor Production by Astrocytes

Abstract: Recent clinical evidence has suggested that interferon-β is efficacious in the treatment of the demyelinating disease, multiple sclerosis. The mechanism of its efficacy remains unclear, and suggested modes of action have focused on immune modulation. Nonimmune effects of interferon-β may also contribute to its efficacy. Given that astrocytes produce a range of neurotrophic factors, we examined the possibility that interferon-β could increase the astrocytic production of nerve growth factor (NGF), which has been reported to cause oligodendrocytes to proliferate and to extend their processes; these phenotypes can impact favorably on remyelination. When the recombinant form of mouse interferon-β was added to mouse astrocyte cultures, a dose-dependent increase in NGF mRNA was obtained. The 40-fold increase in NGF mRNA elicited by 1,000 U/ml interferon-β was far more potent than that produced by other NGF-elevating agents in this study. In concordance, the protein for NGF was elevated by interferon-β. The production of NGF by interferon-β may be relevant to its clinical efficacy in multiple sclerosis. Furthermore, we suggest the potential utility of interferon-β in Alzheimer's disease.