Astrocytes in Oligodendrocyte Lineage Development and White Matter Pathology

Abstract

White matter is primarily composed of myelin and myelinated axons. Structural and functional completeness of myelin is critical for the reliable and efficient transmission of information. White matter injury has been associated with the development of many demyelinating diseases. Despite a variety of scientific advances aimed at promoting re-myelination, their benefit has proven at best to be marginal. Research suggests that the failure of the re-myelination process may be the result of an unfavorable microenvironment. Astrocytes, are the most ample and diverse type of glial cells in central nervous system (CNS) which display multiple functions for the cells of the oligodendrocytes lineage. As such, much attention has recently been drawn to astrocyte function in terms of white matter myelin repair. They are different in white matter from those in gray matter in specific regards to development, morphology, location, protein expression and other supportive functions. During the process of demyelination and re-myelination, the functions of astrocytes are dynamic in that they are able to change functions in accordance to different time points, triggers or reactive pathways resulting in vastly different biologic effects. They have pivotal effects on oligodendrocytes and other cell types in the oligodendrocyte lineage by serving as an energy supplier, a participant of immunological and inflammatory functions, a source of trophic factors and iron and a sustainer of homeostasis. Astrocytic impairment has been shown to be directly linked to the development of neuromyelities optica (NMO). In addition, astroctyes have also been implicated in other white matter conditions such as psychiatric disorders and neurodegenerative diseases such as Alzheimer’s disease (AD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Inhibiting specifically detrimental signaling pathways in astrocytes while preserving their beneficial functions may be a promising approach for remyelination strategies. As such, the ability to manipulate astrocyte function represents a novel therapeutic approach that can repair the damaged myelin that is known to occur in a variety of white matter-related disorders.

Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination

“…It is possible that these antibodies may induce secondary demyelination as observed with AQP4-targeted rAbs [32, 33]. The impact of injured astrocytes and neurons on oligodendrocytes through glia-glia [12, 17] and axon-glia interactions [6, 7, 31] has been well documented. These antibodies may also cause primary degeneration or facilitate the removal of cellular debris.…”

CD133-Positive Membrane Particles in Cerebrospinal Fluid of Patients with Inflammatory and Degenerative Neurological Diseases

“…Astrocytes and especially their reduced astrocytic response have been linked to neurodegenerative disease such as Alzheimer’s disease and amyotrophic lateral sclerosis (Li et al, 2016). Results suggest that astrocytes affect oligodendrocytes via Aß pathways in Alzheimer’s disease, moreover, they are linked to progressive loss of corticospinal and spinal motor neurons by progressive reactive astrogliosis and reduction in myelin (Kang et al, 2013; Fu et al, 2015; Li et al, 2016). As shown here, also Parkinson’s disease patients show increased CSF-associated CD133.…”

“…In multiple sclerosis, proinflammatory cytokines are assumed to attack pathogenic cells and destroy oligodendrocytes, myelin, and axons. Then protective trophic factors may modify the blood-brain barrier and modulate the extracellular matrix (Nait-Oumesmar et al, 2008; Guo et al, 2011; Kummerfeld et al, 2012; Cristofanilli et al, 2014; Li et al, 2016; Ludwin et al, 2016). Reactive gliogenesis on the one hand, massive myelin destruction with the release of myelin-derived CD133 into CSF on the other hand, may explain the high CD133-levels in multiple sclerosis, especially in those patients with a very high disease activity.…”

Mechanisms Involved in the Remyelinating Effect of Sildenafil

“…OLs can have over 50 extensions reaching axons, and can myelinate them simultaneously (Copray et al 2006, Liu et al 2007, Nave 2010. OLs can interact with surrounding cells that influence OLs migration, differentiation and myelination (Kimelberg 2010, Li et al 2016, Talbott et al 2005. OL proliferation and differentiation is regulated by cytokines and growth factors (Nave 2010), such as BDNF (De Santi et al 2009, Weishaupt et al 2012 and CNTF (Stankoff et al 2002).…”