How factors secreted from astrocytes impact myelin repair

Abstract

Over a century ago, hypertrophy of astrocytes was noted as a pathology of multiple sclerosis (MS) and was hypothesized to play an important role in this disease, yet the contribution of astrocytes has been largely underemphasized in the pathophysiology of CNS demyelination. Astrocytes perform many homeostatic functions within the developing and adult CNS, including enhancing formation and maintenance of the blood-brain barrier, moderating neuronal connections through the tripartite synapse, and perhaps even offering intercellular communication independently of neurons. Although there is a significant body of literature characterizing different types of MS lesions, the inflammatory demyelination in an active MS lesion is accompanied by the presence of macrophages, lymphocytes, and large reactive astrocytes. The astrocyte has long been viewed as a cell that promotes inflammation and demyelination, while also forming the glial scar, thus hindering remyelination and axon growth. Renewed interest in the astrocyte has been brought about by recent studies demonstrating that astrocytes can also function as cellular mediators of CNS myelination by promoting oligodendrocyte progenitor migration, proliferation, and differentiation. Thus, refining our knowledge of astrocytic functions in the regulation of CNS myelination may help us to better understand why remyelination fails in MS.

Peripherally derived FGF21 promotes remyelination in the central nervous system

“…OPC proliferation and subsequent remyelination processes (e.g., migration, differentiation into mature oligodendrocytes) ensure the restoration of saltatory conduction (7), provision of trophic support for axons (8), and promotion of functional recovery (9); therefore, the mechanism of remyelination has attracted considerable attention in regard to its potential applications in regenerative medicine aimed at treating CNS demyelinating diseases. Remyelination is thought to be dependent on factors derived from the CNS microenvironment (10,11). For example, plateletderived growth factor (PDGF) and basic fibroblast growth factor (FGF), which are expressed by astrocytes (10), are both important for OPC proliferation (12).…”

“…Remyelination is thought to be dependent on factors derived from the CNS microenvironment (10,11). For example, plateletderived growth factor (PDGF) and basic fibroblast growth factor (FGF), which are expressed by astrocytes (10), are both important for OPC proliferation (12). Other studies have shown that factors secreted by vascular cells promote remyelination (13,14).…”

Gene expression profiling of the astrocyte transcriptome in multiple sclerosis normal appearing white matter reveals a neuroprotective role

“…While it has been suggested that astrocytes play a neuroprotective role in MS by inhibiting demyelination (Miljkovic et al, 2011), releasing anti-inflammatory cytokines (Bsibsi et al, 2006) and secreting proteins involved in myelin repair and neurotrophins to support regeneration of neurons (Marz et al, 1999, Moore et al, 2011a, Moore et al, 2011b, Mason et al, 2001, Miljkovic et al, 2011, it has also been proposed that astrocytes are detrimental in disease pathogenesis by releasing proinflammatory cytokines, contributing to BBB dysfunction (Argaw et al, 2006, Argaw et al, 2012 and preventing oligodendrocyte precursor cell (OPC) maturation into remyelinating oligodendrocytes (Messersmith et al, 2000, Sarchielli et al, 2008.…”

Methylthioadenosine promotes remyelination by inducing oligodendrocyte differentiation

“…The identification of pathways that control OPC differentiation and myelination has paved the way for the development of new approaches to achieve remyelination [34]. CNTF is produced by microglia and astrocytes following brain injury [35,36], and it enhances the survival and differentiation of OLs [30][31][32][33]. Finally, methylthioadenosine is signalling through adenosine receptors [37], and activation of adenosine receptor in OPCs promote myelination [38].…”