Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

Abstract

There is an increasing number of neurologic disorders found to be associated with loss and/or dysfunction of the CNS myelin sheath, ranging from the classic demyelinating disease, Multiple Sclerosis, through CNS injury, to neuropsychiatric diseases. The disabling burden of these diseases has sparked a growing interest in gaining a better understanding of the molecular mechanisms regulating the differentiation of the myelinating cells of the CNS, oligodendrocytes (OLGs), and the process of (re)myelination. In this context, the importance of the extracellular milieu is becoming increasingly recognized. Under pathological conditions, changes in inhibitory as well as permissive/promotional cues are thought to lead to an overall extracellular environment that is obstructive for the regeneration of the myelin sheath. Given the general view that remyelination is, even though limited in human, a natural response to demyelination, targeting pathologically ‘dysregulated’ extracellular cues and their downstream pathways is regarded as a promising approach toward the enhancement of remyelination by endogenous (or if necessary transplanted) OLG progenitor cells. In this review, we will introduce the extracellular cues that have been implicated in the modulation of (re)myelination. These cues can be soluble, part of the extracellular matrix (ECM) or mediators of cell-cell interactions. Their inhibitory and permissive/promotional roles with regard to remyelination as well as their potential for therapeutic intervention will be discussed.

A single‐cell analysis reveals multiple roles of oligodendroglial lineage cells during post‐ischemic regeneration

“…However, majority of such studies focus on OL lineage cells solely in the context of myelination/ remyelination, as reviewed in many articles (Hughes & Appel, 2016;Chamberlain, Nanescu, & Psachoulia, 2016;Spitzer et al, 2016;Wheeler & Fuss, 2016). However, majority of such studies focus on OL lineage cells solely in the context of myelination/ remyelination, as reviewed in many articles (Hughes & Appel, 2016;Chamberlain, Nanescu, & Psachoulia, 2016;Spitzer et al, 2016;Wheeler & Fuss, 2016).…”

“…The intensive investigation of OL lineage cells brings an enormous amount of information about OLs and their precursors in the healthy CNS, as well as in many pathological states. However, majority of such studies focus on OL lineage cells solely in the context of myelination/ remyelination, as reviewed in many articles (Hughes & Appel, 2016;Chamberlain, Nanescu, & Psachoulia, 2016;Spitzer et al, 2016;Wheeler & Fuss, 2016). Nevertheless, there is also a growing body of evidence proposing the ability of NG2 cells to give rise to other cell types than OLs during development and after CNS injuries, such as ischemia, stab wound injury or demyelinating injury (Honsa et al, , 2012Huang et al, 2014;Komitova, Serwanski, Richard Lu, & Nishiyama, 2011;Zawadzka et al, 2010).…”

The logistics of myelin biogenesis in the central nervous system

“…A perplexingly long list of extracellular signals regulates oligodendrocyte differentiation. Among those are growth factors and signaling molecules (Pdgf, Shh, Wnt, Notch, IGF‐1, Semaphorins), cytokines (LIF, Cxcl1), neurotransmitters (Glutamate, ATP, adenosine), hormones (thyoroid hormone, insulin), extracellular matrix molecules (fibronectin, laminin, CSPGs, Tenascin C, Hyaluranan), metabolic signals (hyopoxia, HIF), physical cues (spatial constrain, rigid substrate), and axonal receptors (Lingo‐1, PSA‐Ncam) (Emery ; Emery and Lu ; Lyons and Talbot ; Mayoral and Chan ; Takebayashi and Ikenaka ; Wheeler and Fuss ). Why are some many different signals needed?…”

The oligodendrocyte growth cone and its actin cytoskeleton: A fundamental element for progenitor cell migration and CNS myelination

“…Once OPCs reach their final destination they differentiate and ultimately myelinate axonal segments. This process of OLG differentiation occurs in a stepwise progression that is characterized by gene expression patterns, which are controlled by both intrinsic and extrinsic signals, and ultimately include typical myelin genes such as proteolipid protein ( Plp1 ) and myelin basic protein ( Mbp ; Elbaz & Popko, ; Emery & Lu, ; Gregath & Lu, ; Liu, Moyon, Hernandez, & Casaccia, ; Pol et al, ; Wheeler & Fuss, ). In addition, OLG differentiation features extensive changes in morphology as OPCs mature first into differentiating, premyelinating OLGs, which extend a complex and expanded process network, and then into mature OLGs generating a fully functional myelin sheath (Bauer, Richter‐Landsberg, & Ffrench‐Constant, ; Michalski & Kothary, ; Pfeiffer, Warrington, & Bansal, ).…”