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, 594 (13), 3539-52

Microenvironmental Regulation of Oligodendrocyte Replacement and Remyelination in Spinal Cord Injury


Microenvironmental Regulation of Oligodendrocyte Replacement and Remyelination in Spinal Cord Injury

Arsalan Alizadeh et al. J Physiol.


Myelin is a proteolipid sheath enwrapping axons in the nervous system that facilitates signal transduction along the axons. In the central nervous system (CNS), oligodendrocytes are specialized glial cells responsible for myelin formation and maintenance. Following spinal cord injury (SCI), oligodendroglia cell death and myelin damage (demyelination) cause chronic axonal damage and irreparable loss of sensory and motor functions. Accumulating evidence shows that replacement of damaged oligodendrocytes and renewal of myelin (remyelination) are promising approaches to prevent axonal degeneration and restore function following SCI. Neural precursor cells (NPCs) and oligodendrocyte progenitor cells (OPCs) are two main resident cell populations in the spinal cord with innate capacities to foster endogenous oligodendrocyte replacement and remyelination. However, due to the hostile microenvironment of SCI, the regenerative capacity of these endogenous precursor cells is conspicuously restricted. Activated resident glia, along with infiltrating immune cells, are among the key modulators of secondary injury mechanisms that create a milieu impermissible to oligodendrocyte differentiation and remyelination. Recent studies have uncovered inhibitory roles for astrocyte-associated molecules such as matrix chondroitin sulfate proteoglycans (CSPGs), and a plethora of pro-inflammatory cytokines and neurotoxic factors produced by activated microglia/macrophages. The quality of axonal remyelination is additionally challenged by dysregulation of the supportive growth factors required for maturation of new oligodendrocytes and axo-oligodendrocyte signalling. Careful understanding of factors that modulate the activity of endogenous precursor cells in the injury microenvironment is a key step in developing efficient repair strategies for remyelination and functional recovery following SCI.


Figure 1
Figure 1. The molecular inhibitors and activators of oligodendrocyte lineage development and myelination
A–E, schematic diagram shows growth factors and cytokines that promote OPC survival and proliferation (A), oligodendrocyte differentiation (B), oligodendrocyte survival (C) and maturation (D), and myelination/remyelination (E) (Almazan et al. 1985; Matthieu et al. 1992; Barres et al. 1993; Vos et al. 1996; Woodruff & Franklin, 1997; Calver et al. 1998; Hinks & Franklin, 1999; Baron et al. 2000; Arnett et al. 2001; Buonanno & Fischbach, 2001; Calaora et al. 2001; Valerio et al. 2002; Falls, 2003; Frost et al. 2003; Knapp & Adams, 2004; Foote & Blakemore, 2005; Chen et al. 2006; Du et al. 2006; Hapner et al. 2006; Hohlfeld et al. 2007; Vana et al. 2007; Zawadzka & Franklin, 2007; Brinkmann et al. 2008; Hu et al. 2008; Van't Veer et al. 2009; Xiao et al. 2010; Breton & Mao‐Draayer, 2011; Fricker et al. 2011; Gauthier et al. 2013; Peferoen et al. 2014; Dyck et al. 2015). F–I, examples of inhibitory factors that impair oligodendrocyte lineage survival, proliferation (F), differentiation (G) and myelination (I) (Mi et al. 2005; Kotter et al. 2006; Syed et al. 2011; as reviewed by Peferoen et al. 2014; Zhang et al. 2015). EGF, epidermal growth factor; CNTF, Ciliary neurotrophic factor.
Figure 2
Figure 2. Signalling mechanisms of oligodendrocyte fate specification and maturation
Schematic diagram showing identified extracellular and intracellular signals involved in regulation of NPCs and OPCs. A, endothelin‐1 (ET‐1) is a soluble factor produced by reactive astrocytes that increases astrocyte expression of Jagged1 (a Notch signalling ligand). Astrocyte derived Jagged‐1 activates Notch signalling in OPCs, and inhibits oligodendrocyte differentiation and remyelination (Hammond et al. 2014). B, LIF promotes OPC differentiation and remyelination through activation of STAT‐3 signalling in OPCs (Mayer et al. 1994; Rittchen et al. 2015). C, CSPGs inhibit oligodendrocyte growth and myelination through LAR and RPTP‐σ signalling pathways and activation of Rho/ROCK pathway in both NPCs and OPCs (Lau et al. 2012; Pendleton et al. 2013; Dyck et al. 2015). D, Nrg‐1 and its signalling receptors form a major regulatory network of oligodendrocyte development and maturation. Nrg‐1 can bind to ErbB3 and ErbB4 with high affinity (Carraway & Cantley, 1994). Upon binding to Nrg‐1, ErbB receptors can form homo‐ or heterodimers and activate multiple pathways through their intracellular tyrosine kinase domain. Nrg‐1 signalling has been shown to activate Jak/STAT, Erk/MAPK and PI3/Akt that are associated with cell survival, proliferation and differentiation (Gambarotta et al. 2004; Shyu et al. 2004; Liu X et al. 2006; Li et al. 2007, 2015; Brinkmann et al. 2008; Mei & Xiong, 2008; Guo et al. 2010; Pirotte et al. 2010; Syed et al. 2010; Jabbour et al. 2011; Liu Z et al. 2011; Ortega et al. 2012; Tao et al. 2013; Gauthier et al. 2013). However, the impact of each specific ErbB receptor in mediating Nrg‐1 effects on each stage of oligodendrocyte lineage development and myelination remains to be elucidated.

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