ReviewOligodendrocyte progenitor programming and reprogramming: Toward myelin regeneration
Introduction
Diseases that result in demyelination in the central nervous system (CNS) such as multiple sclerosis (MS), leukodystrophies, and cerebral palsy are major causes of neurological mortality and morbidity (Fancy et al., 2011, Franklin and Ffrench-Constant, 2008). In MS lesions, the myelin sheaths that wrap axons are damaged, resulting in impaired axonal conduction and neurological dysfunctions. Although MS is thought to be an autoimmune-mediated demyelinating disease, several immune-focused treatment methods for this disease show only partial benefits and do not result in lesion repair (Franklin and Ffrench-Constant, 2008, Zawadzka and Franklin, 2007). Loss of oligodendrocytes (OLs) that produce myelin is a hallmark of MS. Although neural stem cells are able to produce OLs in the adult brain (Alvarez-Buylla et al., 2000, Dimou et al., 2008, Rivers et al., 2008), their capacity to replenish OLs is limited. This has sparked considerable interest in treating demyelinating diseases in the CNS by enhancing the production of OLs and their precursors, OL precursor cells (OPCs). During development and adulthood, OPCs reside throughout the CNS and could be an important cell source for myelin regeneration in multifocal demyelinating lesions in MS.
OPCs are characterized by expression of platelet-derived growth factor receptor alpha (PDGFRα) and the proteoglycan NG2 (Levison et al., 1999, Nishiyama et al., 2002, Rivers et al., 2008, Zhu et al., 2008). OPCs produce differentiating and mature OLs in the CNS throughout the lifespan of the animals (Dawson et al., 2003). Moreover, in their undifferentiated state, OPCs exhibit specific electrophysiological properties and integrate into the cellular network that modulates neuronal activity and responds to pathological insults (Bergles et al., 2010). Recent studies indicate that OPCs may become multipotent and capable of adopting different cell fates under certain circumstances. For instance, a misguided differentiation of OPCs into astrocytes may exhaust the reparative cell pool, which contributes to remyelination failure in MS (Kotter et al., 2011).
In this review, we will discuss recent advances in OPC programming and reprogramming, including their developmental origins, plasticity, and the factors that direct OL lineage progression. We will also evaluate recently described strategies of mobilizing endogenous neural progenitor cells and reprograming of differentiated cells into OPCs, and their respective effectiveness in remyelination. Finally, we discuss how to harness current knowledge to develop effective therapeutic strategies to replace OL loss and promote myelin repair in MS patients.
Section snippets
Distribution, developmental origins, and heterogeneity of OPCs
OPCs are found throughout the CNS and reside in both the gray and white matter. Approximately 5–8% of the cells in the brain are OPCs (Dawson et al., 2003, Levine et al., 2001). OPCs represent a major proliferative population in the adult CNS of mammals, including humans (Alonso, 2000, Dawson et al., 2003, Geha et al., 2010, Peters, 2004, Smart and Leblond, 1961, Tamura et al., 2007). Due to their distribution and abundance, it has been proposed that OPCs represent the fourth major glial cell
Adult OPC generation and functions
A population of OPCs generated during development are maintained as an immature slowly proliferative or quiescent state in the adult CNS (Dawson et al., 2003). Studies have demonstrated that NG2+ OPCs in the adult brain display a very long cell cycle length with a prolonged G1-phase (Simon et al., 2011). In line with this, analysis of the integration of nuclear bomb test-derived C14 reveals that OLs in the white matter are remarkably stable during adult life of humans and have low turnover
OPCs exhibit cell-fate plasticity
The developmental process of OPCs is highly plastic. OPCs have the potential to differentiate into astrocytes and even neurons depending on the signals available within a given niche. The ability of OPCs to form OLs and type 2 astrocytes in vitro has been well established (Raff et al., 1983); however, whether this plasticity of OPCs is a cell-culture artifact or actually occurs during normal development has been a matter of intense debate. Cultured OPCs can differentiate into astrocytes in
Diverse extrinsic factors regulate OPC specification and plasticity
Distinct and opposing extrinsic factors modulate and balance OPC fate specification (Fig. 1). In the developing neural tube, OPCs originate in the ventral neural epithelium under the influence of extracellular ligands such as sonic hedgehog (Shh) and BMP, which exert opposing effects on OPC specification. Shh secreted from the ventral neural tube and floor plate induces OPC specification, whereas BMP signaling inhibits the process (Orentas et al., 1999, Poncet et al., 1996, Pringle et al., 1996
Control of OPC specification and plasticity by intrinsic factors
OPC fate specification and their lineage plasticity are coordinated and fine-tuned by a series of cell-intrinsic regulators (Fig. 1). During development, the basic helix-loop-helix transcription factor Olig2 is not only necessary for OPC specification and their differentiation, but also, in some contexts, sufficient for OPC generation (Liu et al., 2007, Lu et al., 2002, Takebayashi et al., 2002, Zhou et al., 2001, Zhou and Anderson, 2002). Olig2 deletion leads to a loss of the majority of OL
Repair of myelin damage by OPC programming and reprogramming
At least two main approaches have been proposed to enhance the production of mature OLs (Vishwakarma et al., 2014). The first is through the transplantation of OPCs, and the second involves mobilization of endogenous OPCs to form mature myelinating OLs (Fig. 2). Transplantation of OPCs into lesions in the injured or diseased CNS is a promising therapeutic strategy; however, generation of OPCs from stem cells or from other somatic sources has proven challenging. A series of strategies have been
Challenges and future directions
The limited self-repair potential of the brain has encouraged the exploration of strategies to replace OLs lost to demyelinating diseases. Direct programming or reprogramming of diverse cell types (from autologous and even endogenous cell sources) toward OPC fate is a promising therapeutic strategy. OPC differentiation and reprogramming are dynamic processes, and the interplay of sustained and transient expression of key regulators controls the ultimate cell fate. During OL lineage progression,
Acknowledgments
This study was funded in part by Grants from the US National Institutes of Health (R01NS072427 and R01NS075243) and the National Multiple Sclerosis Society (RG3978) to QRL.
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2019, Free Radical Biology and MedicineCitation Excerpt :The oligodendrocyte progenitor cells (OPCs) persist in substantial numbers in the adult optic nerve in a quiescent state and provide a source of new oligodendrocytes after injury [14,15]. The proliferation and differentiation of OPCs into oligodendrocytes is critical for myelination of optic nerves, which is required to establish the proper communication between the retina and the brain [16–18]. Damage to the myelin sheath and oligodendrocytes of the optic nerve fibers directly affects the neurofilament composition and functions of axons following TBI [19].
Oligodendrocyte precursor cells as a therapeutic target for demyelinating diseases
2019, Progress in Brain ResearchCitation Excerpt :It is thus not surprising that research efforts are shifting to the next phase of MS therapy, namely, remyelination/regeneration (Deshmukh et al., 2013; Franklin and ffrench-Constant, 2017; Luessi et al., 2014; Olsen and Akirav, 2015; Plemel et al., 2017; Ransohoff et al., 2015, Stangel et al., 2017; Tremer et al., 2016). Such strategies are based on both cell replacement/reprogramming of differentiated cells into OPCs and application of small molecule compounds that control OPC specification and differentiation to promote remyelination and neuroprotection (Deshmukh et al., 2013; Lopez Juarez et al., 2015; Mei et al., 2014; Najm et al., 2015; Wang et al., 2013). MS lesions are distinguished by the presence of undifferentiated OPCs, highlighting their inability to mature into myelin-producing oligodendrocytes (Chang et al., 2002).
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These authors contributed equally.