Derivation of Oligodendrocyte Precursors from Adult Bone Marrow Stromal Cells for Remyelination Therapy

Transplantation of oligodendrocyte precursors (OPs) is potentially therapeutic for myelin disorders but a safe and accessible cell source remains to be identified. Here we report a two-step protocol for derivation of highly enriched populations of OPs from bone marrow stromal cells of young adult rats (aMSCs). Neural progenitors among the aMSCs were expanded in non-adherent sphere-forming cultures and subsequently directed along the OP lineage with the use of glial-inducing growth factors. Immunocytochemical and flow cytometric analyses of these cells confirmed OP-like expression of Olig2, PDGFRα, NG2, and Sox10. OPs so derived formed compact myelin both in vitro, as in co-culture with purified neurons, and in vivo, following transplantation into the corpus callosum of neonatal shiverer mice. Not only did the density of myelinated axons in the corpus callosum of recipient shiverer mice reach levels comparable to those in age-matched wild-type mice, but the mean lifespan of recipient shiverer mice also far exceeded those of non-recipient shiverer mice. Our results thus promise progress in harnessing the OP-generating potential of aMSCs towards cell therapy for myelin disorders.

Wiring and plumbing: Oligodendrocyte precursors and angiogenesis in the oligovascular niche

For efficient stroke recovery, the entire neurovascular unit must be repaired. A recent study underscores this concept by highlighting the importance of cellular crosstalk for white mater remodeling. In developing brains and in brains injured by hypoxia, interactions between oligodendrocyte precursors and endothelium play an essential role for physiological and compensatory angiogenesis. Further studies are warranted to build on these emerging findings in the oligovascular niche in order to identify novel therapeutic targets for stroke and other CNS diseases.

The dynamics of oligodendrocyte generation: how distinct is the mouse from the human?

Murine oligodendrocyte generation dynamics are considered distinct from those in the human, with implications for cross-species differences in neural homeostasis, injury response and ability to functionally adapt circuits through myelin plasticity. We identify that murine oligodendrocyte precursors do not vary their cell division times in vivo and determine how daily production rates change over a lifespan. We show that murine oligodendrogenesis closely resembles what is reported for the human.

Epigenome and transcriptome landscapes highlight dual roles of proinflammatory players in a perinatal model of white matter injury

Premature birth is the commonest cause of death and disability in young children. Diffuse white matter injury (DWMI), provoked by inflammatory insults accompanying prematurity, is associated with increased risk of neurodevelopmental disorders – such as autism spectrum disorders – and is due to maturation arrest in oligodendrocyte precursors (OPCs). The lack of therapeutic solutions is a strong impetus to unveil the molecular mechanisms underlying neuroinflammation impact on OPC cell fate. We used a validated mouse model of DWMI, induced by systemic- and neuro-inflammation – as observed in preterm infants – and based on interleukin-1B administration from postnatal day P1 to P5. Using integrated genome-wide approaches we showed that neuroinflammation induced limited epigenomic disturbances in OPCs, but marked transcriptomic alterations of genes of the immune/inflammatory pathways. We found that these genes were expressed in control OPCs and physiologically downregulated between P3-P10, as part of the OPC normal developmental trajectory. We observed that transcription factors of the inflammatory pathways occupied DNA both in unstressed and inflamed OPCs. Thus, rather than altering genome-wide chromatin accessibility, neuroinflammation takes advantage of open chromatin regions and deeply counteracts the stage-dependent downregulation of these active transcriptional programs by the sustained upregulation of transcript levels. The intricate dual roles – stress-responsive and potentially developmental – of these proinflammatory mediators strongly suggest that the mere suppression of these inflammatory mediators, as currently proposed, may not be a valid neurotherapeutic strategy. Our study provides new insights for the future development of more targeted approaches to protect the preterm brain.Significance statementNeuroinflammation provokes premature birth, the commonest cause of death and disability in children, including autism. Neuroinflammation-induced neurological damage encompasses white matter injury. The actual therapeutic strategies are orientated towards global repression of proinflammatory actors. We explore the epigenomic and transcriptomic impacts of neuroinflammation on a purified cell population of oligodendrocyte precursors cells (OPCs). Rather than altering genome-wide chromatin accessibility, neuroinflammation takes advantage of open chromatin regions and deeply counteracts the stage-dependent downregulation of these active transcriptional programs, in particular that of the inflammatory pathway. These proinflammatory genes are constitutively expressed by OPCs and their physiological downregulation during OPC maturation process is counteracted by neuroinflammation. The intricacy between the OPC physiological and neuroinflammation-responsive expression of these proinflammatory mediators reorientates neuroprotective strategies.

Signalling through AMPA receptors on oligodendrocyte precursors promotes myelination by enhancing oligodendrocyte survival

Myelin, made by oligodendrocytes, is essential for rapid information transfer in the central nervous system. Oligodendrocyte precursors (OPs) receive glutamatergic synaptic input from axons but how this affects their development is unclear. Murine OPs in white matter express AMPA receptor (AMPAR) subunits GluA2, GluA3 and GluA4. We generated mice in which OPs lack both GluA2 and GluA3, or all three subunits GluA2/3/4, which respectively reduced or abolished AMPAR-mediated input to OPs. In both double- and triple-knockouts OP proliferation and number were unchanged but ~25% fewer oligodendrocytes survived in the subcortical white matter during development. In triple knockouts, this shortfall persisted into adulthood. The oligodendrocyte deficit resulted in ~20% fewer myelin sheaths but the average length, number and thickness of myelin internodes made by individual oligodendrocytes appeared normal. Thus, AMPAR-mediated signalling from active axons stimulates myelin production in developing white matter by enhancing oligodendrocyte survival, without influencing myelin synthesis per se.