Origin and dynamics of oligodendrocytes in the developing brain: Implications for perinatal white matter injury

Abstract

Infants born prematurely are at high risk to develop white matter injury (WMI), due to exposure to hypoxic and/or inflammatory insults. Such perinatal insults negatively impact the maturation of oligodendrocytes (OLs), thereby causing deficits in myelination. To elucidate the precise pathophysiology underlying perinatal WMI, it is essential to fully understand the cellular mechanisms contributing to healthy/normal white matter development. OLs are responsible for myelination of axons. During brain development, OLs are generally derived from neuroepithelial zones, where neural stem cells committed to the OL lineage differentiate into OL precursor cells (OPCs). OPCs, in turn, develop into premyelinating OLs and finally mature into myelinating OLs. Recent studies revealed that OPCs develop in multiple waves and form potentially heterogeneous populations. Furthermore, it has been shown that myelination is a dynamic and plastic process with an excess of OPCs being generated and then abolished if not integrated into neural circuits. Myelination patterns between rodents and humans show high spatial and temporal similarity. Therefore, experimental studies on OL biology may provide novel insights into the pathophysiology of WMI in the preterm infant and offers new perspectives on potential treatments for these patients.

Human Umbilical Cord Blood Therapy Protects Cerebral White Matter from Systemic LPS Exposure in Preterm Fetal Sheep

“…This could be attributed to the well-characterised selective vulnerability of white matter regions and cells as gestation progresses [42]. Whilst the white matter regions were selected based on expected regional vulnerability near the lateral ventricles, each animal may be developmentally different; the process of maturation of oligodendrocyte lineage cells demonstrates a high degree of developmental plasticity over this highly dynamic period for white matter development [13]. In some cases, we were also limited by a small sample size for tissue analysis; that is, due to the nature of the fragile preterm tissue, analysis often could only be conducted in 5-6 animals/group (see Figure legends).…”

“…In modern cohorts of preterm infants, white matter pathology most commonly takes the form of non-cystic diffuse periventricular leukomalacia [13], wherein cerebral injury is microscopic and isolated to the central white matter with evidence of glial scarring, but without large cystic formations [12]. With advancing knowledge of the relationship between chorioamnionitis, fetal inflammation, preterm birth, and poor neurological outcome, treatment strategies must target cerebral inflammation to protect against injury to the developing brain following chorioamnionitis.…”

NG2 Glia: Novel Roles beyond Re-/Myelination

“…A detailed and comprehensive examination of NG2 glia behaviors/molecular changes upon lesion will likely unveil some elements of cell heterogeneity (see above). Indeed, diverse NG2 glia subpopulations have also been described in the intact CNS based on their origin, proliferative activity, division modality, differentiation potential, expression of diverse transcription factors, Ca 2+ -binding molecules, neurotransmitter receptors, and ionic currents [5,23,48,69,212]. Thus, it is conceivable that subsets of functionally specialized NG2 glia may be differentially tailored to contribute to distinct aspects of CNS homeostasis, including oligodendrogenesis and additional/alternative functions.…”

“…This indicates that the reactivity and amplification of NG2 glia (or at least of some NG2 glia subsets) per se does not simply reflect a regenerative event. The post-injury emergence of transient NG2 glia populations is reminiscent of the developmental scenario, where three waves of NG2 glia are sequentially produced in the forebrain, and the first embryonically-generated cells are entirely replaced during the first week of life [23]. The generation of such cell populations that do not contribute to myelination suggests again that NG2 glia/glial subsets exert additional/alternative functions in specific developmental/post-injury phases.…”

Spontaneous development of intratumoral heterogeneity in a transposon‐induced mouse model of glioma

“…PDGF signaling is a key regulator of oligodendrocyte development and for glioma. 14,15 The PDGF family consists of covalently linked hetero-or homodimers of A-, B-, C-, and D-chains (PDGF-AA, -AB, -BB, -CC, and -DD). These ligands bind to heterodimeric a and b tyrosine kinase receptors and activate downstream signaling.…”