Differential effects of glucose deprivation on the survival of fetal versus adult neural stem cells‐derived oligodendrocyte precursor cells

Abstract

Impaired myelination is a key feature in neonatal hypoxia/ischemia (HI), the most common perinatal/neonatal cause of death and permanent disabilities, which is triggered by the establishment of an inflammatory and hypoxic environment during the most critical period of myelin development. This process is dependent on oligodendrocyte precursor cells (OPCs) and their capability to differentiate into mature oligodendrocytes. In this study, we investigated the vulnerability of fetal and adult OPCs derived from neural stem cells (NSCs) to inflammatory and HI insults. The resulting OPCs/astrocytes cultures were exposed to cytokines to mimic inflammation, or to oxygen–glucose deprivation (OGD) to mimic an HI condition. The differentiation of both fetal and adult OPCs is completely abolished following exposure to inflammatory cytokines, while only fetal‐derived OPCs degenerate when exposed to OGD. We then investigated possible mechanisms involved in OGD‐mediated toxicity: (a) T3‐mediated maturation induction; (b) glutamate excitotoxicity; (c) glucose metabolism. We found that while no substantial differences were observed in T3 intracellular content regulation and glutamate‐mediated toxicity, glucose deprivation lead to selective OPC cell death and impaired differentiation in fetal cultures only. These results indicate that the biological response of OPCs to inflammation and demyelination is different in fetal and adult cells, and that the glucose metabolism perturbation in fetal central nervous system (CNS) may significantly contribute to neonatal pathologies. An understanding of the underlying molecular mechanism will contribute greatly to differentiating myelination enhancing and neuroprotective therapies for neonatal and adult CNS white matter lesions.

White Matter and Neuroprotection in Alzheimer’s Dementia

“…This has been proven by the comparison between OPCs derived from fetal and from adult neural stem cells (NSCs) exposed to OGD, the in vitro model of HI. These experiments lead show that only fetal cells are vulnerable to OGD-mediated cell toxicity [45] while, notably, both fetal and adult OPCs respond in the same way to inflammation-induced differentiation block. The differing responses of fetal and adult OPCs in the HI context is not surprising, since the two cell types, even with the same derivation (i.e., the NSC) show differences in their biology and differentiation processes [70].…”

“…However, the damage of myelin and myelin-forming cells contribute to a wide range of neurodegenerative diseases and CNS injuries, a predictable finding given the complex role exerted by these cells in neuronal functions, not only in providing physical and anatomical support, but also as a functional player in neuronal processes, from metabolism to signaling regulation [41,42]. Cells belonging to the OL lineage are as vulnerable as neurons to noxious stimuli, enough to be considered as the most vulnerable cells of the CNS [43][44][45] highlighting their implication in the onset and progression of neurodegenerative diseases. A comparative analysis of cell death in neuronal pure and neurons-astrocytes mixed culture, in OPC at different differentiation stages (NG2-positivity for OPC, CNPase-positivity for mature OLs and MBP-positivity for myelinating OLs), and astrocytes after exposure to OGD is presented in Figure 3.…”

“…The graph shows vulnerability to the in vitro model of hypoxia/ischemia, the oxygen-glucose deprivation (OGD), analyzed in three different in vitro models: pure neuronal, mixed neuronal/astroglial and neural stem cells (NSCs)-derived OPCs cultures. This is a summary chart of already published data [45,46], measured by cell-based high content screening and represented as percentage of condensed nuclei. Statistical analysis has been performed by Student's t-test and asterisks represent the differences between normoxia and OGD exposed cells of the same lineage (* p < 0.05, ** p < 0.01, *** p = 0.001).…”

Relevance of Porcine Stroke Models to Bridge the Gap from Pre-Clinical Findings to Clinical Implementation

“…Especially in the neonatal period, the brain is consolidating the myelination process with most of the OPCs switching to myelin-synthesizing mature OLs and, thus, perinatal damage in WM results mainly from the impairment of the perinatal myelination process. Moreover, recent evidence suggests that fetal OPCs are more vulnerable than adult ones to oxygen and glucose deprivation [ 57 ].…”

The Function of the NMDA Receptor in Hypoxic-Ischemic Encephalopathy

“…Moreover, it is recently reported that HIE could also impact brain development by interfering with the maturation of several types of cells in the central nervous system. For example, the maturation of oligodendrocytes is impaired after HIE and therefore causes abnormal myelination (Ziemka-Nalecz et al, 2018;Baldassarro et al, 2020;Janowska et al, 2020). Another study found that HIE impairs GABAergic development in hippocampus which might be the cause of HIE-induced long-term memory deficiency (Chavez-Valdez et al, 2020).…”