Oligodendrocyte lineage regulation during development, adult life, inflammatory lesions and hypoxia/ischemia insults. Focus on Nuclear Receptors.

Abstract

Oligodendrocyte precursor cells (OPCs) are the main actors involved in developmental myelination and adult myelination dynamic, including remyelination. The recapitualtion hypothesis states that adult remyelination is a complete recapitulation of developmental myelination. However, their different nature could reflect different myelination mechanism and response to demyelinating insults. The main objective of the present study is the investigation of foetal and adult OPCs vulnerability to demyelinating diseases environment. Cell-based high content screening approach was set up as the elective technique in order to obtain robust and reproducible data. First we analysed the physiological differentiation process, driven by thyroid hormone and exerted by nuclear receptors. We described different expression of NRs in early precursors, different response to T3-mediated differentiation, the selective importance of PARP activity for foetal OPCs and the fundamental role of RXRγ in both systems. Differences in physiological differentiation can reflect different responses to noxious stimuli. Thus, we exposed OPCs to inflammatory cytokines mix or to oxygen-glucose deprivation (OGD), in order to mimic demyelinating disease environment. OGD was first characterized in primary neuronal cultures and tested for its reliability in disease model studies and pharmacological analysis. Foetal and adult OPCs show both a cytokines-mediated differentiation block, linked to an increase of deiodinase 3 (D3), the enzyme inactivating T3. However, only foetal OPCs/OLs are sensitive to OGD. Since we found an increase in D3 expression after OGD, further studies will elucidate the mechanism underlying the foetal-selective OPCs cell death, analysing the role of D3 in the process and glutamate-mediated excitotxicity, the major triggerer of HI-induced cell death. The better understanding of OPCs biology and mechanisms underlying physiological and pathological conditions, bound to information about differences in foetal and adult OPCs, will open the way to new therapies based on differential strategies for demyelinating diseases affecting foetal or adult life.