Abstract
Poly (ADP-ribose) polymerase (PARP) family members are ubiquitously expressed and play a key role in cellular processes, including DNA repair and cell death/survival balance. Accordingly, PARP inhibition is an emerging pharmacological strategy for cancer and neurodegenerative diseases. Consistent evidences support the critical involvement of PARP family members in cell differentiation and phenotype maturation. In this study we used an oligodendrocyte precursor cells (OPCs) enriched system derived from fetal and adult brain to investigate the role of PARP in OPCs proliferation, survival, and differentiation. The PARP inhibitors PJ34, TIQ-A and Olaparib were used as pharmacological tools. The main results of the study are: (i) PARP mRNA expression and PARP activity are much higher in fetal than in adult-derived OPCs; (ii) the culture treatment with PARP inhibitors is cytotoxic for OPCs derived from fetal, but not from adult, brain; (iii) PARP inhibition reduces cell number, according to the inhibitory potency of the compounds; (iv) PARP inhibition effect on fetal OPCs is a slow process; (v) PARP inhibition impairs OPCs maturation into myelinating OL in fetal, but not in adult cultures, according to the inhibitory potency of the compounds. These results have implications for PARP-inhibition therapies for diseases and lesions of the central nervous system, in particular for neonatal hypoxic/ischemic encephalopathy.
Highlights
Oligodendrocytes, the cells wrapping the axons of the central nervous system (CNS) with the myelin sheath, derive from the oligodendrocyte precursor cells (OPCs) generated during development from multipotent neuroectodermal derivatives in the cortex and spinal cord (Bergles and Richardson, 2015)
Lineage progression from NG2-positive OPC (DIV0) through CNPase-mature OL as far as myelinating MBP-positive OL is illustrated in Fig. 1C–E
Human fetal OPCs from different gestational stages exhibit differences in the myelination profile (Cui et al, 2012), such as human OPCs derived from fetal brain during the period of maximum oligoneogenesis or from adult subcortical white matter (Windrem et al, 2004)
Summary
Oligodendrocytes, the cells wrapping the axons of the central nervous system (CNS) with the myelin sheath, derive from the oligodendrocyte precursor cells (OPCs) generated during development from multipotent neuroectodermal derivatives in the cortex and spinal cord (Bergles and Richardson, 2015). New OPCs can be generated in the adult CNS from neural stem cells (NSCs; Agathou et al, 2013) and by mitosis, as OPCs are the major proliferating population of the CNS under appropriate stimuli (Fernandez-Castaneda and Gaultier, 2016). These cells are responsible for myelin formation during development (Bergles and Richardson, 2015), and for myelin turnover and repair during adulthood (Young et al, 2013).
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