Abstract
Olfactory ensheathing cells (OECs) are crucial for promoting the regeneration of the primary olfactory nervous system that occurs throughout life. Transplantation of OECs has emerged as a promising therapy for nervous system injuries, in particular for spinal cord injury repair. Functional outcomes in both animals and humans are, however, highly variable, primarily because it is difficult to rapidly obtain enough OECs for transplantation. Compounds which can stimulate OEC proliferation without changing the phenotype of the cells are therefore highly sought after. Additionally, compounds which can stimulate favourable cell behaviours such as migration and phagocytic activity are desirable. We conducted a medium-throughput screen testing the Davis open access natural product-based library (472 compounds) and subsequently identified the known plant natural product 2-methoxy-1,4-naphthoquinone as a stimulant of OEC viability. We showed that 2-methoxy-1,4-naphthoquinone: (i) strongly stimulates proliferation over several weeks in culture whilst maintaining the OEC phenotype; (ii) stimulates the phagocytic activity of OECs, and (iii) modulates the cell cycle. We also identified the transcription factor Nrf2 as the compound’s potential molecular target. From these extensive investigations we conclude that 2-methoxy-1,4-naphthoquinone may enhance the therapeutic potential of OECs by stimulating proliferation prior to transplantation.
Highlights
The primary olfactory nervous system undergoes regeneration throughout life
Compounds that can enhance Olfactory ensheathing cells (OECs) viability, as well as cellular functions associated with neural repair, are likely to increase the therapeutic potential of OEC transplantation
We have previously identified that two serrulatane diterpenoid natural products, RAD288 (3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid) and RAD289 (3,7,8-trihydroxyserrulat-14-en-19-oic, Fig. 1a), stimulate viability of OECs, in particular RAD28915
Summary
The primary olfactory nervous system undergoes regeneration throughout life. The glial cells of this system, olfactory ensheathing cells (OECs), are thought to be critical for the regeneration. Compounds capable of enhancing key OEC functions crucial for neural repair, such as migration and phagocytic activity, are desirable[16,17]. Some studies show that transplanted OECs exhibit strong capacity for migration into the injury site[21,22], but others show that OEC migration is relatively limited[23]; promoting OEC migration may lead to better nerve repair Another important function of OECs is phagocytosis of cell debris. Eremophila microtheca compounds have been shown to enhance phagocytic activity, migration and cell viability of OECs15. These findings show that it is possible to stimulate OEC functions that are important for neural repair. We performed more detailed studies to investigate how this compound affects the cell cycle, migration and phagocytic activity of OECs
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