Abstract
Olfactory ensheathing cells (OECs) are being trialled for cell transplantation therapies for neural repair as they have unique properties which can enhance neuron regeneration. However, improvements in cell viability, proliferation and migration are needed to enhance therapeutic outcomes. Growth factors can enhance cell activity, but they can also induce side effects as they can act on numerous cell types. An alternative approach is to identify natural products (NPs) that more selectively activate specific cell functions. We have examined two pure NPs, 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid (RAD288) and 3,7,8-trihydroxyserrulat-14-en-19-oic acid (RAD289) isolated from the Australian plant Eremophila microtheca. We determined that RAD288 and RAD289 stimulated the viability and proliferation of OECs in two-dimensional cultures and increased cell viability in three-dimensional spheroids. Both compounds also enhanced OEC-mediated phagocytosis of neural debris. However, only RAD288 stimulated migration of OECs, demonstrating that key structural changes to the compound can dramatically affect the resultant cellular action. In addition, cell-type specific action is highlighted by the result that neither compound stimulated the viability of Schwann cells which are a closely-related glial cell type. Therefore, these small molecules may have high potential for selective activation of specific therapeutically-useful activities of OECs for transplantation therapies to repair the nervous system.
Highlights
Olfactory ensheathing cells (OECs), a subtype of glia located within the olfactory mucosa and the olfactory bulb, facilitate the regeneration of olfactory neurons throughout the life of mammals[1]
We examined the effect of the natural products (NPs) 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid (RAD288) and 3,7,8-trihydroxyserrulat-14-en-19-oic acid (RAD289) (Fig. 1) that have been isolated from the aerial parts of the Australian desert plant Eremophila microtheca[17]
The positive control G5 Supplement alone exhibited a significant 24.31% increase in mouse OECs (mOECs) cell viability (p < 0.05) compared to the control treatment. We found that both RAD288 and RAD289 promoted mOEC cell viability (Fig. 2a)
Summary
Olfactory ensheathing cells (OECs), a subtype of glia located within the olfactory mucosa and the olfactory bulb, facilitate the regeneration of olfactory neurons throughout the life of mammals[1] Due to their ability to promote nerve regeneration, the transplantation of OECs is a promising approach for neural repair therapies including spinal cord injury (SCI) repair. An alternative approach for neural repair is to administer exogenous growth factors into the injury site to enhance proliferation of transplanted glial cells[13]. When tested on the closely related glial cell type, Schwann cells, the compounds had no effect on proliferation These results indicate that RAD288 and RAD289 stimulate specific but different activities of OECs, and are active on select cell types. These serrulatane diterpenoids are potentially useful for improving glial cell activity in cell transplantation therapies
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