Leukotriene B₄ and lipoxin A₄ are regulatory signals for neural stem cell proliferation and differentiation

Leukotrienes (LTs) and lipoxins (LXs) are lipid mediators that play a key role in regulating acute inflammatory responses. Their roles in neural stem cell (NSC) functions are of interest. We showed here that LTB₄ and LXA₄ regulated proliferation and differentiation of murine NSCs that were isolated from embryo brains. Proliferation of NSCs was stimulated by LTB₄ (3 to 100 nM) and blocked by receptor antagonist (IC ₅₀=2.7 μM). In contrast, LXA₄, and its aspirin-triggered-15-epi-LXA₄ stable analog attenuated growth of NSCs at as little as 1 nM. Both lipoxygenase (LOX) inhibitors and LTB₄ receptor antagonists caused apoptosis and cell death. Gene chip analysis revealed that growth-related gene expressions such as epidermal growth factor (EGF) receptor, cyclin E, p27, and caspase 8 were tightly regulated by LTB ₄; LXA₄ gave the opposite gene expressions. In addition to proliferation, LTB₄ induced differentiation of NSCs into neurons as monitored by neurite outgrowth and MAP2 expression. These results indicate for the first time that LTB₄ and LXA₄ directly regulate proliferation and differentiation of NSCs, suggesting these new pathways may be useful in restoring stem cells.