As stated above, the STAT3-Ser/Hes3 signaling axis regulates the number of neural stem cells (as well as other cell types) in culture. This prompted experiments to determine if the same pathway can also regulate the number of naturally resident (endogenous) neural stem cells in the adult rodent brain. If so, this would generate a new experimental approach to study the effects of increasing the number of endogenous neural stem cells (eNSCs). For example, would this lead to the replacement of lost cells by newly generated cells from eNSCs? Or, could this lead to the rescue of damaged neurons in models of neurodegenerative disease, since eNSCs are known to produce factors that can protect injured neurons?
Various treatments that input into the STAT3-Ser/Hes3 signaling axis (Delta4, Angiopoietin 2, insulin, or a combined treatment consisting of all three factors and an inhibitor of JAK) induce the increase in numbers of endogenous neural stem cells as well as behavioral recovery in models of neurodegenerative disease. Several pieces of evidence suggest that in the adult brain, pharmacological activation of the STAT3-Ser/Hes3 signaling axis protects compromised neurons through increased neurotrophic support provided by activated neural stem cells / neural precursor cells, which can be identified by their expression of Hes3:
:* These treatments increase the number of Hes3+ cells by several-fold.
:* Hes3+ cells can be isolated and placed in culture where they exhibit stem cell properties.
:* In culture and in vivo, Hes3+ cells express Shh, which supports the survival of certain neurons [Hes3+ cells may also express other pro-survival factors, yet unidentified].
:* The distribution of Hes3+ cells in the adult brain is widespread and can be found in close physical proximity to different types of neurons.
:* Diverse treatments that converge to the STAT3-Ser/Hes3 signaling axis exert similar effects in the normal brain (increase in the number of Hes3+ cells) and in the compromised brain (increase in the number of Hes3+ cells, oppose neuronal death, and improve behavioral state).
:* Macrophage migration inhibitory factor stimulates this signaling pathway and promotes the survival of neural stem cells.
:* Mice genetically engineered to lack the Hes3 gene exhibit differences in the amount of myelin basic protein (a protein expressed on myelinating oligodendrocytes), relative to normal mice; Hes3-lacking mice also exhibit a different regulation of this protein after oligodendrocyte damage induced by the chemical cuprizone.