In tissues, many different cell types interact with one another. In the brain, for example, neurons, astrocytes, and oligodendrocytes (specialized cells of the neural tissue, each with specific functions) interact with one another as well as with cells that comprise blood vessels. All these different cell types may interact with all others by the production of ligands that may activate receptors on the cell surface of other cell types. Understanding the way these different cell types interact with one another will allow to predict ways of activating eNSCs. For example, because eNSCs are found in close proximity with blood vessels, it has been hypothesized that signals (e.g., ligands) from cells comprising the blood vessel act on receptors found on the cell surface of eNSCs.
Endogenous neural stem cells are often in close physical proximity to blood vessels. Signals from blood vessels regulate their interaction with stem cells and contribute to the cytoarchitecture of the tissue. The STAT3-Ser/Hes3 signaling axis operating in Hes3+ cells is a convergence point for several of these signals (e.g. Delta4, Angiopoietin 2). Hes3, in turn, by regulating the expression of Shh and potentially other factors, can also exert an effect on blood vessels and other cells comprising their microenvironment.