Epidermal and fibroblast growth factors behave as mitogenic regulators fora single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain

The subventricular zone (SVZ) of the adult mammalian forebrain contains kin etically distinct precursor populations that contribute new neurons to the olfactory bulb. Because among forebrain precursors there are stem-like cell s that can be cultured in the presence of mitogens such as epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), we asked whether disti nct subsets of stem-like cells coexist within the SVZ or whether the prolif eration of a single type of SVZ stem-like cell is controlled by several GFs . We show that the latter is the case. Thus cells isolated from the SVZ coe xpress the EGF and FGF receptors; by quantitative analysis, the number of s tem-like cells isolated from the SVZ by either FGF2 or EGF is the same, whe reas no additive effect occurs when these factors are used together. Furthe rmore, short-term administration of high-dose [H-3]thymidine in vivo deplet es both the EGF- and FGF2-responsive stem-like cell populations equally, sh owing they possess closely similar proliferation kinetics and likely belong to the constitutively proliferating SVZ compartment. By subcloning and pop ulation analysis, we demonstrate that responsiveness to more than one GF en dows SVZ cells with an essential stem cell feature, the ability to vary sel f-renewal, that was until now undocumented in CNS stem-like cells. The mult ipotent stem cell-like population that expands slowly in the presence of FG F2 in culture switches to a faster growth mode when exposed to EGF alone an d expands even faster when exposed to both GFs together. Analogous response s are observed when the GFs are used in the reverse order, and furthermore, these growth rate modifications are fully reversible.