Fibroblast growth factor-2 (FGF-2) is a neurotrophic factor that promotes stem cell renewal for cultured neurogenitor precursor cells, such as those from adult rat hippocampus (AHPs). However, FGF-2 is only effective alone if the cells are initially plated at a high density, suggesting that there may be a factor produced by the culture that cooperates with FGF-2 to stimulate stem cell proliferation without stimulating differentiation. Taupin et al. isolated a 21-kD protein from AHP-conditioned medium, identified as glycosylated form of the cysteine protease inhibitor cystatin C (CCg), which was responsible for promoting the effects of FGF-2. Furthermore, the carbohydrate moiety on CCg was essential for this activity, but the protease inhibitor activity of CCg was dispensable. The dividing AHP cells in culture and mitotic neural stem cells in vivo were labeled by an anti-CCg antibody. Finally, injection of AHP cells engineered to produce a secreted form of FGF-2 and CCg, but not the cells that produced the nonglycosylated form of CCg, stimulated proliferation of neural progenitors in adult rat dentate gyrus. Thus, a combination of paracrine and neurotrophic factors appears to regulate neurogenesis.
Taupin, P., Ray, J., Fischer, W.H., Suhr, S.T., Hakansson, K., Grubb, A., and Gage, F.H. (2000) FGF-2-responsive neural stem cell proleferation requires CCg, a novel autocrine/paracrine cofactor. Neuron 28: 385-397. [Online Journal]