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The Journal of Neuroscience, February 1, 2003, 23(3):895
Locally Born Olfactory Bulb Stem Cells Proliferate in Response to
Insulin-Related Factors and Require Endogenous Insulin-Like Growth
Factor-I for Differentiation into Neurons and Glia
Carlos
Vicario-Abejón,
María J.
Yusta-Boyo,
Carmen
Fernández-Moreno, and
Flora
de
Pablo
Group of Growth Factors in Vertebrate Development, Centro de
Investigaciones Biológicas, Consejo Superior de Investigaciones
Científicas, E-28006 Madrid, Spain
After late embryogenesis, new neurons are continuously added to the
olfactory bulb (OB) from stem cells located in the forebrain subventricular zone. Nonetheless, stem cells have not been described within the embryonic olfactory bulb. Here we report the isolation of
local olfactory bulb stem cells from the embryonic day 12.5-14.5 mouse
embryo. These cells were 99.2% nestin positive and proliferated extensively in culture to at least 150 cell doublings. Clonal analysis
demonstrated that neurons (TuJ1+), astrocytes
(GFAP+), and oligodendrocytes
(O4+) could be generated from single-plated cells,
indicating that they are multipotent. At least 90% of proliferating
cells expressed insulin-like growth factor-I (IGF-I), (pro)insulin, and
their cognate receptors; these growth factors collaborated with
fibroblast growth factor-2 plus epidermal growth factor (EGF) to
promote stem cell proliferation and sphere formation. Cells from
Igf-I /
mice, however, proliferated as extensively as did
Igf-I+/+ cells. Differentiation and
survival of stem cell-generated neurons and glia showed strong
dependence on exogenous IGF-I, but oligodendrocyte differentiation also
required insulin at low concentration. Furthermore, the percentages of
stem cell-generated neurons, astrocytes, and oligodendrocytes were
markedly lower in the cultures prepared from the
Igf-I/
mice compared with those of
Igf-I+/+.
Concordantly, lack of IGF-I resulted in abnormal formation of the
olfactory bulb mitral cell layer and altered radial glia morphology. These results support the presence within the embryonic mouse olfactory
bulb of stem cells with specific requirements for insulin-related growth factors for proliferation or differentiation. They demonstrate that IGF-I is an endogenous factor regulating the differentiation of
stem and other precursor cells within the olfactory bulb.
Key words:
olfactory bulb stem cells; mitral neurons; IGF-I; insulin; proinsulin; proliferation; differentiation
Copyright © 2003 Society for Neuroscience 0270-6474/03/233895-12$05.00/0
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