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Volume 17, Number 1,
Issue of January 1, 1997
pp. 216-226
Copyright ©1997 Society for Neuroscience
Induction of Cell Proliferation by Fibroblast and Insulin-Like
Growth Factors in Pure Rat Inner Ear Epithelial Cell Cultures
Received Aug. 8, 1996; revised Oct. 16, 1996; accepted Oct. 21, 1996.
J. Lisa Zheng,
Christian Helbig, and
Wei-Qiang Gao
Department of Neuroscience, Genentech, Incorporated, South San
Francisco, California 94080
Proliferation of supporting cells in the inner ear is the early
major event occurring during hair cell regeneration after acoustic
trauma or aminoglycoside treatment. In the present study, we examined
the possible influence of 30 growth factors on the proliferation of
pure rat utricular epithelial cells in culture. Utricular epithelial
sheets were separated and partially dissociated from early postnatal
rats via a combined enzymatic and mechanical method. The cultured
utricular epithelial cells expressed exclusively epithelial cell
antigens, but not fibroblast, glial, or neuronal antigens. With
tritiated thymidine incorporation assays, we found that several
fibroblast growth factor (FGF) family members, insulin-like growth
factor-1 (IGF-1), IGF-2, transforming growth factor- (TGF-), and
epidermal growth factor (EGF), stimulated proliferation of the
utricular epithelial cells. In contrast, neurotrophins and other growth
factors did not elicit any detectable mitogenic effects. Among all of
the growth factors examined, FGF-2 was the most potent mitogen. When
FGF-2 was added in combination with IGF-1 or TGF- to the medium,
combined effects were seen. These results were confirmed with BrdU
immunocytochemistry. Thus, the present culture system provides a rapid
and reliable assay system to screen novel growth factors involved in
proliferation of mammalian inner ear supporting cells. Furthermore,
immunostainings revealed that the cultured utricular epithelial cells
expressed FGF and IGF-1 receptors, and utricular hair cells produced
FGF-2 in vivo. The addition of neutralizing antibodies
against FGF-2 or IGF-1 to the cultures significantly inhibited the
utricular epithelial cell proliferation. This work suggests that FGF-2
and IGF-1 may regulate the proliferation step during hair cell
development and regeneration.
Key words:
hair cell regeneration;
supporting cells;
proliferation;
differentiation;
utricle;
vestibular;
growth factors;
FGF;
IGF
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