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The Journal of Neuroscience, May 1, 1999, 19(9):3287-3297
Epidermal and Fibroblast Growth Factors Behave as Mitogenic
Regulators for a Single Multipotent Stem Cell-Like Population from the
Subventricular Region of the Adult Mouse Forebrain
Angela
Gritti1,
Paola
Frölichsthal-Schoeller1,
Rossella
Galli1,
Eugenio A.
Parati1,
Lidia
Cova1,
Stefano F.
Pagano1,
Christopher R.
Bjornson2, and
Angelo L.
Vescovi1
1 Laboratory of Neuropharmacology, National
Neurological Institute C. Besta, Milan, Italy I-20133, and
2 Department of Biochemistry, University of Washington,
Seattle, Washington 98195-7350
The subventricular zone (SVZ) of the adult mammalian forebrain
contains kinetically distinct precursor populations that contribute new
neurons to the olfactory bulb. Because among forebrain precursors there
are stem-like cells that can be cultured in the presence of mitogens
such as epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), we asked whether distinct subsets of stem-like cells coexist
within the SVZ or whether the proliferation 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 coexpress the EGF and FGF
receptors; by quantitative analysis, the number of stem-like cells
isolated from the SVZ by either FGF2 or EGF is the same, whereas no
additive effect occurs when these factors are used together.
Furthermore, short-term administration of high-dose
[3H]thymidine in vivo depletes both
the EGF- and FGF2-responsive stem-like cell populations equally,
showing they possess closely similar proliferation kinetics and likely
belong to the constitutively proliferating SVZ compartment. By
subcloning and population analysis, we demonstrate that responsiveness
to more than one GF endows SVZ cells with an essential stem cell
feature, the ability to vary self-renewal, that was until now
undocumented in CNS stem-like cells. The multipotent stem cell-like
population that expands slowly in the presence of FGF2 in culture
switches to a faster growth mode when exposed to EGF alone and expands
even faster when exposed to both GFs together. Analogous responses are
observed when the GFs are used in the reverse order, and furthermore,
these growth rate modifications are fully reversible.
Key words:
EGF; FGF; stem cells; adult brain; neurogenesis; neural
progenitors
Copyright © 1999 Society for Neuroscience 0270-6474/99/1993287-11$05.00/0
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