Biomedical Engineering Reference
In-Depth Information
7.2.2
FGF2 and CSF1
While GDNF is essential for SSC self-renewal
in vitro
, the rate of proliferation is
slow, suggesting that other growth factors could also influence this fate decision.
Additional exposure to both fibroblast growth factor 2 (FGF2) and CSF1 enhances
mouse SSC self-renewal
in vitro
; however, exposure to either of these factors alone
does not support SSC expansion (Kubota et al.
2004a
; Oatley et al.
2009
). Similarly,
proliferation of mouse PGCs, the embryonic precursors of SSCs,
in vitro
also
requires supplementation of culture media with FGF2 (Resnick et al.
1992
). Also,
self-renewal of rat and hamster SSCs
in vitro
requires the supplementation of both
FGF2 and GDNF (Ryu et al.
2005
; Kanatsu-Shinohara et al.
2008
). Similar to
GDNF, production of FGF2 has been localized to Sertoli cells in the mouse testis
further supporting the belief that these cells are major contributors of the SSC niche
(Mullaney and Skinner
1991
).
Using microarray transcript profiling, specific genes with augmented expression
in the SSC-enriched THY1+ germ cell fraction of pre-pubertal mouse testes were
identified (Oatley et al.
2009
). These analyses revealed that colony stimulating factor
1 receptor (
Csf1r
) gene expression is highly (>400-fold) enriched in THY1+ germ
cells compared to other testis cell types (Oatley et al.
2009
). Subsequent experiments
showed that addition of recombinant CSF1, the specific ligand for CSF1R, to culture
media significantly enhances the self-renewal of mouse SSCs (Oatley et al.
2009
).
In a similar study, microarray analysis of the Gfra1+ cell fraction isolated from pre-
pubertal mouse testes also revealed enriched expression (~2-fold) of
Csf1r
compared
to other testis cells (Kokkinaki et al.
2009
).
In vivo
, expression of CSF1 in both pre-
pubertal and adult testes was localized to clusters of Leydig cells and selected peri-
tubular myoid cells (Oatley et al.
2009
). Collectively, these observations indicate that
CSF1 is an extrinsic stimulator of SSC self-renewal and implicate Leydig and myoid
cells as contributors of the testicular stem cell niche in mammals. A niche microen-
vironment that supports stem cell self-renewal is composed of a milieu of growth
factors produced by multiple support cells. Currently, our understanding of these
components for the SSC niche includes the growth factors GDNF, FGF2, and CSF1;
with the supporting cell component consisting of Sertoli, Leydig, and myoid cells.
Many more components of the SSC niche await discovery in the coming decades
before complete understanding of the regulation of SSC fate decisions is made.
7.3
Internal Molecular Pathways Regulating
SSC Self-Renewal
The effect of extrinsic stimuli from niche microenvironments, including growth
factor stimulation on stem cell self-renewal, is mediated via activation of specific
molecular pathways. Over the last 5 years these mechanisms in SSCs have begun
to be examined, yet understanding is still very limited. A major area of study has
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