Biomedical Engineering Reference
In-Depth Information
7.1
Spermatogenesis and Spermatogonial Stem Cell Biology
In mammals, continual spermatogenesis is dependent on an adult tissue-specific
stem cell population, termed spermatogonial stem cells (SSCs) whose biological
activities provide the foundation for high output of spermatozoa throughout the life
span of males. SSCs arise from gonocytes, a more undifferentiated precursor germ
cell derived from primordial germ cells (PGCs) that are formed during fetal devel-
opment (Clermont and Perey
1957
; Wartenberg
1976
; Curtis and Amann
1981
;
McLaren
2003
). Transition from gonocytes to SSCs generally occurs during the
first 6 days postpartum in male mice (Huckins and Clermont
1968
; Bellve et al.
1977
; de Rooij and Russell
2000
), with the first biologically active SSCs appearing
3-4 days after birth (McLean et al.
2003
). In the adult testis, SSCs are few in number,
estimated to be present at a concentration of 1 in 3,000 cells in the mouse
(Tegelenbosch and de Rooij
1993
), and comprise a sub-fraction of the proliferating
spermatogonial population that consists of A
single
(A
s
), A
paired
(A
pr
), and A
aligned
(A
al
)
spermatogonia (Huckins
1971
; Huckins and Oakberg
1978
; Russell et al.
1990
; de
Rooij and Russell
2000
).
Similar to other tissue-specific stem cell populations, SSCs possess the capacity
for both self-renewal and cellular differentiation. Self-renewal, a putatively infinite
process, results in maintenance of a stem cell pool. The A
s
spermatogonia have clas-
sically been considered SSCs, and during steady-state spermatogenesis their differ-
entiation results in formation of A
pr
and A
al
spermatogonia, a process that marks the
beginning of eventual spermatozoa production (Huckins
1971
; Oakberg
1971
; de
Rooij and Russell
2000
). Along this course of differentiation, A
pr
spermatogonia
undergo further mitotic divisions, becoming A
al(4)
, A
al(8)
, and A
al(16)
spermatogonia in
the mouse testis. These A
al(16)
spermatogonia then give rise to the differentiating
spermatogonia population, A
1
, A
2
, A
3
, and A
4
spermatogonia. The A
4
spermatogonia
transition into intermediate and type B spermatogonia, which enter meiosis, becoming
primary and secondary spermatocytes, leading to the development of haploid sper-
matids and eventually transforming into spermatozoa (Russell et al.
1990
).
Mechanisms regulating the balance between SSC self-renewal and differentiation
have been explored, though understanding of these processes is still limited. In general,
SSC fate decisions are controlled extrinsically by a niche microenvironment that
consists of a milieu of growth factors and internally by activation of specific molecular
signaling and gene expression pathways. Currently, understanding of the character-
istics of the SSC niche and mechanisms regulating SSC fate decisions is limited.
Niches are formed by contributions of support cells (Spradling et al.
2001
; Scadden
2006
), and in the mammalian testis Sertoli cells have been regarded as the major
contributor of this microenvironment. However, studies by Chiarini-Garcia et al.
(
2003
) suggested that proliferating spermatogonia (A
s
, A
pr
, and A
al
) in the rat testis
are predominately present in areas of seminiferous tubules adjacent to interstitial
tissue. Furthermore, results of Yoshida et al. (
2007
) indicate that proliferating sper-
matogonia in the mouse testes are focally located in seminiferous tubules bordering
the vasculature. Together these observations indicate that the SSC niche in mammalian
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