Regenerative Potential of Spermatogenesis after Gonadotoxic Therapies - Male Germline Stem Cells Developmental and Regenerative Potential - page 190

Recovery of stem cells and sperm production continues for about 25 weeks and
then reaches a plateau. Complete recovery is observed after doses of 6 Gy or less,
but the plateau becomes progressively lower after higher doses. Recovery kinetics
of sperm production, based on equivalent levels of stem cell survival, are similar
after chemotherapy as was described above for radiation (Meistrich 1982, 1986b ).
The recovery of the numbers of functional stem cells measured by the transplanta-
tion assay, showed a fourfold increase between 3 and 15 days after busulfan treat-
ment (Kanatsu-Shinohara et al. 2003 ).
In rats, complete regeneration of the numbers of A s spermatogonia occurs
between 8 and 16 weeks after 6 Gy irradiation (Erickson and Hall 1983 ). However,
the extent of recovery of spermatogenesis from these surviving stem cells depends
on the strain (Fig. 9.3 ). After radiation or procarbazine exposure, recovery is more
vigorous in outbred, such as Sprague-Dawley, than in inbred rats such as Wistar,
Lewis, PVG, and LBNF 1 (Delic et al. 1987 ; Dym and Clermont 1970 ; Kangasniemi
et al. 1996b ; Parchuri et al. 1993 ; Ward et al. 1989, 1990 ). Morphological examina-
tion of the atrophic testes in the sensitive LBNF 1 rats after these gonadotoxic thera-
pies revealed that many type A spermatogonia, including the A s spermatogonia,
were still present and actively proliferating, but their progeny underwent apoptosis
when they attempted to differentiate (Meistrich et al. 1999 ; Shuttlesworth et al.
2000 ). This block continued for at least 60 weeks after irradiation (Kangasniemi
et al. 1996b ). Spermatogonial transplantation revealed that these stem spermatogo-
nia were functional and that their failure to undergo differentiation was due to dam-
age to the somatic environment of the testis (Zhang et al. 2006 ). We presume that
radiation produces this spermatogonial block in other strains, but to a lesser degree,
as Sprague-Dawley rats show a lower percentage of tubules with differentiating
cells (Delic et al. 1987 ) than do mice (Withers et al. 1974 ) given the same dose of
radiation, despite similar levels of stem cell survival (Erickson and Hall 1983 ).
When Sprague-Dawley or Fischer 344 rats are treated with hexanedione (Allard
and Boekelheide 1996 ) or testicular heating (Setchell et al. 2001 ), a high percentage
of seminiferous tubules do lack differentiating germ cells even though they contain
type A spermatogonia.
In monkeys, regeneration and recovery are dose dependent. At doses below
2 Gy, the A spermatogonia have already begun to increase their numbers and pro-
duce type B spermatogonia or later cell types at 3 months after irradiation. In con-
trast, at 2 Gy or more, there is less regeneration of type A spermatogonia and 80%
of the colonies of these cells have not yet begun differentiation at this time (van
Alphen et al. 1988b ). However, by 8 months they all have produced differentiating
cells. The gradual progressive recovery of sperm count, which lasts for 1 year after
4 Gy irradiation, may also indicate a very gradual regeneration of stem cell numbers
and/or a gradual reinitiation of spermatogenesis from those surviving stem cells
(Kamischke et al. 2003 ). Although a few stem cells survived a dose of 7 Gy, no
progressive recovery was observed (Boekelheide et al. 2005 ).
In human, the regeneration of the numbers of type A spermatogonia begins at
about 160 days (5-6 months) after irradiation, for single doses up to 6 Gy (Clifton
and Bremner 1983 ; Paulsen 1973 ; Rowley et al. 1974 ). They may take about