Testicular Xenografting - Male Germline Stem Cells Developmental and Regenerative Potential - page 217

rhesus monkeys (Honaramooz et al. 2004 ; Rathi et al. 2008 ). One potential reason
for failure to achieve complete spermatogenic differentiation appears to be incom-
plete Sertoli cell maturation in the grafted tissue (Rathi et al. 2008 ).
Several other factors that depend on the status of the donor are also of impor-
tance for graft survival and development. One of the most significant parameters is
the developmental or functional stage of the donor testis. Survival of xenografts
declines with increasing maturity of the donor tissue. Tissue from adult donors
shows poor survival and a marked tendency to degenerate, making it unsuitable for
transplantation (Schlatt et al. 2002 ; Geens et al. 2006 ; Kim et al. 2007 ; Arregui
et al. 2008b ). Some spermatozoa were produced from transplanted adult mouse and
human testicular tissue. However, these spermatozoa were believed to be from
differentiating germ cells that completed spermatogenesis after grafting, rather than
arising de novo from spermatogonial stem cells (Schlatt et al. 2002, 2006 ; Geens
et al. 2006 ). Degeneration of adult testis xenografts occurs faster compared to
immature donor tissue (Arregui et al. 2008b ). Several reasons have been proposed
to explain poor survival of adult testis tissue, including lack of proliferation of
Sertoli cells, increased sensitivity to ischemia and a decreased angiogenic ability of
the adult tissue (Schlatt et al. 2002 ; Arregui et al. 2008a, b ). Once meiosis is initi-
ated the developmental capacity of the tissue declines dramatically (Rathi et al.
2006 ; Kim et al. 2007 ). Ischemic damage is problematic for any type of transplanta-
tion. Initial depletion of germ cells and necrotic damage following xenografting
have been noted (Rathi et al. 2006 ; Rodriguez-Sosa et al. 2010 ). Post-grafting
establishment of spermatogenesis in testis xenografts requires intense and coordi-
nated proliferation of somatic components and recolonization of spermatogonial
stem cells (Rathi et al. 2006 ; Huang et al. 2008 ; Rodriguez-Sosa et al. 2010 ). It can
be speculated that differences in stem cell cohorts between prepubertal and pubertal
donors may contribute to the variable ability of graft survival and development.
Furthermore, the developmental capacity may be influenced by post-grafting
damage of somatic components (Kim et al. 2007 ; Rodriguez-Sosa et al. 2010 ).
At initiation of meiosis, Sertoli cells have reached a more mature degree of physi-
ological and morphological differentiation and their proliferative activity decreases
(Meachem et al. 2005 ). This may render Sertoli cells more sensitive to grafting-
related injuries and certainly limit their ability to repair tissue damage through
extensive proliferation. A negative impact of degenerating maturing germ cells is
also likely in pubertal and postpubertal donor tissue. Meiotic and postmeiotic germ
cells are killed by exposure to hypoxia since they are highly depending on oxidative
metabolism (Rathi et al. 2006 ; Kim et al. 2007 ; Rodriguez-Sosa et al. 2010 ). It is
interesting to note that the grafting success was markedly different between testicular
tissue from pubertal and photoinhibited Djungarian hamsters. While xenografts
from adult hamsters showed the expected poor graft survival, grafts from immature
hamster testes showed excellent capacity to grow, differentiate, and initiate full
spermatogenesis (Schlatt et al. 2002 ). Surprisingly, photoinhibited hamster testes in
which spermatogenesis is blocked at the level of premeiotic germ cells, like in
immature hamsters, showed poor survival and no initiation of spermatogenesis.
The fact that the postpubertal hamster testis reveals poor developmental capacity