Testicular Xenografting - Male Germline Stem Cells Developmental and Regenerative Potential - page 208

strong immunorejection (Dobrinski et al . 2000 ). Xenotransplantation of testicular
tissue (human fetal testis into the abdominal wall of adult nude mice) was first
performed in 1974 (Skakkebaek et al . 1974 ) and revealed survival of the tissue but
no progression of germ cell development beyond the gonocyte stage. Subsequently
Hochereau-de-Reviers and Perreau ( 1997 ) transplanted ovine fetal testis into the
scrotum of intact nude mice and reported differentiation of gonocytes into sper-
matogonia and primary spermatocytes (Hochereau-de-Reviers and Perreau 1997 ).
However, complete cross-species spermatogenesis was first reported in 2002
(Honaramooz et al. 2002 ). In that report, fragments of testis tissue from newborn
pigs and goats were able to survive and displayed complete development with
production of sperm. Testicular xenografting has since been tested in numerous
species (Table 10.1 ), and testes from almost all of them appear to be responsive to
mouse gonadotropins as demonstrated by initiation of spermatogenesis after xeno-
grafting. A notable exception is the marmoset, which appears insensitive to mouse
LH due to a deletion in exon 10 of its luteinizing hormone-receptor gene (Michel
et al. 2007 ). This blocks androgen production and results in poor spermatogenesis
after grafting (Schlatt et al. 2002 ; Wistuba et al. 2004 ). The limited development
of marmoset xenografts indicates a response to the stimulation by mouse FSH in
the absence of androgen-dependent differentiation processes. Co-grafting experi-
ments combining marmoset and hamster tissue, however, revealed no beneficial
impact of well developing hamster xenografts on marmoset testis tissue (Wistuba
et al. 2004 ). Nonetheless, such studies promote interesting experimental approaches
to explore hormonal regulation of testicular development.
In most studies, the testicular grafts consist of small fragments of ~0.5-1 mm 3
weighing 3-10 mg (Honaramooz et al. 2002 ; Schlatt et al. 2002 ; Schmidt et al.
2006a, b ), but the use of bigger fragments (9 × 5 × 1 mm) is also feasible (Rodriguez-
Sosa et al. 2010 ). Two to eight fragments of tissue are commonly transplanted into
multiple sites under the dorsal skin on either side of the spinal column. As immuno-
deficient recipients, Nude (T-cell deficient) mice (Honaramooz et al. 2002 ; Schlatt et al.
2002 ; Oatley et al. 2004, 2005 ; Rathi et al. 2005, 2006 ; Zeng et al. 2006 ), SCID (T-
and B-cell-deficient) mice (Honaramooz et al. 2004 ; Snedaker et al. 2004 ; Rathi et al.
2005, 2006 ; Schlatt et al. 2006 ) and RAG-1 (T- and B-cell-deficient) mice (Rodriguez-
Sosa et al. 2010 ) have been used. No difference has been found between xenografts
transplanted into Nude and SCID mice (Rathi et al. 2005, 2006 ; Geens et al. 2006 ).
The recipients are usually adult males that are castrated prior to or during the
transplantation surgery. Turner ( 1938 ) found that survival of homologous testicular
grafts in rats was better (less degeneration, more sperm) when the recipient was
castrated (Turner 1938 ). Rathi et al. ( 2006 ) observed that horse xenografts under
the dorsal skin of mice did not develop in intact males (Rathi et al. 2006 ). In con-
trast, Shinohara et al. ( 2002 ) obtained functional sperm from rabbit testis orthotopic
xenografts in intact mice (Shinohara et al. 2002 ). These data indicate that xeno-
grafting works in principle irrespective of the sex and gonadal status of the
recipient. In addition to improved graft survival, castration of recipients at the time
of grafting has several more advantages. It avoids interference of the host testis and
the grafted donor testis tissue towards the hormonal stimulation of the recipient and