Translating Spermatogonial Stem Cell Transplantation to the Clinic - Male Germline Stem Cells Developmental and Regenerative Potential - page 232

Ehmcke et al. 2005 ) and conflicting views about whether these “undifferentiated”
spermatogonia function as SSCs.
The prevailing model of spermatogenesis in primates suggests that A dark and
A pale are reserve and renewing stem cells, respectively (Clermont 1969 ;
Clermont and Antar 1973 ; Fouquet and Dadoune 1986 ; van Alphen and de
Rooij 1986 ; Plant and Marshall 2001 ; Ehmcke et al. 2005 ; Simorangkir et al.
2005, 2009 ). This “reserve stem cell” model holds that A pale function as “renewing
stem cells” that divide regularly to maintain spermatogenesis under normal
conditions. A dark are considered “reserve stem cells” that rarely divide in the
adult and only function to rescue spermatogenesis in cases where spermatogen-
esis is destroyed by cytotoxic insult [e.g., radiation; (van Alphen and de Rooij
1986 )]. A recent comparative study examined molecular markers of rodent
spermatogonia in the rhesus macaque testis and found a substantial proportion
of A dark and A pale spermatogonia in the adult rhesus testis that exhibited a molec-
ular phenotype similar to rodent SSCs (Hermann et al. 2009 ). This study raised
the possibility that A dark and A pale are part of the same functional cell population
rather than distinct populations of reserve and renewing stem cells. Numerous
other recent studies have sought to elucidate the fundamental characteristics of
undifferentiated spermatogonia in the nonhuman primate testis [(Hermann
et al. 2007, 2009, 2010 ; Ehmcke et al. 2006 ; Ehmcke and Schlatt 2006 ; Muller
et al. 2008 ; Maki et al. 2009 ; Simorangkir et al. 2009 )]. This momentum has
laid a foundation of fundamental biological information about primate SSCs
upon which to build future studies investigating their regenerative capacity at
a preclinical/translational level. Certainly, identification of the human SSC and
clear understanding of its role in normal human spermatogenesis are key goals
of future studies.

11.3 Nonhuman Primate Model for Developing SSC

Transplantation

11.3.1 SSC Transplantation in Rodents

In rodents, the definitive endpoint demonstrating that a given spermatogonium
exhibits the functional property of a SSC is the ability to produce and maintain
spermatogenesis in a transplantation paradigm (see Chap. 5). As originally described
by Brinster and colleagues for mice, suspensions of testis cells containing SSCs are
isolated from the testes of donor animals and transplanted into the testes of infertile
recipients where stem cells produce colonies of normal spermatogenesis and func-
tional sperm (Brinster and Avarbock 1994 ; Brinster and Zimmermann 1994 ). By
definition, only a stem cell can produce and maintain a colony of spermatogenesis
and each colony arises from the clonogenic proliferation and differentiation of a
single SSC (Dobrinski et al. 1999 ; Zhang et al. 2003 ; Kanatsu-Shinohara et al.
2006 ). Therefore, the SSC transplantation technique is a functional assay to