Making Germ Cells from Human Embryonic Stem Cells - Male Germline Stem Cells Developmental and Regenerative Potential - page 52

gametes. The ability to derive and differentiate human male and female germ cells
in vitro holds great promise for not only better understanding early gamete develop-
ment and disease, but also may have important clinical implications for treating
reproductive disorders. As infertility affects about 15% of reproductive-aged cou-
ples (Hull 1985 ), most commonly due to quantitative and qualitative defects in
sperm and egg production, human ES and iPS cells might one day provide clinical
applications for the treatment of infertility. Further, a human egg-like cell generated
from hESCs or iPSCs in vitro has the potential for use in somatic cell nuclear trans-
fer (SCNT). Thus, embryonic and pluripotent stem cells have the great potential to
revolutionize regenerative and reproductive medicine.

3.2 The Formation and Differentiation of Gametes In Vivo

3.2.1 Germ Plasm Versus Inductive Signaling

The formation and differentiation of the gametes, sperm and eggs, are arguably two
of the most important events for sexually reproducing species. In animals, the
specification and formation of the primordial germ cells (PGCs), the founding cells
of the germ cell lineage, occur by one of two distinct mechanisms: a germ plasm
mode of inheritance or inductive signaling (Santos and Lehmann 2004 ; Strome and
Lehmann 2007 ). In most organisms including invertebrate species such as flies and
worms, and non-mammalian vertebrates such as frogs and fish, the germ cells arise
through the inheritance of the germ plasm. This microscopically distinct, special-
ized cytoplasm is a maternally deposited collection of specific RNAs, RNA-binding
proteins, and ribosomes that are set aside early in embryonic development from the
somatic cells that form the rest of the embryo. The germ plasm is segregated within
the zygote and the subsequent primordial germ cells are prevented from differenti-
ating into somatic cells by repression of the global transcriptional and translational
machinery (Santos and Lehmann 2004 ; Strome and Lehmann 2007 ). Elegant studies
in the early twentieth century demonstrated that the germ cell lineage is established
by the assembly, segregation, and deposition of this microscopically detectable
germ plasm from the oocyte to the cells that are destined to become the germ cells.
Later work demonstrated that this germ plasm is sufficient for the formation and
maintenance of early germ cell populations and that several specific proteins,
RNAs, and genes are involved in germ plasm assembly, germ cell formation, identity,
and migration (Santos and Lehmann 2004 ; Zhou and King 2004 ).
In contrast, in mice and probably all mammals, the germ cells arise later in
embryonic development through the process of inductive signaling, whereby spe-
cific signals are secreted by neighboring cells that serve to induce the formation of
the germ cells. Although a germ plasm is not detectable in the mammalian oocyte,
recent evidence indicates that many genes that encode homologs of germ plasm
components are conserved and expressed in germ cells in mammals. These germ
plasm homologs include DAZ ( Deleted in AZoospermia ), DAZL ( DAZ-Like ),