Abstract
The urge to have one’s own biological child supersedes any desire in life. Several options have been used to obtain gametes including pluripotent stem cells (embryonic ES and induced pluripotent iPS stem cells); gonadal stem cells (spermatogonial SSCs, ovarian OSCs stem cells), bone marrow, mesenchymal cells and fetal skin. However, the field poses a huge challenge including inefficient existing protocols for differentiation, epigenetic and genetic changes associated with extensive in vitro manipulation and also ethical/regulatory constraints. A tremendous leap in the field occurred using mouse ES and iPS cells wherein they were first differentiated into epiblast-like cells and then primordial germ cell-like cells. These on further development produced sperm, oocytes and live offspring (had associated genetic problems). Evidently differentiating pluripotent stem cells into primordial germ cells (PGCs) remains a major bottleneck. Against this backdrop, we propose that a novel population of pluripotent stem cells termed very small embryonic-like stem cells (VSELs) may serve as an alternative, potential source of autologus gametes, keeping in mind that they are indeed PGCs surviving in adult mammalian ovaries and testes. Both VSELs and PGCs are pluripotent, relatively quiescent because of epigenetic modifications of parentally imprinted genes loci like Igf2-H19 and KCNQ1p57, share several markers like Stella, Fragilis, Mvh, Dppa2, Dppa4, Sall4, Blimp1 and functional receptors. VSELs are localized in the basement membrane of seminiferous tubules in testis and in the ovary surface epithelium. Ovarian stem cells from mouse, rabbit, sheep, marmoset and humans (menopausal women and those with premature ovarian failure) spontaneously differentiate into oocyte-like structures in vitro with no additional requirement of growth factors. Thus a more pragmatic option to obtain autologus gametes may be the pluripotent VSELs and if we could manipulate them in vivo – existing ethical and epigenetic/genetic concerns associated with in vitro culture may also be minimized. The field of oncofertility may undergo a sea-change and existing strategies of cryopreservation of gametes and gonadal tissue for fertility preservation in cancer patients will necessitate a revision. However, first the scientific community needs to arrive at a consensus about VSELs in the gonads and then work towards exploiting their potential.
Highlights
Gametes derived from pluripotent stem cells may provide potential reproductive options to individuals who are rendered infertile due to injuries, exposure to toxicants or immune-suppressive treatments, in cases with gonadal insufficiency due to premature ovarian failure or azoospermia, reproductive aging and idiopathic cases of poor gametes quality and IVF failure
We have further shown that these very small embryonic-like stem cells (VSELs) are responsible for neo-oogenesis and primordial follicle assembly in mice [47], are regulated by Follicle stimulating hormone (FSH) [70], form Balbiani bodies, undergo cytoplasmic streaming and germ cell clusters do form during the process in adult ovary [46,71] as against the recent conclusions made by Lei and Spradling [72]
It may be possible to obtain human gametes provided efficient and directed differentiation of embryonic stem (ES) or iPS cells into primordial germ cells (PGCs) is achieved. This may not be mandatory since emerging literature suggests that PGCs persist as a subpopulation of VSELs along with spermatogonial stem cells (SSCs) in testis and ovarian stem cells (OSCs) in ovary
Summary
Gametes derived from pluripotent stem cells may provide potential reproductive options to individuals who are rendered infertile due to injuries, exposure to toxicants or immune-suppressive treatments, in cases with gonadal insufficiency due to premature ovarian failure or azoospermia, reproductive aging and idiopathic cases of poor gametes quality and IVF failure. Genes like H19 (maternally imprinted gene), VASA (germ cell marker) and PLD6 (required for gametogenesis and meiosis) are up regulated in VSELs compared to hES cells This distinct expression profile of VSELs isolated from adult human ovary shows that they are more related to PGCs than ES cells. We noted that the presence of germ cell nests, Balbiani body-like structures and cytoplasmic streaming extensively described during fetal ovary development, are well recapitulated during in vitro oogenesis in adult human OSE cultures along with characteristic expression of stem/germ cell/ oocyte markers [46]. The reason for this spontaneous differentiation of VSELs into oocyte-like structures is that the VSELs closely resemble PGCs (Table 1 and Figure 1)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
