Making gametes from alternate sources of stem cells: past, present and future

Abstract

Infertile couples including cancer survivors stand to benefit from gametes differentiated from embryonic or induced pluripotent stem (ES/iPS) cells. It remains challenging to convert human ES/iPS cells into primordial germ-like cells (PGCLCs) en route to obtaining gametes. Considerable success was achieved in 2016 to obtain fertile offspring starting with mouse ES/iPS cells, however the specification of human ES/iPS cells into PGCLCs in vitro is still not achieved. Human ES cells will not yield patient-specific gametes unless and until hES cells are derived by somatic cell nuclear transfer (therapeutic cloning) whereas iPS cells retain the residual epigenetic memory of the somatic cells from which they are derived and also harbor genomic and mitochondrial DNA mutations. Thus, they may not be ideal starting material to produce autologus gametes, especially for aged couples. Pluripotent, very small embryonic-like stem cells (VSELs) have been reported in adult tissues including gonads, are relatively quiescent in nature, survive oncotherapy and can be detected in aged, non-functional gonads. Being developmentally equivalent to PGCs (natural precursors to gametes), VSELs spontaneously differentiate into gametes in vitro. It is also being understood that gonadal stem cells niche is compromised by oncotherapy and with age. Improving the gonadal somatic niche could regenerate non-functional gonads from endogenous VSELs to restore fertility. Niche cells (Sertoli/mesenchymal cells) can be directly transplanted and restore gonadal function by providing paracrine support to endogenous VSELs. This strategy has been successful in several mice studies already and resulted in live birth in a woman with pre-mature ovarian failure.

In Vitro Generation of Oocyte Like Cells and Their In Vivo Efficacy: How Far We have been Succeeded

“…More importantly, under conditions like organ damage, activated VSELs can contribute to the regeneration of damaged organ tissues by their mobilization in peripheral blood [99]. Due to their detection in PGCs, gonadal tissue (both functional and non-functional), and ability to survive oncotherapy (due to quiescent nature), VSELs have been given preference for the development of gametes in vitro [45,100]. Adult mammalian ovaries not only acts as reservoirs for oocytes but also have the presence of other valuable stem cell sources such as OSCs and VSELs.…”

Wharton's jelly derived mesenchymal stem cells differentiate into oocyte like cells in vitro by follicular fluid and cumulus cells conditioned medium

“…Production of germ cells from stem cells is a very interesting and promising area in the field of reproductive medicine. It has been shown that stem cells derived from different regions, such as menstrual blood, amniotic fluid, lung, skin and pancreas, have the capacity to differentiate into germ cell-like cells [ 22 , 23 , 24 ]. MSCs can be isolated from various sources especial from neonatal tissues, such as placenta, umbilical cord and Wharton's jelly may offer certain advantages.…”

Derivation and propagation of spermatogonial stem cells from human pluripotent cells

“…Recently, researchers found that there exists a novel population of pluripotent stem cells termed very small embryonic-like stem cells (VSELs) in the testes which can survive chemotherapy. Mesenchymal cells or Sertoli cells transplanted into busulfan-treated testes could secret some paracrine factors to restore healthy stem niche and support surviving VSELs to undergo spermatogenesis [ 56 , 57 ]. Surprisingly, our study showed that SSCLCs could restore the spermatogenesis of busulfan-treated recipient mice (Fig.…”