Pluripotent Very Small Embryonic-like Stem Cells in Adult Mammalian Gonads

Abstract

The presence of very small embryonic-like stem cells (VSELs) in adult mammalian gonads is set to disrupt several existing paradigms in the field of reproductive biology. Being pluripotent, VSELs are present at the top of hierarchy among the tissue-specific stem cells. In the testis, they exist as a sub-population of small spherical cells with high nucleo-cytoplasmic ratio among the spermatogonial stem cells (SSCs) along the basement membrane of the seminiferous tubules. They undergo asymmetric cell division to self-renew, give rise to the SSCs and may also be responsible for the embryonic stem (ES) cell-like colonies observed on culturing testicular biopsy. The SSCs undergo rapid division (clonal expansion as chains), meiosis, and further differentiate into sperm. In the ovary, VSELs are lodged in the ovary surface epithelium (OSE) along with immediate progenitors termed ovarian germ stem cells (OGSCs). Ovarian VSELs also undergo asymmetric cell division to give rise to OGSCs which undergo clonal expansion to form nests (cysts) and further differentiate into oocytes which assemble as primordial follicles below the OSE. Stem cell function in the adult mammalian ovary is modulated by follicle stimulating hormone (FSH) via a novel FSH receptor isoform R3. These results are in contradiction to the existing paradigm that initial primordial follicle growth is independent of FSH and that it acts on the granulosa cells of growing follicles through a G protein-coupled FSH receptor. Being relatively quiescent in nature, VSELs survive oncotherapy in both testis and ovary but are unable to differentiate because of a compromised niche. Their functionality may be restored by providing a healthy niche. This newer understanding of VSELs biology in mammalian gonads will provide deep insight in various fields of reproductive health.