Very Small Embryonic-Like Stem Cells: Implications in Reproductive Biology

Abstract

The most primitive germ cells in adult mammalian testis are the spermatogonial stem cells (SSCs) whereas primordial follicles (PFs) are considered the fundamental functional unit in ovary. However, this central dogma has recently been modified with the identification of a novel population of very small embryonic-like stem cells (VSELs) in the adult mammalian gonads. These stem cells are more primitive to SSCs and are also implicated during postnatal ovarian neo-oogenesis and primordial follicle assembly. VSELs are pluripotent in nature and characterized by nuclear Oct-4A, cell surface SSEA-4, and other pluripotent markers like Nanog, Sox2, and TERT. VSELs are considered to be the descendants of epiblast stem cells and possibly the primordial germ cells that persist into adulthood and undergo asymmetric cell division to replenish the gonadal germ cells throughout life. Elucidation of their role during infertility, endometrial repair, superovulation, and pathogenesis of various reproductive diseases like PCOS, endometriosis, cancer, and so on needs to be addressed. Hence, a detailed review of current understanding of VSEL biology is pertinent, which will hopefully open up new avenues for research to better understand various reproductive processes and cancers. It will also be relevant for future regenerative medicine, translational research, and clinical applications in human reproduction.

Very small embryonic-like stem cells as a novel developmental concept and the hierarchy of the stem cell compartment

“…This observation laid the foundation for the concept that G-CSF mobilization can be employed to harvest these cells from patients for therapeutic purposes in regenerative medicine. Several reports also provided evidence that VSELs are mobilized into PB during strenuous exercise, infections, and sepsis as well as in patients suffering from heart infarct, stroke, skin burns, active inflammatory bowel disease, and several types of cancer [83][84][85][86][87][88][89][90][91] More importantly, based on our preliminary data, we also envision that in several clinical situations the number of VSELs circulating in PB in patients could be of prognostic value. This possibility, however, requires further study and long-term clinical correlations.…”

“…The role of VSELs in stromalization of growing prostate cancers has recently been demonstrated by one of our groups [83]. However, more studies are needed to shed further light on the role of VSELs in cancerogenesis [81,110].…”

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

“…Although the concept of stem cells in adult ovaries is still not well accepted -the conflict appears to be more technical (Bhartiya 2012, Bhartiya et al 2013a) and hopefully will be resolved in due course. In addition to the seminal contributions made by Jonathan Tilly's group in the field, recently equating ovarian stem cells (OSCs) to spermatogonial stem cells (SSCs) in testis , and their protocols to isolate OSCs , our group has reported an additional population of stem cells (VSELs) in both ovary and testis (Bhartiya et al 2010, 2013b, Parte et al 2011, in addition to the OSCs/OGSCs.…”

Mouse Ovarian Very Small Embryonic-Like Stem Cells Resist Chemotherapy and Retain Ability to Initiate Oocyte-Specific Differentiation

“…19,20 We have recently reviewed how VSELs and the progenitors are implicated in reproductive biology. 21 The 2 populations can be differentiated from each other based on their size, expression of octamer-binding transforming factor 4 (OCT-4) isoforms, and their ability to proliferate 2,18 The VSELs express nuclear OCT-4A isoform, which is known to be critically required for maintaining pluripotency in embryonic stem cells and primordial germ cells. 22 The progenitors express OCT-4 in cytoplasm (OCT-4B) and subsequently with differentiation, the expression of OCT-4 is lost in the differentiated germ cells.…”