The Role of Very Small Embryonic-Like Stem Cells (VSELs) in Reproductive Tissues

Abstract

Introduction: Adult reproductive tissues including testes, ovary, and uterus harbor two populations of stem cells namely very small embryonic-like stem cells (VSELs) and tissue specific progenitors (immediate descendants of VSELs) spermatogonial stem cells (SSCs) in testis, ovarian stem cells (OSCs) in ovary, and endometrial stem cells (EnSCs) in uterus. Methods: We summarize new knowledge about VSELs in reproductive tissues and organs. Results: VSELs are small (2–6 µm) in size, pluripotent (express embryonic markers and differentiate into 3 germ layers in vitro), and can be studied with a cell surface profile of LIN-CD45-SCA-1+ in mice and LIN-CD45-CD133+ in humans by flow cytometry. They undergo asymmetrical cell divisions to give rise to slightly bigger progenitors (SSCs, OSCs, and EnSCs) which divide rapidly in a symmetrical manner and undergo clonal expansion prior to initiating differentiation. Being quiescent in nature, VSELs in the ovaries and testes survive oncotherapy and they also survive in atrophied uterus after bilateral ovariectomy. Non-functional gonads as well as the uterus can be rejuvenated by transplanting mesenchymal stromal cells (MSCs) ‘paracrine providers’, extracellular vesicles, or exosomes secreted by the MSCs that facilitate the tissue-resident stem cells (VSELs) to undergo differentiation and enable regeneration. Stem cells do not pellet down (remain buoyant) when cells suspensions are centrifuged at 200–600 g to collect cells for various studies. This low speed is used to ensure viability of the somatic cells, but the stem cells get discarded unknowingly. Stem cells can be enriched by further centrifuging the supernatant at 1000 g. Negative data reported by various groups on the stem cells by single cell RNAseq in adult tissues is because they spin cells at lower speed for the experiments and unknowingly discard the stem cells. Conclusions: VSELs serve as a back-up pool for tissue committed progenitors which further differentiate and thus tissue homeostasis is maintained life-long. Any disruption to the stem cells compartment results in various pathologies including cancer. KeywordsCancerInfertilityOvaryStem cellsTestesUterusVery small embryonic-like stem cells (VSELs)