Relationship Between VSELs, MUSE Cells and MSCs in Health and Disease

A comprehensive understanding of how diverse adult stem cell populations function in harmony is crucial for maintaining homeostasis and ensuring the normal functioning of body tissues. Two types of stem cells in adult tissues have attracted attention, including very small embryonic-like stem cells (VSELs) and multi-lineage differentiating stress-enduring cells (MUSE), reported for the first time in 2006 and 2010, respectively. VSELs are pluripotent stem cells developmentally linked to the primordial germ cells, while MUSE cells, initially described as multipotent, are now being defined as having pluripotent characteristics and further differentiate into MSCs. VSELs are the most primitive, virtually immortal and pluripotent stem cells that survive lifelong in all tissues in small numbers and undergo asymmetrical divisions to give rise to tissue-specific progenitors of different sizes and fates. VSELs are 5-7 μm in size, spherical in shape, with a cell surface profile of LIN-CD133 + CD45- while MUSE cells are 10-15 μm in size, with abundant cytoplasm, horseshoe/bean-shaped nuclei, cytoplasmic OCT-4 and are CD45+, like hematopoietic stem cells. In the mouse uterus, VSELs undergo cyclic changes in response to circulatory hormones, regenerate both the epithelial and stromal compartments in an atrophied uterus (upon bilateral ovariectomy, in the absence of macrophages) and also upon chronic injury. Exposure to endocrine-disrupting chemicals disrupts the functions of VSELs and results in various pathologies, including endometrial cancer. The crucial role of dysfunctional VSELs resulting in cancer initiation, progression, metastasis and recurrence was recently discussed. On the other hand, multiple clinical trials have reported the potential of MUSE cells for ensuring regeneration upon transplantation. VSELs regenerate damaged and diseased tissues when a healthy paracrine support is provided by the transplanted MUSE cells/MSCs; however, remain elusive due to their small size and scarce nature. In summary, the view that MUSE cells phagocytose damaged cells and subsequently differentiate into the same cell type is fundamentally challenged and requires careful re-evaluation.