Very Small Embryonic/Epiblast-Like Stem Cells (VSELs) Residing in Adult Tissues and Their Role in Tissue Rejuvenation and Regeneration

Abstract

Embryonic development and later rejuvenation of adult tissues are regulated by a population of stem cells (SCs) that, by undergoing self-renewal, maintain their own pool and, by giving rise to differentiated progenitors, replace cells used up during life (Ratajczak et al., 2007). Thus, SCs are guardians of tissue/organ integrity and regulate the life span of an adult organism. The most important SCs, from a regenerative potential point of view, are pluripotent stem cells (PSCs). According to their definition, such cells must meet certain in vitro and in vivo criteria. PSCs must: i) give rise to cells from all three germ layers; ii) complete blastocyst development; and iii) form teratomas after inoculation into experimental animals. The SC compartment shows a high degree of hierarchy (Hayashi & Surani, 2009). In embryonic development, the most primitive stem cells are the fertilized oocyte (zygote) and the first blastomers in the morula. These cells are called totipotent, possessing the ability to give rise to both embryo and placenta. The developing morula gives rise to the blastocyst, where PSCs are found in the inner cell mass (ICM). These cells may give rise to all three germ layers of the developing embryo; however, they have lost the ability to differentiate into placenta. The PSCs at this stage can be expanded ex vivo as immortalized embryonic stem cell (ESC) lines (Evans & Kaufman, 1981). After implantation of the blastocyst, PSCs from the blastocyst ICM give rise to pluripotent epiblast stem cells (EpiSCs) that will form the entire embryo proper (Brons et al., 2007; Tesar et al., 2007). During the gastrulation process, cell lineage determination programs are initiated and EpiSCs respond to the signals from surrounding extra-embryonic tissues, which leads to their differentiation into several types of tissue-committed stem cells (TCSCs) (Ratajczak et al., 2007). TCSCs are monopotent (unipotent), which means they are restricted in their differentiation potential to cells for one tissue only (e.g., epidermis, intestinal epithelium, liver, skeletal muscles, or lympho-hematopoietic). TCSCs terminate expression of pluripotent genes and, at the same time, turn on lineage-specific molecular programs. The first population of SCs, which at around embryonic day 7.25 (E7.25) become specified in the proximal epiblast, are primordial germ cells (PGCs), and alkaline phosphatase (AP)-