A Novel View of the Adult Stem Cell Compartment From the Perspective of a Quiescent Population of Very Small Embryonic-Like Stem Cells

Abstract

Evidence has accumulated that adult hematopoietic tissues and other organs contain a population of dormant stem cells (SCs) that are more primitive than other, already restricted, monopotent tissue-committed stem cells (TCSCs). These observations raise several questions, such as the developmental origin of these cells, their true pluripotent or multipotent nature, which surface markers they express, how they can be efficiently isolated from adult tissues, and what role they play in the adult organism. The phenotype of these cells and expression of some genes characteristic of embryonic SCs (ESCs), epiblast SCs (EPiSCs), and primordial germ cells (PGCs) suggests their early-embryonic deposition in developing tissues as precursors of adult SCs. In this review we will critically discuss all these questions and the concept that small dormant stem cells related to migratory PGCs, described as very small embryonic-like stem cells (VSELs), are deposited during embryogenesis in bone marrow and other organs as a backup population for adult tissue committed stem cells (TCSCs) and are involved in several processes related to tissue or organ rejuvenation, aging, and cancerogenesis. The most recent results on successful ex vivo expansion of human VSELs in chemically defined media free from feeder-layer cells opens up new and exciting possibilities for their application in regenerative medicine.

Cancer stem cells, their origin and niche: A search for the therapeutic target

“…In contrast, some groups have reported Sox2 expression in VSELs [67]. They also express other germ line markers like Mouse vasa homologue (MVH), STELLA, NOBAX, FRAGALLIS, Dead end protein homolog 1 (DND1), Histone deacetylase 6 (HDAC6) [68]. VSELs have a high telomerase activity [69] and do not express MHC I [70].…”

Shox2: The Role in Differentiation and Development of Cardiac Conduction System

“…The biological pacemaker is formed by electroactive cells, not only with the corresponding morphological and electrophysiological characteristics, but also with the dynamic gene expression program of autonomic response and pacemaker cell specificity (Ma et al 2011;Vedantham 2015). Recently, with the maturation of experimental techniques for various pluripotent stem cells (Braam et al 2009;Bernstein and Srivastava 2012;Burridge et al 2012;Priori et al 2013;Karakikes et al 2015;Broughton and Sussman 2016;Atmanli and Domian 2017;Ratajczak et al 2017), the research on induction of stem cells to directionally differentiate into pacemaker cells to form biological pacemakers has shown a breakthrough and thus should promote the CCS regeneration and in vivo transplantation therapies (Davis et al 2011;Bernstein and Srivastava 2012;Xin et al 2013;Broughton and Sussman 2016;Kishore and Khan 2016). Exogenous overexpression of human SHOX2 in mouse embryonic stem cells can enhance the expression of Cx45, Hcn4, and endogenous Shox2 and inhibit the expression of Nkx2.5 and Cx43 (Ionta et al 2015).…”

The DLK1-MEG3 locus in malignant cells of proposed primordial germ cell origins.

“…Incredibly, over a decade of VSELs research has recently culminated in the successful expansion of these cells via treatment with the pan-histone deacetylase inhibitor (HDACi) valproic acid (VPA) [9]. This global epigenetic modifier was found to upregulate the expression of DLK1 in human umbilical cord blood hematopoietic stem cells in addition to promoting their expansion ex vivo [48].…”

“…In addition, quiescent adult pluripotent stem cells which exhibit hypomethylation at the IGF2-H19 ICR, named very small embryonic-like stem cells (VSELs), displayed increases in methylation at the ICR upon in vitro expansion and differentiation [8,9]. Thus, genomic imprinting at these loci is especially important for maintaining the stemness of somatic and pluripotent stem cells.…”

“…Collectively, these characteristics arguably place VSELs near the top of the adult stem cell hierarchy. Surprisingly, successful expansion of these cells was very recently reported to occur in response to treatment with VPA, a compound which was also shown to enhance the ex vivo expansion of HSCs while promoting their expression of DLK1, suggesting that an increase in DLK1 expression may also be related to the exit from quiescence by VSELs [9,48]. In contrast to their hypomethylated Igf2-H19 locus,…”