Fig. 1.

Very small embryonic-like stem cells (VSELs) support the embryonic rest theory. Primordial germ cells (PGCs) and VSELs are connected by a similar molecular signature. VSELs are present in variety of tissues and are thought to be a source of mesenchymal stem cells (MSCs), hematopoietic stem cell (HSCs), and endothelial progenitor cells (EPCs) in bone marrow as well as tissue-specific stem/progenitor cells in other tissues. Microenvironment condition, mutations, and epigenetic modifications can change the fate of VSELs into cancer initiating cells or cancer stem cells (CSCs). In the quiescent state, VSELs highly express growth-repressive imprinted gene transcripts such as H19 and show the downregulation of growth-promoting ones like IGF2. However, in activated VSELs, there is higher expression of IGF2 compared to H19, which ultimately leads to uncontrolled cell proliferation and can promote cancer formation. The cartoon in all figures of this article was created using Servier Medical Art templates (https://smart.servier.com) licensed under a Creative Commons License (https://creativecommons.org/licenses/by/3.0/)