Pluripotent stem cells (PSCs) have been considered as the most important cells in regenerative medicine as they are able to differentiate into all types of cells in the human body.
PSCs have been established from several sources of embryo tissue or by reprogramming of terminally differentiated adult tissue by transduction of so-called Yamanaka factors (Oct4, Sox2, Klf4, and cMyc). Interestingly, accumulating evidence has demonstrated the residence of PSCs in adult tissue and with the ability to differentiate into multiple types of tissue-committed stem cells (TCSCs). We also recently demonstrated that a population of pluripotent Oct4(+) SSEA-1(+)Sca-1(+)Lin(-)CD45(-) very small embryonic-like stem cells (VSELs) resides in the adult murine bone marrow (BM) and in other murine tissue. These very small (∼3-6 μm) cells express pluripotent markers such as Oct4, Nanog, and SSEA-1. VSELs could be specified into several tissue-residing TCSCs in response to tissue/organ injury, and thus suggesting that these cells have a physiological role in the rejuvenation of a pool of TCSCs under steady-state conditions.
In this review article, we discuss the molecular nature of the rare population of VSELs which have a crucial role in regulating the pluripotency, proliferation, differentiation, and aging of these cells.
Epigenetic modification of VSELs during embryogenesis and tissue regeneration. Epigenetic modifications control the differentiation potential of stem cells during embryogenesis and tissue regeneration. During the implantation of embryo, ICM-derived epiblast stem cells methylated again i) X chromosome, ii) promoters for the genes characteristic for PSCs in ICM (Rex-1 and Stella), and iii) repetitive sequences. However, at the beginning of gastrulation the proximal, epiblast-specified PGCs can reset their epigenetic profile to one that characterizes ICM-derived PSCs. Subsequently, during PGCs migration to genital ridges, the global DNA demethylation leads to erase the genomic imprints. As it is hypothesized that VSELs originate from the epiblast-derived PGCs population, they show the PGCs-like epigenetic profiles, including the partial DNA demethylation in the regulatory DNA elements of several pluripotency, germ-line genes, and genomic imprints. The epigenetic profiles of developing VSELs are retained after their deposition into adult tissue. This parental-specific reprogramming of genomic imprinting of VSELs deposited in adult -tissue, e.g. BM, functions as i) a “lock-in mechanism” to prevent their unleashed proliferation and ii) a mechanism to restrict their sensitivity to Ins/Igf signaling. After exposure to tissue injury, quiescent VSELs de-repress “locked-in” genomic imprints along with progressive methylation of DNA in the Oct4 promoter. As a result of these epigenetic changes, VSELs become involved in the tissue regeneration process by differentiation into cells of all three germ layers, i.e. meso-, ecto-, and endoderm.
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