M.Z. Ratajczak, M. Kucia, D. Myung-Shin, M. Masternak, A. Bartke

Pluripotent very small embryonic/epiblast derived stem cells (VSELs) as we hypothesize are deposited at begin of gastrulation in developing tissues and play an important role as backup population of pluripotent stem cells (PSCs) for tissue committed stem cells (TCSCs). Molecular analysis of adult bone marrow (BM)-derived purified VSELs revealed that they i) express pluripotent stem cells markers e.g., Oct4, Nanog, Klf-4, SSEA-1 ii) share several markers characteristic for epiblast as well as migratory primordial germ cells (PGCs), and iii) posses a unique pattern of genomic imprinting (e.g., erasure of differently methylated regions at Igf2-H19 and Rasgrf1 loci and hypermethylation at KCNQ1 and Igf2R loci). We hypothesize that these pluripotent stem cells play an important role in tissue/organ rejuvenation, and their proliferation and potentially premature depletion is negatively controlled by epigenetic changes of imprinted genes that regulate insulin factor signaling (Igf2-H19 locus, Igf2R and RasGRF1). Since the attenuation of insulin/insulin growth factor (Ins/Igf) signaling positively correlates with longevity, we propose, based on our experimental data in animal models, that gradual decrease in the number of VSELs deposited in adult tissues, which occurs throughout life in an Ins/Igf signaling-dependent manner is an important mechanism of aging. In contrast, a decrease in Ins/Igf stimulation of VSELs as seen for example during calorie restriction extends the half life of these cells in adult organs and has a beneficial effect on life span. On other hand the same epigenetic changes in the epigenetic signature of imprinted genes keep these cells quiescent in adult tissues and prevent them from teratoma formation. In contrast epigenetic changes/mutations that lead to activation of imprinted genes could potentially lead to tumor formation by these cells. Mounting evidence accumulates that perturbation of expression of imprinted genes is a common phenomenon observed in developing tumors. We envision that mutated VSELs in addition to teratomas are origin of several malignancies including germinal tumors and pediatric sarcomas.

Keywords (Optional): 
pluripotent stem cells and aging
insulin/insulin growth factors
cancer stem cells
imprinted genes