Poster Board I-503
We demonstrated the presence of very small (smaller than erythrocytes) Oct-4+ SSEA-1+Sca-1+Lin−CD45− VSELs in bone marrow (BM) and several adult organs and tissues (Leukemia 2006:20;857, Cytometry 2009:73;1116). Furthermore, our recent promoter methylation studies and analysis of chromatin's structure revealed that the Oct-4 gene is truly expressed in these cells. The epigenetic changes in selected somatic-imprinted genes govern their quiescent status, thus preventing them from unleashed proliferation and the spontaneous growth of teratomas (Leukemia 2009: in press). In the current study, we addressed the developmental origin of VSELs and significance of their presence in adult tissues. We first evaluated a number of VSELs in developing murine embryos (7-16 dpc). These cells were easily identified at the early stages of embryonic development. Studies in heartbeat-deficient mice (Ncx1−/−) revealed that VSELs are present in the embryo proper before initiation of circulation, which is in contrast to hematopoietic stem cells. Their number rapidly increases to ∼325k/embryo around 10-11 dpc during rapid vascularization of developing tissues/organs. These cells survive into adulthood; however, their number decreases with age. Molecular analysis revealed that VSELs express several primary epiblast- (Gbx2, Fgf5, Nodal) as well as epiblast-derived migratory primordial germ cell markers (Stella, Blimp1, Dnd1, and Nanos3). Furthermore, our recent BrdU staining studies revealed that, e.g., BM-residing VSELs are highly resistant to lethal irradiation and begin to proliferate even after lethal myeloablasia. This suggests that these cells could be a source of tissue-committed stem cells during tissue/organ damage and regeneration. Finally, in direct chemotactic studies we noticed that VSELs are highly mobile and respond robustly to SDF-1 and HGF gradients. This explains why they are mobilized into peripheral blood after heart infarct (Circulation 2004:110;3213, JACC 2009:53;1), stroke (Stroke 2009: 40,1237), and skeletal muscle and toxic liver damage (Stem Cells 2008:26;2083). Based on this, we propose a novel and challenging concept that during embryogenesis, a pool of highly migratory PSCs emerges (VSELs) in proximal epiblasts that contributes to organogenesis, tissue development, and specification of primordial germ cells. Furthermore, these cells survive into adulthood as a pool of PSCs that play some role in: i) steady-state conditions of tissue rejuvenation as a back up for tissue-committed stem cells; and ii) regeneration of damaged organs during emergencies. As such, we postulate that VSELs could somehow be a mammalian counterpart of blastema-like cells present in lower organisms. In mammalian tissues, they are kept in quiescent status due to epigenetic modification of selected imprinted genes. In addition, the age-related decrease of these cells in adult tissues and their primitive nature could explain the aging process. On the other hand, embryonic/epiblast-derived remnants in adult tissues could potentially initiate tumorogenesis (Virchow & Connheim). Finally, identification of VSELs supports the concept of a so-called ‘memoderm’, a putative 4th, highly migratory, germ layer (Gaillard & Hernandez). Identification of VSELs in embryonic and adult tissues and our most recent data lend support to all these theories and provide novel view on regeneration, senescence and tumorigenesis.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.