Review Volume 4, Issue 4 pp 235—246

Figure 2. VSELs deposited in adult tissues are protected from excessive insulin/insulin-like growth factor signaling (IIS). VSELs are deposited in adult tissues as a backup population for tissue-committed stem cells (TCSCs) and are protected from IIS, which would otherwise lead to their premature depletion from adult tissues, as well as trigger uncontrolled proliferation and teratoma formation. Left panel - VSELs are protected from autocrine IIS by changes in expression of imprinted genes that are important in IIS. Downregulation of autocrine expression of IGF2, upregulation of IGF2R (a non-signaling receptor that binds IGF2 and prevents its binding to signaling IGF1R), and downregulation of RasGRF1 (which is involved in signal transduction from IGF2R), makes VSELs less sensitive to autocrine/paracrine IGF2 signaling. Right panel - Downregulation of RasGRF1, which is involved in signaling from activated IGF1R and InsR in VSELs, also plays an important role in attenuation of IIS signaling by paracrine circulating levels of IGF1 and insulin. However, in the presence of chronic elevated levels of IGF1 and insulin in blood, VSELs deposited in adult tissues may proliferate in an uncontrolled manner and become depleted much faster over time. This may contribute to the accelerated aging observed in situations with high circulating IGF1 and insulin levels (e.g., Laron dwarf mice, Ames dwarf mice, or chronic high caloric uptake). At the same time, chronic exposure to IIS may also trigger uncontrolled activation of VSELs and their malignant transformation. For reasons of simplicity, other imprinted genes not involved in IIS that negatively affect VSEL proliferation (H19 and p57^Kip2) are not shown.